MK-6482-033

Étude de phase 3, randomisée, en ouvert, comparant l'association Belzutifan + Zanzalintinib au Cabozantinib chez des participants atteints d'un Carcinome à Cellules Rénales (CCR) avancé ayant connu une récidive de la maladie pendant ou après un traitement adjuvant anti-PD-1/L1 (LITESPARK-033)

Critères d'inclusion :

1. Has a histologically confirmed diagnosis of unresectable, advanced RCC with clear cell component (with or without sarcomatoid features) ie, Stage IV RCC per AJCC (8th Edition).

2. 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.

3. Has disease recurrence during adjuvant anti-PD-1/L1 therapy or recurrence ≤24 monthsfollowing the last dose of adjuvant anti-PD-1/L1 therapy.

4. Has received no other prior systemic therapy for their RCC except for their adjuvantanti-PD-1/L1 therapy.

5. Has declined or is not considered a candidate for retreatment

6. Is an individual of any sex/gender, at least 18 years of age, at the time of providing the informed consent, or assent, as applicable. Follow local regulatory requirements if the legal age of consent for participation is >18 years of age.

7. If capable of producing sperm, the participant agrees to the following 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:
 - Belzutifan: 7 days
 - Zanzalintinib: 96 days

 - Cabozantinib: 120 days
• Refrains from donating sperm
• Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method (refer to Section 10.4.3), as a condom may break or leak

8. A participant assigned female sex at birth is eligible to participate if not breastfeding during the study intervention period and for at least 120 days after the last dose of study intervention.

9. A POCBP is eligible to participate if not pregnant and if a negative highly sensitive pregnancy test (urine or serum), as required by local regulations, has been obtained within 24 hours (for a urine test) or 72 hours (for a 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. Additional requirements for pregnancy testing during and after study intervention

10. A POCBP is eligible to participate if they use a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or if they adhere to penile-vaginal intercourse abstinence as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 4, during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. In addition, the participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for each study intervention is:
◦ Belzutifan: 30 days
◦ Zanzalintinib: 186 days
◦ Cabozantinib: 120 days

11. The participant (or legally acceptable representative) has provided documented informed consent and the participant has provided documented assent, when applicable, for the study.

12. Has adequately controlled BP with or without antihypertensive medication, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before randomization.

13. Archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated has been provided. Details pertaining to tumor tissue submission can be found in the Laboratory Manual.

14. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline (prior to receiving the previous anticancer therapies). Participants with endocrine-related AEs who are adequately treated with hormone replacement or
participants who have ≤Grade 2 neuropathy are eligible.

15. Has a KPS ≥70% assessed within 7 days before randomization.

16. Adequate organ function as defined in the following table (Table 2). Specimens must be collected within 7 days before randomization of study intervention.

Critères de non inclusion :

1. Has any of the following:
 A pulse oximeter reading <92% at rest, or
 Requires intermittent supplemental oxygen, or
 Requires chronic supplemental oxygen.

2. 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, new-onset angina, pulmonary embolism, myocardial
infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
Note: Medically controlled arrhythmia would be permitted.

3. Prolongation of QTcF interval to >480 ms.

4. DVT within 3 months before randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before randomization.

5. Has a LVEF ≤50% or below the institutional (or local laboratory) normal range as
determined by MUGA or ECHO.

6. Has had major surgery within 8 weeks before randomization.

7. Has current pneumonitis/interstitial lung disease.

8. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage within 4 weeks prior to randomization. A participant who is clinically stable after treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.

9. Has a GI disorder including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI tract from external viscera.
ii. Active peptic ulcer disease, inflammatory bowel disease (not including colitis considered related to the previous anti-PD-1/L1 therapy), diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis, or acute pancreatitis.
iii. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months of randomization unless cause of obstruction is definitively managed and participant is asymptomatic.
iv. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization. Note: Complete healing of an intraabdominal abscess must be confirmed before randomization.

10. 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.

11. Has a serious active nonhealing wound/ulcer/bone fracture.

12. Requirement for hemodialysis or peritoneal dialysis.

13. Has moderate to severe hepatic impairment (Child-Pugh B or C).

14. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) within 28 days prior to intervention randomization.

15. Hypersensitivity to any of the study interventions and/or any of their excipients.

16. Is unable to swallow orally administered medication or has a GI disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption).

17. History of HIV infection. HIV testing is not required unless mandated by local health authority.

18. Hepatitis B (defined as HBsAg reactive) or hepatitis C virus (defined as detectable HCV RNA [qualitative]) infection.
Note: Testing for hepatitis B or C is not required unless mandated by local health guidelines

19. Has received prior treatment with a HIF-2α inhibitor and/or a VEGFR-TKI.

20. Received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids.
Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last palliative radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

21. Is currently receiving strong inhibitors or inducers of CYP3A4 that cannot be discontinued for the duration of the study.
Note: A current list of strong inducers and inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drugdevelopment- and-drug-interactions-table-substrates-inhibitors-and-inducers

22. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.

23. Is currently receiving anticoagulants (eg, warfarin, direct thrombin inhibitors) or platelet inhibitors (eg, clopidogrel) that cannot be discontinued for the duration of the study, except for:
 Prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines).

 LMWH or specified direct factor Xa inhibitors (rivaroxaban, edoxaban, fondaparinux, or apixaban) in participants without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before intervention allocation/randomization
and without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
Note: Participants must have discontinued nonpermissible anticoagulants within 3 days or 5 half-lives (whichever is longer) prior to randomization.

24. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

25. Known additional malignancy 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.

26. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat
imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.

27. Active infection requiring systemic therapy. 28. Has radiographic evidence (as determined by the investigator) of encasement or invasion of a major blood vessel, or of intratumoral cavitation.
Note: The degree of tumor invasion/infiltration of major blood vessels should be evaluated and may be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis.

29. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.

30. History of solid organ transplant.

31. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.