Studien

Institute
Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Oliver Hoffmann

+49 (0)201 723-2742
oliver.hoffmann@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Westdeutsche Studiengruppe GmbH (WSG), Mönchengladbach

Einschlusskriterien
Patients eligible for inclusion in this study must meet all the following criteria:
1. Female patients with invasive, untreated HER2+ breast cancer (as assessed by local pathology) maximum 6 weeks before registration (standard-of-care diagnostic biopsy according to current AGO guidelines)
2. Age ≥18 years
3a. Cohort 1: low- to intermediate-risk for recurrence as per investigator´s decision (recommendation: cT1c – cT2 (1 - ≤3cm), cN0; cT1a/b excluded), OR
3b. Cohort 2: intermediate- to high-risk for recurrence as per investigator´s decision (recommendation: cT2 (>3 - ≤5cm), cN0)
3c. Elderly patients (≥ 65 years) may be assigned to any cohort as per investigator’s decision
4. Written informed consent
5. LVEF ≥ 50% within 28 days before randomisation
6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1
7. Adequate bone marrow and organ function within 14 days before randomisation as defined by the following laboratory values:
• absolute neutrophil count ≥ 1.5 × 109/L,
• platelets ≥ 100 × 109/L,
• hemoglobin ≥ 9.0 g/dL:
• estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula,
• INR ≤ 1.5,
• serum creatinine < 1.5 mg/dL,
• total bilirubin < ULN, except for patients with Gilbert’s Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN,
• aspartate transaminase (AST) < 2.5 × ULN,
• alanine transaminase (ALT) < 2.5 × ULN.
8. Adequate treatment washout period before randomisation (refer to protocol for detailed information)
9. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential (refer to protocol for detailed information)
Post-menopausal status is accepted for women, who at the time of initiation of study medication, either
• had underwent bilateral oophorectomy, or
• are ≥ 60 years of age, or
• are < 60 years of age and amenorrhoeic for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression)
• and/or whose FSH- and estradiol-blood values are within the postmenopausal range per local laboratory normal range.
10. Female subjects must not donate, or retrieve for their own use, ova from the time of randomisation and throughout the study treatment period, and for at least 7 months after the final study drug administration. (refer to protocol for detailed information)

Patienten, die für die Aufnahme in diese Studie in Frage kommen, müssen alle folgenden Kriterien erfüllen:
1. Weibliche Patienten mit invasivem, unbehandeltem HER2+ Brustkrebs (nach lokaler Pathologie) maximal 6 Wochen vor Registrierung (Standard-of-Care diagnostische Biopsie nach aktuellen AGO-Leitlinien)
2. Alter ≥18 Jahre
3 a. Kohorte 1: niedrig- bis intermediäres Rezidivrisiko gemäß Prüfarztentscheidung (Empfehlung: cT1c – cT2 (1 - ≤3cm), cN0; cT1a/b ausgeschlossen), ODER
3 b. Kohorte 2: intermediär- bis hohes Rezidivrisiko gemäß Untersucherentscheidung (Empfehlung: cT2 (>3 - ≤5cm), cN0)
3 c. Ältere Patienten (≥ 65 Jahre) können gemäß der Entscheidung des Prüfarztes jeder Kohorte zugeordnet werden
4. Schriftliche Einverständniserklärung
5. LVEF ≥ 50 % innerhalb von 28 Tagen vor Randomisierung
6. Leistungsstatus der Eastern Cooperative Oncology Group (ECOG PS) 0-1
7. Ausreichende Organ- und Knochenmarkfunktion innerhalb von 14 Tagen vor Randomisierung:
• absolute Neutrophile ≥ 1.5 × 109/L,
• Thrombocyten ≥ 100 × 109/L,
• Hämoglobin ≥ 9.0 g/dL:
• geschätzte glomeruläre Filtrationsrate (eGFR) ≥ 30 mL/min (Cockcroft-Gault-Formel),
• INR ≤ 1.5,
• Serum Kreatinin < 1.5 mg/dL,
• Totales Bilirubin < 1.5 ULN, mit Ausnahme von Patienten mit Gilbert’s Syndrom, die nur dann eingeschlossen werden können, wenn das totale Bilirubin ≤ 3.0 × ULN oder das direkte Bilirubin ≤ 1.5 × ULN ist,
• Aspartat-Transaminase (AST) < 2.5 × ULN,
• Alanin-Transaminase (ALT) < 2.5 × ULN.
8. Angemessene Auswaschzeit für die Behandlung vor der Randomisierung (siehe Protokoll für detaillierte Informationen)
9. Nachweis eines postmenopausalen Status oder negativen Serum-Schwangerschaftstests für Frauen im gebärfähigen Alter (siehe Protokoll für detaillierte Informationen)
Der post-menopausale Status ist definiert als Frauen, die zum Zeitpunkt der ersten Applikation der Studienmedikation entweder
• eine beidseitige Oophorektomie hatten, oder
• ≥ 60 Jahre alt sind, oder
• < 60 Jahre alt sind und amenorrhoeisch für 12 oder mehr Monate (ohne Einnahme von Chemotherapie, Tamoxifen, Toremifen oder ovarieller Suppression)
• und/oder deren FSH- und Estradiol-Blutwerte innerhalb der postmenopausalen Grenzwerte (nach lokalen Laborgrenzwerten) liegen.
10. Weibliche Probanden dürfen ab dem Zeitpunkt der Randomisierung und während des gesamten Studienbehandlungszeitraums und für mindestens 7 Monate nach der letzten Verabreichung des Studienmedikaments keine Eizellen spenden oder für den eigenen Gebrauch entnehmen. (siehe Protokoll für detaillierte Informationen)

Ausschlusskriterien
Patients eligible for inclusion in this study must not meet any of the following criteria:
1. Non-operable breast cancer including inflammatory breast cancer
2. cT1a/b, cN0 breast cancer
3. Any previous history of invasive breast cancer
4. Primary malignancies within 5 years, with the exception of
• adequately resected non-melanoma skin cancer
• curatively treated in-situ disease
5. Any evidence for existing metastatic disease (confirmed by CT Thorax/Abdomen, bone scan, or other methods according to clinical practice
6. Previous or concurrent treatment with cytotoxic agents for any reason (except non-oncological reasons)
7. Concurrent treatment with other experimental drugs and participation in another clinical trial with any investigational drug within 30 days prior to study entry
8. Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study/inadequate organ function
9. Reasons indicating risk of poor compliance
10. Woman of child-bearing potential defined as a woman physiologically capable of becoming pregnant, and not using highly effective methods of contraception during the study treatment and for 7 months after stopping the treatment.
11. Use of oral (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.
12. Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
13. Patients with a medical history of myocardial infarction (MI) within 6 months before randomisation, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrolment to rule out MI.
14. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG.
15. History of (non-infectious) ILD / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
16. Lung criteria:
- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder
- Any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of randomisation.
- Prior pneumonectomy (complete)
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
17. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to randomisation if required by local regulations or ethics committee (EC).
18. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan or carboplatin. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
19. Known allergy or hypersensitivity to study treatment (T-DXd), to comparator (SoC-) treatment, or any of the study drug / comparator (SoC-) excipients.
20. History of severe hypersensitivity reactions to other monoclonal antibodies.
21. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.

Patienten, die für die Aufnahme in diese Studie in Frage kommen, dürfen keines der folgenden Kriterien erfüllen:
1. Nicht operierbarer Brustkrebs, einschließlich entzündlicher Brustkrebs
2. cT1a/b-Brustkrebs
3. Jede Vorgeschichte von invasivem Brustkrebs
4. Primärmalignome innerhalb von 5 Jahren, mit Ausnahme von
a. adäquat resezierter nicht-melanozytärer Hautkrebs
b. kurativ behandelte In-situ-Krankheit
5. Jeglicher Hinweis auf eine bestehende metastatische Erkrankung (bestätigt durch CT Thorax/Abdomen, Knochenscan oder andere Methoden gemäß der klinischen Praxis
6. Vorherige oder gleichzeitige Behandlung mit Zytostatika aus irgendeinem Grund (außer nicht-onkologische Gründe)
7. Gleichzeitige Behandlung mit anderen experimentellen Arzneimitteln und Teilnahme an einer anderen klinischen Studie mit einem Prüfpräparat innerhalb von 30 Tagen vor Studieneintritt
8. Schwerwiegende und relevante Komorbidität, die mit der Applikation von Zytostatika oder der Teilnahme an der Studie interagieren würde/unzureichende Organfunktion
9. Gründe, die auf das Risiko einer unzureichenden Einhaltung hinweisen
10. Frau im gebärfähigen Alter, definiert als eine Frau, die physiologisch in der Lage ist, schwanger zu werden, und während der Studienbehandlung und für 7 Monate nach Beendigung der Behandlung keine besonders wirksamen Verhütungsmethoden anwendet.
11. Anwendung von oralen (Östrogen und Progesteron), transdermalen, injizierten oder implantierten hormonellen Verhütungsmethoden sowie Hormonersatztherapien.
12. Hat Drogenmissbrauch oder andere Erkrankungen wie klinisch signifikante kardiale oder psychische Erkrankungen, die nach Ansicht des Ermittlers die Teilnahme des Probanden an der klinischen Studie oder die Bewertung der Ergebnisse der klinischen Studie beeinträchtigen können.
13. Patienten mit einer medizinischen Vorgeschichte von Myokardinfarkt (MI) innerhalb von 6 Monaten vor Randomisierung, symptomatischer kongestiver Herzinsuffizienz (CHF) (New York Heart Association Klasse II bis IV), Patienten mit Troponinwerten über ULN beim Screening (wie definiert durch die Hersteller) und ohne myokardial bedingte Symptome, sollten vor der Einschreibung eine kardiologische Beratung erhalten, um einen Myokardinfarkt auszuschließen.
14. Korrigierte Verlängerung des QT-Intervalls (QTcF) auf >470 ms (Frauen) basierend auf dem Durchschnitt des dreifachen 12-Kanal-Screening-EKG.
15. Vorgeschichte einer (nicht infektiösen) ILD/Pneumonitis, die Steroide erforderte, eine aktuelle ILD/Pneumonitis oder wenn der Verdacht auf ILD/Pneumonitis nicht durch Bildgebung beim Screening ausgeschlossen werden kann.
16. Lungenkriterien:
o Lungenspezifische interkurrente klinisch signifikante Erkrankungen, einschließlich, aber nicht beschränkt auf jede zugrunde liegende Lungenerkrankung
o Alle Autoimmun-, Bindegewebs- oder entzündlichen Erkrankungen (z. B. rheumatoide Arthritis, Sjögren-Krankheit, Sarkoidose usw.), bei denen zum Zeitpunkt der Randomisierung eine Lungenbeteiligung dokumentiert ist oder der Verdacht besteht.
o Vorherige Pneumonektomie (vollständig)
Unkontrollierte Infektion, die IV-Antibiotika, Virostatika oder Antimykotika erfordert
17. Aktiver primärer Immundefekt, bekannte Infektion mit dem humanen Immundefizienzvirus (HIV) oder aktive Hepatitis B- oder C-Infektion. Patienten, die positiv für Hepatitis C (HCV)-Antikörper sind, kommen nur infrage, wenn die Polymerase-Kettenreaktion negativ für HCV-RNA ist. Patienten sollten vor der Randomisierung auf HIV getestet werden, wenn dies von den örtlichen Vorschriften oder der Ethikkommission (EK) gefordert wird.
18. Erhalt eines attenuierten Lebendimpfstoffs (mRNA- und replikationsdefiziente adenovirale Impfstoffe gelten nicht als attenuierte Lebendimpfstoffe) innerhalb von 30 Tagen vor der ersten Dosis von Trastuzumab-Deruxtecan oder Carboplatin.
Hinweis: Patienten, sofern sie eingeschrieben sind, sollten während der Studie und bis zu 30 Tage nach der letzten IMP-Dosis keinen Lebendimpfstoff erhalten.
19. Bekannte Allergie oder Überempfindlichkeit gegen das Studienmedikament (T-DXd), die Vergleichsmedikamente (Standardbehandlung) oder einen der Hilfsstoffe des Studienmedikaments oder der Vergleichsmedikamente (Standardbehandlung).
20. Schwere Überempfindlichkeitsreaktionen auf andere monoklonale Antikörper in der Anamnese.
21. Schwangere oder stillende Patientinnen oder Patientinnen, die eine Schwangerschaft planen.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Brustkrebs

Medizinischer Befund
HER2+ early breast cancer\n\nHER2+ früher Brustkrebs

MedDRA Term
Breast cancer, Breast cancer female, HER2 positive breast cancer

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Michael Schündeln

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

Hufelandstr 55
45147 Essen

Sponsor

Innovationsausschuss des Gemeinsamen Bundesausschusses

Einschlusskriterien
Ehemals krebskranke Kinder und Jugendliche

Indikation
KIK-Onko

Institute
Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med Pawel Mach

pawel.mach@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

AGO Research GmbH, Wiesbaden

Einschlusskriterien
1. Signed written informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient’s awareness
and willingness to comply with the study requirements
2. Female patients = 18 years with histologically confirmed primary advanced invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement) according to recent FIGO classification (= FIGO IIIB-IV according to FIGO 2009 classification)
3. All patients must have had either upfront primary debulking surgery OR plan to undergo chemotherapy with interval debulking surgery
4. Patients must have available tumor samples to be sent to central laboratory as formalin-fixed, paraffin-embedded (FFPE) sample for determination of BRCA status prior to randomization for stratification
5. Patients must be able to commence systemic therapy within 8 weeks of cytoreductive surgery
6. ECOG performance status (PS) 0-1 (Appendix 1)
7. Estimated life expectancy > 3 months
8. Adequate bone marrow function (within 28 days prior to day 1, cycle 1)
- Absolute Neutrophil Count (ANC) = 1.5 x 109/L
- Platelets (PLT) = 100 x 109/L
- Hemoglobin (Hb) = 9 g/dL (can be post-transfusion)
9. Adequate coagulation parameters (within 28 days prior to day 1, cycle 1)
- Patients not receiving anticoagulant medication who have an International Normalized Ratio
(INR) = 1.5 and an Activated ProThrombin Time (aPTT) = 1.5 x institutional upper limit of normal (ULN)
- The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of day 1, cycle 1
10. Adequate liver and kidney function (within 28 days prior to day 1, cycle 1)
- Total bilirubin = 1.5 x ULN (= 2.0 x ULN in patients with known Gilbert’s syndrome) OR
direct bilirubin = 1.0 x ULN
- Aspartate aminotransferase / Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT) and Alanine aminotransferase / Serum Glutamic Pyruvate Transaminase (ALAT/SGPT) = 2.5 x ULN, unless liver metastases are present, in case of liver metastases values must be = 5 x ULN
- Urine dipstick for proteinuria < 2+. If urine dipstick is = 2+, 24 hour urine must demonstrate = 1 g of protein in 24 hours
- Serum creatinine = 1.5 x upper limit of normal (ULN) or calculated creatinine clearance = 30 mL/min using the Cockcroft-Gault equation (see Appendix 2)
11. Patients must have normal blood pressure (BP) or adequately treated and controlled BP, with a systolic BP of = 140 mmHg and diastolic BP of = 90 mmHg for eligibility. Patients must have a BP
of = 140/90 mmHg taken in the clinic setting by a medical professional within 4 weeks prior to day 1, cycle 1
12. Negative highly sensitive urine or serum pregnancy test within 7 days prior to day 1, cycle 1 in women of childbearing potential (WOCBP), confirmed prior to treatment on day 1
13. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 6 months after administration of the last dose of medication. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include but are not limited to bilateral tubal ligation and/or occlusion, male sterilization, and intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, that include the completion of patient-reported outcomes questionnaires

Ausschlusskriterien
1. Non-epithelial tumor origin of the ovary
2. Ovarian tumors of low malignant potential (e.g. borderline tumors) and low grade tumors
3. Planned intraperitoneal cytotoxic chemotherapy
4. Malignancies other than ovarian cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ of the breast, or stage I p53 wild type endometrial cancer)
5. Prior systemic treatment for ovarian cancer
6. Prior treatment with PARP inhibitor
7. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted)
8. Prior randomization in AGO-OVAR 28
9. Major surgery within 7 days prior to day 1, cycle 1 (C1D1) or patient who has not completely recovered from the effects of any major surgery. Core biopsy or other minor surgical procedure within 7 days prior to C1D1 is permitted.
10. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to C1D1) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to C1D1) in case of suspected spinal cord compression.
11. Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab
12. Previous Cerebro-Vascular Accident, Transient Ischemic Attack or Sub-Arachnoids Hemorrhage within 6 months prior to C1D1
13. History or evidence of thrombotic or hemorrhagic disorders within 3 months prior to C1D1
14. History or evidence upon neurological examination of central nervous system disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures
15. Pregnant or lactating women
16. Treatment with any other investigational agent, or participation in another clinical trial
testing a drug within 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to C1D1 or concomitantly with this trial
17. Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Known hypersensitivity to niraparib, paclitaxel and carboplatin and its components or excipients
18. Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3-weekly wound examinations
19. Clinically significant cardiovascular disease, including
- Myocardial infarction or unstable angina within 6 months of C1D1
- New York Heart Association Grade 2 Congestive Heart Failure
- Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
- Grade = 3 peripheral vascular disease (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)
- Significant vascular disease including aortic aneurysm requiring surgical repair
20. Pre-existing sensory or motor neuropathy = Grade 2
21. Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy
22. Patients with a history of or current Nephrotic syndrome
23. Bowel obstruction (including subocclusive disease)
24. History of abdominal fistula or tracheoesophageal fistula or gastrointestinal perforation
or active gastrointestinal bleeding or anastomotic insufficiency or intraabdominal
abscess within 6 months of C1D1
25. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of niraparib
26. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
27. Any known history or current diagnosis of myelodysplastic syndrome or acute myeloid leukemia
28. Previous allogeneic bone marrow transplant or previous solid organ transplantation
29. Current or recent (within 10 days prior to C1D1) chronic use of aspirin > 325 mg/day. Patients treated with other inhibitors of platelet aggregation such as clopidogrel, prasugrel, ticlopidine, tirofibane or dipyridamole should not be included into the trial
30. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. This includes also any psychiatric disorder that prohibits obtaining informed consent
31. Patient has known active hepatitis B or hepatitis C
32. Patient has a history of Posterior Reversible Encephalopathy Syndrome

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Gynäkologische Tumore

Medizinischer Befund
Patients with newly diagnosed, histologically confirmed, primary advanced invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer, FIGO stage III\/IV (except FIGO IIIA2 without nodal involvement), with indication for a platin\/paclitaxel chemotherapy, who have either undergone upfront primary surgery or plan to undergo chemotherapy with interval debulking surgery (IDS)

MedDRA Term
Fallopian tube cancer, Peritoneal carcinoma, Ovarian cancer

Institute
Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Michael Schündeln

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

Hufelandstr 55
45147 Essen

Sponsor

GPOH gGmbH

Einschlusskriterien
Für alle Gruppen:

- die schriftliche Erlaubnis der Eltern bzw. des/der gesetzlichen Vertreter(s) verstehen und dem ICF freiwillig vor der Durchführung aller studienbezogenen Beurteilungen/Verfahren, auch in Bezug auf Daten und Protokoll AML-AIEOP-BFM 2020 V1.2 Seite 14 von 139
Biomaterialtransfer gemäß ICH/GCP und nationalen/lokalen Vorschriften
- Fähigkeit, den Zeitplan der Studienbesuche und andere Anforderungen des Protokolls einzuhalten
- Negative Serum-Schwangerschaftstests für Frauen im gebärfähigen Alter innerhalb von 10 Tagen vor der Behandlung

Gruppe A:
- Diagnose einer AML (nach WHO-Klassifikation 2016)
- Akute Leukämie unklarer Abstammung (MPAL; nach WHO-Klassifikation 2016: akute undifferenzierte Leukämie (AUL, bilineare Leukämie; biphenotypische Leukämie, dominant myelogen; Lineage-Switch)
- Kinder und Jugendliche < 18 Jahre bei Beginn der ersten Chemotherapie
-Zustimmung, dass Lebendimpfungen während der Studienteilnahme nicht möglich sind

Gruppe B:
- Patienten mit erstrezidivierter (einschließlich Rezidiv nach SCT) oder primär refraktärer AML
- Kinder und Jugendliche < 18 Jahre bei Beginn der ersten Chemotherapie und < 21 Jahre bei Beginn der Behandlung dieser rezidivierten AML

Gruppe C:
- Patienten mit AML und Indikation zur ersten allogenen HSCT eines HLA-identischen Spenders (mindestens hochauflösende Typisierung minimal 9/10,)
- Alter zum Zeitpunkt des Einschlusses ab 1 Monat (28 Tage) bis unter 18 Jahre bei Diagnose; bis zu 21 Jahre zum Zeitpunkt der HSCT
- Kriterien für allogene HSCT:
• in AML-Vollremission (CR)
• vorhandene MSD, MFD oder MUD; matched ist definiert als mindestens 9/10 nach 4-stelliger Typisierung für HLA-A, B, C,DRB1, DQB1 Loci

Ausschlusskriterien
Alle Gruppen:
- Bestehende Syndrome, die eine Behandlung ausschließen
- Patienten mit Trisomie 21 und ML-DS und/oder transientem myeloproliferativen Syndrom
- Patienten mit einer akuten promyelozytären Leukämie (APL), AML mit t(15;17)
- Behandlungsbedingte oder sekundäre AML
- Symptomatische kardiale Funktionsstörung (CTCAE 5.0 Grad 3 oder 4)
- Jede andere Organfunktionsstörung (CTCAE 5.0 Grad 3 oder 4)
- Nachweis einer invasiven Pilzinfektion oder einer anderen schweren systemischen Infektion, die eine systemische/parenterale Therapie erfordert, einschließlich einer bekannten aktiven Virusinfektion mit dem humanen Immundefizienzvirus (HIV) oder Hepatitis Typ B und C
- Teilnahme an einer anderen klinischen Studie mit einer Intervention, die mit den Zielen dieser Studie interferiert
- Schwangere oder stillende Patientinnen
- Weibliche und männliche Probanden mit Kinderwunsch, die keine hochwirksamen antikonzeptiven Maßnahmen anwenden
- Überempfindlichkeit gegen den Wirkstoff oder andere im Prüfpräparat enthaltene Hilfsstoffe, die in der Zusammenfassung der Merkmale des Arzneimittels (SmPC) oder der Prüferinformation (IB) aufgeführt sind.

Gruppe A:
- Vorherige Therapie mit zytostatischen Medikamenten von mehr als 14 Tagen und anderen als die im Prüfplan als erlaubte Vorphase angegebenen
- Diagnostizierte Wilson-Krankheit

Gruppe B:
- Fractional Shortening bei der Echokardiographie unter 29%
- Ein Karnofsky-Performance-Status < 40% (Kinder = 16 Jahre) oder ein Lansky-Performance-Status von < 40% (Kinder < 16 Jahre) vor Beginn des ersten Zyklus
- Eingeschränkte Leberfunktion: Bilirubin > 3-fache obere Normgrenze; Transaminasen > 5-fache obere Normgrenze
- Vorgeschichte von VOD
- Vorgeschichte Hepatitis-C-Positivität
- Niereninsuffizienz mit Kreatinin < 30 ml/min
- Dekompensierte hämolytische Anämie

Gruppe C:
- Ein Karnofsky-Performance-Status < 60% (Kinder = 16 Jahre) oder ein Lansky-Performance-Status von < 60% (Kinder < 16 Jahre) vor Beginn der Gruppenbehandlung
- Behandlung mit zytotoxischen Arzneimitteln innerhalb von 10 Tagen vor der geplanten Verabreichung des Studienmedikaments
- Beeinträchtigte Leberfunktion: Bilirubin = 3-fache obere Normgrenze; Transaminasen = 5-fache obere Normgrenze
- Niereninsuffizienz mit Kreatinin <30 ml/min
- Behandlungsbedürftige Herzinsuffizienz; LVEF = 35 % (bei Patienten mit Herzerkrankungen in der Vorgeschichte oder Anthrazyklin-Exposition)
- Beeinträchtigte pulmonale Funktion: PO2 = 70 mm Hg oder DLCO = 60%
- Erfordernis einer zusätzlichen kontinuierlichen Sauerstoffzufuhr
- symptomatische Beteiligung des ZNS: leukämische Infiltration, die nicht durch vorherige intrathekale Chemotherapie und/oder kraniale Strahlentherapie beseitigt wurde
- andere Krankheiten, Komorbiditäten oder Zustände, die die Lebenserwartung stark einschränken würden

Studienteilnehmende Mindestalter
0 Jahr(e)

Studienteilnehmende Höchstalter
21 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Akute myeloblastische Leukämie AML

Institute
Klinik für Gastroenterologie und Hepatologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Hartmut Schmidt

+49 (0)201 723-3610
hartmut.schmidt@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Universitätsklinikum der Ludwig-Maximilians-Universität München

Einschlusskriterien
1. Vom Patienten unterschriebene Einverständniserklärung zur Studienteilnahme
2. Alter ≥ 18 Jahre bei Unterzeichnung der Einverständniserklärung
3. Nach Einschätzung des Prüfarztes geeignet zur Erfüllung der Anforderungen des Studienprotokolls
4. Lebenserwartung von ≥ 12 Wochen
5. HCC (histologisch bestätigte Diagnose)
6. Krankheit, die einer kurativen Behandlung mit Chirurg. Maßnahmen/ lokalen Ablation nach Konsens eines multidisziplinären lokalen Tumorboards nicht zugänglich ist, jedoch für TACE auswählbar ist, mit einer Tumorlast < 50% des Lebervol.
7. Mind. eine nach RECIST 1.1 messbare, unbehandelte Läsion
8. ECOG 0 oder 1
9. Child-Pugh Klasse A oder B7
10. Adäquate hämat. Funktion und Endorganfunktion, innerhalb von 14 Tagen (sofern nicht anders spezifiziert) vor Random. definiert durch:
- neut. Granulozyten ≥1,5 x 109/L (1500/μL) ohne Granulozyten-Kolonie stimulierende Faktoren
- Lymphozyten ≥ 0,5 x 109/L (500/μL)
- Thrombozyten ≥ 75 x109/L (75,000/μL) ohne Transfusion
- Hämoglobin ≥ 90 g/L (9 g/dL); Patienten transfundiert worden sein
- AST, ALT, und AP ≤ 5 x ULN
- Bilirubin im Serum ≤ 3 x ULN
- Kreatinin im Serum ≤ 1,5 x ULN oder Kreatinin Clearance ≥ 50 mL/min
(Cockcroft-Gault Formel)
- Albumin im Serum ≥ 28 g/L (2,8 g/dL)
- Bei Patienten, die keine therapeutische Antikoagulation erhalten: INR <1,25
- Urinuntersuchung mit Teststreifen auf Proteinurie < 2+ (innerhalb von 14 Tagen vor Start), es sei denn, eine nachfolgende Untersuchung im 24 Stunden Sammelurin weist < 1g Protein nach
11. Negativer HIV Test beim Screening
12. Dokumentierter virologischer Status im Hinblick auf Hepatitis, bestätigt durch serologische Testung auf HBV und HCV beim Screening. Bei Patienten mit aktiver Hepatitis B Virus –Infektion: HBV DNS < 500 IU/mL innerhalb von 28 Tagen vor Randomisierung, und Anti-HBV Behandlung nach lokalem Behandlungsstandard für mindestens 14 Tage vor Randomisierung sowie Bereitschaft, diese für die Dauer der Studie fortzufahren.
13. Bei gebärfähigen Frauen: negativer Schwangerschaftstest innerhalb von 14 Tagen vor Randomisierung und Bereitschaft, entweder vollständig enthaltsam zu bleiben (vollständige Enthaltsamkeit von heterosexuellem Geschlechtsverkehr) oder empfängnisverhütende Mittel mit einer Versagensquote unter 1% pro Jahr während der gesamten Dauer der Behandlung sowie für mindestens 5 Monate nach letzter Gabe von Atezolizumab und 6 Monate nach letzter Gabe von Bevacizumab zu
benutzen.
Eine Frau wird als gebärfähig eingeschätzt, wenn sie die Menarche hatte, nicht einen postmenopausalen Status erreicht hat (≥ 12 Monate Amenorrhoe ohne einen anderen identifizierten Grund als die Menopause) und nicht einer chirurgischen Sterilisation (Entfernung der Eierstöcke und/oder des Uterus) unterzogen wurde. Beispiele für Methoden zur Empfängnisverhütung mit einer Versagensquote <1% pro Jahr sind die beidseitige Tubenligatur, die Sterilisation des männlichen Partner, hormonale Kontrazeptiva, die die Ovulation verhindern, Hormonspiralen und Kupferspiralen. Die Verlässlichkeit der sexuellen Enthaltsamkeit sollte in Bezug auf die Dauer der klinischen Prüfung und den bevorzugten und gewöhnlichen Lebensstil des Patienten beurteilt werden. Periodische Abstinenz (z.B. nach der Kalendermethode oder um den Zeitpunkt des Eisprungs, symptothermale Methoden oder periodische sexuelle Enthaltsamkeit von der Menstruation bis nach erfolgtem Eisprung) und Coitus interruptus
sind keine akzeptierten Methoden zur Empfängnisverhütung.
14. Für Männer: Bereitschaft, entweder vollständig enthaltsam zu bleiben (vollständige Enthaltsamkeit von heterosexuellem Geschlechtsverkehr) oder empfängnisverhütende Methoden zu benutzen sowie Bereitschaft, sich einer Samenspende zu enthalten wie im Folgenden definiert: Bei weiblichen gebärfähigen Partnern müssen Männer während der gesamten Behandlungsperiode und für 6 Monate nach letzter Gabe von Bevacizumab entweder vollständig enthaltsam bleiben oder ein Kondom
zusammen mit einer zusätzlichen empfängnisverhütenden Methode benutzen, die zusammen eine Versagensquote von < 1% pro Jahr haben. Männer dürfen während dieses Zeitraums keine Samenspende vornehmen. Falls der weibliche Partner schwanger ist, müssen Männer sexuell enthaltsam bleiben oder während der gesamten Behandlungsperiode und für 6 Monate nach letzter Gabe von Bevacizumab ein Kondom benutzen, um eine Exposition des Embryo zu vermeiden. Die Verlässlichkeit der sexuellen Enthaltsamkeit sollte in Bezug auf die Dauer der klinischen Prüfung und den bevorzugten und gewöhnlichen Lebensstil des Patienten beurteilt werden. Periodische Abstinenz (z.B. nach der Kalendermethode oder um den Zeitpunkt des Eisprungs, symptothermale Methoden oder periodische sexuelle Enthaltsamkeit von der Menstruation bis nach erfolgtem Eisprung) und Coitus interruptus sind keine akzeptierten Methoden zur Empfängnisverhütung.

Ausschlusskriterien
1. Diffuses HCC , Gefäßeinbruchs durch den Tumor, extrahep, Ausbreitung oder > 7 Läsionen oder eine Läsion = 7 cm
2. Bekanntes fibrolamelläres HCC, sarkomatoides HCC, oder gemischtes Gallengangskarzinom und HCC
3. Klinisch relevanter Aszites (Details s. Prüfplan)
4. Unkontr. Pleura- oder Perikarderguss
5. Anamnese oder Vorliegen von hep. Enzephalopathie
6. Koinfektion mit HBV und HCV, anamnet. HCV Infektion mit neg. PCR auf HCV RNS, gelten als nicht HCV infiziert
7. Patienten, die aktiv auf einer Lebertransplantationsliste gelistet sind oder potentiell transplantiert werden können (siehe Prüfplan)
8. systemische Vor-Behandlung des HCC
9. Vor-Behandlung mit TACE oder SIRT
10. Vorbehandlung mit lokal ablativen Verfahren (Details s. Prüfplan)
11. Jeder Kontraindikation für TACE
12. Größere gastrointestinale Blutungen in den letzten 4 Wochen
13. Unbehandelte oder unvollst. Behandel. Oesophagusvarizen mit Blutung oder hohem Blutungs-Risiko (Details siehe Prüfpaln)
14. Aktive Autoimmunerkrankung, Immunschwäche oder Anamnese einer solchen(Details s. Prüfplan)
15. Frühere allogene Stammzelltransplantation oder Organtransplantation.
16. Bekannte idiop. Pulm. Fibrose, organisierende Pneumonie, Arzneimittel-induz. Pneumonitis, idiopathische Pneumonitis oder Nachweis einer aktiven Pneumonitis im CT (Details siehe Prüfplan)
17. Aktive Tuberkulose (Details siehe Protokoll)
18. Schwere Infektion innerhalb der letzten 4 Wochen (Details s. Prüfplan)
19. Signifikante kardiovaskuläre Erkrankung (Details siehe Prüfplan)
20. Bekanntes angeborenes Langes-QT Syndrom, korr. QT-Interval > 500 msec oder wiederholt korr. QT-Intervall von >450 ms
21. Unkontrollierte art. Hypertonie, frühere Anamnese einer hypertensiven Krise oder einer hypertensiven Enzephalopathie.
22. Signif. Gefäßerkrankung (Details s. Prüfplan)
23. Anamnese einer abdom. oder tracheoösophagealen Fistel, einer gastroint. Perforation oder intraabdominalen Abszesses innerhalb der letzten 6 Monaten
24. Anamnese oder klin. Zeichen einer gastroint. Obstruktion, routinemäßige parenterale Flüssigkeitszufuhr/Ernährung oder Ernährungssonde.
25. Bekannter intra-abdominaler entzündlicher Prozess innerhalb der letzten 6 Monaten
26. Blutungsneigung oder signifikanten Gerinnungsstörung
27. Jede andere Kontraindikation für den Gebrauch der Prüfpräparte oder die die Interpretation der Ergebnisse beeinflussen könnten oder den Patienten einem hohen Risiko aussetzen könnten.
28. Nicht kontrollierter tumorbedingter Schmerz
29. Schwere, nicht heilende/klaffende Wunden, aktives Ulkus oder unbehandelte Knochenfraktur
30. andere malignen Erkrankung als ein HCC (Ausnahmen s. Prüfplan)
31. Fortbestehende oder kürzliche Gabe von Acetylsalicylsäure oder Behandlung mit Dipyramidol, Ticlopidin, Clopidogrel und Cilostazol
32. Fortbestehende oder kürzliche Gabe von voll dosierten oral oder parenteral verabreichten Antikoagulantien, thrombolytischen Agentien (Details s. Prüfplan)
33. Chronische tägl. Gabe von NSAID
34. Impfung mit Lebendimpfstoff innerhalb der letzten 4 Wochen (Details s. Prüfplan)
35. Frühere Behandlung mit CD137 Agonisten oder Immun-Checkpoint-Blockade Therapien
36. Überempfindlichkeit auf Atezolizumab oder Bevacizumab oder Bestandteile ihrer Zubereitung, gegen Produkte aus CHO-Zellen oder gegen humane oderhumanisierte Antikörper
37. Behandlung mit syst. immunstimulierenden Wirkstoffen (Details s. Prüfplan)
38. Behandlung mit systemischer immunsuppressiver Medikation (Details s. Prüfplan)
39. Größerer chirurgischer Eingriff mit Ausnahme solcher zur Diagnosestellung, eine offene Biopsie oder eine signifikante traumatische Verletzung innerhalb von 28 Tagen vor Randomisierung, oder ein chirurgischer Eingriff im Bauch, chirurgische Interventionen oder eine signifikante traumatische Bauchverletzung innerhalb von 60 Tagen vor Randomisierung oder die Annahme, dass im Verlauf der Studie größere chirurgische Maßnahmen erforderlich sein könnten oder ausgebliebene Erholung von den Nebenwirkungen solcher Eingriffe.
40. Stanz- oder Feinnadelbiopsien, andere kleinere chirurgische Maßnahmen innerhalb von 3 Tagen vor erster Gabe von Bevacizumabmit Ausnahme von Legen von Gefäßzugängen.
41. Schwangere oder stillende Frauen.
42. Teilnahme an einer klinischen Studie oder experimentelle medikamentöse Therapie innerhalb von 28 Tagen vor Studieneinschluss oder innerhalb von 5 Halbwertzeiten der in einer klinischen Prüfung oder während einer experimentellen medikamentösen Behandlung verabreichten Wirkstoffe vor Studieneinschluss in Abhängigkeit davon, welcher Zeitraum länger ist, oder gleichzeitige Teilnahme an einer anderen klinischen Studie während der Teilnahme an dieser klinischen Studie.
43. Patient ist auf Grund einer gerichtlichen Verfügung oder Anordnung der administrativen Behörden in eine Anstalt eingewiesen.
44. Mögliche Abhängigkeit des Patienten vom Prüfarzt, einschließlich Ehegatte, Kinder und naher Verwandter eines jeden Prüfarztes

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Nicht-resezierbares Hepatozelluläres Karzinom

MedDRA Term
Hepatocellular carcinoma non-resectable

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

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)

Dr. med. Isabel Virchow

isabel.virchow@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

AMGEN GmbH

+49 89 149096 0

Riesstraße 24
80992 München

Einschlusskriterien
pathologically documented metastatic colorectal adenocarcinoma
central confirmation of KRAS p.G12C mutation
measurable disease per RECIST v1.1 criteria. Lesions previously radiated are
not considered measurable unless they have progressed after radiation
age 18 years (or legal age within the country if it is more than 18 years)
Eastern Cooperative Oncology Group (ECOG) Performance Status of 1
life expectancy of 6 months, in the opinion of the investigator
adequate hematologic and end organ function
ability to take oral medications and willing to record daily adherence to
investigational product

Ausschlusskriterien
prior systemic therapy for metastatic disease except for a maximum of 1 dose of
SOC FOLFIRI (chemotherapy backbone) administered during the screening
period
active, untreated brain metastases
leptomeningeal disease
tumor is known to have B-raf proto-oncogene serine/threonine kinase
(BRAF) V600E mutation
tumor is known to be microsatellite instability high (MSI-H)
previous treatment with a KRAS p.G12C inhibitor
known dihydropyrimidine dehydrogenase (DPD) deficiency
known UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or
diagnosis of
subject has required a dose reduction or dose delay of either 5-fluorouracil
(5-FU) or irinotecan in any prior chemotherapy regimen in the past for toxicity, to
history of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial
pneumonitis or pulmonary fibrosis on baseline CT scan

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Treatment-naïve Subjects With Metastatic Colorectal Cancer With KRAS p.G12C Mutation

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
Participants are eligible to be included in the study only if all of the following criteria apply:
• Participant has provided informed consent prior to initiation of any study specific activities/procedures.
• Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
• Histologically or cytologically confirmed small-cell lung cancer (SCLC).
• Diagnosed and treated for LS-SCLC with concurrent chemotherapy and radiotherapy.
• Has completed chemoradiotherapy without progression per Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1.) (ie, achieved complete response [CR], partial response [PR], or stable disease [SD]).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
• Minimum life expectancy of 12 weeks.
• Adequate organ function.
• Toxicities attributed to concurrent chemoradiotherapy resolved to grade ≤ 1, unless otherwise specified. Excluding alopecia or fatigue.

Ausschlusskriterien
Participants are excluded from the study if any of the following criteria apply:
Disease Related
• Extensive-stage SCLC (ES-SCLC).
• Any previous diagnosis of transformed non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) activating mutation positive NSCLC that has transformed to SCLC, or mixed SCLC NSCLC histology.
• Evidence of interstitial lung disease or active, non-infectious pneumonitis. Other Medical Conditions
• History of other malignancy within the past 2 years, with certain exceptions.
• History of solid organ transplantation.
• Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 6 months prior to first dose of study treatment.
• History of arterial thrombosis (eg, stroke or transient ischemic attack) within 6 months prior to first dose of study treatment.
• Exclusion of human immunodeficiency virus (HIV) and hepatitis infection based on criteria per protocol.
• Participant with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of study treatment.

Prior/Concomitant Therapy
• Received sequential chemotherapy and thoracic radiotherapy (no overlap of thoracic radiotherapy with chemotherapy) during chemoradiation.
• Prior therapy with any selective inhibitor of the delta-like ligand 3 (DLL3) pathway.
• Prior history of severe or life-threatening events from any immune-mediated therapy.
• Receiving another anti-cancer therapy. Adjuvant hormonal therapy for resected breast cancer is permitted.
• Receiving systemic corticosteroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment.
• Major surgical procedures within 28 days prior to first dose of study treatment.
• Treatment with live virus, including live-attenuated vaccination, within 14 days prior to the first dose of study treatment. Inactive vaccines and live viral non-replicating vaccines within 3 days prior to first dose of study treatment.
• Prior/Concurrent Clinical Study Experience
• Treatment in an alternative investigational trial within 28 days prior to enrollment.

Other Exclusions
• Female participants of childbearing potential unwilling to use protocol specified method of contraception during treatment and for an additional 72 days after the last dose of study treatment.
• Female participants who are breastfeeding or who plan to breastfeed while on study through 72 days after the last dose of study treatment.
• Female participants planning to become pregnant or donate eggs while on study through 72 days after the last dose of study treatment.
• Female participants of childbearing potential with a positive pregnancy test assessed at screening by a highly sensitive serum pregnancy test.
• Male participants with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 132 days after the last dose of study treatment.
• Male participants with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 132 days after the last dose of study treatment.
• Male participants unwilling to abstain from donating sperm during treatment and for an additional 132 days after the last dose of study treatment.
• Participant has known sensitivity to any of the products or components to be administered during dosing.
• Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the participant and investigator's knowledge.
History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Limited-Stage Small-Cell Lung Cancer (LS-SCLC)\nSmall Cell Lung Cancer (SCLC)

MedDRA Term
Small cell lung cancer limited stage

Institute
Innere Klinik (Tumorforschung), 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

Amgen Inc, USA

Einschlusskriterien
- Parts 1, 2, and 5: prior taxane exposure Participants with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (eg, abiraterone acetate and/or enzalutamide, apalutamide, darolutamide, bicalutamide, or equivalent) and have failed at least 1 (but not more than 2) taxane regimens including for mHSPC (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen). Note: A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane.
1. Dose exploration phase: Novel antiandrogen therapy must have been given for treatment of metastatic disease.
2. Dose expansion phase: participants must not have had more than 2 NHTs and 2 taxane regimens in any setting, and an additional up to 2 other systemic anti-cancer treatments are allowed (eg, anti-PD1, PARP inhibitors, radioligand therapies, sipuleucel-T, experimental agents) Note: Combinations are considered one systemic anti-cancer treatment.
- Parts 4A and 4B: prior taxane exposure
1. Participants with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide, bicalutamide or equivalent) given for hormone-sensitive prostate cancer (HSPC) or non-metastatic CRPC and have failed up to 1 taxane regimen which must have been given for HSPC only (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen).
2. 4A: Participants planning to receive abiraterone acetate for the first time (participants who received prior abiraterone acetate are not eligible).
3. 4B: Participants planning to receive enzalutamide for the first time (participants who received prior enzalutamide/apalutamide or daralutamide are not eligible).
- Parts 3 and 4C: no prior taxane exposure
a. Participants with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide, bicalutamide or equivalent) given in any disease setting and who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen.
- Participants must have undergone bilateral orchiectomy or be on continuous androgen-deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist.
- Total serum testosterone <= 50 ng/dL or 1.7 nmol/L.
- Evidence of progressive disease, defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria:
1. PSA level >= 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart.
2. nodal or visceral progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with PCGW3 modifications.
3. appearance of 2 or more new lesions in bone scan.
- Eastern Cooperative Oncology Group performance status of 0-1.
- Adequate organ function, defined as follows:
1. Hematological function:
a. absolute neutrophil count >= 1 x 10^9/L (without growth factor support within 7 days from screening assessment).
b. platelet count >= 75 x 10^9/L (without platelet transfusion within 7 days from screening assessment).
c. hemoglobin >= 9 g/dL (90 g/L) (without blood transfusion within 7 days from screening assessment).
2. Renal function:
1. estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation >= 30 ml/min/1.73 m^2.
3. Hepatic function:
a. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (or < 5 x ULN for participants with liver involvement).
b. total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants with liver metastases).
4. Cardiac function:
a. left ventricular ejection fraction > 50% (2-D transthoracic echocardiogram [ECHO] is the preferred method of evaluation; multi-gated acquisition scan is acceptable if ECHO is not available).
b. Baseline electrocardiogram (ECG) QTcF <= 470 msec.

Ausschlusskriterien
- Pathological finding consistent with pure small cell, neuroendocrine carcinoma of the prostate or any other histology different from adenocarcinoma.
- Radiation therapy within 4 weeks of first dose (or local or focal radiotherapy within 2 weeks of first dose).
- Untreated central nervous system (CNS) metastases or leptomeningeal disease. Participants with a history of treated CNS metastases are eligible if there is radiographic evidence of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.
- Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy.
- History of arterial or venous thrombosis (eg, stroke, transient ischemic attack, pulmonary embolism, or deep vein thrombosis); for arterial thrombosis within 12 months of AMG 509 initiation; for venous thrombosis, 6 months and stable on anti-coagulation.
- Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of AMG 509 with the exception of ischemia or non-ST segment elevation myocardial infarction controlled with stent placement and confirmed by a cardiologist more than 6 months prior to first dose of AMG 509.
- Any anti-cancer therapy or immunotherapy within 4 weeks of start of first dose, not including luteinizing hormone-releasing hormone (LHRH)/GnRH analogue (agonist/antagonist). Participants on a stable bisphosphonate or denosumab regimen for >= 30 days prior to enrollment are eligible.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Metastatic Castration-Resistant Prostate Cancer (mCRPC)

MedDRA Term
Castration-resistant prostate cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
• Participant has provided inform consent to the main study prior to initiation of any study specific activities/procedures
• Male or female participants age = 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Participants with histologically or cytologically documented selected solid tumor diseases. Participants must have exhausted available standard of care (SOC) systemic therapy or must not be candidates for such available therapy
• For dose expansion cohorts: participants with at least 1 measurable lesion =10 mm which has not undergone biopsy within 3 months of screening scan. This lesion cannot be biopsied at any time during the study
• Life expectancy > 3 months
• Adequate organ function

Ausschlusskriterien
• Untreated central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression
• History of other malignancy within the past 2 years
• Ongoing or active infection
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Known interstitial lung disease
• Positive test for human immunodeficiency virus (HIV)
• Positive hepatitis B surface antigen or positive hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR)
• Anticancer therapies including radiotherapy (with the exception of palliative radiation) chemotherapy or molecularly targeted treatments or tyrosine kinase inhibitors (TKI) within 4 weeks or 5 half lives (whichever is longer) of administration of a first dose of study treatment; immunotherapies/monoclonal antibodies within 3 weeks of administration of a first dose of study treatment.
• Has had a major surgery within 4 weeks of administration of a first dose of study treatment
• Autoimmune disorders requiring chronic systemic steroid therapy or any other form of immunosuppressive therapy while on study (eg, ulcerative colitis, Crohn's disease)
• Live and/or live-attenuated vaccines received within 28 days (or longer, if required locally) prior to the first dose of AMG 305
• Currently receiving treatment in another investigational device or drug study
• Female participants of childbearing potential or male participants unwilling to use protocol specified method of contraception
• Females who are pregnant, breastfeeding or who plan to breastfeed or become pregnant while on study
• History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
100 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Lungenkrebs, Solide Tumoren

Medizinischer Befund
Advanced solid tumors including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), mesothelioma, pancreatic carcinoma gastric cancer (GC), head and neck carcinoma, ovarian cancer, cervical carcinoma, uterine carcinoma, and breast cancer.

MedDRA Term
Ovarian cancer, Uterine cancer, Mesothelioma, Cervix carcinoma, Head and neck cancer, Pancreatic neoplasms, Gastric cancer, Non-small cell lung cancer, Breast cancer, Colorectal cancer

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

Amgen Inc, USA

Einschlusskriterien
* Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
* Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas.
* Tumor tissue (FFPE sample) or an archival block must be available. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before dosing.
* Homozygous MTAP-deletion.
* Disease measurable as defined by RECIST v1.1.
* Adequate organ function as defined in the protocol

Ausschlusskriterien
* Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
* Radiation therapy within 28 days of first dose.
* Major surgery within 28 days of first dose of AMG 193.
* Cardiovascular and pulmonary exclusion criteria as defined in the protocol.
* Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
* History of solid organ transplantation.

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
100 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Locally advanced or met. PDAC with MTAP deletion (Gastrointestinal, Biliary Tract, and Pancreatic Cancers)

MedDRA Term
Ductal adenocarcinoma of pancreas, Biliary cancer metastatic

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@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
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 für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Stefan Schönberger

stefan.schoenberger@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universität Tübingen

Einschlusskriterien
• Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph chromosome [t(9;22)(q34;q11)].
• Ph negative cases or patients with variant translocations who are BCR-ABL positive in multiplex PCR (Cross, et al 1994) are eligible as well.
• Pretreatment with hydroxyurea for 6 months and imatinib or nilotinib for a duration of up to 6 weeks is permitted.
• Age ≥ 18 years old (no upper age limit given)
• Normal serum levels ≥LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin, or corrected to within normal limits with supplements.
• ASAT and ALAT ≤ 2.5 x ULN (upper limit of normal) or ≤ 5.0 x ULN if considered due to leukemia
• Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia
• Total bilirubin ≤ 1.5 x ULN, except known Mb. Gilbert
• Serum lipase and amylase ≤ 1.5 x ULN
• Serum creatinine ≤ 2 x ULN
• Written informed consent prior to any study procedures being performed.

Ausschlusskriterien
• Known impaired cardiac function, including any of the following:
- Left ventricular ejection fraction (LVEF) < 45%
- Congenital long QT syndrome
- History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Clinically significant resting bradycardia (< 50 beats per minute)
• QTc>450 msec on screening ECG. If QTc > 450 ms and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTc criterion.
• Myocardial infarction within 12 months prior to starting therapy.
• Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
• History of acute (i.e., within 1 year of starting study medication) or chronic pancreatitis
• Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled.
• Other concurrent uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
• Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
• Concomitant medications with potential QT prolongation (see link for complete list: http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm)
• Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4:
see link for complete list (http://medicine.iupui.edu/flockhart/table.htm)
• Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who are pregnant or breast feeding, or women of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. Female patients 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
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
• Active autoimmune disorder, including autoimmune hepatitis
• Known serious hypersensitivity reactions to peginterferon alfa-2b or interferon alfa-2b or drug excipients
• Known serious hypersensitivity reactions to nilotinib
• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
• Patients unwilling or unable to comply with the protocol.

Indikation
KIK-Onko

Medizinischer Befund
Leukemia

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

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 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
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

Universitätsklinikum Jena

Einschlusskriterien
- Written informed consent
- Males ≥18 years of age
- Histologically or cytologically confirmed adenocarcinoma of prostate
- Investigator assessed metastatic disease documented either by a positive bone scan, or for soft tissue or visceral metastases, either by contrast-enhanced abdominal/pelvic/chest computed tomography (CT) or magnetic resonance imaging (MRI) scan assessed. Metastatic disease is defined as either malignant lesions in bone scan or soft tissue/visceral lesions according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Lymph nodes are measurable if the short axis diameter is ≥15 mm, soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm.
- Subjects with lymph node metastases only (either below the aortic bifurcation (N1) or above the aortic bifurcation (M1a)) will not be eligible for the study.
- Subjects must be candidates for ADT, docetaxel and darolutamide therapy per Investigator's judgment
- Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but no longer than 12 weeks before randomization. For subjects receiving LHRH agonists, treatment in combination with a first generation anti-androgen for at least 4 weeks, prior to randomization is recommended. First generation anti-androgen has to be stopped prior to randomization.
- An Eastern Cooperative Oncology Group performance status of 0 or 1
- Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L, platelet count ≥100x109/L (subject must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening)
- Screening values of serum alanine aminotransferase and/or aspartate transaminase ≤1.5x upper limit of normal (ULN), total bilirubin ≤ULN, creatinine ≤2.0x ULN
Sexually active male subjects must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with darolutamide and for 3 months after the end of the treatment with darolutamide and 6 months after treatment with docetaxel.

Ausschlusskriterien
- Prior treatment with:
- LHRH agonist/antagonists started more than 12 weeks before randomization Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide, other investigational AR inhibitors
- Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer
- Chemotherapy, immunotherapy, radium or other therapeutic radiopharmaceuticals for prostate cancer (e.g. Lutetium177-PSMA) prior to randomization
- Treatment with radiotherapy (external beam radiation therapy, brachytherapy) within 2 weeks before randomization
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
- Contraindication to both CT and MRI contrast agent
- Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris,coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)
- Uncontrolled hypertension as indicated by a resting systolic blood pressure (BP) =160 mmHg or diastolic BP =100 mmHg despite medical management
- Had a prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed =5 years before randomization and from which the subject has been disease-free
- A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug
- An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need for treatment
- Previous (within 28 days before the start of study drug or 5 half-lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s)
- Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results
- Inability to swallow oral medications
- Previous assignment to treatment in this study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universität des Saarlandes

Studienteilnehmende Mindestalter
60 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
DLBCL - Diffuses großzelliges B-Zell-Lymphom

Medizinischer Befund
Diffuse Large B-cell lymphoma (DLBCL)

Institute
Klinik für Dermatologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Selma Ugurel

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

Hufelandstr 55
45147 Essen

Indikation
Melanom

Medizinischer Befund
maligne Melanome

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

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

Merck Serono GmbH, Darmstadt

Einschlusskriterien
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
• Adult patients, aged ≥ 18 years of age at the time of signing the informed consent form (ICF)
• Patients with locally advanced or metastatic urothelial cancer of any histological subtype
• Patients who have completed first-line platinum-based chemotherapy with no evidence of disease progression
• Patients who are treatment naive for Avelumab first-line maintenance therapy, or who have received a maximum one cycle of Avelumab first-line maintenance therapy according to the Avelumab SmPC or the respective local label or any other regional requirements
• Patients who have provided written informed consent to participate in this study

Ausschlusskriterien
Patients are not eligible for this study if they fulfill any of the following exclusion criteria:
• Patients with contraindications for Avelumab according to the Avelumab SmPC or the respective local label or any other regional requirements
• Patients who have participated in any interventional clinical trial of a drug or device within 28 days prior to the start of Avelumab maintenance therapy

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
urothelial cancer

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

Merck Healthcare KGaA, Darmstadt

Einschlusskriterien
- Participants with the Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Participants with a histologically confirmed diagnosis of RCC with any histological origin
- Participants with a locally advanced/metastatic disease (that is [ie], newly diagnosed Stage 4 RCC per American Joint Committee on Cancer) or has recurrent disease
- Participants has received 1 or 2 cycles of Avelumab plus Axitinib treatment as a first-line therapy according to the approved Summary of Product Characteristics (SmPC)
- Participants willing to sign the written informed consent form (ICF) to participate in this study

Ausschlusskriterien
- Participants with contraindications for Avelumab or Axitinib according to the approved SmPC
- Participants who have participated in any interventional clinical study of a drug or device within 28 days prior to the start of Avelumab plus Axitinib

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Carcinoma, Renal Cell

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

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Gudrun Fleischhack

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

Hufelandstr. 55
45147 Essen

Sponsor

Pfizer Inc., USA

Indikation
KIK-Onko

Medizinischer Befund
ACUTE LYMPHOBLASTIC LEUKAEMIA

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Isabel Virchow

isabel.virchow@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Pierre Fabre Pharma GmbH, Freiburg

Einschlusskriterien
Inclusion Criteria:

Written informed consent of the patient with regard to the pseudonymized documentation of his/her data in the frame of this non-interventional study
Legally capable patient ≥ 18 years of age (no upper limit)
Metastatic colorectal carcinoma with BRAFV600E-mutation, pretreated with systemic therapy
Decision was taken to treat the patient with the doublet therapy (encorafenib and cetuximab) in accordance with the current SmPC and by prescription; this decision was taken prior to and independent from the inclusion into the study;
Treatment with the doublet therapy (encorafenib plus cetuximab) has been started ≤ 3 months prior to providing written informed consent for this study or is planned to be started in the near future.

Ausschlusskriterien
Exclusion Criteria:

More than 2 prior systemic regimens in the metastatic setting (adjuvant systemic therapy with relapse = 6 months will be counted as metastatic treatment line; maintenance treatment will not be counted as separate metastatic treatment line)
Prior treatment with any RAF-inhibitor or MEK-inhibitor.
Presence of any contraindication with regard to the doublet therapy (encorafenib plus cetuximab) as specified in the corresponding SmPCs
Current or upcoming participation in an interventional clinical trial
Current or upcoming systemic treatment of any other tumor than metastatic colorectal carcinoma
Prisoners or persons who are compulsorily detained (involuntarily incarcerated).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Metastatic Colorectal Carcinoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Isabel Virchow

isabel.virchow@uk-essen.de

Hufelandstr 55
45147 Essen

Indikation
Solide Tumoren

Medizinischer Befund
advanced solid tumors

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

Bristol-Myers Squibb International Corporation, Belgien

Einschlusskriterien
• Fresh pre-treatment and on-treatment tumor biopsy must be provided for biomarker analysis
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and at least 1 lesion accessible for biopsy
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Radiographically documented progressive disease on or after the most recent therapy
• Received standard-of-care therapies, including an available programmed death (ligand)-1 inhibitor known to be effective in the tumor type for which they are being evaluated
• Parts 1A, 1B, and 2A: Advanced or metastatic non-small cell lung cancer, squamous cell carcinoma of head and neck, microsatellite stable colorectal cancer, gastric/ gastroesophageal junction adenocarcinoma, or cervical cancer, and have received, be refractory to, not be a candidate for, or be intolerant of existing therapies known to provide clinical benefit for the condition of the participant

Ausschlusskriterien
• Women who are pregnant or breastfeeding
• Primary central nervous system (CNS) malignancy
• Untreated CNS metastases
• Leptomeningeal metastases
• Concurrent malignancy requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment
• Active, known, or suspected autoimmune disease
• Condition requiring systemic treatment with either corticosteroids within 14
days or other immunosuppressive medications within 30 days of the first dose of study treatment
• Prior organ or tissue allograft
• Uncontrolled or significant cardiovascular disease
• Major surgery within 4 weeks of study drug administration
• History of or with active interstitial lung disease or pulmonary fibrosis
Other protocol-defined inclusion/exclusion criteria apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Multientity/Biomarker driven

Medizinischer Befund
Male and female participants = 18 years of age with advanced or metastatic cancers .\n\nCervical Cancer\nGastric\/Gastroesophageal Junction Adenocarcinoma\nMicrosatellite Stable Colorectal Cancer\nNon-Small-Cell Lung Cancer\nSquamous Cell Carcinoma of Head and Neck\nCarcinoma, Renal Cell\nUrothelial Carcinoma\nPancreatic Adenocarcinoma\nMelanoma\nOvarian Neoplasms\nTriple Negative Breast Neoplasms

MedDRA Term
Advanced 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

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
• Male or female participants:
a. Pediatric formulation group: ≥1 and less than 18 years of age at study entry.
b. Adult formulation group: ≥14 and less than 18 years of age and body weight of ≥40 kg at study entry.
• Participants must meet all of the following laboratory values at the screening visit. In the case where bone marrow blast and promyelocyte counts are available, these will be accepted if done within 56 days prior to the screening visit, to avoid unnecessary repetition of this test.
a. 15% blasts in peripheral blood and bone marrow
b. < 30% combined blasts plus promyelocytes in peripheral blood and bone marrow
c. < 20% basophils in the peripheral blood
d. Neutrophils ≥ 1.5 x 10^9/L (or white blood cell (WBC) ≥ 3 x 10^9/L if neutrophils are not available) and platelet count ≥ 100 x 10^9/L
e. No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
• Prior treatment with a minimum of one TKI.
• Failure or intolerance to the most recent TKI therapy at the time of screening.
• Evidence of typical BCR-ABL fusion gene (BCR-ABL1) transcript [e14a2 and/or e13a2] at the time of screening which are amenable to standardized real time quantitative polymerase chain reaction (RQ-PCR) quantification.

Ausschlusskriterien
• Known presence of the T315I mutation prior to study entry.
• Known second chronic phase of CML after previous progression to AP/BC.
• Previous treatment with a hematopoietic stem-cell transplantation.
• Patient planning to undergo allogeneic hematopoietic stem cell transplantation.
• Cardiac or cardiac repolarization abnormality.

Studienteilnehmende Mindestalter
28 Tag(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP), previously treated with one or more tyrosine kinase inhibitors

MedDRA Term
Philadelphia positive chronic myeloid leukemia, Juvenile chronic myeloid leukemia, Chronic phase chronic myeloid leukemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Klinikum LMU München

Indikation
MCL - Mantelzelllymphom

Institute
Klinik für Frauenheilkunde und Geburtshilfe, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med Pawel Mach

pawel.mach@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

NOGGO e.V., Berlin

Einschlusskriterien
- einwilligungsfähige Patient*innen > 18 Jahre
- rezidiviertes, platin-sensitivem Ovarial-, Tuben- oder primärem Bauchfellkarzinom, die für eine Erhaltungstherapie mit Niraparib vorgesehen sind bzw.
diese bereits bis zu max. 3 Monate erhalten

Ausschlusskriterien
- Hypersensibilität gegenüber Niraparib
- schwanger oder stillend
-Teilnahme an einer interventionellen klinischen Prüfung (während der Behandlung mit Niraparib)

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Weiblich

Indikation
Gynäkologische Tumore

Medizinischer Befund
Eierstockkrebs

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

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
Subjects eligible for inclusion in this study must meet all of the following criteria:
All subjects
1. Written informed consent, according to local guidelines, signed by the patients and / or by the parents or legal guardian prior to any study related screening procedures are performed.
2. Participation in a Novartis sponsored study such as TMT212X2101, DRB436G2201, DRB436A2102, regardless of current age
3. Parent study (or cohort of parent study) is planned to be closed
4. Patient has demonstrated treatment compliance, as assessed by the Investigator, within the parent study protocol requirement(s).
5. Willingness and ability to comply with scheduled visits, treatment plans and any other study procedures.
For Subjects Entering the Treatment Period
6. Patient is currently receiving treatment with dabrafenib/trametinib monotherapy or combination within a Novartis Sponsored Drug Development study.
7. In the opinion of the Investigator, the subject is likely to benefit from continued treatment.
8. Does not require treatment with prohibited concomitant medications.

Ausschlusskriterien
1. Patient has participated in a combination trial where dabrafenib and/or trametinib was dispensed in combination with another study medication. (Exception: Patients who were on the chemotherapy arm of the CDRB436G2201 study are eligible for this study after crossing over into the experimental treatment arm of the CDRB436G2201 study or have discontinued the study treatment and are now in follow-up)
2. Patient has permanently discontinued from study treatment in the parent protocol due to any reason.
3. Treatment with dabrafenib and/or trametinib for the patient’s indication is approved for marketing and the appropriate dosage form is commercially available and reimbursed in the local country
4. Patient currently has unresolved drug related severe toxicities for which dabrafenib and/or trametinib dosing has been interrupted in the parent study. If the patient should meet criteria to resume treatment on the parent protocol then they may be eligible for enrolment in this study.
5. Women of childbearing potential, defined as all females physiologically capable of becoming pregnant, must continue to use highly effective form of birth control method (contraception) during the study and for 16 weeks after stopping treatment with trametinib monotherapy or dabrafenib in combination with trametinib, and 2 weeks after stopping treatment with dabrafenib monotherapy, whichever is longer.
a. Total abstinence, (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (i.e calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
b. Female sterilization, surgically sterilized prior to the study (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when reproductive status of woman has been confirmed by follow-up hormone level assessment.
c. Sterilization (at least 6 months prior to screening) for male partners. The sterilized male partner should be the sole partner for that subject.
d. For subjects on dabrafenib monotherapy / trametinib in combination with dabrafenib: Placement of a hormonal or non-hormonal intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year.
e. For subjects on trametinib monotherapy: Use of oral (estrogen and progesterone) injected or implanted combined hormonal methods of contraception, or placement of an intrauterine device (IUD), or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. Male subjects (including those that have had a vasectomy) not willing to use a condom during intercourse while taking trametinib and/or dabrafenib and not to father a child during the study and for the period of 16 weeks (for patients taking trametinib only, or in combination) or 2 weeks (for patients taking dabrafenib only) following stopping of study treatment.
6. Lactating females who are actively breast feeding.
7. Concurrent participation in other clinical trials using experimental therapies

Studienteilnehmende Mindestalter
1 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Children and Adolescents with Cancers Harboring V600 mutations

Institute
Innere Klinik (Tumorforschung), 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

Universitätsklinik Essen (AöR)

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

Hufelandstraße 55
45147 Essen

Einschlusskriterien
Diagnosis: Histologically confirmed, localized or metastatic EwS or Ewing-like sarcoma of bone and/or soft tissue
lnformed consent form (ICF): According to national and GCP guidelines and signed prior to registry entry

Ausschlusskriterien
Withdrawal from ICF

Geschlecht
Divers, Männlich, Weiblich

Indikation
KIK-Onko, Sarkome

Medizinischer Befund
Ewing Sarcomas (EwS) and related small round cell sarcomas (SRCSs)

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

C4 Therapeutics, Inc.

(617)231-0770
clinicaltrials@c4therapeutics.com

490 Arsenal Way Suite 120
MA 02472 Watertown

Einschlusskriterien
* Subject (or legal guardian, where applicable) is willing and able to provide signed informed consent and can follow protocol requirements
* Subject is ≥18 years of age at time of informed consent
* Eastern Cooperative Oncology Group performance status of 0 or 1
* Subject has documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy: (other protocol conditions may apply)
* Subject must have received ≥1 prior line of SoC therapy for their locally advanced or metastatic disease, NSCLC, CRC, ATC or other BRAF-V600 mutation positive tumors:
- Melanoma or NSCLC (Phase 1 and Phase 2 Arms A1 and B1): Prior receipt of a BRAF inhibitor and an immune checkpoint inhibitor (any sequence or combination). Prior (neo)adjuvant immunotherapy may be acceptable.
- NSCLC (Phase 2 Arm B2): Prior receipt of a regimen including an immune checkpoint inhibitor (any sequence or combination). BRAF inhibitor naïve. Prior (neo)adjuvant immunotherapy may be acceptable.
- CRC: Receipt of a SoC chemotherapy regimen and a prior BRAF inhibitor in combination with an EGFR monoclonal antibody. Subjects with documented MSI-H or dMMR CRC must have received prior immunotherapy. Subjects with MSS disease must have received at least 2 prior treatments. Subjects who received neo(adjuvant) chemotherapy regimens may be eligible.
- ATC: Subjects must have received SoC therapy options including BRAF inhibitor if available and of benefit to the subject
- Other BRAF V600 mutant solid tumors (non-CNS): Subjects must have received SoC therapy options per their Investigator's best judgment and be BRAF inhibitor naïve
* Subject has measurable disease per RECIST v1.1
* Adequate bone marrow, liver, renal, and cardiac organ function
* A female subject may be eligible if not pregnant, planning a pregnancy, not breast feeding, a women of non-child bearing potential or a WOCBP willing to comply with protocol conditions relating to the use contraception, ova or blood donation and pregnancy testing prior to the first dose
* A male subject must agree to comply with protocol conditions relating to the use of contraception, sperm and blood donation
* Subject can safely swallow a tablet or pill

Ausschlusskriterien
Subject has had major surgery within 21 days prior to the planned first dose. Minor surgery is permitted within 21 days prior to enrollment
* Subject with CNS involvement (primary tumor or metastatic disease), except if clinically stable, have no evidence of new or enlarging brain metastases and are on stable or tapering doses of steroids for at least 7 days prior to first dose. Subjects with untreated brain metastases may be eligible to enter without prior radiation therapy.
* Subject with known malignancy other than trial indication that is progressing or has required treatment within the past 3 years, except for conditions that have undergone potentially curative therapy
* Subject with history of thromboembolic or cerebrovascular events =6 months as defined in the protocol
* Subject with impaired cardiac function or clinically significant cardiac disease, as defined in the protocol
* Subject with history of uncontrolled diabetes mellitus (only for subjects who will receive CFT1946 + trametinib)
* Subject with history or current evidence of retinal vein occlusion (RVO), chorioretinopathy, or current risk factors for RVO (only for subjects who will receive CFT1946 + trametinib)
* Subject has received live, attenuated vaccine within 28 days prior to first dose administration
* Subject has history of pneumonitis or interstitial lung disease
* Subject has history of uveitis
* Subject has known human immunodeficiency virus (HIV) infection (with exceptions)
* Subject has history of or known HBV or active HCV infection
* Subject has concurrent administration of strong CYP3A4/5 inhibitors and inducers, including any herbal medications/supplements
* Subject has presence of Grade =2 toxicity due to prior cancer therapy, excepting alopecia and hypothyroidism requiring thyroid replacement therapy
* Subject has initiation or receipt of the following =7 days prior to first dose administration: Hematopoietic colony-stimulating growth factors, transfusion of packed red blood cells (pRBC), and transfusion of platelets
* Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Solide Tumoren

Medizinischer Befund
Solid Tumors\nMelanoma\nNSCLC\nCRC\nATC

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Martin Metzenmacher

martin.metzenmacher@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma GmbH

+499112730
infoservice.novartis@novartis.com

Roonstraße 25
90429 Nürnberg

Indikation
Lungenkrebs

Medizinischer Befund
advanced Mesothelioma and other solid tumors

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

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Nina Kristin Steckel

+49 (0)201 723-3712
nina-kristin.steckel@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
- Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or
cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
- Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive
therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
- Confirmed diagnosis of corticosteroid refractory aGvHD (confirmed within 48h prior to study treatment start) defined as:
• Patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:
• Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
• Requirement for an increase in the corticosteroid dose to methylprednisolone =2 mg/kg/day (or equivalent prednisone dose =2.5 mg/kg/day)
OR
• Failure to taper the methylprednisolone dose to <1 mg/kg/day (or equivalent prednisone dose <1.25 mg/kg/day) for a minimum 7 days.

Ausschlusskriterien
- Has received more than one systemic treatment for steriod refractory aGvHD,
- Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
- Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection.
Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or HCV based on assessment by the treating physicial.
- Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
Other protocol-defined inclusion/exclusion criteria may apply.

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation

MedDRA Term
Acute graft versus host disease in skin, Acute graft versus host disease, Acute graft versus host disease in intestine, Acute graft versus host disease in liver

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

Studienteilnehmende Mindestalter
18 Jahr(e)

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Stephanie Sasse

+49 (0)201 723-82530
stephanie.sasse@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Universitätsklinikum Köln

Einschlusskriterien
1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)
2. Confirmed histopathological diagnosis of RT (diffuse large B-cell lymphoma or Hodgkin's lymphoma [Hodgkin's lymphoma only when not eligible for more in-tensive treatment])
3. Previously untreated RT or patients with objective response or non-tolerance to first-line RT treatment
4. Adequate bone marrow function as defined by:
o Absolute neutrophil count (ANC) = 1000/mm3, except for patients with bone marrow involvement in which ANC must be = 500/mm3
o Platelet = 75,000/mm3, except for patients with bone marrow involvement in which the platelet count must be = 30,000/mm3
5. Creatinine clearance =30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection or an equivalent method.
6. Adequate liver function as indicated by a total bilirubin= 2 x, AST/ALT = 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL/RT or to Gilbert's Syndrome, in which case a max. total bilirubin = 3 x and AST/ALT = 5 x the institutional ULN value are required.
7. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc nega-tive; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every two months until 2 months af-ter last dose of zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
8. Age at least 18 years
9. ECOG performance status 0-2, ECOG 3 is only permitted if related to CLL or RT (e.g. due to anaemia or severe constitutional symptoms)
10. Life expectancy = 3 months
11. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Ausschlusskriterien
1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients)
2. Patients with more than one prior line of RT therapy
3. Allogenic stem cell transplantation within the last 100 days or signs of active GVHD after prior allogeneic stem cell transplantation within any time
4. Patients with confirmed PML
5. Uncontrolled autoimmune condition
6. Malignancies other than CLL currently requiring systemic therapies (unless the malignant disease is in a stable remission at the discretion of the treating phy-sician)
7. Uncontrolled infection currently requiring systemic treatment
8. Any comorbidity or organ system impairment rated with a CIRS (cumulative ill-ness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system , or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs
9. Requirement of therapy with strong CYP3A4 inhibitors/ inducers
10. Requirement of therapy with phenprocoumon or other vitamin K antagonists.
11. Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:
o Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core anti-body (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU), and if they are willing to undergo monitoring every 4 weeks for HBV reactivation.
o Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
12. Major surgery within 4 weeks of the first dose of study drug.
13. Any uncontrolled or clinically significant cardiovascular disease including the following:
o Myocardial infarction within 6 months before screening
o Unstable angina within 3 months before screening
o New York Heart Association class III or IV congestive heart failure
o History of clinically significant arrhythmias (eg, sustained ventricular tachy-cardia, ventricular fibrillation, torsades de pointes)
14. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood trans-fusion or other medical intervention
15. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
16. Severe or debilitating pulmonary disease
17. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
18. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times half-life [t1/2] of the compound, whichever is longer) prior to registration
19. Known hypersensitivity to tislelizumab, zanubrutinib, sonrotoclax or any of the excipients
20. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
21. Fertile men or women of childbearing potential unless:
o surgically sterile or = 2 years after the onset of menopause, or
o willing to use two methods of reliable contraception including one highly ef-fective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 6 months after the end of study treatment.
22. Vaccination with a live vaccine <28 days prior to randomization
23. Legal incapacity
24. Prisoners or subjects who are institutionalized by regulatory or court order
25. Persons who are in dependence to the sponsor or an investigator

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CLL - Chronische lymphatische Leukämie

Medizinischer Befund
Richter Transformation\nPatients with previously untreated Richter Transformation or patients who responded to up to one prior line of RT therapy

MedDRA Term
Chronic lymphocytic leukaemia variants

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Stephanie Sasse

+49 (0)201 723-82530
stephanie.sasse@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Deutsche CLL Studiengruppe (DCLLSG), Universitätsklinik Köln

Einschlusskriterien
01. Documented CLL/SLL³ requiring treatment according to iwCLL criteria1.
02. Age at least 18 years.
03. At least one of the following risk factors: 17p- deletion, TP53 mutation, complex karyotype (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases.
04. Life expectancy ≥ 6 months.
05. Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2.
06. Ability and willingness to provide written informed consent and to adhere to the study visitschedule and other protocol requirements.
07. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directlyattributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy).
08. GFR >30 ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85) or an equally accurate method. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.
9. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
10. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBVDNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.

³ Patients with SLL are eligible with confirmation of clonal b-cells in the peripheral blood by immunophenotyping. Patients with
SLL without any leukemic manifestation are not eligible.

Ausschlusskriterien
01. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
02. Transformation of CLL (Richter‘s transformation).
03. Known central nervous system involvement.
04. An individual organ/system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system (note that symptoms related to CLL should not be included in the patient’s screening CIRS score). Investigators should consult the General Rules for Severity Rating as well as the Organ-Specific Categories when assigning scores for certain conditions (i.e., pulmonary embolism) and consider the level of morbidity associated with a patient’s condition. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk.
05. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for hemolysis. Prior treatment with rituximab also for other indications than CLL is not permitted.
06. Patients with a history of confirmed progressive multifocal leukoencephalopathy.
07. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician) or showing signs of progression after curative treatment.
08. Patients with active infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrollment.
09. Patients with known infection with human immunodeficiency virus (HIV).
10. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.
11. Anticoagulant therapy with warfarin or phenoprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed
about the potential risk of bleeding under treatment with acalabrutinib).
12. Requirement of treatment with a PPI (proton pump inhibitor). If treatment with an acid reducing agent is required, consider using an antacid (e.g., calcium carbonate) or an H2- receptor antagonist (e.g. ranitidine or famotidine) instead.
13. History of stroke or intracranial hemorrhage within 6 months prior to registration.
14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
15. Vaccination with live vaccines 28 days prior to registration.
16. Major surgery less than 30 days before start of treatment.
17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
18. Known hypersensitivity to any active substance or to any of the excipients of one of the
drugs used in the trial.
19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly see chapter 2.3.1.5).
20. Fertile men or women of childbearing potential unless:
a. surgically sterile or = 2 years after the onset of menopause.
b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
21. Inability to swallow a large number of tablets.
22. Legal incapacity.
23. Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator.

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
CLL - Chronische lymphatische Leukämie

Medizinischer Befund
Chronic lymphocytic leukemia (CLL): High risk patients defined as having at least one of the following risk factors: 17p-deletion, TP53-mutation or complex karyotype

Institute
Ruhr-Universität Bochum, Westdeutsches Tumorzentrum

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 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

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Documented diagnosis of previously untreated de novo AML according to WHO 2016 criteria except acute promyelocytic leukemia. Patients may have received up to 7 days of hydroxyurea or low-dose cytarabine therapy prior to the first chemotherapy dose administered in Block 1, if clinically indicated at the discretion of the investigator. Administration of intrathecal chemotherapy is permitted before receiving study treatment when administered as part of an initial diagnostic lumbar puncture or thereafter according to local Standard of Care (SOC). Patients may begin the first local induction chemotherapy as part of Block 1 while the results of their FLT3 analysis are pending.
2. Presence of a FLT3 mutation, with results available prior to first dose of midostaurin:
● (juxtamembrane internal tandem duplication (ITD), as determined by PCR based on a mutant/wild type signal ratio cutoff of ≥ 0.05
● and/or mutation in the tyrosine kinase domain (TKD) as determined by PCR (mutant/wild type signal ratio cutoff of ≥ 0.05) or NGS
3. Patients from 3 months of age to less than 18 years of age with expected survival of greater than 12 weeks.
4. Patients with Lansky or Karnofsky performance status ≥ 60. The Lansky performance
status will be used for patients from 1 year to 16 years old, and the Karnofsky performance
status will be used for patients ≥16 years old.
5. Patients with the following laboratory values that indicate adequate organ function:
● Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times upper limit of normal (ULN)
● Serum total bilirubin ≤ 1.5 times ULN, unless in case of hyperbilirubinemia due to an isolated Gilbert syndrome
● Estimated creatinine clearance ≥ 30 mL/min based on “bedside formula” by Schwartz and Work 2009.
● These values should be collected at baseline/before the start of the local chemotherapy and also prior to midostaurin intake.
6. The parent or legal guardian and/or the patient will have provided written informed consent according to local laws and regulations prior to any study related screening procedures being performed.

Ausschlusskriterien
Patients eligible for this study must not meet any of the following criteria:
1. Patients with any of the following oncologic diagnoses are not eligible:
a) Any concurrent malignancy, juvenile myelomonocytic leukemia (JMML), Philadelphia chromosome or bcr-abl1 positive AML, biphenotypic or bilineal acute leukemia, acute myeloid leukemia associated to down syndrome (AML-DS), acute myeloid leukemia arising from myelodysplasia or other preceding hematologic malignancy, or therapy-related myeloid neoplasms.
b) Patients with symptomatic leukemic CNS involvement.
c) Patients with isolated extramedullary leukemia, secondary AML and MDS.
d) Patients with Acute Promyelocytic Leukemia (APL).
2. Any prior chemotherapy (excluding Block 1 local induction chemotherapy), radiation or any other treatment for leukemia, or any prior allogeneic, syngeneic or autologous bone marrow or stem cell transplant; however patients may have received up to 7 days of hydroxyurea or low-dose cytarabine therapy prior to the first dose of chemotherapy administration in Block 1, if clinically indicated at the discretion of the investigator. Administration of intrathecal chemotherapy is permitted before receiving study treatment when administered as part of an initial diagnostic lumbar puncture or thereafter according to local Standard of Care (SOC).
3. Patients who have received any investigational agent (excluding Block 1 local induction chemotherapy) within 30 days or 5 half-lives, whichever is greater, prior to the start of study treatment.
4. Patients who have received prior treatment with a FLT3 inhibitor (including sorafenib, lestaurtinib, or quizartinib).
5. Patients who take strong CYP3A4/5 enzyme inducing drugs or strong CYP3A4/5 enzyme inducing herbal supplements (see protocol Appendix 2) unless they can be discontinued or replaced prior to enrollment.
6. Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g., skin or bone marrow biopsy), within 14 days of start of study treatment.
7. Patients with any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study.
8. Presence of clinically active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs; worsening radiography finding in the optional chest X-ray attributable to infection or other clinically significant pulmonary conditions. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
9. Patients with Fanconi anemia, Schwachman syndrome, any other known bone marrow failure syndrome, or constitutional trisomy 21 or with constitutional mosaicism of trisomy 21.
10. Known impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin.
11. Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis.
12. Left ventricular shortening fraction of < 27%, as determined by MUGA scan or echocardiogram.
13. Patients who are under 2.5 kg of body weight.
14. Abnormal electrocardiogram (ECG) finding, including:
? QTcF = 450 msec (for female children over 12 years: QTcF = 460 msec), PR = 200 msec, or QRS complex = 110 msec at screening or prior to the first dose of study drug.
? Any clinically relevant cardiac conduction abnormality.
? Any clinically relevant morphologic abnormality.
? Any clinically relevant ST/T wave abnormality.
? Any clinically relevant atrial or ventricular arrhythmia.
15. Pregnant or nursing (lactating) females.
16. Female patients of child-bearing potential (e.g., are menstruating), who do not agree to abstinence or, if sexually active, do not agree to the use of effective contraception during dosing and for at least 4 months after stopping midostaurin (or as per their respective local labels of the chemotherapeutic drugs, whichever is longer) (as defined in protocol). Highly effective contraception methods defined in protocol.
17. If they don’t agree to abstinence, sexually active males must use condom during intercourse while taking the drug and for at least 4 months after stopping midostaurin (or as per their respective local labels of the chemotherapeutic drugs, whichever is longer) and should not father a child in this period.
18. Patients/parents unwilling or unable to comply with the protocol.
19. Hypersensitivity to midostaurin, cytarabine, daunorubicin/idarubicin, fludarabine, etoposide or mitoxantrone or to any of the excipients.

Studienteilnehmende Mindestalter
3 Monat(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
untreated FLT3-mutated Acute Myeloid Leukemia

MedDRA Term
Acute myeloid leukemia

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
1. Signed informed consent must be obtained prior to participation in the study.
2. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow-up.
3. Adult men and women ≥ 18 years of age.
4. Histologically confirmed and documented advanced malignancies (locally advanced malignancies, non-curable by surgery or radiotherapy and metastatic disease). Disease must be measurable, including presence of at least one measurable lesion, as determined by RECIST v1.1 (Refer to Appendix
5. In the opinion of the treating investigator, patients must have received, but are not benefitting from standard therapies, be intolerant or ineligible to receive such therapy, or have no standard therapy option. At minimum the following therapies listed below must
have been given in the past for the respective disease type, as well as any other therapies deemed to be standard by local/institutional standard.
• Non-small cell lung cancer: Histologically confirmed non-squamous or squamous histology with historic PD-L1 ≥ 1% by local IHC staining. Patients must have received prior treatment that includes anti-PD(L)-1 and a platinum-based chemotherapy regimen, either in combination or in sequence, unless patient was ineligible to receive such therapy. Tumors must not have known activating alterations in EGFR, ALK, ROS1, or RET.
• Esophageal squamous cell carcinoma: Histologically confirmed esophageal squamous cell carcinoma with historic PD-L1 ≥ 1% by local IHC staining. Patients must have received prior treatment that includes a platinum-based chemotherapy regimen and if appropriate, anti- Programmed cell death protein 1 (PD-1) therapy, either in combination or separately, unless patient was ineligible to receive such therapy.
• Renal cell carcinoma: Histologically confirmed renal cell carcinoma. For clear cell histology, patients must have received prior treatment including anti-PD-(L)1 and VEGFR TKI, either in combination or in sequence, unless patient was ineligible to receive such therapy.
For dose expansion, only clear cell histology is allowed.
• HPV-associated head and neck squamous cell carcinoma: Histologically confirmed head and neck squamous cell carcinoma with historic positive p16 and PD-L1 ≥ 1% by local IHC staining. Patients must have received prior treatment that includes platinum-based chemotherapy regimen, and if appropriate, anti-PD-1 therapy, either in combination or separately, unless patient was ineligible to receive such therapy.
6. Must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution’s guidelines. The patient must be willing to undergo a new tumor biopsy at screening and during treatment. Exceptions may be granted following a documented discussion with Novartis medical monitor. Refer to Section 8.8.1 for further details regarding biopsy requirements. For the screening biopsy, exceptions may be made for patients who have recently undergone a fresh tumor biopsy outside of the screening window after documented discussion with Novartis who meet the following provisions:
• Biopsy was collected ≤ 3 months before screening
• No anti-cancer treatment was given to the patient since collection of biopsy.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Patients must have a life expectancy of 3 months or more.

Ausschlusskriterien
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Presence of symptomatic Central Nervous System (CNS) metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids =2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of =10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
2. History of allogeneic bone marrow or solid organ transplant.
3. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
• = 4 weeks for radiation therapy or limited field radiation for palliation within = 2 weeks prior to the first dose of study treatment.
• = 4 weeks or = 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
• = 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
• Patients who have undergone major surgery = 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
4. Active previously documented or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur should not be excluded. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
5. Patients with a history of or current interstitial lung disease (ILD) or pneumonitis = Grade 2.
6. Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related toxicity
7. Patients who required discontinuation of treatment due to treatment-related toxicities during prior therapy directed against the same target as the drug under study in this protocol
8. Clinically significant cardiac disease or risk factors at screening including any of the following:
• Clinically significant and / or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade = 2), uncontrolled hypertension, defined by blood pressure = 140/90 mmHg at rest (average of 3 consecutive readings) despite medical treatment or clinically significant arrhythmia despite medical treatment.
• QT corrected with Fredericia’s (QTcF) > 470 ms on screening ECG or congenital long QT syndrome
• Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry.
9. History of severe hypersensitivity reactions to any ingredient of study drug(s) and/or their excipients which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
10. Insufficient bone marrow function at screening:
a. Laboratory value meeting any of the following:
• Absolute Neutrophil Count (ANC) < 1.5 x 109/L
• Hemoglobin (Hgb) < 9.0 g/dL (without transfusion support within 7 days prior to the first dose of study drug)
• Platelets < 75 x 109/L without transfusion support within 7 days prior to the first dose of study drug
OR
b. Use of hematopoietic colony-stimulating factors (e.g. G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics, or erythroid stimulating agents =2 weeks prior to start of study treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained
11. Insufficient hepatic or renal function at screening:
• Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN or > 5 x ULN if liver metastases are present
• Creatinine clearance < 45 mL/min (calculated using Cockcroft-Gault equation)
12. Patients who have not had resolution, except where otherwise stated in the inclusion/exclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade =1 (except for alopecia, vitiligo, residual hypothyroidism requiring only hormone replacement or other endocrinopathies adequately treated with replacement therapy, ototoxicity, or peripheral neuropathy (both ototoxicity and peripheral neuropathy) if present, must be = Grade 2)
13. Malignant disease, other than that is being treated in this study. Exceptions to this criterion include the following: malignancies that were treated curatively and have not recurred within two years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
14. Patients who are taking a prohibited medication that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study (see Section 6.8.2).
15. Any medical condition that would, in the investigator’s judgement, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures. Any severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient inappropriate for the study.
Novartis Confidential Page 41 of 166
Amended Protocol Version v02 (Clean) Protocol No. CQEQ278A12101
16. Infections:
• Known history of testing positive for Human Immunodeficiency Virus (HIV) infection. For countries where known HIV status is mandatory: Test HIV status during screening using a local test.
• Active Hepatitis B (HBV) and / or Hepatitis C (HCV).
a. Active HBV is defined by positive HBsAg and detectable HBV DNA level in serum. Patients with positive HBsAg and HBV DNA level below the limit of quantification can be enrolled with concurrent antiviral therapy.
b. Active HCV is defined by quantitative HCV RNA results greater than the lower detection limits of the assay.
• Active, documented COVID-19 infection
• Known history of tuberculosis
• Any serious uncontrolled (untreated or unresponsive to treatment) infection (acute or chronic), such as but not limited to those caused by bacteria, viruses, or fungi, confirmed by clinical evidence, imaging, and/or relevant positive laboratory tests (e.g., blood cultures, polymerase chain reaction (PCR) for DNA/RNA, etc).
17. Use of any live or attenuated vaccines against infectious diseases within 4 weeks of initiation of study treatment.
18. Participation in any additional, parallel, investigational drug or device studies.
19. Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal insufficiency, within 7 days of the first dose of study treatment. Topical, inhaled, and ophthalmic steroids are allowed.
20. Pregnant or breast-feeding (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
21. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 90 days after stopping study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
Novartis Confidential Page 42 of 166
Amended Protocol Version v02 (Clean) Protocol No. CQEQ278A12101
• Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate (generally age from 40 to 59 years), history of vasomotor symptoms (i.e., hot flush)). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child bearing potential.
NOTE: If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the Informed Consent form (ICF).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Solide Tumoren

Medizinischer Befund
advanced solid tumors

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Martin Metzenmacher

martin.metzenmacher@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

AIO-Studien-gGmbH, Berlin

Einschlusskriterien
Patients who meet all of the following criteria are eligible for the project:

Age ≥ 18 years
Able to understand and willing to sign written Informed Consent and to complete patient-reported-outcome assessment instruments
Main project (Metatstatic NSCLC):

Confirmed non-small cell lung cancer (NSCLC)
Informed consent no later than four weeks after start of first-line systemic treatment
Stage IV, or stage IIIB/C (UICC8) if patient is ineligible for curative surgery and/or radiochemotherapy
Systemic therapy
Satellite Stage II/III (NSCLC):

Confirmed non-small cell lung cancer (NSCLC)
Informed consent no later than four weeks after start of first anti-tumor treatment
Stage II, stage IIIA, or stage IIIB/C (UICC8) if patient is eligible for curative surgery and/or radiochemotherapy
Systemic (chemo)therapy and/or radiation therapy and/or surgery
Satellite SCLC

Confirmed Small cell lung cancer (SCLC)
Informed consent no later than four weeks after start of first anti-tumor treatment or no later than four weeks after diagnosis for patients receiving "best supportive care only" (i.e. no anti-tumor treatment = no surgery, radiotherapy or systemic therapy)
Systemic (chemo)therapy and/or radiation therapy and/or surgery or best supportive care

Ausschlusskriterien
none

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Metastatic Non-small Cell Lung Cancer (NSCLC)\nNon-small Cell Lung Cancer Metastatic\nNon-small Cell Lung Cancer Stage I\nNon-small Cell Lung Cancer Stage II\nNon Small Cell Lung Cancer Stage III\nSmall-cell Lung Cancer

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharmaceuticals

+1 888-669-6682
novartis.email@novartis.com

1000 S Pine Island Rd #410
33324 Florida

Einschlusskriterien
- ECOG performance status 0-1
- CLL or SLL diagnosis according to iwCLL criteria
- CLL/SLL in SD or PR after at least 6 months of ibrutinib, either as second or subsequent line of therapy
- DLBCL diagnosis by local histopathology
- DLBCL relapsed or refractory after 2 or more lines of therapy, including autologous hematopoietic stem cell transplantation (HSCT)
- Refractory or relapsed CD19-positive ALL
- ALL with morphologic disease in the bone marrow 1L HR LBCL - Considered to be high-risk based on at least 1 of the following at diagnosis:
-- IPI score of 3, 4 or 5
-- MYC and BCL2 and/or BCL6 rearrangement (DH/THL)
- Participants must have received 2 cycles of frontline therapy for LBCL with R-CHOP or Pola-R-CHP or DA-EPOCH-R. Participants with DH/TH lymphoma must have received DA-EPOCH-R.
- Participants must have a positive PET per Lugano classific

Ausschlusskriterien
- Prior CD19-directed therapy
- Prior administration of a genetically engineered cellular product
- Prior allogeneic HSCT
- Richter's transformation
-- For 1L HR LBCL: Richter's transformation, Burkitt lymphoma, primary DLBCL of CNS, DLBCL associated with chronic inflammation, intravascular large B-cell lymphoma, ALK- positive large B-cell lymphoma, HHV8 positive LBCL, DLBCL leg type or EBV positive DLBCL, NOS.
- Active CNS lymphoma
-- For 1L HR LBCL: Active CNS involvement by malignancy
- Targeted small molecule or kinase inhibitor within 2 weeks from leukapheresis

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
ALL - Akute lymphatische Leukämie, CLL - Chronische lymphatische Leukämie, DLBCL - Diffuses großzelliges B-Zell-Lymphom, SLL - kleinzelliges lymphozytisches Lymphom

Medizinischer Befund
Chronic Lymphocytic Leukemia\nSmall Lymphocytic Lymphoma\nDiffuse Large B-cell Lymphoma\nAcute Lymphoblastic Leukemia\nLarge B-cell Lymphoma

MedDRA Term
Acute lymphocytic leukaemia, Primary mediastinal large B-cell lymphoma, High-grade B-cell lymphoma, Chronic lymphocytic leukaemia, Follicular lymphoma, Diffuse large B-cell lymphoma, B-cell small lymphocytic lymphoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Isabel Virchow

isabel.virchow@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest

Einschlusskriterien
1. Have provided written informed consent
2. In the investigator’s judgement, is willing and able to comply with the study protocol including the planned surgical treatment
3. Female and male patients* ≥ 18 years of age
4. Diagnosed with histologically confirmed adenocarcinoma of the GEJ (Type I-III) or the stomach (cT2, cT3, cT4, any N category, M0), or (any T, N+, M0) that:
a. is not infiltrating any adjacent organs or structures by CT or MRI evaluation
b. does not involve peritoneal carcinomatosis
c. is considered medically and technically resectable
Note: the absence of distant metastases must be confirmed by CT or MRI of the thorax and abdomen, and, if there is clinical suspicion of osseous lesions, a bone scan. If peritoneal carcinomatosis is suspected clinically, its absence must be confirmed by laparoscopy. Diagnostic laparoscopy is mandatory in patients with T3 or T4 tumors of the diffuse type histology in the stomach.
5. No prior cytotoxic or targeted therapy
6. No prior partial or complete esophagogastric tumor resection
7. ECOG ≤ 1
8. Availability of a representative tumor specimen that is suitable for determination of PD-L1 and MSI status via central testing; PD-L1 and MSI assessment will be performed prior to randomization. The analysis requires paraffin embedded biopsy samples. Patients are included in the trial upon available results only.
9. Females of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 5 months after the last study treatment.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (has not had ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
10. Males must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm, as defined below:
a. With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 3 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
11. Adequate hematological, hepatic and renal function as indicated by the following parameters:
o Leukocytes ≥ 3.000/mm³, platelets ≥ 100.000/mm3 without transfusion, absolute neutrophil count (ANC) ≥ 1500/mm3 without granulocyte colony-stimulating factor support, Hemoglobin ≥ 90 g/L (9 g/dL) - Patients may be transfused to meet this criterion.
o Bilirubin ≤ 1.5 x upper limit of normal, aspartate transaminase and alanine transaminase ≤ 2.5 x upper limit of normal, alkaline phosphatase ≤ 2.5 x upper limit of normal
o Serum creatinine ≤ 1.5 x upper limit of normal, or glomerular filtration rate > 45 ml/min (calculated using the Cockcroft-Gault formula)
o Serum albumin ≥ 25 g/L (2.5 g/dL)
o For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN; for patients receiving therapeutic anticoagulation: stable anticoagulant regimen

Ausschlusskriterien
1. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein; Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
2. Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, leucovorin, or oxaliplatin.
3. Active or History of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
4. Prior allogeneic bone marrow transplantation or prior solid organ transplantation
5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
Note: History of radiation pneumonitis within the radiation field (fibrosis) is permitted.
6. Positive test for human immunodeficiency virus (HIV)
7. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C
Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
8. Active tuberculosis
9. Known Dihydropyrimidine dehydrogenase (DPD) deficiency
10. Uncontrolled tumor-related pain; Patients requiring pain medication must be on a stable regimen at study entry
11. Administration of a live, attenuated vaccine within four weeks prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab
12. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibodies
13. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to study enrollment
14. Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to study enrollment. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.
15. Requirement for use of denosumab during the study. Patients who are receiving denosumab for any reason (including hypercalcemia) must be willing and eligible to receive a bisphosphonate instead while in the study.
16. Significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina.
17. Clinically significant valvular defect
18. History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
19. Known central nervous system metastases
20. Peripheral polyneuropathy = NCI CTCAE grade 2
21. Serum albumin < 2.5 g/dL.
22. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
23. Serious infection requiring oral or IV antibiotics within 14 days prior to study enrollment
24. Chronic inflammatory bowel disease
25. Clinically significant active gastrointestinal bleeding
26. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment
27. Evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results
28. Participation in another interventional clinical study = 30 days prior to study enrollment or planned participation in such a study at the same time as this study
29. Receipt of an investigational drug within 28 days prior to initiation of study drug
30. Pregnancy or breast feeding, or planning to become pregnant within 5 months after the end of treatment.
Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
locally advanced resectable adenocarcinoma of the oesophagogastric junction or the stomach

MedDRA Term
Gastrooesophageal cancer

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

Deciphera Pharmaceuticals, LLC, USA

Einschlusskriterien
1. Male or female ≥18 years of age.
2. Histologic diagnosis of GIST with co-occurring KIT exons 11+17/18 mutations confirmed by ctDNA sample.
3. Participants must have advanced GIST and radiologic progression on imatinib treatment.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2 at screening.
5. Female participants of childbearing potential must have a negative pregnancy test at screening and prior to the first dose of study drug.
6. Participants of reproductive potential must agree to follow contraception requirements.
7. Participants must have at least 1 measurable lesion according to mRECIST v1.1 within 21 days prior to the first dose of study drug.
8. Adequate organ function and bone marrow reserve based on laboratory assessments performed at screening.
9. Resolution of all toxicities from prior therapy to Grade ≤1 (or participant baseline) within 1 week prior to the first dose of study drug.

Ausschlusskriterien
1. History of KIT exon 9 mutation or detection of KIT exon 9, 13, or 14 mutations in a ctDNA sample.
2. Has known active central nervous system metastases.
3. New York Heart Association Class II-IV heart disease, myocardial infarction within 6 months of Cycle 1 Day 1, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.
4. Use of strong or moderate inhibitors or inducers of cytochrome P450 (CYP) 3A prior to the first dose of study drug, and consumption of grapefruit or grapefruit juice within 14 days prior to the first dose of study drug.
5. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug.
6. Known human immunodeficiency virus or hepatitis C infection only if the participant is taking medications that are excluded per protocol, acute or chronic hepatitis B, or acute or chronic hepatitis C infection.
7. Gastrointestinal abnormalities including, but not limited to:
- inability to take oral medication
- malabsorption syndromes
- requirement for intravenous alimentation
8. Any active bleeding excluding hemorrhoidal or gum bleeding.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes, GIST - Gastrointestinaler Stromatumor

Medizinischer Befund
Advanced Gastrointestinal Stromal Tumor (GIST)

MedDRA Term
Gastrointestinal stromal tumour

Institute
Klinik für Dermatologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Lisa Zimmer

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

Hufelandstr 55
45147 Essen

Indikation
Melanom

Institute
Klinik für Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Glas

neuroonkologie@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Novocure GmbH

Einschlusskriterien
1. Histologically confirmed diagnosis of GBM according to WHO classification criteria.
2. Age ≥ 18 years
3. Recovered from maximal debulking surgery, if applicable (gross total resection, partial
resection and biopsy-only patients are all acceptable)
4. Planned treatment with RT/TMZ followed by TTFields and maintenance TMZ (150-200
mg/m2 daily x 5 d, q28 days)
5. Karnofsky performance status ≥ 70
6. Life expectancy ≥ least 3 months
7. Participants of childbearing age must use highly effective contraception. An effective method
of birth control is defined as one that results in a failure rate of less than 1% per year when
used consistently and correctly. The Investigator must approve the selected method, and
may consult with a gynecologist as needed.
8. All patients must understand and voluntarily sign an informed consent document prior to any
study related assessments/procedures being conducted.
9. Stable or decreasing dose of corticosteroids for the last 7 days prior to randomization, if
applicable.
10. Concomitant RT with TMZ treatment planned to start no later than 8 weeks from surgery
11. Women of childbearing potential must have a negative β-HCG pregnancy test documented
within 14 days prior to registration
12. Is able to have MRI with contrast of the brain

Ausschlusskriterien
1. Progressive disease (per investigator’s assessment)
2. Infratentorial or leptomeningeal disease
3. Participation in another clinical treatment study during the pre-treatment and/or the treatment
phase of the study
4. Pregnancy or breast-feeding.
5. Significant co-morbidities at baseline which would preclude maintenance RT or TMZ
treatment, as determined by the investigator:
a. Thrombocytopenia (platelet count < 100 x 103/µL)
b. Neutropenia (absolute neutrophil count < 1.5 x 103/µL)
c. CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)
d. Significant liver function impairment - AST or ALT > 3 times the upper limit of normal
e. Total bilirubin > 1.5 x upper limit of normal
f. Significant renal impairment (serum creatinine > 1.7 mg/dL, or > 150 µmol/l)
g. History of any psychiatric condition that might impair patient’s ability to understand or
comply with the requirements of the study or to provide consent
6. Implanted pacemaker, defibrillator, deep brain stimulator, other implanted electronic devices
in the brain, or documented clinically significant arrhythmias.
7. Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant
papilledema, vomiting and nausea or reduced level of consciousness)
8. History of hypersensitivity reaction to TMZ or a history of hypersensitivity to DTIC.
9. Any other cytotoxic or biologic anti-tumor therapy received prior to enrollment will be
considered exclusion.
10. Admitted to an institution by administrative or court order.
11. Known allergies to medical adhesives or hydrogel
12. A skull defect (such as, missing bone with no replacement)
13. Prior radiation treatment to the brain for the treatment of GBM
14. Any serious surgical/post-operative condition that may risk the patient according to the
investigator
15. Standard TTFields exclusion criteria include
a. Active implanted medical devices
b. Bullet fragments
c. Skull defects

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Glioblastom

Medizinischer Befund
Glioblastom

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Deutsche Krebshilfe e.V.

+49 (0)228 72990-0
deutsche@krebshilfe.de

Buschstr. 32
53113 Bonn

Einschlusskriterien
• Histologisch gesicherte Erstdiagnose eines Hodgkin-Lymphoms
• Patientin/Patient ist in Bezug auf das HL therapienaiv
• Schriftliche Einverständniserklärung zur Teilnahme an der Studie vorliegend
• Patientin/Patient ist damit einverstanden, dass die personenbezogenen Daten unter Wahrung des Datenschutzes der Studie zur Verfügung gestellt werden.

Ausschlusskriterien
• Unfähigkeit, sich auf Deutsch zu verständigen
• mangelnde Compliance

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
60 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
HD - Hodgkin Lymphom

Medizinischer Befund
Hodgkin-Lymphom Lymphogranulomatose

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 Tumorerkrankungen

Medizinischer Befund
Diagnose eines Hirn- oder Schädelbasistumors

Institute
Klinik für Endokrinologie, Diabetologie und Stoffwechsel, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. Dr. Dagmar Führer-Sakel

Dagmar.Fuehrer-Sakel@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

EORTC, Berlin

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Solide Tumoren

Medizinischer Befund
Schildrüsen-CA

Institute
Klinik und Poliklinik für Strahlentherapie, Innere Klinik (Tumorforschung), Ruhrlandklinik - Klinik für Thoraxchirurgie und thorakale Endoskopie, 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)

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
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

Charité - Universitätsmedizin Berlin

Einschlusskriterien
1. Patient’s signed informed consent.
2. Patient’s age ?18 years at the time of signing the informed consent.
3. Histologically confirmed adenocarcinoma of the colon or rectum.
4. Resected (R0 or R1) and/or effectively treated metastases (all techniques allowed) of colorectal cancer within 3-10 weeks before randomization AND resected primary tumor (synchronous or metachronous).
5. Absence of significant active wound healing complications (if applicable) prior to randomization. Resolved wound healing complications after resection/ablation are acceptable for inclusion into the trial.
6. No radiographic evidence of active metastatic disease at study entry in a CT and/or MRI scan not older than 8 weeks. Pre-surgery/ablation images are eligible for the study if all lesions have been addressed in the interval.
7. ECOG performance status 0-2.
8. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:
• Absolute neutrophil count ? 1.5 x 109/L (1500/µL)
• Hemoglobin ? 80 g/L (8 g/dL)
• Platelet count ? 100 x109/L (100000/µL) without transfusion
• Total serum bilirubin of ? 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST/GOT) ? 3.0 × ULN.
• Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ? 50 mL/min or serum creatinine ? 1.5 x ULN
9. Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
10. Proficient fluorouracil metabolism as defined:
a) Prior treatment with 5-FU or capecitabine without unusal toxicity
or
b) If tested, normal DPD deficiency test according to the standard of the study site
or
c) If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50%
11. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment.
A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (? 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
For men: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.

Ausschlusskriterien
1. Treatment of metastases greater than 3 cm with radio-frequency/microwave ablation within 24 months prior to study entry if applicable.
2. Treatment of metastases greater than 5 cm with radiation (stereotactic/ brachytherapy) within 24 months prior to study entry if applicable.
3. Previous chemotherapy for metastatic or localized disease with > 6 cycles of FOLFOX (or FOLFOXIRI) or > 4 cycles of CAPOX/XELOX.
4. New York Heart Association Class III or greater heart failure by clinical judgement.
5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
6. Unstable angina pectoris.
7. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.
8. Ongoing toxicities > grade 2 NCI CTCAE, in particular peripheral neuropathy.
9. Active uncontrolled infection by investigator’s perspective.
10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
11. Known hypersensitivity to 5-FU, leucovorin, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
12. Bone marrow depression after radio- or chemotherapy.
13. Severe kidney dysfunction (creatinine clearance < 30 ml/min) or changes in blood count.
14. Recent or concomitant treatment with brivudine.
15. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 5.0 (see appendix)).
16. Inflammatory bowel disease and/or bowel obstruction.
17. Simultaneous application of Johannis herbs preparations.
18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
19. If tested, DPD deficiency test with a CPIC activity score <1.
20. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 21 days prior to randomization or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.
21. 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 complications.
22. Medical history of malignant disease other than mCRC with the following exceptions:
- patients who have been disease-free for at least three years before randomization
- patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer
- patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ? 90% and does not require active therapy
23. Known alcohol or drug abuse.
24. Pregnant or breastfeeding females.
25. Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
26. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
27. Limited legal capacity.

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Metastatic colorectal cancer after definite interventional therapy of all lesions

MedDRA Term
Metastatic colorectal cancer

Institute
Klinik und Poliklinik für Strahlentherapie, Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Stephanie Sasse

+49 (0)201 723-82530
stephanie.sasse@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Ruprecht-Karls-Universität Heidelberg

Einschlusskriterien
• Centrally reviewed CD20-positive follicular lymphoma grade 1/2 or 3a based on WHO classification (2008)
• Untreated (radiation-, chemo- or immunotherapy) nodal follicular lymphoma (including involvement of Waldeyer´s ring)
• Age: ≥18 years
• ECOG: 0-2
• Stage: clinical stage I or II (Ann Arbor classification) based on FDG-PET Staging
• Risk profile: Largest diameter of the lymphoma ≤ 7 cm (sectional images)
• Written informed consent and willingness to cooperate during the course of the trial
• Adequate bone marrow capacity: ANC ≥ 1.5 x 103/ml, thrombocytes ≥ 100000 x 10 3/ml, hemoglobin ≥ 10 g/dL
• Capability to understand the intention and the consequences of the clinical trial
• Adequate contraception for men and women of child-bearing age during therapy and 18 months thereafter

Ausschlusskriterien
• Extra nodal manifestation of follicular lymphoma
• Secondary cancer in the patient's medical history (exclusion: basalioma, spinalioma, melanoma in situ, bladder cancer T1a, non-metastasized solid tumor in constant remission, which was diagnosed >3 years ago)
• Serious disease interfering with a regular therapy according to the study protocol, e.g: congenital or acquired immune-deficiency syndromes, active infections including viral hepatitis, uncontrolled concomitant diseases including significant cardiovascular or pulmonary disease
• Severe psychiatric disease
• Pregnancy / lactation
• Known hypersensitivity against Obinutuzumab or Rituximab drugs with similar chemical structure or any other additive of the pharmaceutical formula of the study drug
• Active hepatitis B infection (inactive hepatitis B infections require additional prophylactic anti-viral medication for 1 year (e.g. Lamivudin, Entecavir, Tenofovir)
• Participation in another interventional trial or follow-up period of a competing trial which can influence the results of this current trial
• Creatinine > 1.5 times the upper limit of normal (ULN)
(unless creatinine clearance normal), or calculated
creatinine clearance < 40 mL/min
• AST or ALT > 2.5 × ULN
• Total bilirubin = 1.5 × ULN
• INR > 1.5 × ULN
• PTT or aPTT > 1.5 × the ULN

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NHL - Non-Hodgkin-Lymphom

Medizinischer Befund
nodal follicular lymphoma grade 1 or grade 2 in the clinical stage I or II (Ann Arbor classification)

MedDRA Term
Non-Hodgkin's lymphoma stage II, Non-Hodgkin's lymphoma stage I

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 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
Glioblastoma

MedDRA Term
Glioblastoma

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

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

Hufelandstraße 55
45147 Essen

Sponsor

Goethe-Universität, Frankfurt

Einschlusskriterien
• Male or female patients >= 18 years, <=65 years
• Philadelphia chromosome or BCR-ABL1 positive ALL
• Not previously treated except with corticosteroids = 7 days, standard GMALL prephase with dexamethasone and cyclophosphamide including intrathecal therapy, hydroxyurea, a single dose vincristine or other cytostatic drugs and start of standard induction for Ph-positive ALL (1 dose vincristine, 1 dose of Rituximab, 2 doses dexamethasone and up to 5 days Imatinib)
• ECOG performance status =2
• Signed written inform consent
• Molecular evaluation for BCR-ABL1 performed
• Negative pregnancy test in women of childbearing potential
• Woman of childbearing potential willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (Pearl-Index <1%). Male who has a female partner of childbearing potential willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (Pearl-Index <1%).
• Normal serum levels > LLN (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication
• Serum lipase = 1.5 x ULN. For serum lipase > ULN - = 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis
• Normal QTcF interval =450 ms for males and =470 ms for females
• Signed and dated written informed consent is available
• Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Ausschlusskriterien
• History of malignancy other than ALL diagnosed within 5 years (yrs) prior to start of protocol-specified therapy with defined exceptions
• Contraindications against the use of Imatinib, Ponatinib, chemotherapy or Blinatumomab
• Patient previously treated with tyrosine kinase inhibitors
• Nursing women
• Known impaired cardiac function, including any of the following: as detailed in protocol
• Symptomatic peripheral vascular disease
• Any history of ischemic stroke or transient ischemic attacks (TIAs)
• Uncontrolled hypertriglyceridaemia
• History or presence of clinically relevant CNS pathology as detailed in protocol
• History or active relevant autoimmune disease
• Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C
• History of pancreatitis within 6 months previous to start of treatment within the trial
• Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
• Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of normal or > 5 times ULN if considered due to leukemia
• Total bilirubin > 1.5-fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
• Concurrent severe diseases which exclude the administration of therapy e.g. severe, uncontrolled acute or chronic infections
• Inability to understand and/or unwillingness to sign a written informed consent

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
65 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
ALL - Akute lymphatische Leukämie

Medizinischer Befund
Blut: Akute lymphatische Leukämie (ALL): Neu diagnostiziert \/ de novo\n\nPhiladelphia Chromosome Positive Acute Lymphoblastic Leukemia

MedDRA Term
Acute lymphatic leukemia, Acute lymphatic leukaemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. 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
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GlaxoSmithKline Research & Development Limited, Großbritannien

Einschlusskriterien
- Histologically or cytologically confirmed diagnosis of locally advanced unresectable NSCLC not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy or metastatic NSCLC (squamous or non squamous)
- No prior systemic therapy for their locally advanced or metastatic NSCLC
- Provides a fresh tumor tissue sample or archival sample collected within 6 months of screening
- PD-L1-high (TC/TPS ≥ 50%) tumor
- Measurable disease based on RECIST 1.1, as determined by the investigator
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
- Adequate baseline organ function
- Female participants of childbearing potential must use adequate contraception

Ausschlusskriterien
- Presence of Epidermal growth factor receptor (EGFR) mutations, Anaplastic lymphoma kinase (ALK) translocations, or other known genomic aberrations or oncogenic driver mutations for which a locally approved therapy is available. All participants with non squamous histology must have been tested for EGFR mutation and ALK translocation status.
- Had major surgery within 4 weeks or lung radiation therapy within 6 months of the first dose of study intervention
- Received prior therapy with any immune checkpoint inhibitors
- Never smoker, defined as smoking <100 tobacco cigarettes in a lifetime
- History of invasive malignancy other than the disease under study within the last 5 years
- Symptomatic, untreated, or actively progressing brain metastases and/or leptomeningeal disease
- Autoimmune disease or syndrome that required systemic treatment within the past 2 years
- Receiving any form of immunosuppressive medication
- Received any live vaccine = 30 days prior to first dose of study intervention
- Any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
- History or evidence of cardiac abnormalities = 3 months prior to enrollment
- Current unstable liver or biliary disease
- Severe infection within 4 weeks prior to randomization
- Positive for tuberculosis, human immunodeficiency virus infection, hepatitis B, or hepatitis C

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Non-small Cell Lung Cancer

MedDRA Term
Non-small cell lung cancer metastatic

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

Indikation
Kopf-Hals-Tumore

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
1. Histologisch oder durch Bildgebung gesichertes HCC im Stadium BCLC A oder B.
a. Zur definitiven Bestrahlung oder
b. Als überbrückende Maßnahme zur Transplantation.
2. Alter ≥ 18 Jahre.
3. Operation wurde ausgeschlossen bzw. Patient zur Transplantation zugelassen mit erwarteter Wartezeit auf Spenderorgan.
4. Aktivitätsstatus entsprechend ECOG /WHO < 2
5. Schriftliches Einverständnis zur Teilnahme an der Studie.
6. Bei Patienten mit portaler Hypertension oder vorbekannten Ösophagusvarizen: Endoskopische Untersuchung und adäquate Therapie 3 Monate vor Studienbeginn.

Ausschlusskriterien
1. Vorbestrahlung im Bereich der Leber oder SIRT
2. Möglichkeit zur kurativen Resektion
3. Tumorstadium BCLC C und D
4. Medizinische oder psychiatrische Einschränkungen, welche die Durchführung der Strahlenbehandlung verhindern oder die Compliance für Behandlung und Nachsorge beeinträchtigen
5. Schwangerschaft oder fehlende Bereitschaft zur Schwangerschaftsverhütung
6. Keine hinreichende Schonung umliegender Gastrointestinaler-Organe möglich
7. Patienten mit Child-Pugh-Score B8-9 oder C
8. Lebenserwartung < 3 Monate
9. Kritisches Verhältnis von Tumor zur Restleber (CTV-Leber >700cc)
10. Nicht ausreichende Leberfunktion definiert als:
- Bilirubin > 3 mg/dl
- Albumin < 2.5 g/dl
11. Alter < 18 Jahre
12. Kein schriftliches Einverständnis zur Teilnahme an der Studie

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Hepatozelluläre Karzinome (HCC)

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

IDRx, Inc

info@IDRX.COM

Einschlusskriterien
Phase 1
1. Male or female participants ≥18 years of age
2. Histologically or cytologically confirmed metastatic and/or surgically unresectable GIST
3. Documented progression on imatinib (Phase 1)
4. Documented pathogenic mutation in KIT OR any PDGFRA mutation other than exon 18 mutations, determined through local testing
5. At least one measurable lesion by mRECIST v1.1 for participants with GIST
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Resolution of any toxicities from prior treatment(s) to ≤ Grade 1 by NCI CTCAE v5.0 criteria, or have resolved to baseline, at the time of first dose of study drug.
8. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.

Additional for Phase 1b Exploratory Cohorts
1. For Cohort 1, progressed on imatinib only (second line therapy)
2. For Cohort 2, progressed on both imatinib and sunitinib (third line therapy) or progressed on imatinib, sunitinib, and an additional agent (i.e., regorafenib or ripretinib) (fourth line therapy)
3. For Cohort 3, progressed on at all U.S. -approved TKI therapies for KIT-mutant GIST [imatinib, sunitinib, regorafenib, and ripretinib] (fifth line or greater therapy)

Ausschlusskriterien
1. Any prior exposure to the following investigational agents NB003 or THE-630 or bezuclastinib plus sunitinib combination.
2. GIST with no documented mutation in both KIT and PDGFRA genes.
3. Any prior primary CNS malignancy or known untreated or active central nervous system metastases.
4. Has an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics.
5. Has significant, uncontrolled, or active cardiovascular disease.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
GIST - Gastrointestinaler Stromatumor

Medizinischer Befund
Gastrointestinal Stromal Tumor (GIST)\nDigestive System Disease\nGastrointestinal Diseases\nMetastatic Cancer

MedDRA Term
Gastrointestinal stromal tumor, Gastrointestinal stromal tumour

Institute
Innere Klinik (Tumorforschung), 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

German Pediatric Oncology Group, GPOH gGmbH, Berlin

Einschlusskriterien
•Histologically (and molecularly) diagnosed primary localised (SR) or metastatic (HR) Ewing sarcoma or so called Ewing-like sarcoma ( i.e. translocation-positive small blue round cell sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue; pathological diagnosis can be performed at the investigational site
•Any sex, age >2 and < 50 years by the date of diagnostic biopsy
•Informed consent must be obtained according to national and GCP guidelines and signed prior to trial entry. Subjects and when applicable parental or legal representative(s) must understand and voluntarily provide permission to the ICF, prior to conducting any trial-related assessments / procedures. Willingness and ability to comply with scheduled visits and trial procedures are required.
•White blood cell (WBC) count > 2000/µl*
•Assessment of cardiac function including LVEF > 40% and SF > 28%*
•Serum creatinine < 1.5 X ULN*
•For patients of childbearing potential, a negative pregnancy test must be documented prior to enrolment and repeated every month during therapy. Female and male patients, who are fertile and sexually active, must agree to use an effective form of contraception from the time of signing the ICF until 6 months after the end of treatment.
*Parameters must be checked within the screening phase of 45 days from biopsy biopsy / surgery and after diagnosis of metastatic disease to registration.

Ausschlusskriterien
•Treatment of more than one cycle of chemotherapy prior to registration in the SR group
•Concurrent treatment within any other clinical trials, excluding trials with different endpoints, which, due to the nature of their endpoints, must run parallel to iEuroEwing trial, e.g. studies on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.
•Clinically significant and uncontrolled, or active cardiac disease
•Evidence of invasive fungal infection or other severe systemic infection requiring systemic / parenteral therapy
•Hypersensitivity to the active substance or other excipients contained in the investigational medical products listed in the summary of product characteristics (SmPC) or investigators brochure (IB).
•Secondary malignancy
•Pregnancy or lactation
•Female and male subjects with child-bearing potential, who avoid using highly effective contraceptive methods
•Any other medical, psychiatric, or social condition which is incompatible with the protocol treatment
•Contraindications according to the respective applicable SmPCs

Additional exclusion criteria iEuroEwing-SR-RT part:
•Primary diagnosed and histologically confirmed metastatic (HR) Ewing sarcoma or Ewing-like sarcoma of bone and/or soft tissue
•Patients who receive preoperative RTX
•Patients who receive Brachytherapy
•Patients who have been diagnosed with pleural effusion
•Patients with previous RT in the same region

Studienteilnehmende Mindestalter
12 Jahr(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Ewing Sarcoma

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

immatics biotechnologies GmbH, Tübingen

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Melanom

Medizinischer Befund
Refractory Cancer\nRecurrent Cancer\nSolid Tumor, Adult\nCancer

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

Immunocore Limited, UK

Einschlusskriterien
- Participants must be HLA-A*02:01-positive
- Participants must have histologically confirmed Stage IV or unresectable Stage III melanoma
- Archived or fresh tumor tissue sample that must be confirmed as adequate
- Participants must have measurable disease per RECIST 1.1
- Participant must have BRAF V600 mutation status determined
- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- Male and female participants of childbearing potential who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the study screening date until 5 months after the final dose of study intervention

Ausschlusskriterien
- Participants with a history of a malignant disease other than those being treated in this study
- Participants with untreated, active, or symptomatic central nervous system (CNS) metastases or carcinomatous meningitis
- Hypersensitivity to IMC-F106C, nivolumab, relatlimab, or any associated excipients
- Participants with clinically significant pulmonary disease or impaired lung function
- Participants with clinically significant cardiac disease or impaired cardiac function
- Participants with active autoimmune disease requiring immunosuppressive treatment
- Participants with any medical condition that is poorly controlled or that would, in the Investigator's or Sponsor's judgment, adversely impact the participant's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results
- Participants who received prior systemic anticancer therapy for unresectable or metastatic melanoma
- Participants with a history of a life-threatening AE related to prior anti-PD-(L)1 or anti-LAG-3

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Melanom

Medizinischer Befund
Advanced melanoma

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

Immunocore Limited, UK

Einschlusskriterien
- HLA-A*02:01-positive.
- unresectable Stage III or Stage IV non-ocular melanoma
- archival tumor tissue sample or a newly obtained biopsy of a tumor lesion not previously irradiated has been provided.
- measurable or non-measurable disease per RECIST 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- If applicable, must agree to use highly effective contraception
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent (ICF) and protocol

Ausschlusskriterien
- Pregnant or lactating women
- diagnosis of ocular or metastatic uveal melanoma
- history of a malignant disease other than those being treated in this study
- ineligible to be retreated with pembrolizumab due to a treatment-related AE
- known untreated or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis
- previous severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
-active autoimmune disease requiring immunosuppressive treatment
- clinically significant medical condition
- known psychiatric or substance abuse disorders
- received prior treatment with a licensed or investigative Immune-mobilizing monoclonal T-cell receptor Against Cancer (ImmTAC) medication
- received chemotherapy or biological cancer therapy (excluding anti-PD(L)1 mAb, ipilimumab, and BRAF TKI regimen) within 14 days of first dose
- received cellular therapies within 90 days of first dose
- received systemic treatment with steroids or any other immunosuppressive drug within 2 weeks of first dose
- have not progressed on treatment with an anti-PD(L)1 mAb
- have not received prior ipilimumab
- a BRAF V600 mutation, who have not received a prior BRAF/MEK TKI regimen
- currently participating or have participated in a study of an investigational agent or using an investigational device within 30 days of the first dose
- known history of chronic viral infections
- Out of range Laboratory values
- history of allogenic tissue/solid organ transplant

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Melanom

Medizinischer Befund
Advanced Melanoma

Institute
Klinik für Nuklearmedizin, Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ken Herrmann

+49 (0) 201 723 2032
ken.herrmann@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Institut für Klinische Krebsforschung IKF GmbH, Frankfurt

Einschlusskriterien
1. Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
2. Age ≥ 18 years.
3. Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic BTC not amenable to curative treatment (tumor resection or ablation), specified as
- Tumor being confined to the liver or
- In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent* AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation.
*Limited extent is defined in this protocol as presence of
-- EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm)
-- OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm).
-- Presence of peritoneal or brain metastatsis excludes patients from study participation (see exclusion criterion #4)
- Tumor tissue (block or at least 4 slides) is available for translational research.
4. Patients with prior chemotherapy can be enrolled if ONE of the following criteria is met:
- Capecitabin or gemcitabine+cisplatin in the adjuvant setting
- Experienced progressive disease under gemcitabine+cisplatin therapy in the advanced setting
- Stable disease after 3 months of gemcitabine+cisplatin treatment
5. Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator decision and after prior consultation with the tumor board if available at site and does not display contraindications against SIRT.
Contraindications against SIRT would be
- hepatic tumor load > 50%
- any Gastrointestinal deposition that cannot be corrected via angiographic techniques
- irreversibly elevated serum bilirubin
- renal insufficiency
- increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs
- gastrointestinal ulceration
- hepatic dysfunction
- biliary complications
- portal hypertension
- vascular injury and lymphopenia.
6. Performance status (PS) ≤ 1 (ECOG scale).
7. Body weight >30 kg
8. At least one measurable site of disease as defined by RECIST 1.1 criteria.
9. Adequate bone marrow and renal function
10. Adequate hepatic function (with stenting for any obstruction, if required)
11. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
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. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
14. Must have a life expectancy of at least 12 weeks.
15. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria:
- Patients with HBV or HCV infection should be monitored for viral levels during study participation.
- Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines.
Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment.
- HCV patients with advanced BTC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug.

Ausschlusskriterien
1. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study.
2. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
3. Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines.
4. Presence of peritoneal carcinomatosis or brain metastases.
5. 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
6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
7. Prior radiotherapy treatment before the first dose of any study drug.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.
9. 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], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis].
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, 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.
11. History of non-infectious pneumonitis requiring steroids, or patients with Grade = 2 pneumonitis.
12. History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease = 5 years before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
13. History of leptomeningeal carcinomatosis
14. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry.
15. History of active primary immunodeficiency
16. History of allogenic organ transplantation.
17. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or active hepatitis B/hepatitis C co-infection.
18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.
19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of durvalumab.
20. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
21. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
23. 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].
24. Receipt of live attenuated vaccine within 30 days prior to the first administration of any of the IMPs and without need to receive any live attenuated vaccines during study conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end of Tremelimumab treatment respectively.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Advanced stage intrahepatic biliary tract cancer (BTC)

MedDRA Term
Cholangiocarcinoma non-resectable, Intrahepatic cholangiocarcinoma

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Köln

Einschlusskriterien
- Age 18-60 for the main trial cohort
- Age ≥ 61 years and eligible for AVD as determined by CIRS-G score and investigator for the exploratory cohort
- First diagnosis of treatment-naïve cHL
- Early-stage unfavorable disease (i.e. stage IA, IB and IIA with risk factors a-d, stage IIB with risk factors c-d):
1.) large mediastinal mass
2.) extranodal lesion(s)
3.) elevated erythrocyte sedimentation rate
4.) ≥ 3 nodal areas

Ausschlusskriterien
- Presence of nodular-lymphocyte predominant Hodgkin lymphoma, grey-zone lymphoma and/or central nervous system involvement of lymphoma

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
HD - Hodgkin Lymphom

Medizinischer Befund
Classical Hodgkin Lymphoma

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
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

Bristol-Myers Squibb

Einschlusskriterien
Patients fulfilling the following criteria will be enrolled in the study:
• adult patients (at least 18 years of age at time of treatment decision)
• diagnosis of advanced or metastatic HER2 negative gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1 with a CPS ≥5
or
• diagnosis of unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (ESCC) with tumour cell PD-L1 expression ≥ 1%
• whose physician has decided to start a treatment with nivolumab plus chemotherapy or nivolumab plus ipilimumab (according to the German marketing authorization) for the treatment of GC, GEJ adenocarcinoma, EAC or ESCC and prior to study participation
• who provided written informed consent to participate in the study

Ausschlusskriterien
• previous malignancy within 3 years or concomitant malignancy, except: those with a 5-year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer.
• patients currently included in an interventional clinical trial for his/her advanced or metastatic GC, GEJ adenocarcinoma, EAC or ESCC. Patients who have completed their participation in an interventional clinical trial or who are not receiving any study drug anymore and who are only in the follow-up phase for OS can be enrolled. For blinded studies, the study drug administered needs to be known at the time of enrolment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
gastric cancer\nadvanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarninoma

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

Charité - Universitätsmedizin Berlin

Einschlusskriterien
• Morphologically confirmed diagnosis of 1st relapsed precursor B-cell or T-cell ALL
• Children less than 18 years of age at date of inclusion into the study
• Meeting HR criteria (any T BM relapse, early/very early isolated BM relapse, very early isolated/combined extramedullary relapse)
• Patient enrolled in a participating centre
• Written informed consent
• Start of treatment falling into the study period
• No participation in other clinical trials 30 day prior to study enrolment that interfere with this protocol, except trials for primary ALL

Ausschlusskriterien
• BCR-ABL/ t(9;22) positive ALL
• Pregnancy or positive pregnancy test (urine sample positive for ß-HCG > 10 U/l)
• Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
• Breast feeding
• Relapse post allogeneic stem-cell transplantation
• Neuropathy > II°
• The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
• Objection to the study participation by a minor patient, able to object
• Any patient being dependent on the investigator
• No consent is given for saving and propagation of pseudonymized 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)
• Subjects unwilling or unable to comply with the study procedures
• Subjects who are legally detained in an official institute

- No consent is given for saving and propagation of pseudonymized 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)
- Subjects unwilling or unable to comply with the study procedures
- Subjects who are legally detained in an official institute

Studienteilnehmende Mindestalter
0 Tag(e)

Studienteilnehmende Höchstalter
17 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Relapsed Acute Lymphoblastic Leukemia (ALL)

MedDRA Term
Leukaemias acute lymphocytic

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

Princess Maxima Center for Pediatric Oncology, Niederlande

Einschlusskriterien
• Age ≥1 year and ≤21 years
• Any ≥ 2nd relapse of AML
• Refractory AML (defined as ≥ 20% blasts in the bone marrow after standard (re-)induction therapy)
• Early 1st relapse (defined as relapse within one year from initial diagnosis) of AML
• Any relapse of AML after prior allogenic HSCT
• Any relapse of AML with high risk cytogenetic characteristics (as defined in Appendix V)


• Complete initial work-up within 7 days prior to study entry, including bone-marrow aspiration, lumbar puncture (without intrathecal therapy)
• Lansky play score ≥ 60 for patients <16 years of age; or Karnofsky performance status ≥ 60 for patients ≥ 16 years of age (see Appendix I for Performance scales).
• Life expectancy > 6 weeks
• The patient must have a calculated GFR ≥ 70mL/min/1.73 m2.
• Liver function: total serum bilirubin ≤ 3 mg/dl or 50 µmol/L and aspartate transaminase (AST) and alanine transaminase (ALT) ≤200 U/L
• Adequate cardiac function (defined as shortening fraction ≥28% or ejection fraction ≥50%)

• For female patients with childbearing potential, a negative test for pregnancy is to be performed before entry on study.
• Male and female patients must use a highly effective contraceptive method during the study and for a minimum of 6 months after study treatment.
• Female patients may not breastfeed during the study and for a minimum of 3 months after study treatment.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule is required; those conditions should be discussed with the patient before registration in the trial.
• Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.

Concomitant treatments:
• Concomitant administration of any other experimental drug under investigation, or concurrent treatment with any other anti-cancer therapy other than specified in the protocol is not allowed.
• GCSF will not be used for priming and no routine GCSF support is allowed during the 1st course, except for life-threatening infections.

Additional criteria:
• At least 6 patients must be enrolled with an M3 or a WBC count >10x109/L with blasts

Ausschlusskriterien
• Evidence of a currently uncontrolled bacterial, viral or parasitic infection
• Evidence of a fungal infection, defined as either:
- Pulmonary infiltrates suggestive of a fungal infection at HR-CT (within 3 weeks prior to enrollment)
- Positive Aspergillus serum test (galactomannan), according to local laboratory practice (within 3 weeks prior to enrollment)
• Evidence of isolated extramedullary relapse, including isolated CNS-relapse
• Evidence of CNS3 or symptomatic CNS leukemia
• Down Syndrome
• Evidence of relapsed/refractory acute promyelocytic leukemia (APL)
• Use of any anticancer therapy within 2 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy (note: hematological toxicities do not need to be considered since the patient has overt leukemia)
• History of prior veno-occlusive disease (VOD)
• Known hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin
• Known copper metabolism deficiency, such as Wilson's disease

Studienteilnehmende Mindestalter
1 Jahr(e)

Studienteilnehmende Höchstalter
21 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Relapsed or refractory pediatric acute myeloid leukemia

MedDRA Term
Acute myeloid leukemia refractory

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

Eli Lilly & Company, USA

Einschlusskriterien
- Diagnosis of Ewing’s sarcoma or Ewing’s sarcoma-like tumor
- Confirmed radiological progression or refractory disease or recurrence following first or later line of treatment of Ewing's sarcoma or Ewing's sarcoma-like tumor, and must have one measurable or evaluable lesion per RECIST 1.1
- Participants aged 1 to <40 years
- Body weight ≥10 kg
- Adequate performance status based on age. For participants <16 years of age, a Lansky score ≥50, or for participants ≥16 years of age, a Karnofsky score ≥50
- The participant has adequate hematologic and organ function ≤14 days prior to Day 1 of Cycle 1
- Must be able to swallow and/or have a gastric/nasogastric tube. Participants in the European Union must be able to swallow intact capsules.
- Discontinued all previous treatments for cancer or investigational agents and recovered from the acute effects to Grade ≤1 at the time of enrollment
- Female patients of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to Cycle 1 Day 1. For France, serum pregnancy test must be performed.

Ausschlusskriterien
- Have received any prior CDK4 and 6 inhibitor
- Progression during prior treatment with irinotecan or temozolomide
- Currently enrolled in a clinical study involving an investigational product, or any other type of medical research judged not to be scientifically or medically compatible with this study
- A serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study.

Studienteilnehmende Mindestalter
28 Tag(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Relapsed or Refractory Ewing's Sarcoma

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 Tumorerkrankungen