Studien für das Tumorboard:
Bonn: Urologische Tumoren

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

Histologisch oder zytologisch bestätigte Diagnose eines Nierenzellkarzinoms mit klarzelliger Komponente gemäß American Joint Committee on Cancer (AJCC) (8. Auflage), mit oder ohne sarkomatoide Merkmale
RCC mit mittelhohem Risiko, hohem Risiko oder M1 ohne Krankheitsanzeichen (NED), definiert durch die folgende pathologische Tumorknotenmetastasierung und Tumoreinstufung:

RCC mit mittelhohem Risiko: pT2, Grad 4 oder sarkomatoid, N0, M0; pT3, beliebiger Grad, N0, M0
Hochrisiko-RCC: pT4, jeder Grad, N0, M0; pT jedes Stadium, jeder Grad, N+, M0
M1 NED RCC-Teilnehmer, die nicht nur den primären Nierentumor, sondern auch solide, isolierte Weichteilmetastasen aufweisen, die zum Zeitpunkt der Nephrektomie (synchron) oder ≤2 Jahre nach der Nephrektomie (metachron) vollständig reseziert werden können
Vollständige Resektion des Primärtumors (partielle oder radikale Nephrektomie) und vollständige Resektion der soliden, isolierten Weichteilmetastasen bei M1 NED-Teilnehmern
Muss sich einer Nephrektomie und/oder Metastasektomie ≤12 Wochen vor der Randomisierung unterzogen haben
Der Leistungsstatus der Eastern Cooperative Oncology Group (ECOG) muss innerhalb von 10 Tagen vor der Randomisierung bei 0 bis 1 liegen.
Männliche Teilnehmer müssen sich verpflichten, mindestens 7 Tage nach der letzten Dosis von Belzutifan/Placebo weiterhin zu verhüten
Weibliche Teilnehmerinnen im gebärfähigen Alter müssen bereit sein, während der gesamten Studiendauer bis 120 Tage nach der letzten Pembrolizumab-Dosis oder mindestens 30 Tage nach der letzten Belzutifan/Placebo-Dosis, je nachdem, was zuletzt eintritt, eine angemessene Verhütungsmethode anzuwenden
eine ausreichende Organfunktion hat

Sonstiges

Kontaktpersonen

guenter.Niegisch@med.uni-duesseldorf.de
Dagmar.Caasen-Findeisen@med.uni-duesseldorf.de

Ausschlusskriterien

Eine größere Operation innerhalb von 4 Wochen vor der Randomisierung, außer Nephrektomie und Resektion bereits vorhandener Metastasen bei Teilnehmern mit M1 NED
Pulsoxymeterwert <92% in Ruhe, intermittierender zusätzlicher Sauerstoff oder chronischer zusätzlicher Sauerstoff erforderlich
Klinisch signifikante kardiovaskuläre Erkrankung innerhalb von 6 Monaten nach der ersten Dosis der Studienintervention
Andere klinisch bedeutsame Erkrankungen wie: schwere aktive nicht heilende Wunden/Geschwüre/Knochenbrüche; Notwendigkeit einer Hämodialyse oder Peritonealdialyse
Vorbestehende metastatische Läsionen im Gehirn oder Knochen
Hat eine vorherige systemische Therapie für RCC erhalten
Hat eine vorherige Strahlentherapie für RCC erhalten
Hat innerhalb von 30 Tagen vor der ersten Dosis der Studienintervention einen Lebendimpfstoff oder einen abgeschwächten Lebendimpfstoff erhalten; die Verabreichung von abgetöteten Impfstoffen ist erlaubt
bei denen eine Immunschwäche diagnostiziert wurde oder die eine chronische systemische Steroidtherapie erhalten
Hat eine bekannte zusätzliche bösartige Erkrankung (außer Nierenkrebs, der mit Nephrektomie und/oder Metastasektomie behandelt wurde), die fortschreitet oder in den letzten 3 Jahren eine aktive Behandlung erfordert hat
Aktive Autoimmunerkrankung, die in den letzten 2 Jahren eine systemische Behandlung erfordert hat (d. h. mit krankheitsmodifizierenden Mitteln, Kortikosteroiden oder immunsuppressiven Medikamenten); eine Ersatztherapie ist zulässig
Eine (nicht infektiöse) Pneumonitis/interstitielle Lungenerkrankung in der Vorgeschichte, die Steroide erforderte, oder eine aktuelle Pneumonitis/interstitielle Lungenerkrankung
Hat eine aktive Infektion, die eine systemische Therapie erfordert
Bekannte Infektion mit dem Humanen Immundefizienz-Virus (HIV), bekannte Hepatitis-B-Infektion oder bekannte aktive Hepatitis-C-Infektion
Hatte eine allogene Gewebe-/Feststofftransplantation

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

• Has histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features.
• Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study treatment.
• Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study treatment through 120 days after the last dose of study treatment.

• Has intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status:

  1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, Any Grade, N0, M0
  2. High risk RCC: pT4, Any Grade N0, M0; pT, Any stage, Any Grade, N+, M0
  3. 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).
• Has received no prior systemic therapy for advanced RCC.
• Has 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.
• Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed consent and ≤12 weeks prior to randomization.
• Must be tumor-free as assessed by the Investigator and validated by either computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain and chest, abdomen, and pelvis and a bone scan ≤28 days from randomization.
• Must have provided adequate tissue per the following: Nephrectomy only: tissue from nephrectomy (required); Synchronous M1 NED: tissue from nephrectomy (required) AND, metastasectomy tissue (if available); Metachronous M1 NED: tissue from metastasectomy (required) AND, nephrectomy tissue (if available).
• Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
• Has adequate organ function.

Sonstiges

Kontaktpersonen

stefan.hauser@ukbonn.de

Ausschlusskriterien

• Has had major surgery, other than nephrectomy and/or resection of pre-existing metastases for M1 NED participants, within 12 weeks prior to randomization.
• Has received prior radiotherapy for RCC.
• Has pre-existing brain or bone metastatic lesions.
• Has residual thrombus post nephrectomy in the vena renalis or vena cava.
• 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 treatment.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is allowed.
• 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.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history of, or is currently on, dialysis.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has known active hepatitis B or hepatitis C virus infection.
• Has a known history of active tuberculosis (Bacillus tuberculosis).
• Has had a prior solid organ transplant.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 120 days after the last dose of study treatment.
• Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (i.e., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137 [tumor necrosis factor receptor superfamily member 9 (TNFRSF9)]) or has previously participated in a Merck pembrolizumab (MK-3475) clinical trial.
• 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 (i.e., must be ≤ Grade 1 or at Baseline) from AEs due to previously administered agents.
• Has received a live vaccine within 30 days prior to the first dose of study treatment.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

1. Must have a histologically confirmed diagnosis of unresectable, locally advanced/metastatic RCC with clear cell component (with or without sarcomatoid features) ie, Stage IV RCC per AJCC (8th Edition). Previous nephrectomy or metastasectomy is allowed.
2. Has experienced disease progression on or after first- or second-line systemic treatment with an anti-PD-1/L1 therapy for locally advanced or metastatic RCC. The anti-PD-1/L1 therapy may have been monotherapy or in combination with other agent(s) such as anti- CTLA4 or VEGF-targeted-TKI. The immediately preceding line of treatment has to have been an anti-PD-1/L1 therapy.
- Treatment progression is defined by meeting ALL of the following criteria:
o Has received at least 2 doses of an anti-PD-1/L1 mAb.
o Has shown radiographic disease progression during or after an anti-PD-1/L1 mAb as assessed by investigator.
3. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
4. Has a KPS ≥70% [Karnofsky, D. A., et al 1948] assessed within 10 days before randomization.
5. Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
6. Has received no more than 2 prior systemic regimens for locally advanced or metastatic RCC.
7. Has received only 1 prior anti-PD-1/L1 therapy for locally advanced or metastatic RCC.
8. Has recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or
hormone replacement may be eligible.
9. If participants received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
10. Is male or female, at least 18 years of age, at the time of signing the informed consent.
11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of belzutifan or lenvatinib in the belzutifan+lenvatinib arm,
whichever occurs last, and 23 days after the last dose of cabozantinib:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent
OR
•Must agree to use contraception unless confirmed to be azoospermic.
-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.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
• Is not a WOCBP.
OR
• Is a WOCBP and using a contraceptive method that is highly effective during the treatment period and for at least 120 days after the last dose of cabozantinib for participants in the cabozantinib arm, or during the treatment period and for at least 30 days after the last dose of belzutifan or lenvatinib (whichever occurs last) for participants in the belzutifan +lenvatinib arm.
- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention.
- Contraceptive use by women 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.
13. The participant (or legally acceptable representative if applicable) has provided documented informed consent for the study.
14. Participants must have adequately controlled BP with or without antihypertensive medication, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week before randomization.
15. Has adequate organ function; all screening laboratory tests will be performed within 10 days before randomization.

Sonstiges

Ausschlusskriterien

1. A WOCBP who has a positive urine pregnancy test within 24 hours before first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has any of the following:
- Hypoxia defined as a pulse oximeter reading <92% at rest, or
- Requires intermittent supplemental oxygen, or
- Requires chronic supplemental oxygen.
3. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
4. Has known CNS metastases and/or carcinomatous meningitis.
5. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia.
6. Prolongation of QTc interval to >480 ms.
7. Has a LVEF below the institutional (or local laboratory) normal range as determined by MUGA or ECHO.
8. Has urine protein ≥1 g/24 hours.
9. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A participant who is clinically stable after treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
10. Has pre-existing ≥Grade 3 gastrointestinal or nongastrointestinal fistula.
11. Has moderate to severe hepatic impairment (Child-Pugh B or C).
12. Has clinically significant hematuria, hematemesis or hemoptysis (>2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 3 months before randomization.
13. Has other clinically significant disorders such as:
a. Serious active nonhealing wound/ulcer/bone fracture
b. Requirement for hemodialysis or peritoneal dialysis
c. History of solid organ transplantation
14. Received colony-stimulating factors (eg, G-CSF, GMCSF or recombinant EPO) within 28 days before randomization.
15. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
16. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption).
17. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan, lenvatinib, or cabozantinib) formulations.
18. Has received prior treatment with belzutifan or another HIF-2α inhibitor.
19. Has received prior treatment with lenvatinib.
20. Has received prior treatment with cabozantinib.
21. Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization.
22. Has received any type of systemic anticancer antibody (including investigational antibody) ≤28 days before randomization.
23. Has received prior radiotherapy within 2 weeks before randomization. Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is required for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
24. Has had major surgery within 3 weeks before randomization.
25. Is receiving concomitant treatment, in therapeutic doses, with anticoagulants such as heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel).
26. Is currently receiving strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) inhibitors of CYP3A4 that cannot be discontinued for the duration of the study.
27. Is currently receiving strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) inducers of CYP3A4 that cannot be discontinued for the duration of the study.
28. Is currently receiving a drug that is a substrate of P-gp (eg, cyclosporin, elacridar, ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, valspodar, verapamil, zosuquidar) that cannot be discontinued for the duration of the study.
29. Is currently participating in a study of an investigational agent or is currently using an investigational device.
30. Has an active infection requiring systemic therapy.
31. Has a known history of HIV infection.
32. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined as HCV RNA [qualitative] is detected) infection.
33. Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel.
34. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not the best interest of the participant to participate, in the opinion of the treating investigator.

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

A participant will be eligible for inclusion in the study if the participant meets the following
criteria:
Type of Participant and Disease Characteristics
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.

Note: Participants with microscopically positive soft tissue or vascular margins without
gross residual disease are permitted.
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).
Note: FFPE tissue blocks are preferred to slides. Details pertaining to tumor tissue
submission can be found in the Laboratory and/or Procedures Manual.
Demographics
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.

Male Participants
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
Note: For male participants who have discontinued belzutifan/placebo and receive only
pembrolizumab, no contraception measures are required after completion of the
contraception period with belzutifan/placebo (as stated above).
 Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent
on a long-term and persistent basis) and agree to remain abstinent
OR
 Uses contraception unless confirmed to be azoospermic (vasectomized or secondary
to medical cause, documented from the site personnel’s review of the participant’s

medical records, medical examination, or medical history interview) 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.
Note: Men with a pregnant or breastfeeding partner must agree to remain
abstinent from penile-vaginal intercourse or use a male condom during each
episode of penile-vaginal penetration.
- 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.
Female Participants
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 (abstinent on a long-term and
persistent basis), as described in Appendix [5] 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 (ie,
noncompliance, recently initiated) 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 (urine or serum as
required by local regulations) 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 (eg, an ambiguous result), a serum pregnancy test is required. In such cases,
the participant must be excluded from participation if the serum pregnancy result is
positive. Additional requirements for pregnancy testing during and after study
intervention are in Section 8.3.5.
- 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
Informed Consent
11. The participant (or legally acceptable representative) 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.
Additional Categories
12. Has adequate organ function as defined in the following table (Table 2). Samples must be
collected within 10 days before randomization.

Table 2 Adequate Organ Function Laboratory Values
System Laboratory Value
Hematological
ANC ≥1500/μL
Platelets ≥100 000/μL
Hemoglobin ≥10.0 g/dL or ≥6.2 mmol/La
Renal
CrCl CrCl estimated ≥30 mL/min using the
Cockcroft-Gault equation
Hepatic
Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for
participants with total bilirubin levels
>1.5 × ULN
AST (SGOT) and ALT (SGPT) ≤2.5 × ULN
07WSJG
PRODUCT: MK-6482 53
PROTOCOL/AMENDMENT NO.: 022-00
MK-6482-022-00 FINAL PROTOCOL 29-OCT-2021
System Laboratory Value
Coagulation
INR OR PT and aPTT ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as INR/PT or
aPTT is within therapeutic range of intended use
of anticoagulants
aPTT =activated partial thromboplastin time; ALT (SGPT)=alanine aminotransferase (serum glutamicpyruvic
transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic-oxaloacetic transaminase);
CrCl=creatinine clearance; INR=international normalized ratio; pRBC=packed red blood cells; PT=
prothrombin time; ULN=upper limit of normal.
a Criteria must be met without erythropoietin dependency and without pRBC transfusion within 4 weeks
before hematology screening assessment.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value
requirements should be adapted according to local regulations and guidelines for treatments.

Sonstiges

Kontaktpersonen

joerg.ellinger@ukbonn.de
guenter.Niegisch@med.uni-duesseldorf.de

Ausschlusskriterien

The participant must be excluded from the study if the participant meets any of the following
criteria:
Medical Conditions
1. Has had a major surgery, other than nephrectomy plus resection of preexisting metastases
for M1 NED participants, within 4 weeks prior to randomization.
Note: If participants received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
intervention.
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.
Note: Medically controlled arrhythmia stable on medication is permitted

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.
Prior/Concomitant Therapy
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.
Note: See Section 6.5 for information on COVID-19 vaccines.

Prior/Concurrent Clinical Study Experience
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.
Note: Participants who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
Diagnostic Assessments
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.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have
undergone potentially curative therapy are not excluded.
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.
Note: No testing for HIV, hepatitis B, and hepatitis C is required unless mandated by
local health authority.
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.
Other Exclusions
22. Has had an allogenic tissue/solid organ transplant.
5.3 Lifestyle Considerations
5.3.1 Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage AEs
such as diarrhea, nausea, or vomiting.
5.3.2 Caffeine, Alcohol, and Tobacco Restrictions
Participants should discuss tobacco and inhalant use with their study physician as it is
important to understand the pulmonary and cardiac health of study participants. It is not
known whether prior tobacco or inhalant use will impact the incidence of hypoxia, an ECI for
belzutifan.
5.3.3 Activity Restrictions
Participants will abstain from strenuous exercise for 2 hours before each blood collection for
clinical laboratory tests. Participants may participate in light recreational activities during
studies (eg, watching television, reading).
5.4 Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but
are not subsequently randomized in the study. A minimal set of screen-failure information is
required to ensure transparent reporting of screen-failure participants to meet the CONSORT
publishing requirements and to respond to queries from regulatory authorities. Minimal
information includes demography, screen-failure details, eligibility criteria, and any AEs or
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5 Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not
be replaced.

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

• männliche und weibliche Patienten mit lokalisiertem, klarzelligem Hochrisikokarzinom der Niere, cT1b-cT2 Grad (G) 4, cT2b G3, cT3a G3-4, cT3b-4 beliebiger Grad, alle cTxcN1cM0
• vollständig resektabler Primärtumor
• männliche und weibliche Patienten im Alter von ³ 18 Jahren
• Histologie des klarzelligen Karzinoms im Primärtumor
• Nierenfunktion, definiert durch die glomeruläre Filtrationsrate ³ 20 ml/min
• ECOG-Leistungsstatus 0-1
• ausreichende hämatologische Funktion (absolute Neutrophilenzahl, Thrombozyten, Hämoglobin)
• ausreichend Leberfunktion

Sonstiges

Kontaktpersonen

axel.heidenreich@uk-koeln.de
Dagmar.Caasen-Findeisen@med.uni-duesseldorf.de
guenter.Niegisch@med.uni-duesseldorf.de

Ausschlusskriterien

• systemische viszerale oder skelettale Metastasen
• retroperitoneale Lymphknotenmetastasen
• Herzinsuffizienz der New York Heart Association Klasse III/IV, Myokardinfarkt innerhalb von 3 Monaten vor Studienbeginn, instabile Angina pectoris oder instabile Herzrhythmusstörungen
• regelmäßige Einnahme von Kortikosteroiden über einer Dosis von 10 mg/kg/Tag
• frühere systemische Therapie von Blasenkrebs
• Anzeichen einer signifikanten unkontrollierten Begleiterkrankung, die die Einhaltung des Protokolls oder die Interpretation der Ergebnisse beeinträchtigen könnte, einschließlich einer signifikanten Lebererkrankung (z. B. Zirrhose, unkontrolliertes schweres Anfallsleiden oder Syndrom der Vena cava superior).
• Schwere Infektionen innerhalb von 4 Wochen vor der Teilnahme an der Studie, einschließlich, aber nicht beschränkt auf Krankenhausaufenthalte wegen Infektionskomplikationen, Bakteriämie oder schwerer Lungenentzündung.
• Autoimmunerkrankungen in der Vorgeschichte, insbesondere Myasthenia gravis, Myositis, Autoimmunhepatitis, systemischer Lupus erythematodes, rheumatoide Arthritis, entzündliche Darmerkrankungen, vaskuläre Thrombose in Verbindung mit Antiphospholipid-Syndrom, Wegener-Granulomatose, Sjögren-Syndrom, Guillain-Barré-Syndrom, multiple Sklerose, Vaskulitis oder Glomerulonephritis.
• Verabreichung eines abgeschwächten Lebendimpfstoffs innerhalb von 4 Wochen vor Studienbeginn oder die Erwartung, dass ein solcher abgeschwächter Lebendimpfstoff während der Studie erforderlich sein wird
• Behandlung mit einem anderen Prüfpräparat oder Teilnahme an einer anderen klinischen Studie mit therapeutischer Absicht innerhalb von 28 Tagen vor der Aufnahme in die Studie
• Behandlung mit systemischen Immunstimulanzien innerhalb von 4 Wochen oder fünf Halbwertszeiten des Medikaments, je nachdem, welcher Zeitraum kürzer ist, vor der Aufnahme in die Studie

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

• Schriftliche Einwilligung nach Aufklärung und alle lokal erforderlichen Genehmigungen (EU-Datenschutzrichtlinie in der EU), die vom Probanden vor der Durchführung aller mit dem Prüfplan zusammenhängenden Verfahren, einschließlich Screening-Untersuchungen, eingeholt wurden
• Alter ≥ 18 Jahre zum Zeitpunkt des Studieneintritts
• Fortgeschrittenes oder metastasiertes Nierenzellkarzinom, das nicht durch eine Operation in kurativer Absicht behandelt werden kann, so dass der Patient für eine Behandlung mit einem Tyrosinkinase-Inhibitor (TKI) mit Sunitinib in Frage kommt
• Beabsichtigte Erstlinienbehandlung mit Sunitinib
• Nachweislich fortschreitende Erkrankung innerhalb von 6 Monaten vor Studieneinschluss
• Patienten mit messbarer Erkrankung (mindestens eine eindimensional messbare Zielläsion mittels CT oder MRT) gemäß den modifizierten Response Evaluation Criteria in Solid Tumors (RECIST 1.1) sowie mit nicht messbarer Erkrankung sind teilnahmeberechtigt.
• Frühere Strahlentherapien und chirurgische Eingriffe sind zulässig, wenn sie 4 Wochen (bei kleineren chirurgischen Eingriffen und palliativer Strahlentherapie bei Knochenschmerzen: 2 Wochen) vor Behandlungsbeginn abgeschlossen wurden und der Patient sich von den toxischen Wirkungen erholt hat.
• Weibliche Probanden müssen entweder nicht reproduktionsfähig sein (d.h. postmenopausal nach Anamnese: ≥60 Jahre alt und keine Menstruation seit ≥1 Jahr ohne alternative medizinische Ursache; ODER Anamnese einer Hysterektomie, ODER Anamnese einer bilateralen Tubenligatur, ODER Anamnese einer bilateralen Oophorektomie) oder müssen bei Studienbeginn einen negativen Serumschwangerschaftstest aufweisen.
• Die Probandin ist bereit, eine zusätzliche begleitende Betreuung in Anspruch zu nehmen, und in der Lage, während der gesamten Studiendauer, einschließlich der geplanten Besuche, Untersuchungen und Nachuntersuchungen, die im Studienprotokoll festgelegten QoL/PRO-Bewertungen (patient-reported outcome) durchzuführen.

Sonstiges

Kontaktpersonen

guenter.Niegisch@med.uni-duesseldorf.de
Dagmar.Caasen-Findeisen@med.uni-duesseldorf.de
joerg.ellinger@ukbonn.de

Ausschlusskriterien

• Jede andere Krebsbehandlung neben Sunitinib für mRCC (außer palliativer Strahlentherapie)
• Frühere bösartige Erkrankungen (außer mRCC), die entweder fortschreiten oder eine aktive Behandlung erfordern.
• Ausnahmen sind: Basalzellkrebs der Haut, präinvasiver Gebärmutterhalskrebs, T1a- oder T1b-Prostatakarzinom oder oberflächlicher Blasentumor [Ta, Tis und T1].
• ZNS-Metastasen, es sei denn, die lokale Therapie ist seit mindestens 3 Monaten abgeschlossen und der Patient benötigt keine Steroide.
• Chronische Lebererkrankung mit Child-Pugh B- oder C-Score
• Frauen, die schwanger sind, stillen oder männliche oder weibliche Patienten im fortpflanzungsfähigen Alter, die keine wirksame Verhütungsmethode anwenden (Versagensrate von weniger als 1% pro Jahr)
• Jeder Zustand, der nach Ansicht des Prüfarztes die Bewertung der begleitenden Betreuung oder der Bewertung der Lebensqualität oder die Interpretation der Patientensicherheit oder der Studienergebnisse beeinträchtigen würde
• Teilnahme an einer anderen klinischen Studie mit einem Prüfpräparat in den letzten 30 Tagen vor Einschluss
• Jede frühere Behandlung mit einem Tyrosinkinase-Inhibitor bei metastasierter Erkrankung. Eine adjuvante oder neoadjuvante Therapie für eine lokalisierte Erkrankung ist zulässig, vorausgesetzt, dass der Rückfall mindestens 6 Monate nach der letzten Exposition aufgetreten ist
• Frühere Einschreibung oder Randomisierung in die vorliegende Studie (dies gilt nicht für das Versagen des Screenings).
• Beteiligung an der Planung und/oder Durchführung der Studie (gilt sowohl für Mitarbeiter von Pfizer als auch für Mitarbeiter des Sponsors und des Studienzentrums)
• Patienten, die möglicherweise mit dem Sponsor, dem Prüfzentrum oder dem Prüfer verbunden oder anderweitig von ihm abhängig sind
• Patienten, die aufgrund einer gerichtlichen oder behördlichen Anordnung inhaftiert oder unfreiwillig eingewiesen wurden [§ 40 Abs. 1 S. 3 Nr. 4 AMG].
• Patienten, die nicht einwilligungsfähig sind, weil sie die Art, Bedeutung und Tragweite der klinischen Prüfung nicht verstehen und daher keinen vernünftigen Willen im Lichte der Sachlage bilden können [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

Sonstiges

Kontaktpersonen

guenter.Niegisch@med.uni-duesseldorf.de

Ausschlusskriterien

Diagnosen

Nierenzellkarzinom

Einschlusskriterien

• Röntgenologische Krankheitsprogression während oder nach einer mindestens 6-wöchigen Behandlung mit ICI bei lokal fortgeschrittenem oder metastasiertem Nierenzellkarzinom mit einer klarzelligen Komponente entweder in der Erst- oder Zweitlinienbehandlung.
• Die Probanden müssen sich von den unerwünschten Ereignissen der vorherigen Therapie erholt haben oder zum Ausgangswert zurückgekehrt sein.
• Histologisch oder zytologisch bestätigtes Nierenzellkarzinom mit einer klarzelligen Komponente.
• Messbare Erkrankung gemäß RECIST-Kriterien Version 1.1.
• Leistungsstatus der Eastern Cooperative Oncology Group von 0 oder 1.
• Alle Teilnehmer müssen die im Protokoll festgelegten Verhütungsmaßnahmen einhalten.

Sonstiges

Kontaktpersonen

Dagmar.Caasen-Findeisen@med.uni-duesseldorf.de
guenter.Niegisch@med.uni-duesseldorf.de

Ausschlusskriterien

• Mehr als 2 vorherige Therapielinien im fortgeschrittenen oder metastasierten Stadium.
• Lebensbedrohliche Toxizität im Zusammenhang mit einer früheren Immuntherapie in der Vorgeschichte.
• Aktive, bekannte oder vermutete Autoimmunerkrankung sowie solche, bei denen eine vorherige immunonkologische Therapie (IO) aufgrund von immunvermittelten SARs abgebrochen werden musste.
• Unkontrollierter Bluthochdruck.
• Mehr als eine vorherige Therapielinie mit einem Checkpoint-Inhibitor in der metastatischen Situation.
• Patienten, die wegen einer Organtransplantation eine immunsuppressive Therapie erhalten, oder Patienten mit einer genetischen oder erworbenen Immunsuppressionserkrankung wie dem humanen Immundefizienzvirus (HIV) [Patienten mit HIV, die eine CD4+ T-Zellzahl von >350 Zellen/µL haben, (Patienten mit HIV, die eine CD4+ T-Zellzahl von >350 ZellenµL haben, ohne eine Vorgeschichte von opportunistischen Infektionen, die das erworbene Immunschwächesyndrom (AIDS) definieren, und die seit mindestens 4 Wochen eine etablierte antiretrovirale Therapie ohne einen Cytochrom P450 (CYP)3A4-Induktor erhalten und eine HIV-Viruslast von weniger als 400 Kopien/ml haben, sind teilnahmeberechtigt).
• Klinisch signifikante interstitielle Lungenerkrankung in der Vorgeschichte oder aktuelle nicht-infektiöse Pneumonitis.