Studien

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GMALL-Studiengruppe

hoelzer@em.uni-frankfurt.de

Schaubstr. 16
60596 Frankfurt

Einschlusskriterien
# Alter mind. 18 Jahre
# Schriftliche Einverständniserklärung des Patienten
# Therapie analog zu einer GMALL Therapieoptimierungsstudie oder einer GMALL-Therapieempfehlung
# Eine der folgenden drei Einschlusskriterien:
# 1. akute lymphatische Leukämie
# 2. andere Leukämien (NK-Zell-Lymphom/Leukämie oder akute biphänotypische Leukämie)
# 3. Non-Hodgkin-Lymphome folgender Subtypen (WHO-Klassifikation): Burkitt-Lymphom (inkl. atypisches Burkitt-Lymphom, Burkitt-like-Lymphom), diffus großzellige B-Zell-Lymphome (insbesondere primär mediastinale DLBCL, DLBCL mit Burkitt-Signatur, c-myc-positive DLBCL), B-lymphoblastisches Lymphom, T-lymphoblastisches Lymphom, Großzellig-anaplastisches Lymphom, Sonstige NHL

Ausschlusskriterien
keine

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
ALL - Akute lymphatische Leukämie

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Richard Noppeney

+49 (0)201 723-82530
richard.noppeney@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Klinikum der Universität München, Klinikum Großhadern

Einschlusskriterien
AML gemäß den WHO-Diagnose-Kriterien, einschließlich Akute Promyelozyten-leukämie (APL)
Alter ≥18 Jahre
unterschriebene Einwilligungserklärung

Ausschlusskriterien
keine

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
AML - Akute myeloische Leukämie

Medizinischer Befund
AML

Institute
Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Beate Timmermann

beate.timmermann@uk-essen.de

Am Mühlenbach 1
45147 Essen

Sponsor

WPE gGmbH, Essen

Einschlusskriterien
• Die Indikation zur Strahlentherapie wurde gestellt.
• Protonentherapie wird als Alternative zur herkömmlichen Strahlentherapie durchgeführt. Bei
einer Protonentherapie im Rahmen der Heilkunde muss für jeden Patienten durch den
fachkundigen Arzt eine rechtfertigende Indikation gemäß § 80 StrlSchV gestellt sowie ausführlich
und belastbar dokumentiert werden. Die vorgesehene Anwendung der Protonentherapie liegt im
Bereich der Heilkunde,
- sofern sie bereits klinisch etabliert ist (z. B. gemäß Leitlinien) oder
- sofern sie hinsichtlich Indikationsstellung und Anwendungsschema (Fraktionierung,
Gesamtdosis) dem für die konventionelle Photonentherapie etablierten Heilkunde-Standard
entspricht.
• Patient nimmt an keiner klinischen Studie zur Protonentherapie teil.
• Kein Anhalt für eine Schwangerschaft. Falls erforderlich Bereitschaft zur
Schwangerschaftsverhütung während der Behandlung vorhanden.
• Patient hat in die Teilnahme an der Registerstudie und in die Datenerfassung und -verwendung
im Rahmen dieser eingewilligt.

Ausschlusskriterien
-

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Diverse

Institute
Frauenheilk \/Gynäkologie, Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Paul Buderath

85239
paul.buderath@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
Adeno- oder Plattenepithelkarzinom der Cervix FIGO IB - IIA
Behandlung durch TMMR (Totale Mesometriale Resektion) + therapeutische Lymphonodektomie
Keine adjuvante Radiatio

Ausschlusskriterien
Keine Behandlung durch Totale Mesometriale Resektionund therapeutische Lymphadenektomie
Adjuvante Radiatio (außer bei R1-Situation)
Fernmetastasen (außer in paraaortalen Lymphknoten)
Sklerodermie
Lupus erythematodes
Mixed connective tissue disease
Zweitmalignom
Vorangegangene Radiatio des Beckens

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Gynäkologische Tumore

Medizinischer Befund
Cervixkarzinom

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

St. Anna Kinderkrebsforschung, Austria

Einschlusskriterien
Patients with ALL (except for patients with mature B-ALL) who fulfil the following criteria: •age at time of diagnosis less or equal 18 years or age at time of HSCT less or equal 21 years•indication for allogeneic HSCT according to the national frontline protocols (Germany: AIEOP-BFM ALL 2009, IntReALL SR 2010, Interfant 2006, CoALL and ALL REZ BFM 2002)•complete remission (CR) before SCT •written consent of the parents (legal guardian) and, if necessary, the minor patient via “Informed Consent Form”•no pregnancy •no secondary malignancy•no previous HSCT•HSCT is performed in a study participating centre

Ausschlusskriterien
•Patients who do not fulfil the inclusion criteria•Non Hodgkin-Lymphoma•The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian•No consent is given for saving and propagation of anonymous medical data for study reasons•Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders; severe pulmonary, hepatic or cardial impairment due to toxicity or infection)•Karnovsky / Lansky score < 50%•Subjects unwilling or unable to comply with the study procedures* Severe renal impairment (GFR< 30% predicted for Age)* Severe liver insufficiency* Pregnancy*

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
akute lymphoblastische Leukämie

Institute
Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Beate Timmermann

beate.timmermann@uk-essen.de

Am Mühlenbach 1
45147 Essen

Sponsor

WPE gGmbH, Essen

Einschlusskriterien
- Die Indikation zur Strahlentherapie wurde gestellt.
- Protonentherapie wird als Alternative zur herkömmlichen Strahlentherapie durchgeführt. Bei einer Protonentherapie im Rahmen der Heilkunde muss für jeden Patienten durch den fachkundigen Arzt eine rechtfertigende Indikation gemäß § 80 StrlSchV gestellt sowie ausführlich und belastbar dokumentiert werden. Die vorgesehene Anwendung der Protonentherapie liegt im Bereich der Heilkunde,
- sofern sie bereits klinisch etabliert ist (z. B. gemäß Leitlinien) oder
- sofern sie hinsichtlich Indikationsstellung und Anwendungsschema (Fraktionierung, Gesamtdosis) dem für die
konventionelle Photonentherapie etablierten Heilkunde-Standard entspricht.
- Patient nimmt an keiner klinischen Studie zur Protonentherapie teil.
- Kein Anhalt für eine Schwangerschaft. Falls erforderlich Bereitschaft zur Schwangerschaftsverhütung während der Behandlung vorhanden.
- Die Eltern und der Patient haben in die Teilnahme an der Registerstudie und in die Datenerfassung und -verwendung im Rahmen dieser eingewilligt.

Ausschlusskriterien
-

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Diverse

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Richard Noppeney

+49 (0)201 723-82530
richard.noppeney@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universität Leipzig

Einschlusskriterien
- newly-diagnosed APL (either de novo or therapy-related), within 12 months of diagnosis or relapsed APL, within 12 months of diagnosis of relapse
- confirmed by the presence of the translocation t(15; 17) and/or confirmed by the detection of the fusion transcript of PML/RARa

Ausschlusskriterien
none

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
APL - Promyelozytenleukämie

Institute
Klinik für Neurochirurgie und Wirbelsäulenchirurgie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Yahya Ahmadipour

yahya.ahmadipour@uk-essen.de

Hufelandstr 55
45147 Essen

Indikation
NONKO - Neuroonkostudien

Medizinischer Befund
Tumore der Sella \n(Hypophysenadenome, Kraniopharyngeome, Rathe-Zysten etc.)

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum RWTH Aachen

Indikation
MPN - Myeloproliferative Neoplasie

Institute
Frauenheilk \/Gynäkologie, Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Oliver Hoffmann

+492017232742
oliver.hoffmann@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Technische Universität München

Einschlusskriterien
- proven pathogenic BRCA1/2 mutation
- age >=18
- written informed consent

Ausschlusskriterien
- current chemotherapy of radiotherapy (inclusion 6 weeks after CTX or RX possible)
- metastatic tumor disease
- life expectancy <3 years
- clinically limiting cardiovascular or respiratory disease (instable CVD, heart failure stage IV, COPD GOLD IV, maximum resting blood pressure 160/100 mmHg)
- significant orthopedic disability which prevents from participating in the group interventions
- severe concomitant diseases which prevents from participating in the group interventions
- Karnofsky index <60
- maximum exercise capacity <50 W
- food allergies which prevent from mediterranean diet
- vegan diet
- body mass index <15 kg/m2
- pregnancy
- insufficient knowledge of German language
- insufficient compliance
- active participation in other interventional trials

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Gynäkologische Tumore

Medizinischer Befund
Brust- und Eierstockkrebs

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Richard Noppeney

+49 (0)201 723-82530
richard.noppeney@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Technische Universität Dresden

Einschlusskriterien
- Informed consent
- women or man with a newly diagnosed APL by cytomorphology, confirmed by molecular analysis
- Age ≥18 and ≤ 65 years
- ECOG performance status 0-3
- WBC at diagnosis > 10 GPt/l
- serum total bilirubin ≤ 3.0 mg/dl (≤ 51 µmol/l)
- serum creatinine ≤ 3.0 mg/dl (≤ 260 µmol/l)
- women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:
o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml)
o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
o Continuous and correct application of a contraception method with a Pearl Index of <1% (e.g. implants, depots, oral contraceptives, intrauterine device – IUD).
o Sexual abstinence
o Vasectomy of the sexual partner

Ausschlusskriterien
- patients who are not eligible for chemotherapy as per discretion of the treating physician
- APL secondary to previous radio- or chemotherapy for non-APL disease
- other active malignancy at time of study entry (exception: Basal-Cell Carcinoma)
- lack of diagnostic confirmation of APL at genetic level
- Significant arrhythmias, ECG abnormalities
- other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
- uncontrolled, life-threatening infections
- severe non controlled pulmonary or cardiac disease
- severe hepatic or renal dysfunction
- HIV and/or active hepatitis C infection
- pregnant or breast-feeding patients
- allergy to trial medication or excipients in study medication
- substance abuse; medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results
- use of other investigational drugs at the time of enrolment or within 30 days before study entry

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
65 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
APL - Promyelozytenleukämie

Medizinischer Befund
newly diagnosed high-risk acute promyelocytic leukemia (APL)

MedDRA Term
Acute promyelocytic leukaemia

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Sebastian Bauer

sebastian.bauer@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Scandinavian Sarcoma Group, Schweden

Einschlusskriterien
1. Age ≥ 18 years.
2. Morphological and immunohistological documentation of GIST (immunostaining for KIT [CD117] and/or DOG-1 positive, or mutation of KIT or PDGFRA present in tumour tissue).
3. Macroscopically complete surgical resection of GIST (either R0 or R1 resection).
4. Mutation analysis of KIT and PDGFR genes has been carried out.
5. A high risk of tumour recurrence following surgery and 3 years of adjuvant imatinib defined as one of the following:
1) gastric GIST with mitotic count >10/50 HPFs HPF, high Power field of the microscope) or >10/5mm2, or
2) non-gastric GIST with mitotic count >5/50 HPFs or >5/5 HPFs mm2, or
3) non-gastric GIST treated with neoadjuvant imatinib and initially larger than 10 cm, or
4) tumour rupture
Tumour rupture may have occurred before or at surgery. Tumour rupture is defined by spillage of the tumour contents into the abdominal cavity. A core needle biopsy from the tumour, or tumour bleed with no apparent spillage of the tumour contents, are not considered ruptures.

If only a small amount of pretreatment tumour tissue is available from a core needle biopsy, it is acceptable to multiply the mitotic count obtained from fewer than 50 HPFs to approximate the counts obtained from 50 HPFs in surgical biopsies, or to multiply the count obtained from a tumour tissue area less than 5 mm2 to approximate the counts obtained from the 5 mm2 area. However, if only minimal amount of tumour tissue is available from a core needle biopsy (from 5 or fewer HPFs, or only 1 mitosis can be identified), multiplication should not be attempted and is not considered acceptable. For further explanation of this expanded high risk classification, please see section 3.2.3.
6. ECOG performance status ≤ 2.
7. Adequate organ function, defined as serum total bilirubin <1.5 x ULN (upper limit of normal), serum AST (SGOT) and ALT (SGPT) <2.5 x ULN, creatinine <1.5 x ULN; blood ANC (neutrophil count) ≥1.0 x 109/L, platelet count ≥100 x 109/L.
8. Female patients of childbearing potential must have a negative pregnancy test within 14 days before initiation of study drug dosing. Postmenopausal women must have amenorrhoea for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
9. Patient willing to be followed up at the study site regardless of the result of randomisation.
10. Patient has provided a written, voluntary informed consent prior to study-specific screening procedures.

Ausschlusskriterien
1. Presence of distant metastases or local recurrence of GIST.
2. Not willing to donate tumour tissue and/or blood samples for the study molecular studies.
3. Presence of a substitution mutation at PDGFRA codon D842 (usually D842V).
4. Administration of adjuvant imatinib longer than for 3 years is planned regardless of the result of randomisation, or “life long” imatinib administration is planned.
5. Prior adjuvant (+ neoadjuvant) therapy with imatinib mesylate for at least 35 months has not been completed, or the total duration of prior adjuvant (+ neoadjuvant) imatinib administration exceeds the total duration of 38 months.
6. Neoadjuvant imatinib for a duration that exceeds 12 months.
7. Longer than 4-week break during adjuvant imatinib administration.
8. The dose of imatinib at completion of 3 years of adjuvant imatinib was 200 mg per day or less or greater than 800 mg per day.
9. Patient has received any investigational anti-cancer agents during adjuvant imatinib or between completion of adjuvant imatinib and the date of randomisation.
10. Patient has been free of another malignancy for less than 5 years except if the other malignancy is not currently clinically significant nor requiring active intervention, or if the other malignancy is one of the following: basal cell skin cancer, a cervical carcinoma in situ, a small (2 cm or less in diameter) node-negative breast cancer (pT1N0M0), a low Gleason score (<8) local (T1 or T2) prostate cancer. Recent existence of any other malignant disease is not allowed.
11. Patient with Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., congestive heart failure, myocardial infarction within 6 months of study entry).
12. Female patients who are pregnant or breast-feeding.
13. Severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, severe chronic renal disease, or active uncontrolled infection).
14. Known diagnosis of human immunodeficiency virus (HIV) infection.
15. Patient with a significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
gastrointestinal stromal tumor (GIST)

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Regina Wieland

+49 (0)201 723-2453
regina.wieland@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Georg-August Universität Göttingen

Einschlusskriterien
• Newly diagnosed, previously untreated diffuse paediatric high grade glioma with central neuropathological review including paedHGG (WHO grade IV) and anaplastic astrocytoma (WHO grade III).
• Newly diagnosed, previously untreated diffuse intrinsic pontine glioma with central neuroradiological review
• Newly diagnosed, previously untreated gliomatosis cerebri of all tumour grades with central neuroradiological review
• Patient = 3 years and < 18 years of age at time of diagnosis
• Written informed consent of the patient and/or the patient’s parents or legal guardian according to national laws

Ausschlusskriterien
• Pre-treatment of paedHGG (WHO grade IV), anaplastic astrocytoma (WHO grade III), diffuse intrinsic pontine glioma (as confirmed by neuroradiological review), and gliomatosis cerebri (as confirmed by neuroradiological review).
• Known hypersensitivity or contraindication to study drugs and/or dacarbazine
• Prior chemotherapy within the last 30 days before HIT-HGG-2013 treatment or radiotherapy which prevents adequate performance of radiotherapy as outlined by the present protocol. This may mainly apply to patients with secondary high grade glioma after previous malignant brain tumour, e.g. medulloblastoma, ependymoma, craniopharyngeoma. If previous treatment does not prevent the adequate performance of the outlined treatment protocol patients with secondary high grade glioma will be eligible for the present trial.
• Other (simultaneous) malignancies
• Pregnancy and / or lactation
• Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly)
• Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial.
• Clinical (e.g. a constitutional mismatch repair deficiency score = 3; Wimmer et al. 2014) and/or other hints (e.g. absent intratumoral immunohistochemical expression of at least one of the MLH1, MSH2, MSH6, or PMS2 mismatch repair proteins and/or high microsatellite instability) for an underlying biallelic (constitutional) mismatch repair deficiency (bMMRD/CMMRD) or a heterozygous mismatch repair deficiency (hereditary non-polyposis colon cancer syndrome/HNPCC syndrome/Lynch syndrome): These patients and their relatives should be offered human genetic counseling and rapid genetic diagnostics to confirm or rule out these conditions. These patients might not benefit from the present study treatment but maybe from other therapeutic strategies (Bouffet et al. 2016). Since patients with clinically suspected neurofibromatosis type 1 may display similar symptoms as in CMMRD, patients with clinically suspected neurofibromatosis type 1 should be also checked for CMMRD as suggested above.
• Very poor clinical condition as defined by demand of mechanical ventilation and/or demand for intravenous catecholamines and/or very severe neurological damage equivalent to a coma and/or tetraplegia with complete incapability for communication (deafness, blindness, mutism)
• Known severe concomitant diseases (e.g. immune deficiency syndrome; known tumour predisposition syndromes which do not affect adequate performance of the trial represent no exclusion criterion a priori
• Known HIV positivity
• Known severe manifest hepatic disease including hepatic porphyria as well as personal or family history of severe hepatic dysfunction, especially drug-related
• Known severe pancreatic disease
• Known lethal hepatic dysfunction in a sibling during valproic acid treatment
• Known urea cycle defect
• Known mitochondrial diseases caused by genetic mutations within the gene coding for the enzyme polymerase gamma (POLG), e.g. Alpers-Huttenlocher syndrome, as well as suspected POLG-related disorders in children under the age of two years
• Known severe coagulation disorders (in regards to thrombopenia see prerequisite for blood cell count before starting treatment)
• Valproic acid as antiepileptc drug for any pre-existing epilepsy (Exception: Valproic acid treatment due to tumour-related epilepsy will be tolerated, if the time interval between start of valproic acid treatmentand and trial enrolment is = 8 weeks.

Studienteilnehmende Mindestalter
3 Jahr(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
First-line therapy of newly diagnosed, previously untreated high grade glioma, diffuse pontine glioma, and gliomatosis cerebri in children and adolescents <18 years.

MedDRA Term
Anaplastic astrocytoma, Malignant glioma, Brain stem glioma, Gliomatosis cerebri, Astrocytoma malignant, Ganglioglioma, Glioblastoma multiforme, Glioblastoma, Gliosarcoma

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. Uta Dirksen

+49 (0)201 723-82025
uta.dirksen@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Erasmus Medical Center

Einschlusskriterien
Age for all strata (Str1A, ph2, Str1B, Str2 and Str3): Patients must be ≥ 1 and < 18 years of age
Patients with Down syndrome are excluded in Stratum 1A and 1B/1BASP but not in the phase 2 cohort and Stratum 3
Additional criteria for Stratum 1A and 1B:
• First 3 patients on dose level 1 must be 6-18 yrs.
• Then at least 2 additional patients must be enrolled from age 1-6 yrs at the same dose level.
• After this: subsequent dose levels may enroll patients aged 1-18 yrs.
• In case 2 younger patients are not yet recruited, patients aged 6-18yrs may continue to be enrolled at dose level 1 until a maximum of 6 patients are enrolled.
Stratum 1A, phase 2 and stratum 1B/1B-ASP: Diagnosis
Patients must have either 1st relapsed BCP-ALL after allo-HSCT or 2nd or greater relapsed or refractory BCP-ALL, or refractory disease (after at least 2 prior regimens):
• M2 or M3 marrow status (≥ 5% blasts by morphology)
• CD22 surface antigen positive (either BM or PB)
• Stratum 1 only: The first 6 patients must have M3 marrow status (≥ 25% blasts by morphology).
Stratum 2: Diagnosis
Patients must have 2nd or greater relapsed or refractory CD22-positive B-cell malignancy including but not limited to diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), Burkitt lymphoma, Burkitt leukemia or B-cell precursor lymphoblastic lymphoma:
• Histologic verification of disease at original diagnosis or subsequent relapse
• Evaluable or measurable disease (by radiographic criteria or BM disease present)
• CD22 surface antigen positive (either biopsy material, BM or PB)
Str3: diagnosis:
• 1st BM or combined relapse of CD22+ VHR BCP-ALL defined as:
- any relapse <18 months from initial diagnosis and/or
- cytogenetic-high risk characteristics: KTM2A/AF4, E2A/TCF3-PBX1 t(1;19) or E2A/TCF3-HLF t(17;19), hypodiploidy (less than 40 chromosomes), TP53 mutation and/or deletion
• excluding patients transplanted in 1st CR.
• M2 or M3 marrow status (≥ 5% blasts by morphology)
• CD22 surface antigen positive (in either the BM or PB)
• Evidence of prior fusion gene abnormalities is acceptable
• cytogenetic-high risk characteristics determined by chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing
All strata:
Performance Level and Life Expectancy:
• Karnofsky > 60% for patients > 16 years of age and Lansky > 60% for patients ≤ 16 years of age.
• life expectancy of at least 6 weeks.

Prior Therapy:
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy defined as resolution of all such non-hematologic toxicities to ≤ Grade 2 per the CTCAE 4.03.
• Chemotherapy: At least 7 days wash-out; except for hydroxyurea, 6-mp and steroids (wash-out 48 hrs) and intrathecal therapy (no wash-out). Patients who relapse while receiving maintenance chemotherapy will not be required to have a waiting period.
• Radiotherapy: At least 28 days must have elapsed since any prior radiation therapy.
• Hematopoietic Stem Cell Transplant: At least 90 days must have elapsed since previous allo-HSCT. No evidence of active GVHD; not receiving GVHD prophylaxis or treatment.
• Hematopoietic growth factors: At least 7 days wash-out of therapy with GCSF or other growth factors. At least 14 days wash-out of pegfilgrastim (Neulasta®).
• Immunotherapy: At least 42 days wash-out of any type of immunotherapy, e.g. CART therapy. No prior CD22-targeted therapy or tumor vaccines permitted.
• Monoclonal antibodies: wash-out of at least 3 half-lives of the antibody (ie: Rituximab = 66 days, Epratuzumab = 69 days), with the exclusion of blinatumomab. Patients must have been off blinatumomab infusion for at least 14 days and all drug-related toxicity must have resolved to grade 2 or lower.
• Investigational drugs: At least 7 days or 5 drug half-lives (whichever is longer) must have elapsed since prior treatment with any experimental drug (with the exception of monoclonal antibodies).
• no prior treatment with a calicheamicin-conjugated antibody (e.g. gemtuzumab ozogamicin).
Renal and Hepatic Function:
• serum creatinine ≤ 1.5 x ULN according to age. If the serum creatinine is > than 1.5 xULN, the patient must have a GFR ≥ 70mL/min/1.73m2.
• AST and ALT ≤ 2.5 x ULN.
• total bilirubin ≤ 1.5 x ULN (unless patient has documented Gilbert syndrome &AST and ALT are <=2.5 x ULN).
Cardiac Function:
• shortening fraction ≥ 30% by ECG or an ejection fraction > 50% by
MUGA.
Reproductive Function:
• If applicable, negative urine or serum pregnancy test confirmed prior to enrollment.
• If applicable, agree not to breastfeed while on this study.
• If applicable, agree using effective method of contraception during the study for 5 months (for male patients) or 8 months (for female patients) after the last dose of InO.

Ausschlusskriterien
Isolated extramedullary relapse:
• Patients with isolated extramedullary disease are excluded (not applicable to lymphoma patients except for isolated CNS-relapse)

VOD/SOS:
• Patients with any history of prior or ongoing VOD/SOS per the modified Seattle criteria are excluded, as specified in appendix 3, or prior liver-failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of =1.5)].

Infection:
Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient may not have:
• A requirement for vasopressors;
• Positive blood culture within 48 hours of study enrollment;
• Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
• A positive fungal culture within 30 days of study enrollment.
• Active fungal, viral, bacterial, or protozoal infection requiring IV or oral treatment. Chronic prophylaxis therapy to prevent infections is allowed.

Other anti-cancer therapy:
• Patients will be excluded if there is a plan to administer non-protocol anti-cancer therapy including but not limited to chemotherapy, radiation therapy, or immunotherapy during the study period.

Allergic reaction:
• Patients with prior Grade 3/4 allergic reaction to a monoclonal antibody are excluded.

Concurrent disease:
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with protocol therapy, interfere with consent, study participation, follow up, or interpretation of study results.
• Patients with Down syndrome are excluded in the dose finding parts (stratum 1A and 1B), but not in the phase 2 cohort or VHR cohort.


Additional exclusion criteria for Stratum 1B
• Patients with grade 3-4 peripheral neuropathy (as defined in the Delphi consensus of acute toxic effects for childhood ALL by Schmiegelow et al.1 ). Patients with prior history of thrombosis during steroid and/or asparaginase are eligible provided they use adequate anti-coagulant prophylaxis, according to institutional guidelines.
• Patients in whom prior experience suggests that a timely delivery of therapy is unlikely or associated with an undue risk because of intolerance.

Additional exclusion criteria for Stratum 1B-ASP cohort only
• Patients with any history of PEG-asparaginase intolerance due to allergic reactions or silent inactivation during prior treatment.
• Patients with any history of prior asparaginase-associated acute pancreatitis (any grade as defined in the Delphi consensus.1).

Patients who are excluded from Stratum 1B-ASP may potentially be enrolled in Stratum 1B expansion cohort.

Additional exclusion criteria for Stratum 3 (VHR cohort) only:
• Patients who are transplanted in CR1 (such patients are eligible for the phase 1B cohort).

Studienteilnehmende Mindestalter
1 Jahr(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
pediatric CD22-positive relapsed\/refractory Acute Lymphoblastic Leukemia

MedDRA Term
Acute lymphoblastic leukemia recurrent

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Erasmus Medical Center

Einschlusskriterien
1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML38 at either time of initial CML diagnosis or at time of study screening:
- Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases.
- Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I-FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted.
- Qualitative RT-PCR should be performed on RNA extracted from freshly collected bone marrow or peripheral blood cells. It identifies the transcript type, either e14a2 or 13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCR-ABL protein weight (P210, rarely P230 or P190).
2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines24) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI).
• The 2013 European LeukemiaNet guidelines24 will be used to define suboptimal response and failure to prior TKI therapy. Details are provided in appendices 3 and 4.
-Intolerance to prior TKI therapy will be determined by the treating investigator, but generally applies to patients who are unable to receive standard or reduced doses of a TKI due to significant drug-related toxicity and/or when the drug-related toxicity is not responding to appropriate medical management. Patients who enroll as a result of intolerance to prior TKI therapy may have any level of response to their prior therapy and still be eligible.
3. Age ≥1 and <18 years at day of attaining the informed consent.
4. Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age (appendix 5).
5. Adequate bone marrow function:
-For second-line and third-line CP CML patients:
-Absolute neutrophil count >1000/mm3 (>1.0 x109/L);
-Platelets ≥75,000/mm3 (≥75 x109/L) without any platelet transfusions during the preceding 7 days.
-For fourth-line CP and all for all AP/BP CML patients:
-Absolute neutrophil count >500/mm3 (>0.5 x109/L);
-Platelets ≥50,000/mm3 (≥50 x109/L) without any platelet transfusions during the preceding 7 days.
6. Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR (see appendix 11).
7. Adequate liver function, including:
• AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.
8. Recovered to Grade 0-1, or to baseline, from any acute toxicities of prior chemotherapy, immunotherapy, radiotherapy, differentiation therapy, or biologic therapy, with the exception of alopecia
9. Able to reliably swallow whole capsules, whole tablets, or drug substance added to a suitable foodstuff (from capsule contents, added to either apple sauce or yoghurt); or tablets and/or capsules dissolved as an oral syringe drinking solution; or tablets dissolved and administered by NG tube when needed.
10. Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.
11. Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.
12. Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)
13. Patients (including legally acceptable representative for minors where applicable) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

For phase 2 ND patients:
Criterion 2 replaced with: Newly diagnosed CP Ph+ CML of ≤ 6 months (from initial diagnosis) without any previous TKI treatment (with the exception of hydroxyurea and/or anagrelide) for CML. Diagnosis of CP CML will be defined as per Appendix 1.
Criterion 5 deleted

Ausschlusskriterien
1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. In patients with AP/BP CML: leptomeningeal leukemia, defined as positive cytology on lumbar puncture (including both CNS2 and CNS3 status), or clinical symptoms or signs present. This assessment is not required for inclusion of CP CML patients.
3. Extramedullary disease only.
4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. This exclusion criterion is based on whether there is a known history of these mutations at the time of study entry. If these mutations become evident during the study the patient will go off study).
5. Any prior treatment with a TKI within 7 days prior to study entry, or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to bosutinib treatment.
6. Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.
7. Concomittant use of moderate or strong CYP3A inducers/inhibitors (see appendix 8).
8. Concomittant use of proton pump inhibitors (pH-modifying agents).
9. Prior radiotherapy within 3 months prior to bosutinib treatment.
10. Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment.
11. Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment.
12. Hereditary bone marrow failure disorder.
13. Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment.
14. Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).
15. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• History of prolonged QTc.
16. Prolonged QTc (>450 msec, average of triplicate ECGs).
17. Need for medications known to prolong the QT interval.
18. Pregnant and/or nursing women
19. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
20. Left ventricular ejection fraction <50% or shortening fraction <28%.
21. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.
22. Evidence of serious active or uncontrolled bacterial, fungal or viral infection.
23. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Chronic Myeloid Leukemia

MedDRA Term
CML

Institute
Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Beate Timmermann

beate.timmermann@uk-essen.de

Am Mühlenbach 1
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
- Alter ≥ 18 Jahre
- Histologisch gesichertes Prostatakarzinom (mittleres oder hohes Risikoprofil, d.h. PSA > 10 ng/ml und/oder Gleason Score ≥ 7 und/oder T-Stadium T2b-T3b)
- Körperlicher Allgemeinzustand nach WHO ≤ 2
- Bereitschaft zur Schwangerschaftsverhütung
- PSA < 50 ng/ml
- Vorliegen der unterschriebenen Einverständniserklärung

Ausschlusskriterien
- Nachweis von Fern- oder Lymphknotenmetastasen
- Indikation zur Bestrahlung des pelvinen Lymphabflusses
- Vorbestrahlung im Bereich der Prostata
- Voroperationen im Bereich der Prostata oder des Rektums
- transurethrale Resektion (TUR) vor < 3 Monaten
- vorhergehende systemische Chemotherapien
- Z. n. vorheriger Tumorerkrankung in einem anderen Organ (Ausnahme weißer Hautkrebs oder Basaliom). Patient muss bereits 3 Jahre tumorfrei sein.
- Hüftimplantate
- Herzschrittmacher
- medizinische oder psychiatrische Einschränkungen, die die Durchführung der Behandlung verhindert oder die spätere Nachsorge beeinflusst
- Diagnose einer chronisch entzündlichen Darmerkrankung (Colitis Ulcerosa oder Morbus Crohn), auch wenn derzeit kontrolliert
- Vorbestehende GI/GU-Toxizität = Grad 2, die als primärer Endpunkt definiert ist

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Prostatakarzinom

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Michael Schündeln

+49 (0)201 723-2500
michael.schuendeln@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Universitätsklinikum Münster

+49 (0)251 83-55555
info@ukmuenster.de

Albert-Schweitzer-Straße 33
48149 Münster

Einschlusskriterien
• newly diagnosed, histological or cytological and immunological proven aggressive mature B-cell Non-Hodgkin lymphoma including Burkitt lymphoma (BL), Burkitt leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), or mature B-cell NHL not further classified according to current WHO classification. For rare subtypes (e.g. primary mediastinal large B-NHL, PMLBL double hit lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements), consultation of the study center is recommended.
• availability of slides/blocks for reference pathology and international pathology panel (except in cases with immunological and cytomorphological assurance of diagnosis)
• age at diagnosis < 18 years
• diagnostics and treatment in one of the participating centers of the trial
• no previous chemotherapy, no previous lymphoma-directed treatment. No application of steroids for more than two days during the last month
• adequate hepatic, renal and cardiac function, except if alteration is due to lymphoma Infiltration. Please contact the study center in case of unclear cases.
• signed informed consent of patient and or parents/guardians for treatment according to the protocol, participation and transfer of data
• follow-up of at least two years after initial diagnosis is expected
• certificate of vaccination against hepatitis B or negative serology, defined as
- evidence of immunization with HBs-antigen negative, anti-HBs positive and anti-HBc negative or
- negative hepatitis B serology with HBs-antigen negative, anti-HBs and anti-HBc negative

Ausschlusskriterien
• patients with insufficient work up not allowing a correct stratification into the risk groups
• B-cell neoplasia as second malignancy
• any other medical, psychiatric, or social condition prohibiting treatment according to the protocol (e.g. previous malignancy, prior organ transplant, HIV infection or AIDS or severe immunodeficiency, etc.)
• participation within a different trial for treatment of B-cell malignancies and/or concurrent treatment within any other clinical trial. Exceptions to this are the NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment which can run parallel to B-NHL 2013 without influencing the outcome of this trial e.g. trials on antiemetics, antibiotics, strategies for psychosocial support etc.
• overt hepatitis B or history of hepatitis B
• hypersensitivity to rituximab or to murine proteins, or to any of the other excipients of the Investigational Medicinal Product or to ingredients of other IMPs
• lack of CD20 expression of the lymphoma cells
• pregnancy and lactation

Studienteilnehmende Mindestalter
28 Woche(n)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
mature aggressive B-cell lymphoma and leukemia in children and adolescents

MedDRA Term
Lymphomas non-Hodgkin's B-cell

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Gudrun Fleischhack

+49 (0)201 / 723 84667
gudrun.fleischhack@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Centre Leon Berard, France

Einschlusskriterien
Overall program
•Main residence in one of the participating countries
•Age < 22 years old at the diagnosis
•Newly diagnosed intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary myxopapillary, clearcell and tanicytic) or anaplastic ependymoma
•Delivery of FFPE tumour tissue blocks (or charged slides with sufficient interpretable material and curls in an Eppendorf tube) to national referral pathology center
•Written informed consent for data and study biological samples collection
•All patients and/or their parents or legal guardians willing and able to comply with protocol schedule and agree to sign a written informed consent
•Patients must be affiliated to a Social Security System in countries where this is mandatory

After Initial surgery, patients will be enrolled in one of 3 different interventional strata where they will be offered a set of therapeutic interventions based on the outcome of the intervention (no measurable residue vs residual inoperable disease), their age and/or their eligibility /suitability to receive radiotherapy.

Patients with centrally and histologically confirmed intracranial ependymoma (histology confirmed by National Reference centre for Biology and Pathology review) meeting the following criteria will be enrolled into one of interventional strata:

•Main residence in one of the participating countries,
•Age below 22 years old at the diagnosis,
•Newly diagnosed with an ependymoma WHO grade II and III, including ependymoma variants: cellular, papillary, clear-cell and tanycytic or anaplastic ependymoma.
•Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial,
•Males and females of reproductive age and childbearing potential with effective contraception (see section 4.1.2.4 Definition of highly effective methods of contraception) for the duration of their treatment and 6 month after the completion of their treatment,
•Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure

Specific inclusion criteria have been defined for each stratum of the program.

Stratum 1:
•Age = 12 months and < 22 years at time of study entry
•No residual measurable ependymoma based on the central neuroradiological review (detailed in protocol)
•Histologically confirmed WHO Grade II-III ependymoma by central pathological review
•No metastasis on spinal MRI and on CSF cytology assessments
•No previous radiotherapy
•No previous chemotherapy
•No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the Patient unable to receive chemotherapy
•No medical contraindication to radiotherapy and chemotherapy,
•No signs of infection
•Adequate bone marrow function(detailed in protocol)
•Adequate liver function (detailed in protocol)
•Adequate renal function (detailed in protocol)

Stratum 2:
•Age = 1 year and <22 years at time of entry to study
•Residual non reoperable measurable ependymoma based on central neuro-radiological review (detailed in protocol)
•Histologically confirmed WHO Grade II-III ependymoma by central pathological review
•No metastasis on spinal MRI and on CSF cytology assessments
•No previous radiotherapy
•No previous chemotherapy
•No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the Patient unable to receive chemotherapy
•No medical contraindication to radiotherapy and chemotherapy,
•No signs of infection
Adequate bone marrow function( detailed in protocol)
•Adequate liver function (detailed in protocol)
•Adequate renal function (detailed in protocol)


Stratum 3
•Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician/parent decision and according to national criteria
•Histologically confirmed WHO Grade II-III ependymoma by central pathological review
•Adequate bone marrow function(detailed in protocol)
•Adequate liver function (detailed in protocol)
•Adequate renal function (detailed in protocol)
•No previous chemotherapy
•No previous radiotherapy
•No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the Patient unable to receive chemotherapy
•No contraindication to chemotherapy

Patients that do not fulfill the inclusion criteria of one of the interventional strata will be enrolled and followed up into an observational study and descriptive analysis will be performed

Ausschlusskriterien
All interventional stata
•Tumour entity other than primary intracranial ependymoma
•Primary diagnosis predating the opening of SIOP Ependymoma II
•Patients with WHO grade I ependymoma including ependymoma variants: myxopapillary ependymomas and subependymomas
•Patients with spinal cord location of the primary tumour
•Participation within a different trial for treatment of ependymoma
•Age = 22 years
•Contraindication to one of the IMP used in this stratum according to the SmPCs in appendix 4 of the study protocol (SmPCs in appendices are those from UK which were chosen for the assessment of the safety as aspects of the study)
•Concurrent treatment with any anti-tumour agents
•Inability to tolerate chemotherapy
•Unable to tolerate intravenous hydration
•Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the Investigator
•Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion
•Pregnancy and breast feeding

Stratum 1 and 2:
•Ineligible to receive radiotherapy
•Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion
•Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator

Stratum 3:
•Pre-existing severe hepatic (liver) and/or renal (kidney) damage
Family history of severe epilepsy
•Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial
•Elevated blood ammonium level = 1.5 x upper limit of the normal
•Elevated Blood lactate level = 1.5 x upper limit of the normal
•Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator

Studienteilnehmende Mindestalter
28 Tag(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Newly diagnosed with an intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary, myxopapillary, clear-cell and tanycytic) or anaplastic ependymoma.

MedDRA Term
Ependymoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med Christian Niedworok

christian.niedworok@uk-essen.de

Hufelandstr. 55
45147 Düsseldorf

Sponsor

MSD Merck Sharp & Dohme LLC

Einschlusskriterien
1. Must have histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features. Diagnosis of RCC with clear cell component is to be made by the investigator and does not require central histology review.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
4. Female participants of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the trial through 120 days after the last dose of trial drug must be collected within 10 days prior to randomization.
5. Male participants of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the trial through 120 days after the last dose of trial drug.
6. The participant provides written informed consent/assent for the trial. The participant may also provide consent/assent for Future Biomedical Research; however the participant may participate in the main trial without participating in Future Biomedical Research.
7. Have intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status:
a) Intermediate-high risk RCC
-pT2, Gr. 4 or sarcomatoid, N0, M0
-pT3, Any Gr., N0, M0
b) High risk RCC
- pT4, Any Gr. N0, M0
-pT Any stage, Any Gr., N+, M0
c) M1 NED RCC -participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following:
- the time of nephrectomy (synchronous) or,
- ≤1 year from nephrectomy (metachronous)
8. Have received no prior systemic therapy for advanced RCC
9. Have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins.
10. Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed consent and ≤12 weeks prior to randomization.
11. Must be tumor-free as assessed by the Investigator and validated by either CT or MRI scan of the brain and CAP and a bone scan ≤28 days from randomization. All baseline scans must be sent to the central imaging vendor and receipt must be confirmed prior to randomization .
12. Must have provided adequate tissue per the following:
- Nephrectomy only: tissue from nephrectomy (required).
- Synchronous M1 NED: tissue from nephrectomy (required) AND, metastasectomy issue (if available).
- Metachronous M1 NED: tissue from metastasectomy (required) AND, nephrectomy tissue (if available).
Adequacy of the samples for biomarker analysis will be evaluated by a central laboratory.
13. Have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
14. Have adequate organ function as defined in the protocol. Specimens.

Ausschlusskriterien
1. Has had major surgery, other than nephrectomy and/or resection of pre-existing metastases for M1 NED participants, within 12 weeks prior to randomization.
2. Has received prior radiotherapy for RCC.
3. Has pre-existing brain or bone metastatic lesions.
4. Has residual thrombus post nephrectomy in the vena renalis or vena cava
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within days prior the first dose of study treatment.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
treatment and is allowed.
7. Has a known additional malignancy that is progressing or required active treatment =3 years ago. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer, or in situ breast cancer that has
undergone potentially curative therapy.
8. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
9. Has an active infection requiring systemic therapy
10. Has a history of, or is currently on, dialysis
11. Has a known history of human immunodeficiency virus infection. No human immunodeficiency virus testing is required unless mandated by local health authority.
12. Has a known active hepatitis B (hepatitis B surface antigen reactive) or hepatitis C virus (eg, hepatitis C virus [HCV] RNA [qualitative] is detected)
13. Has a known history of active tuberculosis (Bacillus tuberculosis).
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial in the opinion of the investigator 16.Has had a prior solid organ transplant.
17. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
18. A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours before randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Participants must be excluded/discontinued from the trial in the event of a positive or borderline positive test result.
19 .Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the Screening visit through 120 days after the last dose of study treatment.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, CD137) or has previously participated in a Merck pembrolizumab (MK 3475) clinical trial.
21. Has received prior anticancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before first dose of study treatment or not recovered (ie, must be =Grade 1 or at baseline) from AEs due to previously administered agents.
22. Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
23. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Treatment of participants with RCC in the adjuvant setting

MedDRA Term
Renal carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Goethe-Universität, Frankfurt

Einschlusskriterien
1. Signed Written Informed Consenta) Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
2. Target Population
a) Histological confirmation of non-clear RCC with at least 50% non-clear cell component according to actual WHO classification36
b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
c) Karnofsky > 70% (See Appendix 2, 14.2)
d) Measurable disease as per RECIST v 1.1 (See Appendix 3, 14.3) documented by an English radiology report
e) Tumor tissue (FFPE archival or recent acquisition) must be available and sent to the central pathological reviewer (see Table 6) in order to confirm the diagnosis. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
f) Patients with all risk categories will be eligible for the study. Patients will be stratified for papillary or non-papillary non-clear cell histology and IMDC risk score Patients will be categorized according to favorable versus intermediate versus poor risk status at registration according to the International Metastatic RCC Database Consortium (IMDC) criteria:
i. KPS equal to 70%
ii. Less than 1 year from diagnosis to randomization
iii. Hemoglobin less than the lower limit of normal (LLN)
iv. Corrected calcium concentration greater than the upper limit of normal (ULN)
v. Absolute neutrophil count greater than the ULN
vi. Platelet count greater than the ULNIf none of the above factors are present, subjects are only eligible for the favorable-risk cohort, if1-2 factors are present subjects are catogerized as intermediate risk and > 3 factors as poor risk.
3. Age and Reproductive Status
a) Males and Females, = 18 years of age
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours. The terminal half-life of other standard of care agents has to be derived from the product information.
i. WOCBP randomized to receive Nivolumab + Ipilimumab should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
ii. WOCBP randomized to receive a standard of care agent should use an adequate method to avoid pregnancy for at least 8 weeks (30 days plus the time required for the active metabolite of the standard of care agent to undergo five half-lives)
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours.
i. Males randomized to receive Nivolumab combined with Ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
ii. Males randomized to receive standard of care who are sexually active with WOCBP must continue contraception for at least 16 weeks (90 days plus the time required for the active metabolite of the standard of care agent to undergo five half-lives) after the last dose of investigational drug.
f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancytesting as described in this section.

Ausschlusskriterien
1) Any active brain metastases requiring systemic corticosteroids.
2) Tumors with a clear-cell component of > 50% Medical History and Concurrent Diseases
3) Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, Sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) or prior treatment with an mTOR inhibitor or cytokines.
4) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
5) Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormonereplacement are permitted to enroll.
6) Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
7) Uncontrolled adrenal insufficiency.
8) Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3vRR
9) Poorly controlled hypertension (defined as systolic blood pressure (SBP) of = 150 mmHg or diastolic blood pressure (DBP) of = 90 mmHg), despite antihypertensive therapy.
10) History of any of the following cardiovascular conditions within 12 months of enrollment:cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
11) History of cerebrovascular accident including transient ischemic attack within the past 12 months.
12) History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin
13) History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
14) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
15) Serious, non-healing wound or ulcer.
16) Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
17) Any requirement for anti-coagulation, except for low molecular weight heparin.
18) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
19) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
20) Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
21) Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
22) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
23) Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
24) Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
25) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Sunitinib
26) Left ventricular ejection fraction (LVEF) less than the LLN as assessed by echocardiography or multigated acquisition (MUGA) scan.
27) Any of the following laboratory test findings:
i. WBC < 2,000/mm3
ii. Neutrophils < 1,500/mm3
iii. Platelets < 100,000/mm3
iv. AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
v. Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
vi. Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula):
28) History of severe hypersensitivity reaction to any monoclonal antibody.
29) Subjects who are incompetent to understand and sign the informed consent.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Non-clear cell RCC

MedDRA Term
Renal cell carcinoma stage unspecified

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Goethe-Universität, Frankfurt

Einschlusskriterien
1. Male or female patients, >56 years of age and fit for therapy
2. Newly diagnosed acute lymphoblastic leukemia (>25% marrow blasts, assessed by morphology; i.e., M2 or M3 marrow)
3. Leukemic blasts must have CD22 surface expression of a least 20%, assessed by local/institutional flow cytometry of a bone marrow aspirate sample (assessment of CD22 via the reference lab for immungenetics is strongly recommended). In the case of an inadequate aspirate sample (dry tap), flow cytometry of peripheral blood specimen may be substituted if the patient has circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
4. No previous ALL-specific treatment with the exception of corticosteroids and/or single dose vincristine and/or a maximum of three doses of cyclophosphamide (cumulative dose of 600mg/m2) and the standard prephase treatment
5. With or without documented CNS involvement
6. Adequate liver function, including total serum bilirubin <2.0 x ULN unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) <2.5 x ULNIf organ function abnormalities are considered due to leukemic infiltration of the liver, total serum bilirubin must be < 2.5 x ULN and AST/ALT <5 x ULN
7. Serum creatinine 40 mL/min
8. WHO performance status <2
9. Signed written inform consent 10. Inclusion in GMALL registry

Ausschlusskriterien
1. Philadelphia-chromosome or BCR-ABL positive ALL
2. Burkitt’s or mixed phenotype acute leukemia based on the WHO 2008 criteria
3. Peripheral absolute lymphoblast count >10,000/µL after pre-phase treatment and before start of study medication
4. Known systemic vasculitis (e.g., Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as HIV infection or severe inflammatory disease)
5. Current or chronic hepatitis B or C infection as evidenced by hepatitis B surface antigen and anti-hepatitis C antibody positivity, respectively, or known seropositivity for human immunodeficiency virus (HIV)
6. Major surgery within <4 weeks before entry on study
7. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function or unstable pulmonary condition)
8. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery; patients with previous malignancies are eligible provided that they have been disease free for >2 years
9. Cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than 45%, or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure
10. Myocardial infarction <6 months before entry on study
11. History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of AV block unless a permanent pacemaker has been implanted
12. Uncontrolled electrolyte disorders that can confound the effects of a QTc prolonging drug (e.g., hypokalemia, hypocalcemia, hypomagnesemia)
13. History of chronic liver disease (e.g., cirrhosis) or suspected alcohol abuse
14. History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)
15. Administration of live vaccine <6 weeks before entry on study
16. Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia) or patients with a recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis
17. Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies or any known hypersensitivity to the active substance or any of its excipients
18. Pregnant females; breastfeeding females; males and females of childbearing potential (a woman is considered of childbearing potential (WOCBP) i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile e.g. after hysterectomy or bilateral ovariectomy. Please refer to chapter 12.4 Contraceptive Requirements.) not using highly effective contraception or not agreeing to continue highly effective contraception for women at least 8 months an for men at least 5 months after the last dose of investigational product19. Participation in other studies involving investigational drug(s) (Phase I-IV) within 4 weeks before study inclusion20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Studienteilnehmende Mindestalter
56 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
ALL - Akute lymphatische Leukämie

Medizinischer Befund
Acute lymphoblastic leukemia, Philadelphia-chromosome and BCR-ABL negative disease, patient aged 56 years or older

MedDRA Term
Acute lymphoblastic leukemia

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Gudrun Fleischhack

+49 (0)201 / 723 84667
gudrun.fleischhack@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Bristol-Myers Squibb Research and Development, USA

Einschlusskriterien
1-Children and adolescents diagnosed with either:
_Diffuse Intrinsic Pontine Glioma (DIPG),
_High Grade Glioma (HGG),
_Medulloblastoma,
_Ependymoma, or
_Other high-grade tumors of the central nervous system.
2-Lansky play score (LPS) for = 16 years of age assessed within two weeks of enrollment must be >= 60.
3-A tumor sample must be available for submission to central laboratory [not required for DIPG].

Ausschlusskriterien
1-Participants with active, known or suspected autoimmune disease.
2-Participants unable to taper steroids due to ongoing mass effect.
3-Participants with low-grade gliomas or tumors of unknown malignant potential.
4-Prior treatment with any drug that targets T cell co-stimulation pathways (such as checkpoint inhibitors).

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Primary central nervous system (CNS) malignancies.

MedDRA Term
Brain tumor

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Jan Dürig

+49 (0)201 723-82530
Jan.Duerig@sjk.uk-essen.de

Sponsor

Universitätsklinikum Tübingen

Einschlusskriterien
1. Subjects must have newly diagnosed, untreated, symptomatic (according to the revised CRAB criteria 2014), documented myeloma and have measurable disease (serum M-protein ≥ 1 g/dL (for IgA ≥ 0.5 g/dL) or urine M-protein ≥ 200 mg/24 hours) or in case of oligosecretory myeloma: involved FLC level ≥ 10 mg/dl, provided sFLC ratio is abnormal or in case of asecretory myeloma: > 1 focal lesions measurable by MRI
Subjects must have high-risk myeloma defined as followed:
• Presence of one or more of the following cytogenetic abnormalities (determined by FISH):
- Del(17p) in ≥ 10% of purified cells
- t(4;14)
- > 3 copies +1q21
- - t(14;16)
• ISS Stage II or III (all patients)
FISH analysis of external laboratories other than Heidelberg is accepted, a list of laboratories will be filed in the study central.
2. Must be ≥ 18 years at the time of signing the informed consent form.
3. Must be able to adhere to the study visit schedule and other protocol requirements in the investigators opinion.
4. WHO performance status 0-3 (WHO=3 is allowed only if caused by MM and not by co-morbid conditions)
5. Females of childbearing potential (FCBP) (1) must agree to refrain from becoming pregnant for 28 days prior to initiation of study drug, while on study drug and for 30 -150 days* after discontinuation from the study drug by using 2 reliable methods of contraception and must agree to regular pregnancy testing during this timeframe.
(1) A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months) 3) has achieved menarche at some point.
6. Females must agree to abstain from breastfeeding during study participation and 30 150 days* after study drug discontinuation.
7. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 90 150 days* following discontinuation from this study, even if he has undergone a successful vasectomy.
8. Males must also agree to refrain from donating semen or sperm while on treatment with any study drug and for 90 150 days* after discontinuation from this study treatment.
9. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
10. All subjects must agree not to share medication.
11. All participating subjects have to follow the requirements of the Lenalidomide Pregnancy Prevention Plan (please refer to section 4)
*28 days after last dose of Lenalidomide, 30 days after last dose of Carfilzomib and 150 days (5 Months) after last dose of Isatuximab, for detailsnumber of days differ for Lenalidomide and Carfilzomib, for details see chapter 4.

Ausschlusskriterien
1. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib), mannitol, sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
2. Patients with known systemic amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
3. Administration of systemic chemotherapy, biological, immunotherapy or any investigational agent (therapeutic or diagnostic) for multiple myeloma except bisphosphonate therapy. Emergency treatment with dexamethasone is allowed when the cumulative dexamethasone dose is less or equal 160 mg. It is allowed to include patients in the trial after 1 cycle (4 weeks) of any anti-myeloma first-line treatment.
4. Any of the following laboratory abnormalities:
o Absolute neutrophil count (ANC) < 1,000/µL, unless related to myeloma
o Platelet count < 30,000/ µL (in case of platelets < 50.000 /µl and = 30.000 /µl myeloma bone marrow infiltration should be = 50%)
o Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L); or free ionized calcium > 6.5 mg/dL (> 1.6 mmol/L)
o Serum GOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN) or serum total bilirubin > 2.0 mg/dL if not due to hereditary abnormalities as Gilbert’s disease or hereditary hemolysis (Note: if the mentioned limits for bilirubin or ASAT/ALAT are exceeded, but there is no significant hepatic dysfunction at investigator’s discretion, the study office has to be consulted prior to inclusion)
o Patients with severe renal impairment (eGFR < 30 ml/min/1.73 m², MDRD formula or CDK-EPI or Creatinine Clearance < 30 ml/min)
5. Active congestive heart failure (NYHA Class III to IV), symptomatic cardiac ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior study entry.
6. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B sAg and core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed). Patients with a history of hepatitis B infection have to be monitored repetively during treatment. In case of signs of hepatitis B reactivation, antiviral treatment has to be initiated and patients have to be referred to a specialist for treatment and monitoring of hepatitis infection.
7. Acute active, uncontrolled infection
8. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain according CTC V4.03)
9. Second malignancy within the past 5 years except:
- adequately treated basal cell or squamous cell skin cancer
- carcinoma in situ of the cervix
- prostate cancer Gleason Score = 6 with stable PSA over the past 12 months
- breast carcinoma in situ with full surgical resection
- treated medullary or papillary thyroid cancer
10. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to study entry.
11. Major surgery within 4 weeks prior to cycle 1 day 1 (kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities.
12. Female patients who are pregnant or lactating
13. Any other clinically significant medical disease or psychiatric condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent.
14. Participation in any other clinical trial (with the exclusion of observational, non-interventional studies))

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MM - Multiples Myelom

Medizinischer Befund
Multiple myeloma

MedDRA Term
Plasma cell myeloma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Bristol-Myers Squibb International Corporation, Belgien

Einschlusskriterien
a) Kidney tumor has been completely resected with negative surgical margins obtained. The randomization must occur greater than 4 weeks and less than (or equal to) 12 weeks from the date of nephrectomy. Partial nephrectomy is allowed provided all inclusion criteria are met.
b) Post-nephrectomy tumor shows RCC with a predominately clear cell histology, including participants with sarcomatoid features.
c) Pathological TNM staging per AJCC staging version 2010:
i) pT2a, G3 or G4, N0M0
ii) pT2b, G any, N0M0
iii) pT3, G any, N0M0
iv) pT4, G any, N0M0
v) pT any, G any, N1M0d) Participants must have no clinical or radiological evidence of macroscopic residual disease or distant metastases (M0) after nephrectomy
i) Baseline tumor assessment, performed 4 to approximately 12 weeks after nephrectomy, shows no metastasis or residual tumor lesions per local review and as confirmed by Blinded Independent Central Review (BICR). Results of BICR of the baseline tumor assessment confirming absence of metastasis or residual tumor lesions must be received before randomization.Note: participants with one or more regional lymph nodes identified with short axis 15 mm on the baseline (post-operative) tumor assessments are considered to have gross residual disease and are therefore ineligible.
e) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.
f) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, obtained within 3 months prior to enrollment, preferably from nephrectomy, with an associated pathology report, must be submitted to the central laboratory prior to randomization. FFPE block or 20 unstained slides is ideal, but a minimum of 10 unstained slides will be acceptable if tumor tissue is limited. Biopsy should be excisional, incisional, or core needle. Fine needle aspiration is unacceptable for submission

Ausschlusskriterien
a) Any severe or serious, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration including ongoing or active infection requiring parental antibiotics
b) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Topical, ocular, intra-articular, intranasal, inhaled steroids, and adrenal replacement steroid doses > 10 mg daily prednisone or theequivalent are permitted in the absence of active immune disease.
c) Uncontrolled adrenal insufficiencyd) Participants with an active known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Early stage localized Renal Cell Carcinoma

MedDRA Term
Renal carcinoma

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Heidelberg

Einschlusskriterien
• Age ≥ 18 years
• Patients with Ph -chromosome and/or the BCR-ABL fusion gene (either b3a2 and/or b2a2) positive CML
• CML in CP having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not
• Pretreatment at least one year with any TKI after 1st stop
• Written informed consent

Ausschlusskriterien
• Vorheriger hämatologischer Rückfall nach dem ersten TKI-Absetzversuch.
• Versagen jeglichen TKIs entsprechend den aktuellen ELN-Kriterien zu jeglicher Zeit während der CML-Behandlung.
• Vorherige geplante oder durchgeführte allogene Stammzell-transplantation.
• Entwicklung zur akzelerierten Phase oder Blastenkrise zu jeglicher Zeit in der Krankheitsgeschichte.
• Hohes Risiko für Herzerkrankungen entsprechend dem ESC score.
• Beeinträchtigte Herzfunktion oder einer der folgenden (Vor)Geschichten:
• Verwendung eines ventrikulär stimulierten Herzschrittmachers; angeborenes oder in der Familienanamnese vorkommendes Lang-QT-Syndrom; signifikante ventrikuläre oder Vorhof-Tachyarrhythmien in der Vergangenheit oder Gegenwart; klinisch signifikante Ruhe-Bradykardie ( 450 ms zu Studienbeginn, Myokardinfarkt vor Studienbeginn; andere klinisch signifikante Herzkrankheiten (beispielsweise instabile Angina pectoris, Herzinsuffizienz oder nicht beherrschbarer Bluthochdruck),
• Eine Behandlung mit CYP3A4-Inhibitoren oder mit Medi-kamenten, bei denen dokumentiert ist, dass diese die QT- Intervall verlängern, ist kontraindiziert,
• Eine akute Pankreatitis innerhalb eines Jahres vor Studienbeginn oder eine chronische Pankreatitis in der Vorgeschichte,
• Positiver serologischer Hepatitis B Virus Test oder HBV Infektion
• Alle anderen bösartige Erkrankungen, außer diese sind weder klinisch signifikant oder erfordern kein aktives Eingreifen,
• Schwerwiegende oder nicht beherrschbare medizinische Zustände (beispielsweise nicht beherrschbare Diabetes, akute oder chronische Lebererkrankungen, Bauchspeicheldrüsen- oder schwere Nierenerkrankung in keinem Zusammenhang mit einem Tumor, aktive oder nicht beherrschbare Infektionen),
• Frauen, die schwanger sind, stillen, oder im gebärfähigem Alter sind und keinen negativen Schwangerschaftstest zu Beginn der Studie aufweisen. Männliche oder weibliche Patienten im gebärfähigen Alter, die nicht bereit sind, eine wirksame Schwangerschaftsverhütungsmethode zu verwenden.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not and are pretreated at least one year with any TKI after 1st stop

Institute
Klinik für Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Glas

neuroonkologie@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

German Cancer Research Center, Heidelberg

Einschlusskriterien
- Age ≥ 18 years, smoking or non-smoking, of any ethnic origin and gender
- Patients present with unequivocal first, second or third recurrence of a histologically confirmed IDH1R132H-mutated glioma WHO grade II, III or IV progressive after radiotherapy and chemotherapy
- Absence of chromosomal 1p/19q co-deletion in the primary tumor tissue and/or
- Loss of nuclear ATRX expression in the primary tumor tissue (partial loss allowed)
- Availability of tumor tissue for analysis (FFPE bulk tissue)
- Patients have received radiotherapy (54 - 60 Gy) and at least six months of alkylating chemotherapy
- Patients are at least three months off radiotherapy
- Patients must be candidates for re-resection and the re-resection must be postponable for seven weeks
- Patients should be immunocompetent (i.e. no concomitant treatment with dexamethasone (or equivalent), or receive stable/decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent) during the last 3 days prior to clinical screening; no severe lymphopenia)
- Karnofsky Performance Status ≥ 70
- Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
- Ability of patient to understand character and individual consequences of the clinical trial
- Evidence of informed consent document personally signed and dated by the patient (or a witness in case the patient is unable to write) and indicating that the patient has been informed of all pertinent aspects of the study and that the patient consents to participate in the trial
- Women of child-bearing potential (WOCBP; i.e. those who have not undergone a hysterectomy, bilateral salpingectomy and bilateral oophorectomy or who have not been post-menopausal for at least 24 consecutive months) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of the investigational medicinal product(s) (IMPs).
- WOCBP must be using an effective method of birth control to avoid pregnancy throughout the study and for 3 months after the last dose of the IMP. This includes two different forms of effective contraception (e.g. hormonal contraceptive and condom, IUD/IUS and condom) or sterilization, resulting in a failure rate less than 1% per year.
- Men must be willing and able to use an effective method of birth control throughout the study for up to 3 months after the last dose of the IMP(s), if their sexual partners are WOCBP (acceptable methods see above).
- Availability of pre-study MRT (magnetic resonance tomography) of latest tumor recurrence
- Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Ausschlusskriterien
- Current use of immunosuppressive medication, EXCEPT for the following:
1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
2. Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone or equivalent;
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
- Pregnancy or lactation
- Previous or concurrent experimental treatment for the tumor other than radiotherapy and alkylating chemotherapy. This includes local therapies such as interstitial radiotherapy or local chemotherapy (i.e. BCNU wafers), loco-regional hyperthermia, electric fields, and antiangiogenic therapy (such as Bevacizumab).
- Abnormal (= Grade 2 CTCAE v4.03) laboratory values for thyroid gland: free T4 and TSH
- Abnormal (= Grade 2 CTCAE v4.03) laboratory values for hematology, liver and renal function (serum creatinine). In detail, the following values apply as exclusion criteria:
1. Hemoglobin < 9 g/dL (5.59 mmol/L)
2. White blood cell count (WBC) decrease ( 10.0 x 109/L)
3. Absolute neutrophil count (ANC) decrease (< 1.5 x 109/L)
4. Platelet count decrease (< 100 x 109/L)
5. Bilirubin > 1.5 x ULN (upper limit of normal according to the performing lab´s reference range)
6. ALT > 2,5 x ULN
7. AST > 2,5 x ULN
8. GGT > 2.5 x ULN
9. Serum creatinine increase (> 1.5 x ULN)
- Patients with history or presence of HIV and/or HBV/HCV positivity (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
- Patients with history or known presence of tuberculosis (positive QuantiFERON®-TB Gold test (or equivalent) or tuberculin skin test). Patients with an indeterminate result of the QuantiFERON®-TB Gold test (or equivalent) are not eligible unless additional testing demonstrates a negative result (tuberculin skin test or repeated QuantiFERON®-TB Gold test/or equivalent). If a tuberculin skin test is performed, an induration of > 6 mm is "positive" for a patient with history of BCG vaccine, while an induration of > 10 mm is "positive" for a patient without history of BCG vaccine. If necessary, a QuantiFERON®-TB Gold or equivalent test might be complemented by additional specific diagnostic tests as per standard procedures.
- Patients with severe infection(s) or signs/symptoms of infection within 2 weeks prior to the first administration of the study drug(s)
- Active infection requiring systemic therapy
- Patients who have received a live, attenuated vaccine within 4 weeks prior to the first administration of the study drug(s)
- Patients with a prior solid organ transplantation or haematopoietic stem cell transplantation
- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
- Clinically significant (i.e., active) cardiovascular disease: Cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
- Persisting toxicity related to prior therapy (NCI CTCAE v.4.03 Grade >1); however, alopecia, sensory neuropathy Grade = 2, or other persisting toxicities Grade = 2 not constituting a safety risk based on investigator´s judgement is acceptable.
- Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade = 3).
- Participation in other clinical trials or their observation period during the last 30 days before the first administration of the IMP(s).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien

Medizinischer Befund
Malignant Glioma

Institute
Klinik und Poliklinik für Strahlentherapie, Klinik für Neurologie, Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Glas

neuroonkologie@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
• Histologisch gesichertes WHO Grad II oder III Gliom mit Indikation zur Durchführung einer Strahlentherapie nach Beschluss der lokalen neuroonkologischen Konferenz des Studienzentrums
• Klassifikation des Tumors gemäß der WHO-Klassifikation 2016 inkl.: mutierter IDH-Status muss nachgewiesen sein, Bestimmung des 1p/19q Deletionsstatus und MGMT- Promotormethylierungsstatus muss vorliegen
• Ein Karnofsky-Index von ≥ 70%
• Patienten müssen ≥ 18 Jahre sein
• Beginn der Strahlentherapie innerhalb 6 Wochen nach Operation
• Zum Zeitpunkt des Studieneinschlusses sollte der Abstand zur letzten Operation ≥ 2 Wochen sein. Die Patienten müssen sich von den Folgen der Operation erholt haben
• Patient muss zustimmen und in der Lage sein eine neurokognitive Baseline-Testung noch vor Gabe der ersten Strahlendosis durchzuführen
• Der Patient muss vor Studieneinschluss die schriftliche Einwilligung zur Studienteilnahme erteilen
• Studienpatient ist in der Lage Sinn und Tragweite der Studie zu verstehen und ist gewillt den Anweisungen der klinischen Studie zu folgen und aller Voraussicht nach die geplanten Studienvisiten einzuhalten.
• Gebährfähige Patientinnen müssen einen negativen Schwangerschaftstest (aus dem Serum oder Urin) aufweisen, der nicht älter als 7 Tage ist zum Zeitpunkt der ersten Studienintervention.
• Laborwerte nicht älter als 3 Wochen vor Studieneinschluss: Absolutwert neutrophiler Granulozyten ≥ 1500/mm³, Thrombozytenzahl ≥ 100 000/mm³, Hämoglobinwert (Hb) >10 g/dL, Gesamtbilirubinwert ≤ 1,5-fach der oberen Normwertgrenze, Werte für Aspartat-Aminotransferase (AST) und Alanin-Aminotransferase (ALT) ≤ 3-fach der oberen Normwertgrenze, Kreatininwert ≤ 1,5-fach der oberen Normwertgrenze

Ausschlusskriterien
• Gleichzeitige Teilnahme an einer anderen klinischen Studie oder Teilnahme an einer klinischen Studie, die die Gabe eines Prüfpräparats innerhalb von 30 Tagen vor Studieneinschluss erfordert.
• Physischer oder psychischer Zustand des Patienten, der, im Ermessen des Studienarzts, den Patienten gefährden könnte, die Studienergebnisse verfälschen könnte oder der die Teilnahme des Patienten an der klinischen Studie negativ beeinflussen könnte.
• Bekannter oder anhaltender Missbrauch von Drogen, Alkohol oder Medikamenten.

Indikationsspezifische Ausschlusskriterien:
• Vorausgegangene Strahlentherapie am Kopf oder im Gesichts-Halsbereich
• Vorausgegangene Chemotherapie aufgrund einer ZNS Neoplasie
• Schwere Komorbidtät, die eine Compliance mit den Studienvorgaben limitiert
• Bösartige invasive Tumorerkrankung mit einer Tumorfreiheit von < 3 Jahren
• Hinweise für eine leptomeningeale Dissiminierung
• Spinale oder infratentorielle Tumorlokalisation
• Patienten mit bekannter Infektion mit dem humanen Immundefizienz-Virus (HIV) und unter laufender retroviraler Therapie.
• Patienten mit neuerlich diagnostizierter Hepatitis-Infektion oder - nach Ermessen des zuständigen Studienarztes - erheblichem Risiko einer Reaktivierung

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien

Medizinischer Befund
Gliom

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

German Pediatric Oncology Group, GPOH gGmbH, Berlin

Einschlusskriterien
1. Aged 3 months to <21 years with documented diagnosis of AML according to WHO classification with at least one quantitative genetic maker, e.g. one of the following aberrations:• t(8;21); RUNX1/RUNX1T1 • inv(16); CBFb/MYH11 • t(9;11); MLL/AF9 • t(10;11); MLL/AF10 • NPM1 • WT1; etc.2. Molecular remission confirmed at the start of last consolidation course or within 1 month after completion of consolidation treatment3. Detection of a confirmed molecular relapse of an AML4. Understand and voluntarily provide permission (subjects and when applicable, parental/legal representative(s)) to the ICF prior to conducting any study related assessments/procedures5. Able to adhere to the study visit schedule and other protocol requirements6. Lansky performance score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable7. Negative serum pregnancy tests for females of child bearing potential within 10 days prior to treatment

Ausschlusskriterien
1. Concomitant treatment with any other anticancer therapy except those specified in protocol2. HSCT within previous 3 months3. Treated by any investigational agent in a clinical study within previous 4 weeks4. Pregnancy or lactating5. FAB type M3 leukemia (acute promyelocytic leukemia)6. Therapy-related AML7. AML of Down syndrome or other congenital syndromes giving rise to leukemia or treatment complications8. Symptomatic cardiac disorders (CTCAE 4.0 Grade 3 or 4)9. Evidence of invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and C10. Any other organ dysfunction (CTCAE 4.0 Grade 3 or 4) that will interfere with the administration of the therapy according to this protocol11. Ongoing severe toxicities (CTCAE 4.0 Grade 3 or 4) of prior chemotherapy/stem cell transplantation12. Hypersensitivity to azacitidine13. Abnormal liver function: • serum bilirubin > 3 x ULN • ALT or AST > 5 times ULN14. Symptomatic CNS-involvement or isolated extramedullary disease at initial diagnosis15. Female and male subjects with child bearing potential who avoid to use secure anti-conceptive measurements

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Intravenous azacitidine 100 mg\/m2, Days 1 to 7 of a 28-day cycle for up to 3 cycles initially. In case of decline of MRD during azacitidine treatment additional cycles are allowed (maximum 6 cycles).

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Schleswig-Holstein, Campus Kiel

Einschlusskriterien
- newly diagnosed acute lymphoblastic leukemia or- newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria:
• biphenotypic with a dominant T or B lineage assignment
• bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen
- newly diagnosed acute undifferentiated leukemia
- age < 18 years (up to 17 years and 365 days) at the day of diagnosis- patient enrolled in a participating center
- written informed consent to trial participation and transfer and processing of data

Ausschlusskriterien
- Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
- bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (= 10% of total cells) blast subset
- pre-treatment with cytostatic drugs- glucocorticoid pre-treatment with = 1 mg/kg/d Prednisolone equivalent for more than two weeks during the last month before diagnosis
- treatment started according to another protocol- underlying diseases that does not allow treatment according to the protocol - ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
- evidence of pregnancy or lactation period
- Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
- participation in another clinical trial that interferes with the protocol
- other condition (either pre-existing or related to leukemia biology as present at diagnosis) or circumstances that significantly conflict with the treatment according to the protocol

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
acute lymphoblastic leukemia in children and adolescents <18 yearsof age

Institute
Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Beate Timmermann

beate.timmermann@uk-essen.de

Am Mühlenbach 1
45147 Essen

Sponsor

WPE gGmbH, Essen

Einschlusskriterien
- Alter ≥18 Jahren bei Beginn der Protonentherapie
- Diagnose eines Hirntumors oder eines Tumors an der Schädelbasis
- Protonentherapie mit rechtfertigender Indikation und Einverständnis zur Protonentherapie
- Teilnahme an Registerstudie Erwachsene des WPE (ProReg) mit entsprechender Einwilligung
- unterschriebene Einwilligungserklärung zur Studie

Ausschlusskriterien
- Re-Bestrahlung
- vollständiger HVL Ausfall und Diabetes insipidus
- Grad 4-Gliome
- Vorliegen von Fernmetastasen (M+ bzw. M1)

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Diverse

Medizinischer Befund
Diagnose eines Hirn- oder Schädelbasistumors

Institute
Frauenheilk \/Gynäkologie, Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Pawel Mach

85289
pawel.mach@uk-essen.de

Hufelandstr 55
45147 Essen

Einschlusskriterien
Vulvakarzinom im Stadium oT1-oT3b,
Vorliegen der schriftlichen Einwilligungserklärung zur Studienteilnahme

Ausschlusskriterien
Hochgradig eingeschränkter Allgemeinzustand (Karnovsky-Index <80%),
Komorbidität welche mit der Durchführung der Operation nicht vereinbar ist,
Fernmetastasen

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Gynäkologische Tumore

Medizinischer Befund
Vulvakarzinom

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Anja Welt

anja.welt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

F. Hoffmann-La Roche AG

Einschlusskriterien
Stage 1
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Metastatic or inoperable locally advanced, histologically documented TNBC
- For patients in the 1L PD-L1 positive cohort: no prior systemic treatment for metastatic or inoperable locally advanced TNBC
- For patients in the 2L CIT-naïve cohort: Eligible for capecitabine monotherapy
- For patients in the 2L CIT-naïve cohort: Radiologic/objective evidence of recurrence or disease progression after 1L treatment with chemotherapy (chemo) for a total of one line of therapy for inoperable locally advanced or metastatic breast cancer
- Life expectancy>= 3 months
- Availability of a representative tumor specimen that is suitable for determination of Programmed death-ligand 1and/or additional biomarker status via central testing
- For patients in the 1L PD-L1 positive cohort: positive PD-L1 expression, defined as >= 1%of the tumor area occupied by PD-L1- expressing tumor-infiltrating immune cells of any intensity Stage 1 and Stage 2
- Measurable disease according to Response Evaluation Criteria in Solid Tumors 1.1
- Tumor accessible for biopsy
- Adequate hematologic and end-organ function
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen during the 14 days prior to initiation of study treatment
- Negative HIV test, hepatitis B surface antigen at screening, and hepatitis C virus (HCV) antibody test or positive HCV antibody test followed by a negative HCV RNA test at screening
- Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL at screening
- For women of childbearing potential: agreement to remain abstinent or use treatment arm-specific contraceptive measures and agreement to refrain from breastfeeding and donating eggs
- For men: agreement to remain abstinent or use treatment arm- specific contraceptive measures, and agreement to refrain from donating sperm for a treatment arm-specific time period Stage 2
- ECOG Performance Status of 0, 1, or 2
- Patients randomly allocated to the control arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, provided that Medical Monitor approval for entry into Stage 2 is obtained, or disease progression per RECIST v1.1 while receiving control treatment
- Patients randomly allocated to an experimental arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab (Atezo), disease progression per RECIST v1.1, or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
- Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1

Ausschlusskriterien
Stage 1
- Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies
- Treatment with investigational therapy within 28 days prior to C1D1
- Biologic treatment or other systemic treatment within 2 weeks (wks) prior to C1D1
- Eligibility only for the control arm Stage 1 (2L CIT naïve cohort only)
- Prior treatment with capecitabine
Stage 1, 2
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, tumor-related pain and uncontrolled or symptomatic hypercalcemia
- Symptomatic, untreated, or actively progressing central nervous system metastases.
- History of leptomeningeal disease, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis or tuberculosis on screening and malignancy other than breast cancer within 2 years prior to screening.
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- History of autoimmune disease or immune deficiency
- Grade >= 3 hemorrhage or bleeding event within 28 days prior to
C1D1
- Severe infection within 4 wks prior C1D1
- Major surgical procedure within 4wks
- Treatment with antibiotics or live, attenuated vaccine within 2 wks or 4wks prior to C1D1 respectively
- Treatment with systemic immunostimulatory agents within 4wks or 5 half-lives of the drug prior to C1D1
- Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at the time of consent Ipatasertib (Ipat) - Containing arm (Stage 1)
- Prior treatment with ipat or other Akt inhibitors
- Grade >= 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceremia
- History of Type I or Type II diabetes mellitus requiring insulin
- Congenital long QT syndrome or screening QT interval corrected through use of Fridericia's formula > 480ms
- Treatment with strong CYP3A4 inducers or inhibitors within 2wks or 5 drug-elimination half-lives prior to C1D1. SGN-LIV1A - Containing arm (Stage 1)
- Prior treatment with SGN-LIV1A or MMAE -based biologic
- Grade>= 2 neuropathy
- Radiotherapy within 2wks prior to C1D1
- AST/ALT > 1.5 x ULN, or 3 x ULN if liver metastases present
- Documented history of a cerebrovascular event, unstable angina, myocardial infarction, or cardiac symptoms consistent with congestive heart failure, within 6 months prior to study enrollment. Bevacizumab (Bev) - Containing arm (Stage 1)
- Inadequately controlled arterial hypertension
- History of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease within 6 months prior to C1D1
- History of hemoptysis within 1 month prior to C1D1 and abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intraabdominal abscess and intestinal obstruction and/or clinical signs or symptoms of GI obstruction and intra-abdominal inflammatory process within 6 months prior to C1D1.
- Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to C1D1
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to C1D1; or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to C1D1 Selicrelumab (Seli)– containing arm (Stage 1)
- Soluble CD25 > 2 x ULN
- Serum ferritin > 1000 ng/mL
- Known hereditary or acquired coagulopathy
- Concomitant treatment with anticoagulants Chemo – containing arm (Stage 2)
- Inability to tolerate atezo during Stage 1 and Patients with congenital long QT syndrome
Exclusion Criteria for the Nab-Paclitaxel-Containing Arms (Stage 1)
- Grade >= 2 neuropathy related to taxanes
Exclusion Criteria for the Tocilizumab-Containing Arm (Stage 1)
- Preexisting CNS demyelinating or seizure disorders
- History of diverticulitis, chronic ulcerative lower GI disease, or other symptomatic lower GI conditions that might predispose a patient to GI perforation
- Current liver disease unrelated to the underlying cancer diagnosis
- Active current infection or history of recurrent bacterial, viral, fungal, mycobacterial, or other infection, including, but not limited to, TB, atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail bed
- Active TB as documented by a positive purified protein derivative (PPD) skin test or TB blood test and confirmed by a positive chest X-ray within 3 months prior to initiation of study treatment
- Untreated latent TB
- History of, or currently active, primary or secondary immunodeficiency
- ALT or AST > 1.5 xULN or, for patients with liver metastases, > 3 x ULN
- Total bilirubin > ULN
Exclusion Criteria for the Sacituzumab Govitecan- Containing Arm (Stage 1)
- Prior treatment with a topoisomerase 1 inhibitor

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Brustkrebs

Medizinischer Befund
Triple-negative breast cancer (TNBC)

MedDRA Term
Triple negative breast cancer

Institute
Klinik für Dermatologie, LVR Kliniken-Essen - Klinik für Psychosomatische Medizin und Psychotherapie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Frau Madeleine Fink

+49 (0)201 7227-208
Madeleine.fink@uni-due.de

Virchowstr 174
45147 Essen

Indikation
Melanom

Medizinischer Befund
malignes Melanom

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GWT-TUD GmbH, Dresden

Ausschlusskriterien
1. Andere Erstlinien Anti CML Behandlung als TKI Therapie (ausgenommen die Therpie mit Hydroxyurea).
2. Andre Zweitlinien-Therapien mit einem Tyrosinkinase Inhibitor (> 1 EMA zugelassener TKI gegen CML, oder jeder andere investigative von der EMA nicht zugelassene TKI)
3. Gleichzeitige Teilnahme an einer weiteren klinischen Prüfung mit einer anderen klinischen Prüfsubstanz innerhalb 4 Wochen vor Beginn und während der gesamten Dauer der Teilnahme an der PONS-Studie
4. Herzerkrankungen die nach NYHA den Klassen 3-4 zuzuordnen sind
5. Kardiale Symptome innerhalb der letzten 12 Monate vor Eintritt in die Studie: Patienten mit folgenden Kriterien sind für die Studie nicht geeignet:
? Krankengeschichte die eine instabile Angina Pectoris, Myocard-Infarkt , TIA, Schlaganfall, periphere arterielle Verschlusserkrankungen oder Lungenempolie aufweisen
? Krankengeschichte mit klinisch signifikanten ventrikulären Arrhythmien (wie zum Beispiel ventrikuläre Tachykardie, ventrikuläre Fibrillation, oder Torsades de pointes)
? Verlängerung des QTc Intervalls im EKG (>450 ms bei Männern, > 470 ms bei Frauen) nach der Friderica-Formel
? Herzinsuffizienz (NYHA Klasse III oder IV) innerhalb von 3 Monaten vor der ersten Dosis Ponatinib.
6. Patienten mit aktiven unkontrollierten psychischen Störungen, einschließlich von Psychosen, schweren Depressionen und bipolaren Störungen
7. Patienten mit unkontrollierter Hypertonie (definiert als anhaltender systolischer Blutdruck > 140 mmHg oder diastolisch > 90 mmHg)
8. Schwangere oder stillende Frauen sind ausgeschlossen.
9. Patienten, die in der Vergangenheit an einer Pankreatitis gelitten haben
10. Patienten in der akzelerierten oder in der Blastenphase, sowie Patienten, bei denen jemals/überhaupt die Blastenphase nachgewiesen werden konnte, sind von der Studie ausgeschlossen. Die von der Studie ausgeschlossenen CML-Phasen sind wie folgt definiert:
? Blastenphase: 30% Blasten oder mehr im peripheren Blut oder im Knochenmark
? Akzelerierte Phase der CML: Bestehen eines oder mehrerer der folgenden Kriterien:
? 15% Blasten im peripheren Blut oder im Knochenmark
? 20% Basophile im peripheren Blut oder im Knochenmark
? nicht Therapie-bedingte Thrombozytopenie < 100 x 109/L
? Nachgewiesene extramedulläre Blastenerkrankung außerhalb der Leber oder der Milz
? Klonale Evolution definiert als das Vorhandensein zusätzlicher Chromosomenannomalien außer dem Ph- Chromosom, wurde historisch als ein Kriterium für die Akzelerierte Phase einbezogen. Patienten jedoch, bei denen die klonale Evolution als einziges Kriterium für die akzelerierte Phase festgestellt wurde, haben eine signifikant bessere Prognose. Daher können Patienten mit klonaler Evolution als einzigem Kriterium für die akzelerierte Phase und keinerlei weiteren Kriterien, in die Studie aufgenommen werden, müssen aber separat analysiert werden.
11. Patienten, die eine Unverträglichkeit gegenüber dem Wirkstoff oder einem der anderen Bestandteile der Prüfsubstanz aufweisen.
12. Patienten, die aufgrund einer gerichtlichen oder verwaltungsbehördlichen Anordnung in einer Anstalt untergebracht sind
13. Patienten, die vom Sponsor, der Prüfstelle oder dem Prüfer anhängig sind,

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
Adult patients (age = 18) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) who have proven to be resistant or intolerant to prior first line Tyrosine Kinase Inhibitor Treatment

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Stefan Schönberger

stefan.schoenberger@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Klinikum der Universität München

Einschlusskriterien
1. Adult or paediatric patients (>2 months of age) after HSCT suffering from new or reactivated CMV, EBV or AdV infection and refractory to standard antiviral treatment for two weeks (defined as =1 log decrease in viral load over two weeks) as confirmed by quantitative blood PCR analysis
2. Original HSCT-donor available with an immune response at least to the virus causing the therapy-refractory infection
3. Written informed consent given (patient or legal representative)

Ausschlusskriterien
1. Acute GvHD > grade II or extensive chronic GvHD at time of T-cell transfer
2. Treatment with steroids (>1 mg/kg Prednisone equivalent) at Screening
3. Therapeutic donor lymphocyte infusion (DLI) from 4 weeks prior to IMP infusion until 8 weeks post IMP infusion. In case of T-cell depleted HSCT, a prescheduled prophylactic DLI =3 x 10e5 T cells/kg BW is not considered an exclusion criteria.
4. Organ dysfunction or failure as determined by Karnofsky (age >16 years) or Lansky (age =16 years) score =30%
5. Concomitant enrolment in another clinical trial interfering with the endpoints of this study
6. Any medical condition which could compromise participation in the study according to the investigator’s assessment
7. Progression of underlying disease (disease that has led to the indication of HSCT, e.g. leukaemia) that will limit the life expectance below the duration of the study
8. Second line or experimental antiviral treatment other than Ganciclovir/Valganciclovir, Foscarnet, Cidofovir and Rituximab from Screening until 8 weeks after IMP infusion
9. Known HIV infection. In case patients do not have a negative HIV test performed within 6 months before enrolment in the study, HIV negativity has to be confirmed by a negative laboratory test.
10. Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control from Screening until the last follow-up visit (FU6, Visit 8) Note: women of childbearing potential must have a negative serum pregnancy test at study entry
11. Known hypersensitivity to iron dextran
12. Patients unwilling or unable to comply with the protocol or unable to give informed consent.

Studienteilnehmende Mindestalter
3 Monat(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Chemo-refactory AdV, CMV and EBV infections after allogeneic stem cell transplantation

MedDRA Term
Allogenic stem cell transplantation, Cytomegalovirus infection, Adenovirus infection, Epstein-Barr virus infection

Institute
Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Beate Timmermann

beate.timmermann@uk-essen.de

Am Mühlenbach 1
45147 Essen

Einschlusskriterien
o Kinder im Alter <18 Jahre
o PT am WPE mit rechtfertigender Indikation und Einverständnis zur PT
o Einschluss in das WPE Register KiProReg (13-5544-BO, Ethikvotum 10.09.2013)
o Histologische gesicherte Tumoren im Bereich des Gesichts, des Hals oder der Schädelbasis (z.B. Sarkome wie Rhabdomyosarkom, Ewing´s Sarkom; außerdem Karzinome inklusive Ästhesioneuroblastom)
o Keine Vorbestrahlung
o unterschriebene Einwilligungserklärung zur KiAPT-Studie

Ausschlusskriterien
o Alter =18 Jahre
o Keine schriftliche Einwilligung zu dem Vorgehen und Datenerhebung
o Behandlung in palliativer Intention
o Folgende Histologie: Retinoblastome, Lymphom, primäre Tumoren des zentralen Nervensystems

Studienteilnehmende Höchstalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Kopf-Hals-Tumore

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. Stephan Tippelt

2768
stephan.tippelt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Università degli Studi Milano Bicocca, Italien

Einschlusskriterien
1. Enrollment on National ALL protocol.
2. Age > 1 year and = 21 years at ALL diagnosis.
3. Newly diagnosed ALL (B-ALL or T-ALL) or mixed phenotypicacute leukemia (MPAL meeting 2016 WHO definition) with definitive evidence of BCR-ABL1 fusion by karyotype, FISH and/or RT-PCR.
4. Previous start of Induction therapy which includes vincristine, a corticosteroid, usually PEG-L-Asparaginase, with or without anthracycline, and/or other standard cytotoxic chemotherapy.
5. Administration of no more than 14 days of multiagent Induction therapy beginning with the first dose of vincristine.
6. Administration of no more than 14 days of imatinib.
7. Performance status corresponding to ECOG scores of 0, 1, or 2.
8. Adequate liver function.
9. Adequate cardiac function.
10. Adequate renal function.

Ausschlusskriterien
1. Known history of chronic myelogenous leukemia (CML).
2. ALL developing after a previous cancer treated with cytotoxic chemotherapy.
3. Active, uncontrolled infection or active systemic illness that requires ongoing vasopressor support or mechanical ventilation.
4. Down syndrome.
5. Pregnancy.
6. Breast feeding.
7. Patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
8. Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block.
9. Prior treatment with dasatinib, or any BCR-ABL1 inhibitor other than imatinib.

Studienteilnehmende Mindestalter
1 Jahr(e)

Studienteilnehmende Höchstalter
21 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Philadelphia positive Acute Lymphoblastic Leukemia

MedDRA Term
Philadelphia chromosome positive, Acute lymphoblastic leukaemia

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Swiss Group for Clinical Cancer Research, Schweiz

Einschlusskriterien
- Histologisch bestätigtes Urothelkarzinom =T2 (=N1, M0) der Blase, Harnröhre, oder des oberen Harntrakts, als geeignet eingestuft für die kurative multimodale Behandlung inklusive Operation durch ein multidisziplinäres Tumor-Board
- Alle histologischen Subtypen sind geeignet, wenn das Urothelkarzinom vorherrschend ist
- WHO Performance Status (Allgemeinzustand) 0-1
- adäquate Knochemarksfunktion, Leber- Nieren- Herzfunktion

Ausschlusskriterien
• pathologischer Nachweis einer kleinzelligen Karzinomkomponente
• Vorhandensein von Fernmetastasen
• Jegliche Vorbehandlung mit einem PD-1- oder PD-L1-Inhibitor, inklusive Durvalumab
• Aktuelle oder frühere Therapie mit immunsupprimierenden Medikamenten innerhalb von 28 Tagen vor Registrierung
• Aktive oder frühere dokumentierte Autoimmunerkrankungen oder entzündliche Erkrankungen
• Medizinische Vorgeschichte einer Infektion mit Humanem Immundefizienz-Virus (HIV) oder aktiver chronischer Hepatitis C oder Hepatitis B Virusinfektion

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
muskelinvasives Urothelkarzinom

MedDRA Term
Urothelial carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

AIO-Studien-gGmbH, Berlin

Einschlusskriterien
Written informed consent and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
Age ≥ 18 years at time of study entry
Advanced or metastatic renal cell carcinoma, not amendable to surgery with curative intent, rendering the patient eligible for Tyrosin Kinase Inhibitor (TKI) treatment with sunitinib
Intended first-line treatment with sunitinib
Documented progressive disease within 6 months prior to study inclusion
Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as well as non-measurable disease are eligible.
Prior radiotherapy and surgery are allowed if completed 4 weeks (for minor surgery and palliative radiotherapy for bone pain: 2 weeks) prior to start of treatment and patient recovered from toxic effects.
Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
Subject is willing to receive additional concomitant coaching and able to comply with the QoL/PRO (patient-reported outcome) assessments specified in the protocol for the duration of the study including scheduled visits, examinations and follow up.

Ausschlusskriterien
Any other anti-cancer treatment aside of sunitinib for mRCC (except palliative radiotherapy)
Previous malignancy (other than mRCC) which either progresses or requires active treatment.

Exceptions are: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or T1b prostate carcinoma, or superficial bladder tumor [Ta, Tis and T1].

CNS metastases, unless local therapy has been completed for at least 3 month and patient does not require the use of steroids.
Chronic liver disease with Child-Pugh B or C score
Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year)
Any condition that, in the opinion of the investigator, would interfere with evaluation of the concomitant coaching or QoL assessments or interpretation of patient safety or study results
Participation in another clinical study with an investigational product during the last 30 days before inclusion
Any previous treatment with a tyrosine kinase inhibitor for metastatic disease. Adjuvant or neoadjuvant therapy for localized disease is permitted, provided that relapse occurred at least 6 months after last exposure
Previous enrollment or randomization in the present study (does not include screening failure).
Involvement in the planning and/or conduct of the study (applies to both Pfizer staff and/or staff of sponsor and study site)
Patient who might be affiliated or otherwise dependent on the sponsor, site or the investigator
Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities [§ 40 Abs. 1 S. 3 Nr. 4 AMG].
Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
advanced or metastatic renal cell carcinoma\nFortgeschrittenes oder metastasiertes Nierenzellkarzinom

MedDRA Term
Renal cell carcinoma stage IV

Institute
Westdeutsches Protonentherapiezentrum (WPE), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Beate Timmermann

beate.timmermann@uk-essen.de

Am Mühlenbach 1
45147 Essen

Sponsor

Italian Sarcoma Group

Einschlusskriterien
- Histologically confirmed diagnosis (brachyury expression) of primary sacral chordoma,of any diameter and arising at any site from S1 to coccyx.
- Age≥18years
- ECOG-performance status (PS) 0-2
- No previous antineoplastic therapy
- Macroscopic tumor detectable at MRI/CT scan
- Patient amenable for surgery
- Patient amenable for RT
- Written informed consent given before the enrolment, according to International Conference on Harmonisation/good clinical practice (ICH/GCP).

Ausschlusskriterien
- Distant metastasis
- Inability to maintain treatment position
- Prior radiotherapy to the pelvic region
- Prior therapy for sacral chordoma (including surgery, cryoablation, hyperthermia, etc)
- Local conditions that increase the risk of RT toxicity (tumor ulcerated skin infiltration, non-healing soft tissue infection, fistula in treatment field)
- Rectal wall infiltration
- General conditions that increase the risk of RT toxicity (active sclerodermia, xeroderma pigmentosum, cutaneous porphyria)
- Presence of a second active cancer (with the exception of non-melanoma skin cancer in-situ cervix neoplasia and other in-situ neoplasia)
- Severe comorbidities resulting in a prognosis of less than 6 months
- Inability to give informed consent
- Other malignancy within the last 5 years
- Performance status = 2 (ECOG).
- Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
- Significant systemic diseases grade >3 on the NCI-CTCAE v4.03 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity
- Women who are pregnant or breast-feeding
- Psychological, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
80 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Sarkome

Medizinischer Befund
Chordoma

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Michael Schündeln

+49 (0)201 723-2500
michael.schuendeln@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

University of Birmingham, UK

Einschlusskriterien
For Trial Entry:
• Clinical diagnosis of HB or histologically defined diagnosis of HB or HCC.
• Age =30 years
• Written informed consent for trial entryFor Allocation/Randomisation to Treatment Group:All Groups
• Written Informed Consent for trial treatment participation
• Patient assessed as fit to receive group specific treatment
• For females of child-bearing potential, a negative pregnancy test prior to trial entry is required. Any patient who is of reproductive age must agree to use adequate contraception for the duration of the trial.Group A (no treatment arm)
At diagnosis:
• Resected Tumour.
• Patient meets Very Low Risk definition according to CHIC guidelines.

Group A1 – No treatment arm
• Central pathology review confirming WDF histology.Group A2 - Treatment arm
• Central pathology review confirming non-WDF histology.
• Adequate renal function determined by:o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate(GFR) =60mL/min/1.73m2
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/Lo Platelet count >75 x 109/L
o International normalised ratio (INR)/Prothrombin time (PT) <1.2x ULN for age-based local reference values
Group B
• Patient meets Low Risk definition according to CHIC Guidelines
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate(GFR) =60mL/min/1.73m2
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o International normalised ratio (INR)/Prothrombin time (PT) <1.2x ULN for age-based local reference valueso K, Mg, Ca within normal range for age

Group C
• Patient meets Intermediate Risk definition according to CHIC Guidelines
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate(GFR) =60mL/min/1.73m2
• Adequate cardiac function determined by:o Shortening fraction =28% by local assessment methodo OR Ejection fraction =47% by local assessment method
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o International normalised ratio (INR)/Prothrombin time (PT) <1.2x ULN for age-based local reference valueso K, Mg, Ca within normal range for age

Group D
• Patient meets High Risk definition according to CHIC Guidelines
• Adequate renal function determined by:o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate(GFR) =60mL/min/1.73m2
• Adequate cardiac function determined by:
o Shortening fraction =28% by local assessment methodo OR Ejection fraction =47% by local assessment method
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o International normalised ratio (INR)/Prothrombin time (PT) <1.2x ULN for age-based local reference valueso K, Mg, Ca within normal range for age

Group E
• Patient has been diagnosed with HCC
• Tumour has been locally assessed as resectable
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate(GFR) =60mL/min/1.73m2
• Adequate cardiac function determined by:
o Shortening fraction =28% by local assessment methodo OR Ejection fraction =47% by local assessment method
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o International normalised ratio (INR)/Prothrombin time (PT) <1.2x ULN for age-based local reference valueso K, Mg, Ca within normal range for age

Group F
• Patient diagnosed with HCC
• Tumour locally assessed as un-resectable, or metastatic HCC disease
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate(GFR) =60mL/min/1.73m2
• Adequate cardiac function determined by:
o Shortening fraction =28% by local assessment methodo OR Ejection fraction =47% by local assessment method
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o International normalised ratio (INR)/Prothrombin time (PT) <1.2x ULN for age-based local reference valueso K, Mg, Ca within normal range for ageo Qt/QTc interval =/<450msec for males, =/<470msec for females

Ausschlusskriterien
• Any previous chemotherapy or currently receiving anti-cancer agents
• Recurrent disease
• Previously received a solid organ transplant
• Uncontrolled infection
• Unable to follow the protocol for any reason
• Second malignancy
• Pregnant or breastfeeding womenTreatment

Group Specific Exclusion Criteria

Group C:
• Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)

Group D:
• Chronic inflammatory bowel disease and/or bowel obstruction
• Concomitant use with St John’s Wort which cannot be stopped prior to start of trial treatment

Group F:
• Peripheral Sensitive Neuropathy with functional impairment
• Personal or family history of congenital long QT syndrome
• QT/QTc interval >450msec for men and >470msec for women (corrected measurement of QT according to BAZETTformula)
• Patients who are unable to swallow tablets, where an oral solution is not available or approved

Studienteilnehmende Mindestalter
0 Tag(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Hepatoblastoma and Hepatocellular Carcinoma.

MedDRA Term
Hepatoblastoma, Hepatocellular carcinoma non-resectable, Hepatocellular carcinoma resectable

Institute
Klinik für Dermatologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Schadendorf

+49 (0)201 723-2225
Hautklinik.Studienzentrum@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

MSD Merck Sharp & Dohme LLC

Einschlusskriterien
1. Participants must have histologically confirmed cSCC as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted)
2. Participant must have undergone complete macroscopic resection of all known cSCC disease with or without microscopic positive margins. For those participants with residual microscopic positive margin
involvement, confirmation that additional re-excision is not possible must be provided. Surgery may consist of 1 or a combination of the following:
a. Resection of the primary lesion
b. Any type of neck dissection(s)
c. Any type of parotidectomy (superficial, total, partial)
3. Participant must have histologically confirmed LA cSCC with a highrisk feature(s) as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary
cancer is not permitted).
High-risk features include at least 1 of the following:
a) Histologically involved nodal disease with the following features:
•Extracapsular extension with either at least 1 lymph node >2 cm in greatest diameter or =2 lymph nodes involved.
b) Any index tumor with =2 of the following high-risk features:
•Tumor =4 cm with a depth >6 mm or invasion beyond subcutaneous fat
•Multi-focal perineural invasion for nerves of <0.1 mm diameter (3 or more foci) or any involved nerve =0.1 mm diameter
•Poor differentiation and/or sarcomatoid and/or spindle cell histology
•Recurrent disease (any cSCC that recurs within 3 years in the previously surgically or topically treated area)
•Satellite lesions (satellitosis) and/or in transit metastases.
c) Any gross cortical bone invasion or skull base invasion and/or skull base foramen invasion.
4. Participant must have completed adjuvant RT for LA cSCC with last dose of RT =4 weeks and =16 weeks from randomization
5. Participant must have completed at least 45 Gy of adjuvant RT for LA cSCC prior to study entry
6. Participant is disease-free as assessed by the investigator with complete radiographic staging assessment =28 days from randomization
7. Participant is male or female and at least 18 years of age at the time of signing the informed consent
8. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis),during the intervention period and for at least 120 days after the last dose of study intervention The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
- A WOCBP must have a negative highly sensitive pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
9. Participant (or legally acceptable representative, if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research
10. Participant provides a tumor tissue sample adequate for PD-L1 testing as determined by central laboratory testing. This tissue sample may be obtained from either the surgical resection, or a prior archival tissue specimen not previously irradiated. FFPE tissue blocks are preferred to slides.
11. Participant has a life expectancy of greater than 3 months.
12. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to treatment initiation.
13. Participant has adequate organ function.Specimens must be collected within 10 days prior to the start of study treatment

Ausschlusskriterien
1. Has macroscopic residual cSCC after surgery and/or recurrence with active cSCC disease before randomization
2. Has any other histologic type of skin cancer other than invasive cSCC, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen’s disease, MCC, melanoma
3. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another costimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
5. Has received prior systemic anticancer therapy including investigational agents for cSCC within 4 weeks prior to randomization
6. Participant must have recovered from all radiation-related toxicities and not have had radiation pneumonitis
7. Has received a live vaccine within 30 days prior to the first dose of study treatment.Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
8. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
10. Has a diagnosed and/or treated additional malignancy within the past 5 years prior to randomization
11. Has known active central nervous system metastases and/or carcinomatous meningitis
12. Has severe hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients
13. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
15. Has an active infection requiring systemic therapy
16. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
17. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV; defined as HCV RNA [qualitative] is detected) infection
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
19. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
21. Has had an allogeneic tissue/solid organ transplant

Geschlecht
Männlich, Weiblich

Indikation
SCC - Plattenepithelkarzinom

Medizinischer Befund
Resectable high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC)

MedDRA Term
Squamous cell carcinoma

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Michael Schündeln

+49 (0)201 723-2500
michael.schuendeln@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Universitätsklinikum Münster

+49 (0)251 83-55555
info@ukmuenster.de

Albert-Schweitzer-Straße 33
48149 Münster

Einschlusskriterien
Patients meeting the following criteria are eligible to the study (inclusion criteria):
• newly diagnosed lymphoblastic lymphoma
• age <18 years at diagnosis
• patient enrolled in a participating center
• written informed consent of patient (>14 years of age or according to local law and regulation) and parents to trial participation and transfer and processing of data
• Willingness of patients and the investigator/pathologist to provide adequate slides/blocks for reference (molecular)pathology and international pathology panel and/or fresh or fresh frozen samples for genetic risk group stratification if these samples are available after standard diagnostic procedures

Ausschlusskriterien
Patients meeting the following criteria are not eligible to the study (exclusion criteria):
• lymphoblastic lymphoma as secondary malignancy
• non-lymphoma related relevant medical, psychiatric or social conditions incompatible with trial treatment including among others:
- prior organ transplant
- severe immunodeficiency
- demyelinating Charcot-Marie Tooth syndrome
- serious acute or chronic infections, such as HIV, VZV and tuberculosis
- urinary tract infection, cystitis, urinary outflow obstruction, severe renal impairment (creatinine clearance less than 20 ml/min)
- severe hepatic impairment (bilirubin >3 times ULN, transaminases >10 times ULN)
- myocardial insufficiency, severe arrhythmias
- ulcers of the oral cavity and known active gastrointestinal ulcer disease
- known hypersensitivity to any IMP and to any excipient
• steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis
• vaccination with live vaccines within 2 weeks before start of protocol Treatment
• treatment started according to another protocol or pre-treatment with cytostatic drugs
• participation in another clinical trial that interferes with the protocol, except NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment, which can run parallel to LBL 2018 without influencing the outcome of this trial (e.g. trials on antiemetics, antibiotics, strategies for psychosocial support)
• evidence of pregnancy or lactation period
• sexually active adolescents not willing to use highly effective contraceptive method (pearl index < 1) until 12 months after end of cytostatic therapy

Studienteilnehmende Mindestalter
0 Tag(e)

Studienteilnehmende Höchstalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Lymphoblastic lymphoma

MedDRA Term
Lymphoblastic lymphoma

Institute
Klinik und Poliklinik für Strahlentherapie, Klinik für Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Glas

neuroonkologie@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

NOXXON Pharma AG, Berlin

Einschlusskriterien
1. Written informed consent
2. Age ≥18 years
3. Patient agreement to diagnostic and scientific work-up of glioblastoma tissue obtained during the preceding surgery or biopsy
4. Patient agrees to subcutaneous port implantation
5. Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
6. Status post biopsy or incomplete resection
7. Unmethylated MGMT promoter status
8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
9. Estimated minimum life expectancy 3 months
10. Stable or decreasing dose of corticosteroids during the week prior to inclusion
11. The following laboratory parameters should be within the ranges specified:
- Total bilirubin ≤ 1.5 x upper limit normal (ULN)
- Creatinine ≤ 1.5 x ULN or glomerular filtration rate ≥ 60 mL/min/1.73m²
- ALT (alanine transaminase) ≤ 3 x ULN
- AST (aspartate transaminase) ≤ 3 x ULN
12. Female patients of child-bearing potential must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly such as contraceptive implants, vaginal rings, sterilization, or sexual abstinence)" during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations)
13. Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP

Ausschlusskriterien
1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents, olaptesed pegol or polyethylene glycol
4. Cytostatic therapy (chemotherapy) within the past 5 years
5. History of other cancers (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for = 5 years)
6. Clinically significant or uncontrolled cardiovascular disease
7. Prior radiotherapy to the head
8. Any other previous or concomitant experimental glioblastoma treatments
9. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
10. Pregnancy or lactation
11. Uncontrolled intercurrent illness; patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations
12. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
13. Prior enrolment into this study

Exclusion Criteria Expansion Group Arms A and B:
1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab (Arm A only) olaptesed pegol or polyethylene glycol
4. Planned hypofractionated radiotherapy
5. Cytostatic therapy (chemotherapy) within the past 5 years
6. History of other cancers (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for = 5 years)
7. Secondary malignancy which is currently active
8. Clinically significant or uncontrolled cardiovascular disease, including
- Myocardial infarction in the previous 12 months
- Uncontrolled angina
- Congestive heart failure (New York Heart Association functional classification of =2)
- Diagnosed or suspected congenital long QT syndrome
- QTc prolongation on an electrocardiogram prior to entry (>470 ms)
- Uncontrolled hypertension (blood pressure = 160/95 mmHg)
- Heart rate <50/min on the baseline electrocardiogram
- History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
- Cerebrovascular accident
9. Prior radiotherapy to the head
10. Any other previous or concomitant experimental glioblastoma treatments
11. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
12. Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants (Arm A only)
13. Pregnancy or lactation
14. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or subjects with either of the following: fasting blood glucose (FBG defined as fasting for at least 8 hours) = 200 mg/dL (7.0 mmol/L), or HbA1c = 8%, chronic renal disease, pancreatitis, chronic pulmonary disease, auto-immune diseases, or psychiatric illness/social situations that would limit compliance with study requirements. Patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations
15. Prolongation of coagulation factors = 2.5 x ULN (Arm A only)
16. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
17. Prior enrolment into this study

Exclusion Criteria Expansion Group Arms C:
1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents olaptesed pegol or polyethylene glycol or pembrolizumab (= Grade 3)
4. Biopsy-only of GBM with less than 20% of tumor removed
5. Presence of extracranial metastatic or leptomeningeal disease
6. Severe hypersensitivity (= Grade 3) to other monoclonal antibodies
7. Receiving immunosuppressive therapy
8. Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent
9. Planned hypofractionated radiotherapy
10. Cytostatic therapy (chemotherapy) within the past 5 years
11. History of other cancers or secondary malignancy which is currently active (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for = 5 years)
12. Clinically significant or uncontrolled cardiovascular disease, including
- Myocardial infarction in the previous 12 months
- Uncontrolled angina
- Congestive heart failure (New York Heart Association functional classification of =2)
- Diagnosed or suspected congenital long QT syndrome
- QTc prolongation on an electrocardiogram prior to entry (>470 ms)
- Uncontrolled hypertension (blood pressure = 160/95 mmHg)
- Heart rate <50/min on the baseline electrocardiogram
- History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
- Cerebrovascular accident
13. Prior radiotherapy to the head
14. Evidence of acute intracranial / intra-tumoral hemorrhage
15. Any other previous or concomitant experimental glioblastoma treatments
16. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
17. Pregnancy or lactation
18. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or subjects with either of the following: fasting blood glucose (FBG defined as fasting for at least 8 hours) = 200 mg/dL (7.0 mmol/L), or HbA1c = 8%, chronic renal disease, pancreatitis, chronic pulmonary disease, auto-immune diseases or psychiatric illness/social situations that would limit compliance with study requirements. Patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations.
19. Received a live vaccine within 30 days prior to the first dose of study drug.
20. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Previously treated brain metastases may participate provided these remain stable
21. Known history of HIV infection, hepatitis B or hepatitis C infection
22. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
23. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or current pneumonitis / interstitial lung disease
24. Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (exceeding 10 mg daily of prednisone) or any other form of immunosuppressive therapy
25. High dose of corticosteroids (> 4mg/day of dexamethasone or equivalent for at least 3 consecutive days) within two weeks prior to the first dose of study drug
26. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
27. Prior enrolment into this study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Glioblastom

Medizinischer Befund
Glioblastom

MedDRA Term
Glioblastoma

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. Uta Dirksen

+49 (0)201 723-82025
uta.dirksen@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Heidelberg

Einschlusskriterien
- Children and adolescents with refractory/relapsed/progressive high-risk
- CNS tumors: medulloblastoma, ependymoma, ATRT, ETMR, pediatric high grade glioma (including DIPG) or other pediatric embryonal CNS tumors
OR
- solid tumors: neuroblastoma, nephroblastoma, rhabdoid tumor, embryonal or alveolar rhabdomyosarcoma or other embryonal small round blue cell tumors including pediatric type (bone) sarcoma
OR
Children and adolescents with newly diagnosed high grade glioma (HGG) in the context of a constitutional mismatch repair deficiency syndrome
- No standard of care treatment available
- Age at registration = 6 to = 21 years.
- Molecular analysis for biomarker identification (SNV load, PDL1 mRNA expression, MYC/N amplification) in laboratories complying with DIN EN ISO/IEC 17025 or similar via INFORM molecular diagnostic platform or equivalently valid molecular pipeline.
- Biomarker determined using whole exome sequencing (SNV load), RNA-sequencing (PDL1 mRNA expression) and whole genome sequencing (MYC/N amplification).
- In case molecular analysis was not performed via INFORM Registry molecular pipeline: transfer of molecular data (whole exome and RNA sequencing)
- Time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration = 12 weeks
- Disease that is measurable as defined by RANO criteria or RECIST v1.1 (as appropriate).
- Life expectancy > 3 months, sufficient general condition score (Lansky = 70 or Karnofsky = 70). Transient states like infections can be accepted, and also stable disabilities resulting from disease/surgery (hemiparesis, amputations etc.) can be accepted and will not be considered for Lansky/Karnofsky assessments.
- Laboratory requirements:
- Hematology: absolute granulocytes = 1.0 × 109/l (unsupported)
platelets = 100 × 109/l
hemoglobin = 8 g/dl or = 5,6 nmol/L
- Biochemistry: Total bilirubin = 1.5 x upper limit of normal (ULN)
AST(SGOT) = 3.0 x ULN
ALT(SGPT) = 3.0 x ULN
serum creatinine = 1.5 x ULN for age
- ECG: normal QTc interval = 480 msec
- Patient is able to swallow oral study medication
- Ability of patient and/or legal representative(s) to understand the character and individual consequences of clinical trial
- Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active male patients must agree to use a condom during the study and for at least 7 months after the last study treatment administration.
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Before patient screening and registration, written informed consent, also concerning data and blood transfer, must be given according to ICH/GCP, and national/local regulations.
- No prior therapy with the combination of immune checkpoint inhibitors and HDACi
- BSA = 0.9m2
- Phase I: molecular analysis performed and biomarker status known (mutational load, PD-L1 mRNA expression AND MYC(N) amplification status).
- Phase II: molecular analysis performed, biomarker status known (mutational load, PD-L1 mRNA expression AND MYC(N) amplification status) and stratification according to the following criteria:
- Group A: high mutational load (defined as > 100 somatic SNVs/exome) based on whole exome sequencing
OR
- Group B: high PD-L1 mRNA expression (defined as reads per million total reads per kilobase of exon model (RPKM) > 3) based on RNA sequencing
OR
- Group C: Focal MYC(N) amplification based on whole genome sequencing
OR
- Group D: Patients with biomarker low tumors according to the definitions of group A-C.

Ausschlusskriterien
- Patients with CNS tumors or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions).
- Patients with low-grade gliomas or tumors of unknown malignant potential are not eligible
- Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
- Participants with bulky CNS tumor on imaging are ineligible; bulky tumor is defined as:
- Tumor with any evidence of uncal herniation or severe midline shift
- Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI
- Tumor that in the opinion of the investigator, shows significant mass effect
- Previous allogeneic bone marrow, stem cell or organ transplantation
- Diagnosis of immunodeficiency
- Diagnosis of prior or active autoimmune disease
- Evidence of interstitial lung disease
- Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Clinically significant, uncontrolled heart disease
- Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
- Any anticancer therapy (e.g., chemotherapy, HDACi (including valproic acid), DNA methyltransferase inhibitors, other immunotherapy, targeted therapy, biological response modifiers, endocrine anticancer therapy or radiotherapy) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug administration.
- Radiologically confirmed radiotherapy induced pseudoprogression in CNS tumors
- Traditional herbal medicines; these therapies are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. For information on CYP substrates and P-gp inhibitors or inducers see section 5.8.
- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form (including benzamide) of the investigational medicinal product
- Participation in other ongoing clinical trials.
- Pregnant or lactating females.
- Presence of underlying medical condition (e.g. gastrointestinal disorders or electrolyte disturbances) that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of entinostat and nivolumab in treated subjects
- Patients receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may be approved after consultation with the Sponsor.
No patient will be allowed to enroll in this trial more than once.

Studienteilnehmende Mindestalter
2 Jahr(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
This trial investigates a novel combination treatment regimen using immune checkpoint inhibition and epigenetic therapy in children with relapsed\/refractory\/progressive high-risk solid tumors or CNS tumors. Thus, this trial focuses on the pediatric population in 4 biomarker-defined cohorts, for which there is no standard of care treatment available.

Institute
LVR Kliniken-Essen - Klinik für Psychosomatische Medizin und Psychotherapie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. Alexander Bäuerle

+49 (0)201 7227-203
Alexander.Baeuerle@uni-due.de

Virchowstraße 174
45147 Essen

Indikation
Diverse

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Jens Siveke

jens.siveke@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GWT-TUD GmbH, Dresden

Einschlusskriterien
1. Patients must have histologically confirmed PDAC
2. Patients must have metastatic disease (stage IV) and not received prior chemotherapy for stage IV disease (adjuvant/additive chemotherapy is allowed if completed at least 6 months prior to study inclusion)
3. Patients must not have received the following drugs before: Azacitidine, Romidepsin, any checkpoint-inhibitor or immunomodulating agents such as IMiDs (Lenalidomide)
4. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1
5. Male or female, age ≥ 18 years
6. Body weight > 30 kg for inclusion into Part 2 (according to Durvalumab treatment)
7. ECOG performance status 0 or 1
8. Patients must have normal organ and marrow function as defined below
• Leukocytes ≥ 2,5*10^9/L
• Absolute neutrophil count ≥ 1,5*10^9/L
• Platelets ≥ 100*10^9/L
• Haemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
• Asparate aminotransferase/alanine aminotransferase (AST/ALT) (SGOT/SGPT) ≤ 2.5 x ULN and ≤ 5 in the case of liver metastasis
• Measured creatinine clearance (CL) >60 mL/min or Calculated creatinine CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
9. Patients must be recovered from the effects of any prior surgery
10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
11. All subjects must agree to refrain from donating blood while on study drug and for 90 days after discontinuation from this study treatment
12. All subjects must have a life expectancy of at least 12 weeks
13. All subjects must agree not to share medication.
14. Females of childbearing potential (FCBP) must
• Understand the potential teratogenic risk to the unborn child
• Understand the need and agree to utilize two reliable forms of contraception simultaneously without interruption for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 90 days after study treatment discontinuation
• Understand and agree to inform the investigator if a change or stop of method of contraception is needed
• Be capable of complying with effective contraceptive measures
• Be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
• Understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test
• Understand the need and accept to undergo pregnancy testing based on the frequency outlined in this protocol
• Acknowledges that she understands the hazards Lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of Lenalidomide
• Females must agree to abstain from breastfeeding during study participation and for at least 90 days after study drug discontinuation
15. Males must
• Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP
• Agree to use a latex condom during any sexual contact with FCBP or a pregnant female while participating in the study and for 90 days following discontinuation from this study, even if he has undergone a successful vasectomy. For treatment with Gemcitabine and nab-Paclitaxel men must avoid fathering a child/ use a condom up to 6 months after their last dose. Depending on duration of Lenalidomide/Durvalumab treatment this period can be longer than 90 days after study discontinuation
• Agree to refrain from donating semen or sperm while on the study drugs and for 90 days after discontinuation from this study treatment. For treatment with nab-Paclitaxel and Gemcitabine male subjects must agree not to father a child or donate semen for at least 6 month afterlast intake of medication
• Agree not to father a child during the course of the trial and for at least 90 days after last administration of study drugs. For Gemcitabine and nab-Paclitaxel treatment up to 6 month after last drug intake.
16. Females of non-childbearing potential:
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhea for at least 24 consecutive months without an alternative medical cause

Ausschlusskriterien
1. Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events from agents administered more than 4 weeks earlier
2. Patients receiving any other investigational agents
3. Patients who have previously received Romidepsin, Azacitidine, Lenalidomide or Durvalumab or any PD1 or PD-L1 inhibitor or participate currently on an other clinical trial, unless it is an observational clinical study or during the follow-up period of an interventional study
4. Patients with untreated or uncontrolled brain metastases or leptomeningeal disease
5. Presence of other active illnesses
6. Any known cardiac abnormalities such as:
• Congenital long QT syndrome
• QTc interval = 470 milliseconds. Calculated from 3 ECGs using Fridericias Correction
7. Myocardial infarction within 6 months of C1D1
8. Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia
9. Symptomatic coronary artery disease, e.g., angina Canadian Class II-IV
10. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or known ejection fraction <40% by MUGA or <50% by echocardiogram and/or MRI
11. A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD)
12. Concomitant use of any drug known to prolong QT interval
13. Concomitant use of strong CYP3A4 inhibitors
14. Lactating, pregnant or breast feeding
15. Patients with any other medical or psychological condition deemed by the investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
16. Diagnosis of immunodeficiency or any condition that requires systemic steroid therapy or other forms of immunosuppressive therapy
17. Prior thromboembolic events
18. History of other malignancies, except:
• Malignancy treated with curative intent and with no known active disease present for = 5 years before the first dose of study drug and felt to be at low risk for recurrence by investigator.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without current evidence of disease
19. Any uncontrolled active systemic infection
20. Major surgery within 4 weeks of first dose of study drug
21. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
22. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
23. History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis
24. Unable to swallow oral medication or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
25. Concomitant use of warfarin or other Vitamin K antagonists
26. Known allergy or hypersensitivity to any study drug or any of the study drug excipients
27. Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information
28. Current or prior use of immunosuppressive medication within 14 days (use 28 days if combining Durvalumab with a novel agent) before the first dose of Durvalumab
29. Active or prior documented autoimmune or inflammatory disorders
30. Any unresolved toxicity NCI CTCAE Grade = 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria .
• Patients with Grade = 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab may be included only after consultation with the Study Physician.
31. History of allogenic organ transplantation
32. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus
33. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP
34. Subject is an employee of GWT-TUD GmbH

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Pancreas Cancer\nPancreatic Adenocarcinoma\nPancreatic Ductal Adenocarcinoma

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Friedrich Schiller Universität, Jena

Ausschlusskriterien
- Allogene Stammzelltransplantation
- Bekannte Beeinträchtigung der Herzfunktion, einschließlich:
o kongenitales Long-QT-Syndrom
o Vorgeschichte/Vorliegen einer signifikanten ventrikulären oder atrialen Tachyarrhythmie
o Myokardinfarkt innerhalb 12 Monate vor Therapiestart
o QTc >450 msec im Screening EKG
o Vorliegen einer klinisch signifikanten oder symptomatischen Bradykardie
o Familiengeschichte von plötzlichem idiopathischen Tod
o Patienten mit Ruhe-QTcF =450 msec (männlich) oder =460 msec (weiblich) in der Vortherapie, oder unbestimmbaren QTcF Intervall
- Patienten mit unkorrigierter Hypokaliämie oder Hypomagnesämie
- Andere klinisch signifikante Herzerkrankung (z.B. instabile Angina pectoris, Herzdekompensation, unkontrollierter Bluthochdruck).
- Akute oder chronische virale Hepatitis mit moderater oder schwerer hepatischer Beeinträchtigung (Child-Pugh scores >6), auch wenn kontrolliert
- Andere derzeitige unkontrollierte Krankheiten (z.B. aktive oder unkontrollierte Infektionen, akute oder chronische Leber- oder Nierenerkrankungen), die zu einem inakzeptablen Sicherheitsrisiko führen können oder eine prüfplankonforme Durchführung gefährden
- Beeinträchtigte Magen-Darm-Funktion oder Erkrankungen, die die Absorption der Prüfmedikation beeinträchtigen können (z. B. Geschwür, unkontrollierte Übelkeit, Erbrechen und Durchfall, Malabsorptions-Syndrom, Dünndarm-Resektion oder Magen-Bypass).
- Bekannte akute oder chronische Pankreatitis
- Einnahme von Medikamenten, die bekanntermaßen zu einer starken Induktion oder Inhibition des CYP450-Isoenzyms CYP3A4 führen.
- Patienten mit Operation = 2 Wochen vor Start der Studienmedikation, oder ausstehender Erholung von Nachwirkungen einer solchen Operation
- Schwangere, stillende oder potentiell gebärfähige Patienten ohne Nutzung effektiver Verhütungsmethoden. Potentiell gebärfähige Patienten benötigen einen negativen Serum-Schwangerschaftstest innerhalb von 14 Tagen nach Studienstart. Postmenopausale
Patienten müssen bereits für mindestens 12 Monate amenorrhoisch sein um als nicht gebärfähig zu gelten. Alle Patienten müssen einer effektiven Verhütungsmethode während, sowie mind. 2 Wochen nach Absetzen der Studienmedikation, zustimmen. Es ist nötig, dass sexuell aktive Männer beim Geschlechtsverkehr während und bis 2 Wochen nach Beendigung der Einnahme der Studienmedikation Kondome verwenden und in diesem Zeitraum kein Kind zeugen. Ein Kondom muss ebenfalls von vasektomierten Männern verwendet werden, um den Übergang des Medikaments über die Samenflüssigkeit zu verhindern. Weiblichen Partnern von männlichen Patienten wird empfohlen, hochwirksame Methoden der Empfängnisverhütung zu verwenden.)
- Bekannte Infektion mit dem humanen Immundefizienzvirus (HIV). Die Testung ist nicht verpflichtend.
- Bekannte ernsthafte Hypersensitivität gegenüber Imatinib, Nilotinib oder Dasatinib
- Patienten mit einer malignen Erkrankung, die zurzeit klinisch signifikant ist oder zurzeit eine aktive Behandlung erfordert.
- Patenten, die nicht bereit oder nicht in der Lage sind, den Anforderungen des Prüfplans Folge zu leisten.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
CML

Institute
Frauenheilk \/Gynäkologie, Klinik für Frauenheilkunde und Geburtshilfe, Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Stefan Schönberger

stefan.schoenberger@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Rheinische Friedrich-Wilhelms-Universität Bonn

Einschlusskriterien
- Confirmed extracranial MGCT up to 17 11/12 years of age or patients with ovarian primaries up to 29 11/12 years of age on the date of written informed consent
- Written informed consent prior to trial entry of parents and/or patient
- Diagnosis of a chemotherapy-naïve extracranial MGCT
- Karnofsky-Index of >70% or ECOG-Status 0-II
- Negative pregnancy test within 7 days prior to start of treatment for female patients of childbearing potential, in case of ß-HCG secreting MGCT pregnancy has to be excluded by appropriate methods

Note: Any patient who is of reproductive age should agree to use adequate contraception for the duration of the trial treatment and until at least 12 months after end of therapy.

Ausschlusskriterien
Exclusion criteria in general:
- Pregnancy
- Lactation
- Incomplete data at trial entry preventing risk group allocation
- HIV-positivity
- Live vaccine immunization within two weeks before start of protocol treatment
- Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of chemotherapy
- Current or recent (within 30 days prior to date of informed written consent) treatment with another investigational drug or participation in another interventional clinical trial, except trials with different end points than MAKEI V that can run in parallel to MAKEI V without influencing that trial, e.g., trials on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.
- Any other medical, psychiatric or drug related condition, or social condition incompatible with protocol treatment.

Exclusion criteria in special indication:
- Second malignancies
- Negative preoperative tumour markers AFP and ß-HCG and solely pure teratoma histology
- Known hypersensitivity against Cisplatin, Carboplatin, Etoposide, Ifosfamide or other ingredients of the medicinal product
- Hearing impairment Grade 3 and 4 (CTCAE Vers.4.03)

Studienteilnehmende Mindestalter
0 Tag(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Extracranial germ cell tumours of any malignant histology, primary site and stage

Institute
Klinik für Dermatologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Schadendorf

+49 (0)201 723-2225
Hautklinik.Studienzentrum@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Regeneron Pharmaceuticals, Inc, USA

Einschlusskriterien
- Men and women ≥18 years old
- For Japan only, men and women ≥21 years old
- Patient with resection of pathologically confirmed CSCC (primary CSCC lesion only, or primary CSCC with nodal involvement, or CSCC nodal metastasis with known primary CSCC lesion previously treated within the draining lymph node echelon), with macroscopic gross resection of all disease - High risk CSCC, as defined in the protocol
- Completion of curative intent post-operative radiation therapy (RT) within 2 to 6 weeks of randomization
- Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1
- Adequate hepatic, renal, and bone marrow function as defined in the protocol

Ausschlusskriterien
- Squamous cell carcinomas (SCCs) arising in non-cutaneous sites as defined in the protocol
- Concurrent malignancy other than localized CSCC and/or history of malignancy other than localized CSCC within 3 years of date of randomization as defined in the protocol
- Patients with hematologic malignancies (eg, chronic lymphocytic leukemia (CLL))
- Patients with history of distantly metastatic CSCC (visceral or distant nodal), unless the disease-free interval is at least 3 years (regional nodal involvement of disease in draining lymph node basin that was resected and radiated prior to enrollment will not be exclusionary
- Ongoing or recent (within 5 years of randomization date) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related adverse events (irAEs). The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment.
- Has had prior systemic anti-cancer immunotherapy for CSCC

Geschlecht
Männlich, Weiblich

Indikation
SCC - Plattenepithelkarzinom

Medizinischer Befund
Patients with features associated with high-risk of recurrent CSCC disease, who have completed surgery and post-operative RT radiation therapy

MedDRA Term
Squamous cell carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Ipsen Pharma S.A., France

Einschlusskriterien
(1) Subjects must provide a signed informed consent prior to any study-related procedures;
(2) Male or female subjects must be aged ≥18 years on the day the informed consent is signed;
(3) Subjects must have histologically confirmed unresectable, locally advanced (defined as disease not eligible for curative surgery or radiation therapy) or metastatic RCC with a clear-cell carcinoma component;
(4) Subjects must have radiographic disease progression, according to Investigator’s judgement, following 1st line treatment with CPI (ipilimumab plus nivolumab) (Cohort A) or CPI in combination with VEGF-targeted therapy (Cohort B);
(5) Subjects present ≥1 target lesion according to RECIST 1.1 per investigator;
(6) Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1;
(7) Subjects with treated brain metastases are eligible if metastases have been shown to be stable as per Investigator’s judgement;
(8) Subjects must have adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 15 days before baseline:
(a) Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
(b) Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
(c) Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
(d) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal.
(e) Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert’s disease ≤ 3 mg/dL (≤ 51.3 μmol/L).
(f) Fasting serum triglycerides ≤ 2.5 × upper limit of normal and total cholesterol ≤ 300 mg/dL (≤ 7.75 mmol/L). Lipid-lowering medication is allowed.
(g) Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation
(h) Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine or 24-hour urine protein < 1 g.
(9) Subject must have recovered to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy as determined by the investigator;
(10) Subject must have completed a steroid taper if he/she experienced an immune-related adverse event associated with previous CPI treatment;
(11) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile) must provide a negative pregnancy test within 7 days prior to the start of study treatment. If a urine test cannot be confirmed as negative, a negative serum pregnancy test is required;
(12) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile) and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 120 days after the last dose of study treatment;
(13) All male participants must agree to refrain from donating sperm and unprotected sexual intercourse with female partners during the study and for 120 days after the last dose of study treatment;
(14) Subjects must be willing and able to comply with study requirements, remain at the investigational site for the required duration of each study visit and be willing to return to the investigational site for the follow up evaluation, as specified in the protocol.
(15) Subjects must be covered by social security or be the beneficiary of such a system (only applicable for French subjects).

Ausschlusskriterien
(1) Inability to swallow tablets;
(2) treated with any other investigational medicinal product (IMP) during a clinical study within the last 30 days before baseline;
(3) previously treated with cabozantinib;
(4) Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium used for Contrast Tomography (CT)-scan;
(5) Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic progression of known brain metastases;
(6) diagnosis of a serious cardiovascular disorder:
(a) Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, or serious cardiac arrhythmias;
(b) Uncontrolled hypertension, defined as sustained blood pressure (BP) (>140 mm Hg systolic or>90 mm Hg diastolic pressure) despite optimal antihypertensive treatment;
(c) Stroke (including transient ischaemic attack (TIA)), myocardial infarction (MI) or other ischaemic event, or thromboembolic event (e.g. deep venous thrombosis, pulmonary embolism) within 6 months before screening;
(d) History of risk factors for torsades de pointes (eg, long QT syndrome);
(7) receiving a concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors
Note:Low dose aspirin for cardioprotection (per local applicable guidelines) and low dose LMWH are permitted.
(8) gastrointestinal (GI) disorder including those associated with a high risk of perforation or fistula formation:
(a) Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction;
(b) Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before screening;
Note: Complete healing of an intra-abdominal abscess must have been confirmed before screening.
(9) Presents a corrected QT (QTc) interval calculated by the Fridericia formula (QTcF)>500 msec within 1 month prior to baseline;
Note: If a single ECG shows a QTcF with an absolute value>500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility
(10) clinically significant haematuria, hematemesis, or haemoptysis of >0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding within 3 months before screening;
(11) cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
(12) lesions invading major pulmonary blood vessels;
(13 ) diagnosed with other clinically significant disorders such as:
(a) Serious nonhealing wound/ulcer/bone fracture;
(b) Malabsorption syndrome;
(c) Uncompensated/symptomatic hypothyroidism (subject with a history of autoimmune-related hypothyroidism on thyroid-replacement hormone are eligible for the study)
(e) Moderate to severe hepatic impairment
(f) Requirement for haemodialysis or peritoneal dialysis
(g) History of solid organ transplantation;
(14) predicted life expectancy of less than 3 months;
(15) prior surgery within 4 weeks prior to baseline. Note: If the subject has undergone major surgery, complete wound healing must have occurred 1 month prior to baseline.
(16) palliative radiation therapy for bone within 2 weeks or for radiation fields including viscera within 4 weeks prior to baseline. Note: Resolution/healing of side effects must be complete prior to baseline;
(17) history of another active malignancy within 3 years from screening except for locally curable cancers that have been apparently cured, such as low-grade thyroid carcinoma, prostate cancer not requiring treatment , basal or squamous cell skin cancer, superficial bladder cancer, in situ melanoma, in situ prostate, cervix or breast carcinoma or other treated malignancies with <5% chance of relapse according to the Investigator;
(18) history of allergy to study treatment components or agents with a similar chemical structure or any excipient used in the formulation as listed in the SmPC document;
(19) rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption;
(20) serious medical or psychiatric condition that render the subject unable to understand the nature, scope and possible consequences of the study, and/or presents an uncooperative attitude;
(21) pregnant or breastfeeding. A ß-human chorionic gonadotrophin (HCG) serum pregnancy test will be performed up to 7 days prior to baseline for all female subjects of childbearing potential ;
(22) likely to require treatment during the study with drugs that are not permitted by the study protocol;
(23) abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject’s safety.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Unresectable, Locally Advanced or Metastatic Renal Cell Carcinoma with a Clear-Cell Component Who Progressed After 1st Line Treatment with Checkpoint Inhibitors

MedDRA Term
Renal cell carcinoma

Institute
Klinik für Dermatologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Schadendorf

+49 (0)201 723-2225
Hautklinik.Studienzentrum@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Alcedis GmbH, Giessen

Indikation
Melanom

Medizinischer Befund
melanoma

Institute
Klinik und Poliklinik für Strahlentherapie, Innere Klinik (Tumorforschung), Ruhrlandklinik - Thorakale Onkologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Wilfried Eberhardt

wilfried.eberhardt@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1. Body weight >30 kg
2. Age = 18 years and < 75 years
3. Male or female patients. Female (as well as male) patients have to take care of effective measures of anticonception
4. Histologically proven non-small cell lung cancer
5. Selected patients with non-small cell lung cancer stages IIIA and IIIB:
• IIIA: one or more lymph node levels involved at EBUS/mediastinoscopy
• IIIA: bulky N2-disease histologically proven at EBUS/cervical mediastinoscopy / parasternal mediastinotomy, not diffuse mediastinal involvement
• selected IIIB: N3-disease with contralateral mediastinal nodes involved at EBUS / mediastinoscopy
• potentially resectable T4-disease:
o involvement of the pulmonary artery (angiogr.-CT/MRI/TEE),
o involvement of the carina (histologically proven),
o involvement of the left atrium (angiogr.-CT/MRI/TEE),
o involvement of the vena cava (angiogr.-CT/MRI/TEE),
o involvement of ipsilateral intrapulmonary satellite nodules,
o mediastinal involvement (not diffuse)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Resectable disease at the time of inclusion
8. Fulfillment of adequate criteria for functional and medical resectability as described in the ERS/ESTS guidelines [Brunelli et al 2009] and acceptable general clinical condition for multimodality treatment (interdisciplinary committee)
9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
10. Must have a life expectancy of > 12 weeks
11. Adequate normal organ and marrow function as defined below:
o Haemoglobin = 9.0 g/dL
o Absolute neutrophil count (ANC) > 1.5 x 109/L (> 1500 per mm3)
o Platelet count = 100 x 109/L (= 100.000 per mm3)
o Serum bilirubin = 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
o AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal
o Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause
13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
14. Stable cardiac function (no Myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV)

Ausschlusskriterien
1. resectable IIB or selected IIIA
2. unresectable disease pre-treatment
3. mixed histology with areas of small cell carcinoma
4. clinically symptomatic vena cava superior syndrome
5. diffuse mediastinal involvement
6. patients with T3N3 and T4N3 tumors
7. invasion of the thoracic aorta
8. invasion of the heart
9. invasion of the esophagus
10. invasion of spine
11. Pancoast-syndrome in tumors of the superior sulcus
12. malignant pericardial effusion
13. malignant pleural effusion
14. involvement of the contralateral hilar nodes
15. endobronchial tumor extension to the contralateral main stem bronchus
16. ipsi- or contralateral supraclavicular nodes
17. lung or heart function not allowing at the time of inclusion the intended surgical procedure
18. previous administration of chemotherapy and/or radiotherapy
19. previous immunotherapy
20. insufficient patients compliance
21. loss of weight > 10 % in the last six months
22. missing written informed consent or definitive refusal for participation
23. Participation in another clinical study with an investigational product during the last 12 months
24. Concurrent enrolment in another clinical study, unless it is an observational clinical study or during the follow-up period of an interventional study
25. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
26. History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan
27. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable
28. Major surgical procedure within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
29. History of allogenic organ transplantation
30. History of a stem cell transplantation
31. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).
32. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
33. History of another primary malignancy
34. History of active primary immunodeficiency
35. Active infection including tuberculosis hepatitis B, hepatitis C, or human immunodeficiency virus. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV RNA
36. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
37. Current or prior use of immunostimulatory agents within 14 days before the first dose of durvalumab
38. Receipt of live attenuated vaccine within 90 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP
39. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
40. Known allergy or hypersensitivity to durvalumab or any excipientFor full text exclusion criteria and exceptions please refer to study protocol section 4.2

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
74 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
non-small cell lung cancer stages IIIA (N2) and selected resectable stages IIIB

MedDRA Term
Non-small cell lung cancer

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

German Pediatric Oncology Group, GPOH gGmbH, Berlin

Einschlusskriterien
• Myeloid Leukemia (ML) or Myelodysplastic Syndrome (MDS), according to WHO
• Trisomy 21: Down syndrome or mosaic
• Age: > 6 months and = 4 years of age with/without GATA1 mutation OR > 4 years of age < 6 years of age with GATA1 mutation
• Morphology/Immunophenotyping: FAB M0, M6 or M7
• Lansky performance score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable
• Understand and voluntarily provide written permission of parental/legal representative(s) to the ICF prior to conducting any study related assessments/procedures, also concerning data and tumor material transfer according to ICH/GCP and national/local regulations
• Able to adhere to the study visit schedule and other protocol requirements

Ausschlusskriterien
• Children with Transient Abnormal Myelopoiesis (TAM), according to WHO
• Cytogenetics: AML with recurrent genetic abnormalities (WHO 2016)
• Previous allogeneic bone marrow, stem cell or organ transplantation
• Evidence of invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and C
• Symptomatic cardiac disorders (CTCAE 4.0 Grade 3 or 4)Major surgery within 21 days of the first dose.
• Any anti-cancer therapy (e.g., intensive chemotherapy, biologics or radiotherapy) for more than 14 days or within 4 weeks before start of therapy, except low-dose cytarabine for the treatment of TAM.
• Concomitant treatment with any other anticancer therapy except those specified in protocol during the study therapy
• Treated by any investigational agent in a clinical study within previous 4 weeks
• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product
• Former Enrolment to this study

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Myeloid Leukemia in Children with Down Syndrome

Institute
Innere Klinik (Tumorforschung), Ruhrlandklinik - Klinik für Thoraxchirurgie und thorakale Endoskopie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1. Patients with histologically or cytologically (EBUS-TBNA) confirmed non-small cell lung cancer (NSCLC) eligible for anatomic resection, with the following specification :• Clinical stages I A3, I B, II and selected stage III A (T3 N1, T4 with satellite nodule in the same lung N0/N1, selected T1a-T2b N2 cases considered suitable for primary surgical approach by the multidisciplinary tumor board) according to UICC 8th edition.• Female and male patients = 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 6 months after the end of treatment. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test2. ECOG = 13. Exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3) by PET/CT and/or mediastinal lymph node sampling by EBUS/TBNA and/or staging mediastinoscopy.4. Exclusion of distant metastases by standard of care imaging studies, which include but are not limited to PET/CT or PET/MRI, or CT or MRI of thorax, abdomen, pelvis, and bone scan. Asymptomatic brain metastases will be excluded by MRI or contrast-enhanced CT as indicated by current guidelines.5. Measurable target tumor prior to immunotherapy using standard imaging techniques.6. Sufficient pulmonary function to undergo curative lung cancer surgery, ppFEV1>30%, ppDLCO>30%, ppVO2max ? 10 ml/min/kg (if CPET was mandated per local guidelines)7. Adequate hematological, hepatic and renal function parameters:o Leukocytes = 2,000/mm³, platelets = 100,000/mm³, absolute neutrophil count (ANC) = 1,500/µL, hemoglobin = 9 g/dL (5.58 mmol/L),o Anti-platelet therapy (such as but not limited to clopidogrel) should be discontinued pre-operative according to local standards. If this therapy cannot but interrupted due to severe cardiovascular comorbidity, patient is ineligible for trialo Adequate coagulation function as defined by International Normalized Ratio (INR) = 1.5, and a partial thromboplastin time (PTT) = 5 seconds above the upper limit of normal (ULN) (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon or direct oral anticoagulants are to be bridged according to local standards and have achieved stable coagulation profile prior to surgery.o Serum creatinine = 1.5 x upper limit of normal o Bilirubin = 1.5 x upper limit of normal, AST and ALT = 3.0 x upper limit of normal, alkaline phosphatase = 6 x upper limit of normal8. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

Ausschlusskriterien
1. Active or history of autoimmune disease or immune deficiency, i? Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.? Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.? skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic immunosuppressive treatment, in particular corticosteroids are permitted to enroll2. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.3. Subjects who have undergone organ transplant or allogeneic stem cell transplantation.4. FEV<30%, DLCO<30%, ppO2 2 × institutional ULN6. Active malignancy or a prior malignancy within the past 3 years ? Patients with completely resected basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and patients with isolated elevation in prostate-specific antigen or low risk prostate cancer managed with active surveillance or watchful waiting in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.7. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.8. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative).9. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications10. Peripheral polyneuropathy NCI CTCAE Grade = 211. History of gastric perforation or fistulae in past 6 months12. Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment.13. The patient has undergone major surgery within 28 days prior to enrollment except staging mediastinoscopy, diagnostic VATS or implantation of a venous port-system.14. Any other concurrent antineoplastic treatment including irradiation15. Breastfeeding women16. Women of childbearing potential unless women who meet the following criteria: ? Post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum FSH > 40 U/mL) ? Postoperatively (six weeks after bilateral ovariectomy with or without hysterectomy) ? Regular and correct use of a contraceptive method with error rate <1% per year such as implants, depot injections, oral contraceptives or intrauterine devices during the treatment and at least up to 5 months after last treatment? Sexual abstinence during the treatment and at least up to 5 months after last treatment? Vasectomy of the partner 17. Men of sexual activity with women of childbearing potential who are not willing to use an effective barrier method of contraception during and up to 7 months after the end of therapy18. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.a. Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy.b. Prior treatment with LAG-3 targeted agent.Other• Participation in another interventional clinical study within the last 3 months prior to inclusion or simultaneous participation in other clinical studies• Previous treatment with nivolumab or relatlimab• Previous immunotherapy for lung cancer• Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety• Any contraindications against nivolumab or relatlimab

Studienteilnehmende Mindestalter
Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
non-small cell lung cancer (NSCLC) of clinical stages I A3, II and selected stage III A

MedDRA Term
Non-small cell lung cancer

Institute
LVR Kliniken-Essen - Klinik für Psychosomatische Medizin und Psychotherapie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Frau Venja Musche

+49 (0)201 438 755-227
Venja.musche@lvr.de

Virchowstr 174
45147 Essen

Geschlecht
Männlich, Weiblich

Indikation
Melanom

Medizinischer Befund
malignes Melanom

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Astellas Pharma Global Development, Inc., USA

Einschlusskriterien
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent and privacy language as required per national regulations (e.g., Health InsurancePortability and Accountability Act Authorization for US sites) must be obtained from the subject or subject’s parent or legal guardian and if required child assent prior to any study-relatedprocedures (including withdrawal of prohibited medication, if applicable).2. Subject is positive for the FLT3/ITD mutation in bone marrow or blood as determined by the local institution.3. Subject is aged = 6 months and < 21 years of age at the time of signing informed consent and/or assent, as applicable.4. Subject has a diagnosis of AML according to The French–American–British (FAB) classification with = 5% blasts in the bone marrow, with or without extramedullary disease (except subjectswith active central nervous system [CNS] leukemia).5. Subject has Karnofsky score = 50 (if the subject is of = 16 years of age) or Lansky score of = 50 (if the subject is < 16 years of age).

Ausschlusskriterien
1. Subject has active CNS leukemia.2. Subject has uncontrolled or significant cardiovascular disease3. Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The subject needs to be off pressors and have negative blood cultures for 48 hours.5. Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.6. Subject has active clinically significant GVHD or is on treatment with systemic corticosteroids and is receiving > 0.5 mg/kg of prednisone (or equivalent) daily dose for GVHD.7. Subject has active malignant tumors other than AML.8. Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels during the screening period is allowed.9. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A.10. Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib.

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
FMS-like Tyrosine Kinase 3 (FLT3)\/Internal Tandem Duplication (ITD) Positive Relapsed orRefractory Acute Myeloid Leukemia (AML)

MedDRA Term
Acute myeloid leukemia

Institute
Klinik für Endokrinologie, Diabetologie und Stoffwechsel, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Harald Lahner

harald.lahner@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
- Subject is currently enrolled in a pre-defined Novartis-sponsored study and is receiving spartalizumab as single agent or in combination with other study treatment,
- Subject is currently deriving clinical benefit from the study treatment, as determined by the investigator.
Other protocol defined inclusion criteria may apply

Ausschlusskriterien
- Subject has been permanently discontinued from spartalizumab in the parent protocol for any reason other than enrollment in the Roll over Study
- Subject does not meet the criteria specified in the parent protocol criteria for continued study treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Phase I Studie

Medizinischer Befund
Advanced Solid Tumors

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GWT-TUD GmbH, Dresden

Einschlusskriterien
1. Adult patients, 18-75 years of age
2. Diagnosis of high risk MDS including oligoblastic non-proliferative (WBC <13 Gpt/l) AML up to 29% of bone marrow blasts
3. Bone marrow blasts = 5% (central morphology Düsseldorf)
4. IPSS score intermediate-2 or high
5. alloHCT intended within the next 6 months
6. ECOG performance status of 0 or 1
7. Signed informed consent
8. Laboratory values fulfilling all of the following:
- Serum creatinine < 2.0 mg/dL- Serum total bilirubin < 2.0 mg/dL
- Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN9. Cardiac ejection fraction (LVEF) = 50% by echocardiography
10. Contraception:
- Female subjects of childbearing potential† must agree to use a medically acceptable method of contraception from signature of ICF (for at least 1 months prior to the first dose of CPX-351) and consent of female patients to use a medically acceptable method of contraception throughout the entire study period and for 6 months following the last dose of CPX-351. Medically acceptable methods of contraception that may be used by the patient include diaphragm and spermicide, intrauterine device (IUD), condom and vaginal spermicide, hormonal contraceptives (patients must be stable on hormonal contraceptives for at least the prior 3 months), surgical sterilization, or post-menopausal (=2 years of amenorrhea). Medically acceptable methods of contraception that may be used by the male partner of a female patient are condom and spermicide or vasectomy (>6 months prior to Day-1) and are to be used throughout the entire study period and for 6 months following the last dose of CPX-351.
- Male patients must be willing to refrain from sperm donation for 6 months following the last dose of CPX-351 and must use adequate contraception throughout the entire study period and for 6 months following the last dose of CPX-351.
- Combined oral contraceptive pills are not recommended. It is recommended that during the study two medically accepted methods of contraception (e.g. as hormonal contraceptive methods along with a condom) apply.

†A female subject or a female partner of a male subject is considered to have childbearing potential unless she meets at least one of the following criteria: Age =50 years and naturally amenorrhoeic for = 1 year (amenorrhoea following cancer therapy does not rule out childbearing potential), premature ovarian failure confirmed by a specialist gynecologist, previous bilateral salpingo-oophorectomy or hysterectomy, XY genotype, Turner syndrome or uterine agenesis.

Ausschlusskriterien
1. Patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible.
2. WHO-2016 defined AML entities: AML with t(15;17), PML-RARA; AML with t(8;21), RUNX1-RUNX1T1, AML with inv(16)/t(16;16), CBFß-MYH11; AML with biallelic CEBPA mutation; AML with mutated FLT3 or NPM1.
3. Clinical evidence of active CNS leukaemia (assessment of CSF is not mandatory for screening).
4. Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy more than 2 years ago and are disease free.
5. Any major surgery or radiation therapy within four weeks prior screening.
6. Patients with prior treatment of either CPX-351, hypomethylating agents, cytarabine or intensive chemotherapy for high-risk MDS or AML.
7. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
8. Recent (<30 days) or planned live vaccinations during the clinical trial
9. Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent.
10. Creatinine clearance < 30 ml/min
11. Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for =72 hrs.
12. Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values).
13. Hypersensitivity to cytarabine, daunorubicin or liposomal products.
14. History of Wilson’s disease or other copper-metabolism disorder, unless the therapy outweighs the risks.15. Female patients who are pregnant or lactating.

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
75 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MDS - Myelodysplastisches Syndrom, AML - Akute myeloische Leukämie

Medizinischer Befund
Untreated patients with higher risk MDS and oligoblastic AML eligible and intended for allogeneic HCT within the next 6 months

MedDRA Term
Acute myeloid leukemia, Myelodysplastic syndromes

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Claudia Kesch

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
1. Must be ≥18 years of age
2. Signed an informed consent form (ICF) indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study; subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol (Section 4.3)
3. Histologically confirmed adenocarcinoma of the prostate
4. Criterion modified per Amendment 1
4.1. Criterion modified per Amendment 2
4.2 High risk disease defined by a total Gleason Sum Score ≥4+3 (=Grade Groups [GG] 3 5) and ≥1 of the following 4 criteria:
• Any combination of Gleason Score 4+3 (=GG 3) and Gleason Score 8 (4+4 or 5+3) in ≥6 systematic cores (with ≥1 core Gleason Score 8 [4+4 or 5+3] included);
• Any combination of Gleason Score 4+3 (=GG 3) and Gleason Score 8 (4+4 or 5+3) in ≥3 systematic cores and PSA ≥20 ng/mL (with ≥1 core Gleason Score 8 [4+4 or 5+3] included);
• Gleason Score ≥9 (=GG 5) in at least 1 systematic or targeted core; or
• At least 2 systematic or targeted cores with continuous Gleason Score ≥8 (=GG 4), each with ≥80% involvement
5. Criterion modified per Amendment 1
5.1. Candidate for RP with pLND as per the investigator
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
7. Criterion modified per Amendment 1
7.1. Criterion modified per Amendment 2
7.2. Adequate organ function determined by the following central laboratory values:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin within normal limits, ie, ≤ the upper limit of normal ([ULN]; note that in subjects with Gilbert's syndrome, if total bilirubin is >1.5 X ULN, measure direct and indirect bilirubin. If direct bilirubin is ≤ 1.5 X ULN, the subject may be eligible);
b. Serum creatinine <1.8 mg/dL;
c. Platelets ≥75,000/microliter, without transfusion and/or growth factors within 1 month prior to randomization;
d. Hemoglobin ≥12.0 g/dL (7.4 mmol), without transfusion and/or growth factors within 1 month prior to randomization
8. Criterion modified per Amendment 4
8.1. Able to receive ADT for at least 13 months, based on cardiovascular risk assessment and the investigator's assessment
9. Criterion modified per Amendment 1
9.1. Be able to swallow whole study drug tablets
10. Criterion modified per Amendment 1
10.1. Criterion modified per Amendment 2
10.2. Criterion modified per Amendment 7
10.3. Contraceptive use by male subjects (and female partners of male subjects enrolled in the study who are of childbearing potential or are pregnant) should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.

Ausschlusskriterien
1. Distant metastasis based on conventional imaging (clinical stage M1). Nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion. Diagnosis of distant metastasis (clinical M stage; M0 versus M1a, M1b, M1c) and pelvic nodal disease (clinical N stage; N1 versus N0) will be assessed by central radiological review. Patients are considered eligible only if the central radiological review confirms clinical stage M0
2. Criterion modified per Amendment 2
2.1. (a) Prior treatment with androgen receptor antagonists.
(b) Treatment with GnRHa analogs prior to ICF signature.
3. Criterion deleted per Amendment 1
4. Criterion deleted per Amendment 1
5. Bilateral orchiectomy
6. Criterion modified per Amendment 1
6.1. Criterion modified per Amendment 2
6.2. History of prior systemic or local therapy for prostate cancer, including pelvic radiation for prostate cancer
7. Criterion modified per Amendment 1
7.1. Use of any investigational agent =4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
8. Major surgery =4 weeks prior to randomization
9. Criterion modified per Amendment 4
9.1. Any of the following within 12 months prior to first dose of study drug: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
10. Human immunodeficiency virus-positive subjects with 1 or more of the following:
a. Not receiving highly active antiretroviral therapy
b. Had a change in antiretroviral therapy within 6 months of the start of screening
c. Receiving antiretroviral therapy that may interfere with study drug (consult sponsor for review of medication prior to enrollment)
d. CD4 count <350 at screening
e. AIDS-defining opportunistic infection within 6 months of start of screening
11. Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction
12. Criterion modified per Amendment 2
12.1. History of seizure; any condition that may predispose to seizure (including, but not limited to, prior stroke, transient ischemic attack, or loss of consciousness =1 year prior to randomization); presence of brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect
13. Treatment with drugs known to lower the seizure threshold within 4 weeks prior to randomization
14. Gastrointestinal conditions affecting absorption
15. Criterion modified per Amendment 1
15.1. Known or suspected contraindications or hypersensitivity to apalutamide, GnRHa analogues or any of the components of the formulations
16. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject
17. Criterion modified per Amendment 2
17.1. Active malignancies (ie, progressing or requiring treatment or treatment change in the last 24 months) other than prostate cancer. The only allowed exceptions are: non-muscle invasive bladder cancer (NMIBC); skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured; breast cancer (adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence); malignancy that is considered cured with minimal risk of recurrence.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
High-risk localized or locally advanced prostate cancer

MedDRA Term
Prostate cancer

Institute
Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Paul Buderath

85239
paul.buderath@uk-essen.de

Hufelandstr 55
45147 Essen

Einschlusskriterien
- Histologically confirmed primary adenocarcinoma, squamous cell carcinoma or adeno-squamous carcinoma of the uterine cervix;
- Patients with histologically confirmed stage IB (IB3 excluded) and IIA1, according to the latest revision of the FIGO staging manual
- Patients undergoing either a Type B or C radical hysterectomy (Querleu and Morrow classification)
- Patients with adequate bone marrow, renal and hepatic function
- ECOG Performance Status of 0, 1 or 2.
- Patient must be suitable candidates for surgery.
- Patients who have signed an approved Informed Consent
- Age 18 years or older

Ausschlusskriterien
- Any histology other than adenocarcinoma, squamous cell carcinoma or adeno-squamous carcinoma of the uterine cervix
- Tumor size greater than 4 cm
- FIGO stage II-IV (except IIA1)
- Patients with a history of pelvic or abdominal radiotherapy
- Patients who are pregnant
- Patients with contraindications to surgery
- Patients with evidence of metastatic disease by conventional imaging, enlarged pelvic or aortic lymph nodes > 2cm; or histologically positive lymph nodes
- Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
- Patients unable to withstand prolonged lithotomy and steep Trendelenburg position
- Patients with secondary invasive neoplasm in the last 5 years (except non-melanoma skin cancer, breast cancer T1N0M0 grade 1 or 2 without any signs of recurrence or activity)

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Gynäkologische Tumore

Medizinischer Befund
Cervical Cancer

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

AOP Orphan Pharmaceuticals AG, Wien

Einschlusskriterien
1. Patients who receive ropeginterferon alfa-2b in the frame of clinical routine and according to its approved labelling: monotherapy in adults (≥ 18 years old) for the
treatment of PV without symptomatic splenomegaly and according to the recommendations in the product information for ropeginterferon alfa-2b (Annex 1)
2. Patient’s medical history is available
3. Patient provides written informed consent prior to study entry

Ausschlusskriterien
1. Patients with any contraindication to ropeginterferon alfa-2b treatment according to the product information for ropeginterferon alfa-2b (Annex 1)
2. Patients involved in any study with another investigational product or therapy (in the prior 30 days)
3. Previous ropeginterferon alfa-2b treatment
4. Patient is a family member or employee of the Investigator

Indikation
MPN - Myeloproliferative Neoplasie

Medizinischer Befund
Polycythämia Vera

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Sanofi-Aventis Recherche & Développement, Frankreich

Einschlusskriterien
- Participant must be 28 days to less than 18 years of age, at the time of signing the informed consent.
- Participants must have a confirmed diagnosis of relapsed Acute Lymphoblastic Leukemia (ALL) of T- or B-cell origin including T-lymphoblastic lymphoma (LBL), or relapsed Acute Myeloblastic Leukemia (AML) including participants with history of myelodysplasia.
- Participants must be previously treated for their disease and have relapsed or are refractory to most recent treatment. Participants in first or second relapse will be eligible regardless of the remission duration.
- Participants with no more than 1 prior salvage therapy.

Ausschlusskriterien
- Any serious active disease or co-morbid condition which, in the opinion of the Investigator, may interfere with the safety of the study treatment or the compliance with the study protocol.
- Participants must have been off prior treatment with immunotherapy/investigational agents and chemotherapy for >2 weeks and must have recovered from acute toxicity before the first study treatment administration. Treatment may start earlier if necessitated by the patient's medical condition (eg, rapidly progressive disease) following discussion with the Sponsor.
- Prior stem cell transplant within 3 months and/or evidence of active systemic Graft versus Host Disease (GVHD) and/or immunosuppressive therapy for GVHD within 1 week before the first study treatment administration.
- Participants with LBL with bone marrow blasts <5%.
- Participants with Burkitt-type ALL.
- Acute leukemia with testicular or central nerve system involvement alone.
- Participants who have developed therapy related acute leukemia.

Studienteilnehmende Mindestalter
28 Tag(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Isatuximab Used in Combination with Chemotherapy in Pediatric Patients from 28 Days to Less than 18 Years of Age with Relapsed\/Refractory B or T Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia in First or Second Relapse

MedDRA Term
Acute lymphocytic leukaemia, Acute myeloid leukaemia

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Stefan Schönberger

stefan.schoenberger@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

German Pediatric Oncology Group, GPOH gGmbH, Berlin

Einschlusskriterien
• Stratification into the standard risk group (SR) by screening:
o Newly diagnosed ALK-positive ALCL
o Stage I not completely resected, or stage II or stage III
o MDD negative
• Age < 18 years
• Informed consent of the parents/legal guardians (and assent of the competent child) for study participation and data collection, storage and handling given before study entry
• Participation in national / study group's reference pathology
• Follow-up for at least 3 years after enrolment is expected
• Application of a highly effective contraceptive method (Pearl index <1) in sexually active patients

Ausschlusskriterien
• Progressive disease during a possible clinically indicated pre-phase treatment before inclusion in the study
• Steroids for more than 2 days or chemotherapy pre-treatment before taking the screening sample for MDD
• Chemotherapy pre-treatment before start of the study treatment except for
o the obligatory initial intrathecal triple therapy with Methotrexate, Cytarabine and Prednisolone (or Hydrocortisone respectively)
o a possible clinically indicated pre-phase including up to 5 days of steroids combined with up to 3 doses of Vinblastine (and up to 2 doses of Cyclophosphamide)
• Pregnancy or lactation period
• Contraindications for the treatment with Vinblastine:
o hypersensitivity against VBL or other vinca-alkaloids
o leukopenia, other than in the context of the ALCL
o severe uncontrolled infection
• Other medical, psychiatric, familial or social condition prohibiting treatment according to the protocol

Studienteilnehmende Mindestalter
0 Tag(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
standard risk ALK-positive anaplastic large cell lymphoma (ALCL)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
Key Inclusion Criteria:

- Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at baseline and during on study therapy. Exceptions may be considered after documented discussion with Novartis.
- All patients must have a BRAF V600 mutation confirmed by local assessment.
- Patients with unresectable advanced/metastatic BRAF V600 cancer of the colon or rectum with measurable disease as determined by RECIST v1.1
- Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease

Ausschlusskriterien
Key Exclusion Criteria:

- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical cancer, or other tumors that will not affect life expectancy
- Impairment of gastrointestinal function or gastrointestinal disease that may signficantly alter the absorption of study drugs
- History of or current evidence/risk of retinal verin occlusion or serous retinopathy
- History of or current interstitial lung disease or non-infectious pneumonitis
- Patients with a known history of testing positive for HIV
- Clinically significant cardiac disease at screening
- Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
- Pregnant or lactating women
Other protocol-defined inclusion/exclusion may apply.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
BRAV V600 Colorectal Cancer

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
- Histologically confirmed adenocarcinoma of the prostate
- Previously treated with radical prostatectomy with or without lymph node dissection and either: a) for biochemical recurrence after radical prostatectomy (RP): any post-operative prostate-specific antigen (PSA) measurement of less than (=) 0.1 ng/mL within the 4 to 8-week period after RP or b) for persistent PSA after RP: PSA >=0.1 ng/mL within the 4 to 8-week period after RP, confirmed by additional measurement at least 3 weeks later
- Be able to swallow whole the study drug tablets or follow the instructions for admixing with apple sauce
- Results of the Prostate specific membrane antigen-positron emission tomography (PSMA-PET) at screening as determined by blinded independent, central review (BICR), must be: PSMA-PET-negative for any prostate cancer lesions (that is, no loco-regional lesion and no distant lesions); or PSMA-PET-positive for at least one loco-regional (pelvic) lesion without distant extra-pelvic lesion; or PSMA PET- positive for at least one loco--regional (pelvic) lesion with extra-pelvic lesion(s).
- High risk of developing metastasis defined as; a) for biochemical recurrence after RP: pathological Gleason score greater than or equal to (>=) 8 evaluated from prostate tissue specimen at radical prostatectomy, or prostate-specific antigen doubling time (PSADT) less than or equal to (=8, evaluated from prostate tissue specimen at radical prostatectomy
- Participants with evidence of distant metastasis on screening PSMA-PET scan must have no evidence of prostate cancer metastases on screening CT/MRI of the chest/abdomen/pelvis, Technetium 99m [99mTc] whole-body bone scan. Participants with a single bone lesion on 99mTc whole-body bone scan should have confirmatory imaging by CT or MRI; if the confirmatory scan confirms the bone lesion, the participant should be excluded from the study. Conventional images (99mTc-bone scan and CT/MRI) from the screening will be evaluated locally before randomization
- Eastern Cooperative Oncology Group Performance Status Grade 0 or 1

Ausschlusskriterien
- History of pelvic radiation for malignancy
- Previous treatment with androgen deprivation therapy (ADT) for prostate cancer
- Previously treated for biochemical recurrence (BCR) or persistent PSA after RP (previous surgical treatment of one or more loco-regional lesions is allowed)
- Prior treatment with a CYP17 inhibitor (example, oral ketoconazole, orteronel, abiraterone acetate, galeterone) or any androgen receptor (AR) antagonist including bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide or darolutamide and any other medications that may lower androgen levels (estrogens, progestins, aminoglutethimide, etc.), including bilateral orchiectomy
- Known or suspected contraindications or hypersensitivity to apalutamide, Luteinizing Hormone-Releasing Hormone (LHRH) agonist or any of the components of the formulations
- Prior chemotherapy for prostate cancer
- Any evidence of prostate cancer metastasis on computed tomography/magnetic resonance imaging (CT/MRI) of the chest/abdomen/pelvis or 99mTc whole-body bone scan, at any time prior to screening

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
High risk recurrent prostate cancer previously treated with radical prostatectomy

MedDRA Term
Prostate cancer recurrent

Institute
Innere Klinik (Tumorforschung), Ruhrlandklinik - Thorakale Onkologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Marcel Wiesweg

marcel.wiesweg@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
- Phase 1 and Phase 1b lazertinib+Amivantamab combination cohorts: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with previously epidermal growth factor receptor (EGFR) mutation (identified locally in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory [or equivalent]) that is metastatic or unresectable, and have progressed after standard of care front-line therapy, and exhausted available options with targeted therapy. A participant who has refused all other currently available therapeutic options is allowed to enroll
- For the Phase 1b Lazertinib, Amivantamab and Platinum-doublet Chemotherapy (LACP) combination cohort: histologically or cytologically confirmed advanced or metastatic EGFR-mutated NSCLC who have progressed on or after an EGFR-TKI as the most recent line of treatment with a maximum of 3 prior lines of therapy in the metastatic setting allowed
- For all expansion cohorts, the EGFR mutation must have been previously histologically or cytologically characterized, as performed by a CLIA-certified (US sites) or an accredited (outside of US) local laboratory, with a copy of the mutation analysis being submitted during screening (Phase 1b expansion Cohort B, C and D)
1. Expansion Cohort A: Participant must have advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) that has progressed on prior treatment with osimertinib in the first or second line, followed by progression on a platinum-based chemotherapy regimen as the last line of therapy prior to study enrollment. Prior use of first or second generation EGFR tyrosine kinase inhibitor (TKI) is allowed if administered prior to osimertinib
2. Expansion Cohort B: Participant must have previously treated, advanced or metastatic NSCLC with documented primary EGFR Exon 20ins activating mutation. Participants should have been treated with standard of care, platinum-based chemotherapy regimens, but may have treated with approved EGFR TKI, investigational EGFR, or immunotherapy agents if refusing front line platinum-based chemotherapy standard of care. Up to 3 lines of prior systemic anti-cancer treatment are allowed
3. Expansion Cohort C: Participant must have advanced or metastatic NSCLC characterized by an uncommon activating mutation Additional uncommon EGFR mutations/alterations, beyond those listed above, may be considered for enrollment after agreement with the medical monitor. Participants may be treatment naïve or have been treated with one prior line of therapy which must be a first or second generation TKI (that is gefitinib, erlotinib, afatinib) in the most recent line of therapy. Prior chemotherapy is allowed if administered prior to EGFR TKI therapy, or as the only systemic anti-cancer therapy prior to study enrollment. Up to 2 lines of prior systemic anti-cancer treatment are allowed
4. Expansion Cohort D: Participant must have advanced or metastatic EGFR-mutated NSCLC (EGFR Exon19 deletion or L858R) that has progressed on prior treatment with osimertinib in the first or second line (after first- or second-generation EGFR TKI), as the immediate prior line of therapy. Only previous treatment in the metastatic setting with a first, second, or third generation EGFR TKI is allowed
- Evaluable disease
- Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
- Participants must meet the study protocol defined laboratory criteria without having a history of red blood cell transfusion, platelet transfusion, or granulocyte-colony stimulating factor support within 7 days prior to the date of the test
- A woman of childbearing potential: Must have a negative serum beta human chorionic gonadotropin at screening; Must agree not to breast-feed during the study and for 6 months after the last dose of study intervention. (Enrollment is not allowed even if a woman who is breast-feeding stops breast-feeding); Must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study intervention

Ausschlusskriterien
- Participant has an uncontrolled illness, including but not limited uncontrolled diabetes, ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics week prior to study treatment] or diagnosed or suspected viral infection); active bleeding diathesis; Impaired oxygenation requiring continuous oxygen supplementation; Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study treatment; or psychiatric illness or any other circumstances including (social circumstances) that would limit compliance with study requirements. Any ophthalmologic condition that is either clinically unstable or requires treatment
- Prior treatment with antiPD-1 or anti Programmed death-ligand 1 (PD-L1) antibody within 6 weeks of planned first dose of study intervention
- Untreated brain or other central nervous system (CNS) metastases whether symptomatic or asymptomatic. Participants who have completed definitive therapy, are not on steroids, and have a stable clinical status for at least 2 weeks prior to study treatment may be eligible for Phase 1b expansion cohorts. If brain metastases are diagnosed on Screening imaging, the participant may be enrolled, or rescreened for eligibility, after definitive treatment if above criteria are met
- Any Toxicities from prior anticancer therapy must have resolved to common terminology criteria for adverse events (CTCAE) version 5.0 Grade 1 or baseline level (except for alopecia [any grade], Grade <=2 peripheral neuropathy, and Grade <=2 hypothyroidism stable on hormone replacement therapy)
- Allergies, hypersensitivity, or intolerance to Lazertinib or JNJ-61186372 or their excipients. For the LACP combination cohort: participant has a contraindication for the use of carboplatin or pemetrexed (refer to local prescribing information for each agent). Participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Advanced Non- Small Cell Lung Cancer

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Eli Lilly & Company, USA

Einschlusskriterien
- Participants must be ≤18 years of age at the time of study enrollment
- Body weight ≥10 kilograms and body surface area (BSA) ≥0.5 meters squared.
- Participants with any relapsed/refractory solid tumor (excluding lymphoma), including central nervous system tumors, that have progressed on standard therapies and, in the judgment of the investigator, are appropriate candidates for the experimental therapy combination in the study part that is currently enrolling.
- A Lansky score ≥50 for participants ≤16 years of age, and Karnofsky score ≥50 for participants >16 years of age.
- Participants must have discontinued all previous treatments for cancer or investigational agents and must have recovered from the acute effects to Grade ≤1 at the time of enrollment.
- Able to swallow intact capsules.
- Adequate hematologic and organ function ≤2 weeks (14 days) prior to first dose of study drug.
- Females of reproductive potential must have negative serum pregnancy test at baseline (within 7 days prior to starting treatment).
- Both female and male participants of reproductive potential must agree to use highly effective contraceptive precautions (and avoid sperm donation for males) during the trial. For abemaciclib, females should use contraception for at least 3 weeks following the last abemaciclib dose (males have no restriction for contraceptive use following treatment with abemaciclib). For other study drugs, highly effective contraceptive precautions (and avoiding sperm donation) must be used according to their label.
- Life expectancy of at least 8 weeks and able to complete at least 1 cycle of treatment.
- Caregivers and participants are willing to make themselves available for the duration of the trial.

Ausschlusskriterien
- Received allogenic bone marrow or solid organ transplant.
- Received live vaccination (within 4 weeks prior to starting study treatment).
- Participants with psychiatric illness/social situation that, in the opinion of the investigator, could cause unacceptable safety risks or compromise compliance with the protocol.
- Have a personal history of any of the following conditions within the last 12 months: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest.
- Intolerability or hypersensitivity to any of the study treatments or its components relevant to the study part that is currently enrolling or a known hypersensitivity to dacarbazine.
- Diagnosed and/or treated additional malignancy within 3 years prior to enrollment that may affect the interpretation of results, with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected in situ cervical and/or breast cancers.
- Pregnant or breastfeeding.
- Active systemic infections or viral load.
- Serious and/or uncontrolled preexisting medical condition(s) that would preclude participation in this study (such as severe renal impairment, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in clinically significant diarrhea).
- Treated with drugs known to be strong inhibitors or inducers of isoenzyme cytochrome P450 3A (CYP3A) or strong inhibitors of UGT1A1 if the treatment cannot be discontinued or switched to a different medication at least 5 half-lives prior to starting study drug.
- Received prior treatment with cyclin-dependent kinase (CDK) 4 & 6 inhibitor.
- Currently enrolled in any other clinical study involving an investigational product or non-approved use of a drug or device.
- Has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer.
- Tumor contains known RB (retinoblastoma) mutation. Screening is not required for enrollment.
- Participants with a bowel obstruction will be excluded from Part A of this study.

Studienteilnehmende Mindestalter
28 Tag(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Pediatric and Young Adult Patients Relapsed\/Refractory Solid Tumors

MedDRA Term
Ewing's sarcoma, Neuroblastoma, Rhabdoid tumor, Rhabdomyosarcoma, Osteosarcoma, Glioblastoma, Diffuse intrinsic pontine glioma, Malignant glioma, Medulloblastoma, Ependymoma, Solid tumor

Institute
Innere Klinik (Tumorforschung), Ruhrlandklinik - Thorakale Onkologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

CatalYm GmbH, Planegg-Martinsried

Einschlusskriterien
- Signed and dated informed consent, and able to comply with the study procedures and any locally required authorization.
- Male or female aged ≥ 18 years.
- Relapsed/refractory patients with histologically or cytologically confirmed diagnosis of advanced-stage or recurrent cancer
- Progressed on/relapsed after at least one prior anti-PD-1/PD-L1 treatment (Part A)
- Biopsy-accessible tumor lesions and willing to undergo triple sequential tumor biopsy (Part A) and dual biopsy (Part B, only for selected cohorts).
- At least 1 radiologically measurable lesion per RECIST V1.1/imRECIST (Part B).
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Life expectancy > 3 months as assessed by the Investigator.
- Adequate organ function (bone marrow, hepatic, renal function and coagulation).

Ausschlusskriterien
- Pregnant or breastfeeding.
- Any tumor-directed therapy within 21 days before study treatment.
- Treatment with investigational agent within 21 days before study treatment.
- Radiotherapy within 14 days before study treatment.
- Pre-existing arrhythmia, uncontrolled angina pectoris, uncontrolled heart failure (NYHA) Grade IV, any myocardial infarction/coronary event, CNS-ischemic event and any thromboembolic event at any time < 6 months prior to Screening or presence of any uncontrolled heart failure NYHA Grade III or higher.
- Left ventricular ejection fraction (LVEF) < 50% measured by echocardiogram or MUGA.
- QTcF > 450 ms for men or > 470 ms for women.
- Any active autoimmune requiring systemic immunosuppressive treatments. .
- Any history of non-infectious pneumonitis < 6 months prior to Screening.
- Any active inflammatory bowel disease such as Crohn's disease or ulcerative colitis which are generally excluded or active autoimmunthyroiditis present < 6 months prior to Screening.
- History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Multientity/Biomarker driven

Medizinischer Befund
Advance-stage, relapsed\/refractory solid tumors in non-curable state, that relapsed post or were refractory to a prior anti-PD-1\/PD-L1 therapy.

MedDRA Term
Solid tumor

Institute
Klinik für Hämatologie und Stammzelltransplantation, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Alexander Carpinteiro

+49 (0)201 723-82530
alexander.carpinteiro@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Caelum Biosciences, Inc., USA

Einschlusskriterien
Key Inclusion Criteria:
1. AL amyloidosis stage IIIa based on the European Modification of the 2004 Standard Mayo Clinic Staging who also have NT-proBNP ≥ 650 ng/L at the time of Screening.
2. Measurable hematologic disease at Screening as defined by at least one of the following:
a. dFLC > 4 mg/dL or
b. iFLC > 4 mg/dL with abnormal Kappa/Lambda ratio or
c. SPEP m-spike > 0.5 g/dL
3. Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following:
a. Immunohistochemistry/Immunofluorescence
b. Mass spectrometry or
c. Characteristic electron microscopy appearance/Immunoelectron microscopy
4. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
AND
b. At least one of the following:
i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or
ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or
iii. Cardiac MRI with gadolinium contrast agent diagnostic of cardiac amyloidosis
5. Planned first-line treatment for plasma cell dyscrasia is a cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC
6. WOCBP must have a negative pregnancy test during Screening and must agree to use highly effective contraception (Section 6.9) from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer
7. Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer

Ausschlusskriterien
1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are obtained and prior to randomization is allowed.
3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed = 3 months prior to signing the ICF or during screening) or biopsy proven (performed = 3 months prior to signing the ICF or during screening) bony or extramedullary plasmacytoma AND any one or more of the following CRAB features:
a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder (e.g., multiple myeloma and POEMS syndrome), specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR
ii. Renal insufficiency: creatinine clearance 177 mol/L (> 2 mg/dL) OR
iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR
iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed = 3 months prior to signing the ICF or during screening): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR
b. Any one of the following biomarkers of malignancy:
i. 60% or greater clonal plasma cells on bone marrow examination OR
ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
AL-Amyloidose

Medizinischer Befund
stage IIIa cardiac AL amyloidosis

MedDRA Term
Cardiac amyloidosis

Institute
Klinik für Hämatologie und Stammzelltransplantation, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Alexander Carpinteiro

+49 (0)201 723-82530
alexander.carpinteiro@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Caelum Biosciences, Inc., USA

Einschlusskriterien
1. AL amyloidosis stage IIIb based on the European Modification of the 2004 Standard Mayo Clinic Staging at the time of Screening, which includes NT-proBNP > 8,500 ng/L.
2. Measurable hematologic disease at Screening as defined by at least one of the following:
a. Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL OR
b. Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio OR
c. Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL
3. Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following:
a. Immunohistochemistry/Immunofluorescence OR
b. Mass spectrometry OR
c. Characteristic electron microscopy appearance/Immunoelectron microscopy
4. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
AND
b. At least one of the following:
i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis OR
ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening OR
iii. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of cardiac amyloidosis
5. Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC.
6. Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her anti-PCD therapy, whichever is longer
7. Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer