| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Confirmed diagnosis of locally advanced/metastatic Renal Cell Carcinoma with clear cell component |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 26.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038409 |
| E.1.2 | Term | Renal cell carcinoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To compare belzutifan+lenvatinib to cabozantinib with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR)
2. To compare belzutifan+lenvatinib to cabozantinib with respect to overall survival (OS)
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|
| E.2.2 | Secondary objectives of the trial |
1. To compare belzutifan+lenvatinib to cabozantinib with respect to objective response rate (ORR) based on RECIST 1.1 as assessed by BICR
2. To evaluate the duration of response (DOR) as assessed by BICR according to RECIST 1.1
3. To evaluate the safety and tolerability of belzutifan+lenvatinib compared to cabozantinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 an anti-PD-1/L1 therapy as either first- or second-line treatment with for locally advanced/metastatic RCC or as adjuvant treatment or neoadjuvant/adjuvant with progression on or within 6 months of last dose. 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. Has received no more than 2 prior systemic regimens including :
-One anti-PD-1/L1 containing adjuvant or neoadjuvant/adjuvant regimens with progression on or within 6 months from the last dose of that regimen
OR
-One or 2 regimens for locoregional/advanced disease
6. Has received only 1 prior anti-PD-1/L1 therapy for adjuvant, neoadjuvant/adjuvant or locally advanced/metastatic RCC.
7. 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.
8. If participants received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
9. Is male or female, at least 18 years of age, at the time of signing the informed consent.
10. 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.
11. A female participant is eligible to participate if they are 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 (urine) or 72 hours (serum) 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.
12. The participant (or legally acceptable representative) has provided documented informed consent for the study.
13. 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.
14. Has adequate organ function; all screening laboratory tests will be performed within 10 days before randomization.
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|
| E.4 | Principal exclusion criteria |
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:
- 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 but not limited to 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 radiationrelated 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 inhibitors of CYP3A4 (eg, boceprevir, cobicistat, itraconazole, ketoconazole, clarithromycin, idelalisib, nefazodone, nelfinavir, and ritonavir in combination with protease inhibitors that cannot be discontinued for the duration of the study.
27. Is currently receiving strong inducers of CYP3A4 (mitotane, phenytoin, rifampin, carbamazepine and St John's Wort) that cannot be discontinued for the duration of the study.
28. Is currently participating in a study of an investigational agent or is currently using an investigational device.
29. Has an active infection requiring systemic therapy.
30. Has a known history of HIV infection.
31. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined as HCV RNA [qualitative] is detected) infection.
32. Had medically significant hemorrhage within prior 3 months before randomization.
33. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not the best interest of the participant to participate, in the opinion of the treating investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
2. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 34 months
2. Up to approximately 44 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
2. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
3. Number of Participants Who Experienced One or More Adverse Events (AEs)
4. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Up to approximately 44 months
3. Up to approximately 44 months
4. Up to approximately 44 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Australia |
| Brazil |
| Canada |
| Japan |
| Russian Federation |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Finland |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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