Studien

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med Christian Niedworok

christian.niedworok@uk-essen.de

Hufelandstr. 55
45147 Düsseldorf

Sponsor

MSD Merck Sharp & Dohme LLC

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Treatment of participants with RCC in the adjuvant setting

MedDRA Term
Renal carcinoma

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

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

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

Hufelandstr. 55
45147 Essen

Sponsor

Goethe-Universität, Frankfurt

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Non-clear cell RCC

MedDRA Term
Renal cell carcinoma stage unspecified

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

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

Hufelandstr. 55
45147 Essen

Sponsor

Bristol-Myers Squibb International Corporation, Belgien

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Early stage localized Renal Cell Carcinoma

MedDRA Term
Renal carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

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

Hufelandstraße 55
45147 Essen

Sponsor

Swiss Group for Clinical Cancer Research, Schweiz

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
muskelinvasives Urothelkarzinom

MedDRA Term
Urothelial carcinoma

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

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

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

Hufelandstr. 55
45147 Essen

Sponsor

AIO-Studien-gGmbH, Berlin

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

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

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

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

MedDRA Term
Renal cell carcinoma stage IV

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

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

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

Hufelandstr. 55
45147 Essen

Sponsor

Ipsen Pharma S.A., France

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

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

MedDRA Term
Renal cell carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Claudia Kesch

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

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
High-risk localized or locally advanced prostate cancer

MedDRA Term
Prostate cancer

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

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

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

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

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

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

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

MedDRA Term
Prostate cancer recurrent

Institute
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

Seattle Genetics, Inc., USA

Einschlusskriterien
1. Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible.
2. Subjects must have measurable disease by investigator assessment according to RECIST v1.1.
a. Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy
3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted
b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted
4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgment.
a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria:
i. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine)
· Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgment
ii. ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects)
iii. NCI CTCAE Grade ≥2 audiometric hearing loss
iv. NYHA Class III heart failure
5. Subjects must be age 18 years or older.
6. Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed.
7. Subjects must have an ECOG Performance Status score of 0, 1, or 2.
a. Subjects with ECOG performance status of 2 must additionally meet the following criteria:
i. Hemoglobin ≥10 g/dL
ii. GFR ≥50 mL/min
iii. May not have NYHA Class III heart failure
8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3 (see protocol)
9. Female subjects of childbearing potential must meet the following conditions:
· Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug.
· Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 1 day prior to administration of the study drug. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation.
· If heterosexually active must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug.
· Female subjects must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug.
10. Male subjects who can father children, must meet the following conditions:
· Must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug. Male subjects will be informed about the negative risk to reproductive function and fertility from the study treatment. Prior to treatment male subjects should be advised to seek information on fertility preservation and sperm cryoconservation.
· Must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening and continue throughout study period and for at least 6 months after the final dose of study drug.
· Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 2 contraception options for preventing secondary exposure to seminal fluid for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final dose of study drug.

Ausschlusskriterien
1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.
2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor.
3. Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor.
4. Subjects who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment.
5. Subjects with uncontrolled diabetes.
6. Subjects with an estimated life expectancy <12 weeks
7. Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.
8. Subjects with active CNS metastases. Subjects with treated CNS metastases are permitted on study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the subject is on a stable dose of =10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) subject does not have leptomeningeal disease.
9. Subjects with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to = Grade 1 or returned to baseline.
10. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
11. Subjects who have known active hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by country health authority. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
13. Subjects with conditions requiring high doses of steroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency.
14. Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy (eligible exceptions see protocol).
15. Subjects with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to randomization.
16. Subjects who have received radiotherapy within 2 weeks prior to randomization.
17. Subjects who have received major surgery within 4 weeks prior to randomization.
18. Subjects with known severe (= Grade 3) hypersensitivity to any excipient contained in the drug formulations of enfortumab vedotin, pembrolizumab, the platinum agent selected by the investigator or gemcitabine.
19. Subjects with active keratitis or corneal ulcerations.
20. History of autoimmune disease that has required systemic treatment in the past 2 years.
a. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
b. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered standard of care.
c. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded.
d. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded.
e. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome will not be excluded.
21. Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
22. Subjects who have received a prior allogeneic stem cell or solid organ transplant.
23. Subjects who have received a live attenuated vaccine within 30 days prior to randomization.
24. Subjects with active tuberculosis.
25. Subjects with another underlying medical condition that, in the opinion of the investigator, would impair the ability of the subject to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Urothelial cancer

MedDRA Term
Urothelial carcinoma bladder, Urothelial carcinoma ureter, Urothelial carcinoma urethra

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

MSD Merck Sharp & Dohme LLC

Einschlusskriterien
- For Cohorts A, B, C, D, E, G: Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
-- For Cohorts F, H, I: Has t-NE or de novo metastatic prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis as determined by the investigational site and confirmed by central histology review prior to enrollment
- Is able to provide tumor tissue from a site not previously irradiated as follows: Cohorts A, E, and G: must provide a core or excisional biopsy from soft tissue or bone biopsy within 1 year of screening and after developing mCRPC; Cohort B: must provide an archival tumor tissue sample or tumor tissue from a newly obtained core or excisional biopsy from soft tissue if the lesion is clinically accessible; Cohorts C and D with soft tissue disease: must provide a core or excisional biopsy from a soft tissue lesion if clinically accessible within 1 year of screening and after developing mCRPC and an archival specimen if available; and Cohorts F, H, and I must provide a core or excisional biopsy from soft tissue or a bone biopsy. For de novo metastatic neuroendocrine prostate participants, biopsies must be performed within 1 year of screening. Participants with bone metastasis only must provide an archival tumor tissue specimen.
- Has prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression in soft tissue based on Response Evaluation Criteria In Solid Tumors Version 1.1 criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Participants with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months
- Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM). Treatment with luteinizing hormone-releasing hormone agonists or antagonists for all cohorts must have been initiated ≥4 weeks prior to first dose of study therapy and must be continued throughout the study. Participants with de novo metastatic NE prostate cancer will not be required to have been previously treated with androgen deprivation therapy (ADT). ADT must be started in these participants by the time of treatment allocation/randomization
- Participants receiving bone resorptive therapy (including, but not limited to bisphosphonate or receptor activator of nuclear factor kappa-β ligand inhibitor) must be on stable doses for ≥4 weeks prior to first dose of study therapy
- Must be abstinent from heterosexual intercourse, refrain from donating sperm, or agree to use contraception (unless confirmed to be azoospermic) during the intervention period starting with the first dose of study therapy. The length of time required to continue contraception after the last dose of study intervention for each study intervention is as follows: 7 days for abiraterone acetate and lenvatinib; 30 days for enzalutamide; and 95 days for olaparib, docetaxel, and carboplatin/etoposide. No contraception measures are required during and after the intervention period for pembrolizumab/vibostolimab coformulation.
- Has a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale for Cohorts A and C and a performance status of 0 or 1 for Cohorts B, D, E, F, G, H, and I within 10 days of study start
- For Cohort A: Has received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (e.g., abiraterone acetate and/or enzalutamide) are allowed. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks have elapsed from the last dose of docetaxel prior to day 1 of Cycle 1
- For Cohort B: Has received prior treatment with either abiraterone acetate or enzalutamide (but not both) in the prechemotherapy mCRPC state. Participants in Cohort B must have received at least 4 weeks of either abiraterone or enzalutamide treatment (but not both) who failed treatment or became intolerant of the drug
- For Cohort C: Has received prior treatment with abiraterone acetate in the pre-chemotherapy mCRPC state without prior enzalutamide. Participants in Cohort C must have received at least 4 weeks of abiraterone treatment who failed treatment or become intolerant of the drug. Participants who received abiraterone acetate in the hormone-sensitive state will not be eligible
- For Cohort D: Has not received chemotherapy for mCRPC and has either not had prior second generation hormonal manipulation for mCRPC OR has previously been treated with enzalutamide for mCRPC and failed treatment or has become intolerant of the drug. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks have elapsed from the last dose of docetaxel. Prior treatment with abiraterone acetate in the hormone-sensitive metastatic setting is allowed as long as there was no progression on this agent and abiraterone acetate was not discontinued due to adverse events (AEs)
- For Cohorts E and G: Has received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide or other next-generation hormonal agents [NHA]) are allowed. Participants who received prior ketoconazole for metastatic disease may be enrolled. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy. Prior docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) is allowed if ≥4 weeks have elapsed from the last dose of docetaxel prior to Day 1 of Cycle 1
- For Cohort F, H, and I: Participants must have received prior treatment with androgen deprivation therapy (ADT) for metastatic disease. Participants must also have received prior treatment with an NHA (eg, abiraterone acetate, apalutamide, darolutamide, enzalutamide, or other NHA) or docetaxel for mHSPC or mCRPC. Prior treatment with up to a total of 2 chemotherapies for mCRPC is allowed, as well as up to 2 second-generation hormonal manipulations for mCRPC. Participants who received prior ketoconazole for metastatic disease may be enrolled. Docetaxel for mHSPC is allowed in addition to docetaxel for mCRPC. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy.

Ausschlusskriterien
- Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first dose study therapy or who has not recovered (i.e., Grade =1 or at baseline) from AEs due to mAbs administered >4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy abiraterone treatment, enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose of study therapy or who has not recovered (ie, Grade =1 or at baseline) from AEs due to a previously administered agent
- Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study drug or used an investigational device within 4 weeks of treatment allocation/randomization
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to treatment allocation/randomization
- Has had prior treatment with therapeutic radiopharmaceuticals for prostate cancer, such as Radium-223 or Leutitium-177, within 4 weeks prior to the first dose of trial treatment
- Has an active autoimmune disease that has required systemic treatment in past 2 years
- Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
- Has previously participated in any other pembrolizumab trial, or received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 1 (anti-PD-L2)
- Has a known history of Human Immunodeficiency Virus (HIV)
- Has known active Hepatitis B or Hepatitis C
- Has received a live vaccine or live-attenuated vaccine within 30 days of the first dose of study therapy. Any licensed COVID-19 vaccine (including for emergency use) in a particular country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. Investigational vaccines (ie, those not licensed or approved for emergency use) are not allowed
- Has known active central nervous system metastases and/or carcinomatous meningitis
- Has a "superscan" bone scan defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated
- Has had prior solid, organ or bone marrow transplant
- For Cohort A: Has experienced a seizure or seizures within 6 months of study start or is currently being treated with cytochrome P450 enzyme (CYP) inducing anti-epileptic drugs for seizures
- For Cohort A: Is currently receiving strong or moderate inhibitors of CYP3A4 including azole antifungals; macrolide antibiotics; or protease inhibitors
- For Cohort A: Is currently receiving strong or moderate inducers of CYP3A4
- For Cohort A: Has myelodysplastic syndrome
- For Cohort A: Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or uncontrolled hypertension
- For Cohort B: Has received prior treatment with docetaxel or another chemotherapy agent for metastatic prostate cancer
- For Cohort B: Has peripheral neuropathy Common Terminology Criteria for Adverse Events =2 except due to trauma
- For Cohort B: Has ascites and/or clinically significant pleural effusion
- For Cohort B: Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
- For Cohort B: Is currently receiving any of the following classes of inhibitors of CYP3A4: azole antifungals; macrolide antibiotics; or protease inhibitors
- For Cohort C: Has received prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if =4 weeks elapsed from last dose of docetaxel. Participants who received abiraterone acetate in the hormone-sensitive state will not be eligible
- For Cohort C: Has a history of seizure or any condition that may predispose to seizure (including, but not limited to prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect)
- For Cohort C: Has known or suspected brain metastasis or leptomeningeal carcinomatosis
- For Cohort C: Has a history of loss of consciousness within 12 months of the screening visit
- For Cohort C: Has hypotension (systolic blood pressure 170 mmHg or diastolic blood pressure >105 mmHg) at the screening visit
- For Cohort C: Has received treatment with 5-a reductase inhibitors (e.g., finasteride, dutasteride), estrogens, and/or cyproterone within 4 weeks prior to Cycle 1
- For Cohort C: Has a history of prostate cancer progression on ketoconazole
- For Cohort D: Has received prior treatment with docetaxel or another chemotherapy agent for metastatic prostate cancer
- For Cohort D: Has progressed on prior abiraterone acetate for treatment of castration sensitive or resistant metastatic prostate cancer
- For Cohort D: Has discontinued prior treatment with abiraterone acetate due to AEs
- For Cohort D: Has previously been treated with ketoconazole for prostate cancer for >7 days
- For Cohort D: Has received prior systemic treatment with an azole drug (eg, fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1
- For Cohort D: Has uncontrolled hypertension (systolic BP = 160 mm Hg or diastolic BP = 95 mm Hg)
- For Cohort D: Has a history of pituitary or adrenal dysfunction
- For Cohort D: Has clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class II-IV heart disease or cardiac ejection fraction measurement of <50% at baseline
- For Cohort D: Has atrial fibrillation, or other cardiac arrhythmia requiring therapy
- For Cohort D: Has a history of chronic liver disease
- For Cohort D: Is currently receiving strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone acetate treatment, CYP2D6 substrates with a narrow therapeutic index (for example thioridazine), or CYP2C8 substrates with a narrow therapeutic index (for example pioglitazone)
- For Cohorts E and F: Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
- For Cohorts E and F: Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
- For Cohorts E and F: Has prolongation of QT interval by Fredericia (QTcF) interval to >480 milliseconds
- For Cohorts E and F: Has had major surgery within 3 weeks prior to first dose of study interventions
- For Cohorts E and F: Has pre-existing =Grade 3 gastrointestinal or non-gastrointestinal fistula
- For Cohorts E and F: Has had significant cardiovascular impairment within 12 months of the first dose of study intervention, such as history of New York Heart Association >Class II congestive heart failure, unstable angina, myocardial infarction, or cerebrovascular accident (CVA)/stroke, cardiac revascularization procedure, or cardiac arrhythmia associated with hemodynamic instability
- For Cohorts E and F: Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of lenvatinib
- For Cohorts E and F: Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
- For Cohorts G, H, and I: Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody
- For Cohorts G, H, and I: Has symptomatic ascites or pleural effusion
- For Cohort I: Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis
- For Cohort I: Has received previous treatment for prostate cancer with platinum-containing compoundsHas had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first dose study therapy or who has not recovered (i.e., Grade =1 or at baseline) from AEs due to mAbs administered >4 weeks earlier

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Metastatic Castration-Resistant Prostate Cancer

MedDRA Term
Castration-resistant prostate cancer

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Lukas Püllen

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

Hufelandstraße 55
45147 Essen

Sponsor

Saving Patients' Lives Medical BV

+49 171 1735476
jurgen.feuerstein@splmed.com

Transistorweg 5
6534 Nijmegen

Einschlusskriterien
1) Voluntarily given and written informed consent.
2) Male ≥18 years of age.
3) Histologically newly-confirmed adenocarcinoma of the prostate.
4) Risk for lymph node metastases of 20-60%, based on Briganti nomogram [Briganti et al., 2012, or Gandaglia et al., 2018]
5) Patients scheduled for radical prostatectomy (RP) with extended lymph node dissection (ePLND) between Day 7 and Day 42 after Ferrotran®-enhanced MRI.
6) Consent to practice contraception until end of study, including female partners of childbearing potential. Effective contraceptive measures include hormonal oral, injected or implanted female contraceptives, male condom, vaginal diaphragm, cervical cap, intrauterine device.
7) Preoperative PSA, clinical T-stage, primary Gleason grade, secondary Gleason grade, positive core % (according the Briganti nomogram 2012; Briganti et al., 2012 ), or respectively preoperative PSA, clinical stage at multiparametric magnetic resonance imaging (mpMRI), maximum lesion diameter at mpMRI, biopsy Gleason grade group at MRI-targeted biopsy, percentage of cores with clinically significant PCA at systematic biopsy (Briganti nomogram; Gandaglia et al., 2018)

Ausschlusskriterien
1) Any contraindication to MRI, as per standard criteria.
2) Prior radiation therapy for prostate cancer.
3) Any radiotherapy or systemic antiproliferative (chemo-, immuno, or hormonal) therapy for prostate cancer (Lupron, Taxotere, Casodex, Eulexin, Zoladex, etc.) prior to screening and until after post-surgery FUP MRI.
4) Known hypersensitivity to Ferrotran® or its components such as dextran
5) Known hypersensitivity to other parenteral iron products.
6) Acute allergy, including drug allergies and allergic asthma.
7) Evidence of iron overload or disturbances in the utilisation of iron (e.g., haemochromatosis, haemosiderosis, chronic haemolytic anaemia with frequent blood transfusions).
8) Presence of liver dysfunction.
9) Any other investigational medicinal product within 30 days prior to receiving study medication until end of study visit.
10) Simultaneous participation in any other clinical trial.
11) Abnormal safety laboratory values at screening or baseline that are assessed by the principal investigator as clinically relevant.
12) Patients not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders), or other vulnerable patients (e.g. under arrest).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
newly-diagnosed prostate cancer (PCA)

MedDRA Term
Prostate cancer

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

MSD Merck Sharp & Dohme LLC

Einschlusskriterien
1. Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per AJCC (8th Edition), with or without sarcomatoid features.
2. Has intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node metastasis and tumor grading:
a) Intermediate-high risk RCC:
• pT2, Grade 4 or sarcomatoid, N0, M0
• pT3, any grade, N0, M0
b) High-risk RCC:
• pT4, any grade, N0, M0
• pT, any stage, any grade, N+, M0
c) M1 NED RCC participants who present not only with the primary kidney tumor, but also solid, isolated, soft tissue metastases that can be completely resected at 1 of the following:
• the time of nephrectomy (synchronous), or
• ≤2 years from nephrectomy (metachronous)
3. Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants.
4. Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to randomization.
5. Must be tumor-free before randomization as assessed by the investigator and verified by BICR by either CT or MRI scan of the brain and CAP (≤28 days from randomization) and a bone scan (≤42 days from randomization).
6. Must have provided tissue per any of the following:
• Nephrectomy only: tissue from nephrectomy (required).
• Synchronous M1 NED: tissue from nephrectomy (required) and tissue from metastasectomy (if available).
• Metachronous M1 NED: tissue from metastasectomy (required) and tissue from nephrectomy (if available).
7. Is male or female, at least 18 years of age, at the time of signing the informed consent.
8. Has ECOG performance status of 0 to 1 within 10 days before randomization.
9. Agrees to the following during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The length of time required to continue contraception for the study intervention is as follows:
- Belzutifan/placebo – at least 7 days after the last dose
• Abstains from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR
• Uses contraception unless confirmed to be azoospermic as detailed below:
- Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
- Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP
OR
• A WOCBP and:
- Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
- At least 120 days after the last dose of pembrolizumab or
- At least 30 days after last dose of belzutifan/placebo, whichever occurs last
• The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. Contraceptive use by female should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• A WOCBP must have a negative highly sensitive pregnancy test within 24 hours for urine test or 72 hours for serum test before the first dose of study intervention. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- At least 120 days after the last dose of pembrolizumab or
- At least 30 days after last dose of belzutifan/placebo, whichever occurs last
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a female with an early undetected pregnancy
11. The participant has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
12. Has adequate organ function.

Ausschlusskriterien
1. Has had a major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization.
2. Has residual thrombus post nephrectomy in the vena renalis or vena cava.
3. Has any of the following:
• Pulse oximeter reading <92% at rest, or
• Requires intermittent supplemental oxygen, or
• Requires chronic supplemental oxygen.
4. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including NYHA III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, undergone CABG or PTCA, or cardiac arrhythmia.
5. Has other clinically significant disorders such as:
• Serious active nonhealing wound/ulcer/bone fracture
• Requirement for hemodialysis or peritoneal dialysis
6. Has preexisting brain or bone metastatic lesions.
7. Has received colony-stimulating factors (eg, G-CSF, GM-CSF) or recombinant EPO or transfusion within 28 days before study intervention initiation.
8. Is unable to swallow orally administered medication or has a history or current evidence of a GI condition (eg, inflammatory bowel disease, Crohn’s disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral study intervention.
9. Has a severe hypersensitivity (Grade =3) reaction to belzutifan/placebo or pembrolizumab and/or any of their excipients.
10. Has received prior systemic therapy for RCC
11. Has received prior radiotherapy for RCC.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
13. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.
15. Has a known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years.
16. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
17. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
18. Has an active infection, requiring systemic therapy.
19. Has a known history of HIV infection, a known history of Hepatitis B (defined as HbsAg reactive), or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
20. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
22. Has had an allogenic tissue/solid organ transplant.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Clear Cell Renal Cell Carcinoma (ccRCC)

MedDRA Term
Renal cell carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Christopher Darr

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

Hufelandstr 55
45147 Essen

Sponsor

Universitätsklinikum Tübingen

Einschlusskriterien
Patients with CRPC will be included in this clinical trial. Patients must meet all of the following inclusion criteria to be eligible for enrolment into the study:
- Existence of a written informed consent
- Patient is able to understand and comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
- CRPC after third line therapy
- Life expectance of > 3 months
- At least one measurable lesion that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment
- Eastern Cooperative Oncology Group Performance (ECOG) Status ≤ 2
- Patient aged ≥ 18, no upper age limit
- Male patients with partners of child-bearing potential, who are sexually active, must agree to the use of two highly effective forms of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment for 3 months after last dose of study drug.
- Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:
- Hemoglobin ≥ 10 g/dl
- Neutrophil count ≥ 1,500/mm3
- Platelet count ≥ 100,000/μl
- Bilirubin ≤ 1.5 x upper limit of normal (ULN)
- ALT and AST ≤ 2.5 x ULN
- Alkaline phosphatase ≤ 2.5 x ULN
- PT-INR/PTT ≤ 1.5 x ULN
- Creatine kinase ≤ 2.5 x ULN
- Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 ml/min

Ausschlusskriterien
Patients fulfilling any of the following criteria cannot be enrolled in the trial:

Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer
Concurrent or previous treatment within 30 days in another interventional clinical trial with an investigational anticancer therapy
Persistent toxicity (=Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia and neurotoxicity (= 2 grade)
Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0)
History of HIV infection
Immunocompromised patients
Active or chronic viral hepatitis (HBV or HCV)
History of autoimmune disease
History of relevant CNS pathology or current relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) Epilepsy requiring pharmacologic treatment
Therapeutic anticoagulation therapy
Major surgery within 4 weeks of starting study treatment. Patients must have recovered from any effects of major surgery.
Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used
Heart failure NYHA III/IV
Severe obstructive or restrictive ventilation disorder
Known history of GI-perforation
Pre-existing HAHA
Known intolerance to CC-1, tocilizumab or other immunoglobulin drug products as well as hypersensitivity to any of the excipients present in the respective drug products (CC-1, tocilizumab)

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Castration-Resistant Prostatic 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 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

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

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

Hufelandstr. 55
45147 Essen

Sponsor

Exelixis, Inc., USA

Einschlusskriterien
- Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic.
- Dose-Escalation Cohorts: Subjects with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective.
- Expansion Cohort 1 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy.
-- Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose.
- Expansion Cohort 2 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear cell component.
-- Must have radiographically progressed after a combination therapy consisting of a PD-1/PD-L1 targeting mAb with a VEGFR-TKI or a PD-1 targeting mAb with a CTLA-4 mAb as the preceding line of therapy.
- Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate.
-- Must have progressed after one NHT given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC.
- Expansion Cohort 4 (UC, ICI-naive): Subjects with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
-- Must have progressed during or after prior first-line platinum-based combination therapy, including subjects who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from the end of last therapy.
- Expansion Cohort 5 (UC, ICI-experienced): Subjects with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
-- Must have progressed during or after prior PD-1/PD-L1 targeting ICI therapy given as monotherapy, combination therapy, or maintenance therapy.
- Expansion Cohort 6 (nccRCC): Subjects with unresectable advanced or metastatic nccRCC of the following subtypes: Papillary RCC (any type), unclassified RCC, sarcomatoid RCC (≥ 50% of the tumor has sarcomatoid features).
-- No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvant therapy if disease recurrence occurred at least 6 months after the last dose.
- Expansion Cohorts 1, 2, 4, 5, 6: Measurable disease per RECIST 1.1 as determined by the Investigator.
- For expansion cohorts only: Archival tumor tissue material, if available, or fresh tumor tissue if it can be safely obtained.
- Recovery to baseline or ≤ Grade 1 CTCAE v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy.
- Karnofsky Performance Status (KPS) ≥ 70%.
- Adequate organ and marrow function.
- Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception.
- Female subjects of childbearing potential must not be pregnant at screening

Ausschlusskriterien
- Prior treatment with XL092, nivolumab, ipilimumab, or agents targeting the IL-2 pathway such as bempegaldesleukin.
- For Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC): Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
- For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen receptor inhibitors within 2 weeks before first dose of study treatment.
- For Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC): Receipt of any type of anticancer antibody or systemic chemotherapy within 3 weeks before first dose of study treatment.
- Prior external radiation therapy within 2 weeks and prior radium-223 therapy within 6 weeks before first dose of study treatment.
- Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy (including radiosurgery) or surgically removed and stable for at least 4 weeks before first dose of study treatment.
- Concomitant anticoagulation with oral anticoagulants and platelet inhibitors.
- Uncontrolled, significant intercurrent or recent illness.
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment.
- Pregnant or lactating females.
- Any other active malignancy within two years before first dose of study treatment, except for locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
Note: Additional Inclusion and Exclusion criteria may apply.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Renal Cell Carcinoma\nMetastatic Castration-resistant Prostate Cancer\nUrothelial Carcinoma\nSolid Tumor

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 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

Merck Healthcare KGaA, Darmstadt

Einschlusskriterien
Participants with histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology
Participants has documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study
Estimated life expectancy of at least 3 months
Participants without progressive disease as per RECIST v1.1 guidelines following completion of 4 to 6 cycles of 1L chemotherapy. Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Adequate hematological, hepatic, and renal function as defined in the protocol
Other protocol defined inclusion criteria could apply

Ausschlusskriterien
Participants with prior immunotherapy with Interleukin-2 (IL-2), IL-15, interferon alfa (IFN-a), or an anti programmed death receptor-1 (PD-1), anti programmed death-ligand 1 (PD-L1), anti PD-L2, anti CD137, or cytotoxic T cell lymphocyte-4 (CTLA-4) antibody (including ipilimumab), anti TROP2, any other antibody or drug specifically targeting T cell costimulation or immune checkpoint pathways, or any of the investigational drugs used in combination with avelumab.
Participants with active infection 48 hours before randomization requiring systemic therapy
Participants with known prior or suspected hypersensitivity to study drugs or any component in their formulations
Participants with prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization
Participants with vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines) and replication-deficient coronavirus vaccines approved or authorized by local Health Authorities
Other protocol defined exclusion criteria could apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Advanced or Metastatic Urothelial Carcinoma

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

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

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
-High grade papillary Ta or T1 or CIS
-BCG naïve (or stopped BCG >3 years before enrolment)

Ausschlusskriterien
- Muscle invasive, locally advanced, non-resectable or metastatic urothelial carcinoma
- Concurrent extra-vesical nonmuscle invasive transitional cell carcinoma of the urothelium

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
BCG-naïve High-Risk Non-Muscle Invasive Bladder Cancer

MedDRA Term
Urothelial carcinoma bladder

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

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

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

Hufelandstraße 55
45147 Essen

Sponsor

Janssen Research & Development, LLC

Einschlusskriterien
- Ineligible for or have elected not to undergo radical cystectomy
- All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade less than (<) 2 prior to randomization
- Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
- Thyroid function tests within normal range or stable on hormone supplementation per investigator assessment.
- Adequate bone marrow, liver, and renal function: Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding two weeks): Absolute neutrophil count (ANC) greater than or equal to (>=) 1,500/cubic millimeters (mm^3); Platelet count >=80,000/mm^3; Hemoglobin >=9.0 grams per deciliter (g/dL); Liver function: (Total bilirubin less than or equal to (<=) 1.5 * upper limit of normal (ULN) or direct bilirubin )1.5*ULN (except participants with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL), and Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to (40 mL/min using the Cockcroft-Gault formula

Ausschlusskriterien
- Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder. Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephrouretrectomy more than 24 months prior to initiating study
- Must not have diffuse CIS based on cystoscopy and biopsy. Diffuse, or multi-focal, CIS is defined as the presence of at least 4 distinct CIS lesions in the bladder at the time of the Screening re-TURBT
- Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging (chest, abdomen, and pelvis must be performed using Computed tomography [CT] or Magnetic resonance imaging [MRI]) within 42 days prior to randomization
- Presence of any bladder or urethral anatomic feature that, in the opinion of the investigator, may prevent the safe placement, indwelling use, or removal of TAR 200
- Evidence of bladder perforation during diagnostic cystoscopy

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder

MedDRA Term
Urothelial carcinoma bladder, Urothelial carcinoma bladder stage II, Urothelial carcinoma bladder stage III, Urothelial carcinoma bladder stage IV

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 Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

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

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
1. Male, 18 years of age or older (or the legal age of consent in the country in which the study is taking place).
2 Signed an Informed Consent Form (ICF) indicating that the participant understands the purpose of, and procedures required for the study and is willing to participate in the study; participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
3. Histologically confirmed adenocarcinoma of the prostate.
4. Criterion changed per Amendment 1.
4.1 Previously treated with radical prostatectomy with lymph node dissection and first post-operative PSA measurement of <0.1 ng/mL between Week 6 and Week 13.
5. Any pathologic stage at initial diagnosis: pTany, pNany, M0 (on CT/MRI and 99mTc bone scan).
6. Criterion changed per Amendment 1.
6.1 Biochemically recurrent prostate cancer after RP with a high risk of developing metastasis defined as
- pathological Gleason score ≥8 at diagnosis or time of surgery, OR
- PSADT ≤12 months at the time of screening using at least 3 consecutive values ≥0.1 ng/mL, from time of BCR, estimated using the Memorial Sloan Kettering Cancer Center online calculator.
7. Criterion changed per Amendment 1.
7.1 PSMA-PET must be performed at screening:
- Patients who are PSMA-PET-positive for at least one loco-regional (pelvic) lesion with or without distant (extra pelvic) lesions at screening, as determined by BICR, will be eligible to be randomized to either arm of the Interventional Cohort. The investigators will be blinded to the location of the PSMA-PET lesions after randomization.
- Patients who are PSMA-PET-negative for any prostate cancer lesions (ie, no loco regional lesion and no distant lesions) at screening, as determined by BICR, will be eligible for inclusion in the Observational Cohort.
8. Criterion changed per Amendment 1.
8.1 No evidence of metastases on screening CT/MRI of the chest/abdomen/pelvis, 99m Tc whole-body bone scan. Participants with a single bone lesion on 99mTc whole-body bone scan should have confirmatory imaging by CT or MRI; if the confirmatory scan confirms the bone lesion, the patient should be excluded from the study.
10. Criterion changed per Amendment 1.
10.1 Adequate organ function as defined by the following criteria:
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 X upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN.
- Serum creatinine <1.8 mg/dL.
- Platelets ≥75,000/μL, without transfusion and/or growth factors within 1 month prior to randomization.
- Hemoglobin ≥10.0 g/dL (6.21 mmol/L), without transfusion and/or growth factors within 1 month prior to randomization.
11. Criterion changed per Amendment 1.
11.1 Be able to swallow whole the study drug tablets or follow the instructions for admixing with apple sauce.
12. Criterion changed per Amendment 1.
12.1 If the participant engages in sexual activity with a woman of childbearing potential, a condom must be used together with another highly effective method of contraception during the Treatment Period and for 3 months after the last dose of study intervention.
13. The participant must agree not to donate sperm for the purpose of reproduction during the Treatment Phase and for a minimum 3 months after receiving the last dose of study intervention.
14. Criterion added per Amendment 1.
Participants receiving bone-loss prevention treatment with bone-sparing agents indicated for the treatment of osteoporosis at doses and dosing schedules appropriate for the treatment of osteoporosis (eg, denosumab [Prolia®], zoledronic acid [Reclast®]) must be on stable doses for at least 4 weeks before randomization.

Ausschlusskriterien
1. History of pelvic radiation for malignancy.
2. Criterion deleted per Amendment 1.
3. Previous treatment with ADT for prostate cancer.
4. Previously treated for BCR prostate cancer.
5. Prior treatment with a CYP17 inhibitor (eg, oral ketoconazole, orteronel, abiraterone acetate, galeterone) or any AR antagonist including bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide or darolutamide and any other medications that may lower androgen levels (estrogens, progestins, aminoglutethimide, etc.), including bilateral orchiectomy.
6. Pathological finding consistent with small cell, or neuroendocrine carcinoma of the prostate.
7. Any of the following within 6 months prior to first dose of study intervention: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
8. Use of 5-alpha-reductase inhibitor =4 weeks prior to randomization.
9. Use of investigational agent =4 weeks prior to randomization.
10. Prior chemotherapy for prostate cancer.
11. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:
- Non-muscle invasive bladder cancer.
- Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
- Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and considered to have a very low risk of recurrence.
- Malignancy that is considered cured with minimal risk of recurrence.
12. Human immunodeficiency virus-positive participants with 1 or more of the following:
- Not receiving highly active antiretroviral therapy
- Had a change in antiretroviral therapy within 6 months of the start of screening
- Receiving antiretroviral therapy that may interfere with study intervention (consult Sponsor for review of medication prior to enrollment)
- CD4 count <350 at screening
- AIDS-defining opportunistic infection within 6 months of start of screening
13. Chronic, active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction.
14. History of seizure or any condition that may predispose to seizure (including, but not limited to, prior stroke, transient ischemic attack, or loss of consciousness =1 year prior to randomization; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect).
15. Treatment with drugs known to lower the seizure threshold within 4 weeks prior to randomization.
16. Known or suspected contraindications or hypersensitivity to apalutamide, LHRH agonist or any of the components of the formulations.
17. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant.
Plans to father a child while enrolled in this study or within 4 weeks after the last dose of study intervention.
18. Criterion deleted per Amendment 1.

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Urogenitale Tumore

Medizinischer Befund
Prostate cancer recurrent

MedDRA Term
Prostate cancer recurrent

Institute
Klinik für Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Boris Hadaschik

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

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
1. ≥18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent
2. Histologically proven, cT2-T4a N0, M0 infiltrating urothelial carcinoma of the bladder. Diagnosis must have been within 90 days of randomization date. Participants with variant histologic subtypes (e.g. squamous cell carcinoma) are allowed if urothelial (transitional cell) differentiation is predominant (e.g. 20% variant histologic subtype). However, the presence of any neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features will make a participant ineligible
3. Ineligible for or have elected not to undergo radical cystectomy.
4. All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade ≤ 2 prior to randomization
5. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
6. Thyroid function tests within normal range or stable on hormone supplementation per investigator assessment.
7. Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding two weeks):
i. Absolute neutrophil count (ANC) ≥ 1,000/mm^3
ii. Platelet count ≥75,000/mm^3
iii. Hemoglobin ≥8.0 g/dL
b. Liver function:
i. Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5xULN (except participants with Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL),
ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x institutional ULN
c. Renal function:
- Creatinine clearance >40 mL/min either directly measured via 24-hour urine collection, calculation using the Cockcroft-Gault formula, or calculation for the Modification of Diet in Renal Disease for adult participants.
8. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
a.) For women of childbearing potential (defined as: fertile, following menarche and until becoming postmenopausal unless permanently sterile):
- Highly effective method of contraception (failure rate of <1% per year when used consistently and correctly).
- Permanent sterilization methods (for the purposes of this study) include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Examples of highly effective contraceptives include:
- user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; vasectomized partner; sexual abstinence: true abstinence when this is in line with the preferred and usual lifestyle of the participant (Note: periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of exposure to study drug, and withdrawal are not acceptable methods of contraception.)
- user-dependent methods: combined (estrogen- and progestogencontaining) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable
- agrees to remain on a highly effective method of contraception during the study and for at least 6 months after the last dose of study drug.
- agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug.
- not breastfeeding and not planning to become pregnant during the study and for at least 6 months after the last dose of study drug
b. For men who are sexually active with women of childbearing potential:
- agrees to use a condom with spermicidal foam/gel/film/cream/suppository
- agrees to not donate sperm during the study and for at least 6 months after the last dose of study drug
- not planning to father a child during the study or within 6 months after the last dose of study drug
9. A woman of childbearing potential must have a negative highly sensitive serum (beta-human chorionic gonadotropin [beta-hCG]) within the Screening Period prior to the first dose of study drug
10. Must sign an Informed Consent Form indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples when applicable

Ausschlusskriterien
1. Active malignancies other than the disease being treated under study.
2. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder.
3. Must not have diffuse carcinoma in situ based on cystoscopy and biopsy. Diffuse, or multi-focal, CIS is defined as the presence of at least 4 distinct CIS lesions in the bladder at the time of the Screening re-TURBT.
4. Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging within 42 days prior to randomization.
5. Presence of any bladder or urethral anatomic feature that, in the opinion of the investigator, may prevent the safe placement, indwelling use, or removal of TAR-200.
6. Evidence of bladder perforation during diagnostic cystoscopy.
7. Bladder post-void residual volume >350 mL at screening after second voided urine.
8. History of clinically significant polyuria with recorded 24-hour urine volumes greater than 4,000-mL.
9. Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to randomization.
10. Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/Transurethral Resection of Bladder Tumor to starting study treatment.
11. Prior therapy with an anti-programmed cell death 1, anti-PD-ligand 2 agent, or with an agent directed to another co-inhibitory T-cell receptor.
12. Participants with a history of Grade =3 toxic effects when using anti-TNF or anti-IL-6 agents.
13. Received prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to starting study treatment or not recovered from adverse events due to a previously administered agent.
14. An active, known or suspected autoimmune disease.
15. Received a live virus vaccine within 30 days prior to planned start of study treatment.
16. Active infection requiring systemic therapy within 14 days prior to randomization.
17. Has had an allogeneic tissue/solid organ transplant.
18. A pyeloureteral tube externalized to the skin is exclusionary. Unilateral nephrostomy tube or ureteral stent is permitted if it does not interfere with placement or retention of TAR-200 in the bladder. Participants with unilateral hydronephrosis are permitted; however, participants with bilateral hydronephrosis are excluded.
19. Indwelling urinary catheters are not permitted; however, intermittent catheterization is acceptable.
20. Participants who require immunosuppressive medications including but not limited to systemic corticosteroid at doses >10 mg/day of prednisone or its equivalence, methotrexate, cyclosporine, azathioprine, and TNF-alpha blockers. Use of immunosuppressive medications for the management of immune related adverse events, infusion related reactions, or in participants with contrast allergies is acceptable. Use of inhaled, topical, and intranasal corticosteroids are permitted.
21. Must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study
22. Known human immunodeficiency virus (HIV) infection, unless the participant has been on a stable anti-retroviral therapy regimen for the last 6 months or more and has had no opportunistic infections and a CD4 count of >350 in the last 6 months.
23. Known evidence of active hepatitis B or C infection
24. Concurrent urinary tract infection
25. History of allergy to protein-based therapies and participants with a history of any significant drug allergy.
26. Known hypersensitivity to any component of the drug formulation for cetrelimab, gemcitabine (or other drug excipients) or chemically-related drugs.
27. Known hypersensitivity to gemcitabine (or other drug excipients) or chemically-related drugs.
28. Known hypersensitivity to the device constituent or the Inserter materials.
29. Evidence of interstitial lung disease or active non-infectious pneumonitis.
30. Must not have active tuberculosis.
31. History of uncontrolled cardiovascular disease including any of the following in the preceding 3 months: unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, cerebrovascular accident, or transient ischemic attack; pulmonary embolism or other venous thromboembolism within the preceding 2 months.
32. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
33. Major surgery within 4 weeks before first dose (TURBT is not considered major surgery).
34. Must not have tumors larger than 3-cm in greatest diameter following screening re- TURBT.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder

MedDRA Term
Urothelial carcinoma bladder, Urothelial carcinoma bladder stage II, Urothelial carcinoma bladder stage III, Urothelial carcinoma bladder stage IV