| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073251 |
| E.1.2 | Term | Clear cell renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 the hypoxia-inducible factor (HIF) triplet to the doublet with respect to 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. To compare the HIF triplet to the doublet with respect to Overall Survival (OS).
3. To compare the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) triplet to the doublet with respect to PFS per RECIST 1.1 as assessed by BICR.
4. To compare the CTLA4 triplet to the doublet with respect to OS.
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| E.2.2 | Secondary objectives of the trial |
1. To compare the HIF triplet and CTLA4 triplet to the doublet with respect to Objective Response Rate (ORR) per 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 the HIF triplet and CTLA4 triplet compared to the doublet. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features, unresectable, locally advanced/metastatic ie, Stage IV RCC per AJCC.
2. Has received no prior systemic therapy for advanced ccRCC.
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 demonstrated in such lesions.
4. Submits 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. Details pertaining to tumor tissue submission can be found in the laboratory manual.
5. Is male or female, at least 18 years of age inclusive, at the time of signing the informed consent.
6. Has a KPS score of at least 70%.
7. Male participants are eligible to participate if they agree to the following during the intervention period with belzutifan or lenvatinib and for at least 7 days after last dose of study intervention with belzutifan or lenvatinib :
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
- Agree to use 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.
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using 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), during the intervention period and for at least and for at least 120 days after the last dose of pembrolizumab or MK-1308A or for at least 30 days after last dose of lenvatinib or belzutifan, whichever occurs last, after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as required by local regulations) within 24 hours 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.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
9. The participant (or legally acceptable representative if applicable) provides written informed consent for the study.
10. Has adequately controlled blood pressure with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization.
11. Has adequate organ function. Specimens must be collected within 10 days prior to randomization.
12. Participants receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to randomization/allocation. |
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| E.4 | Principal exclusion criteria |
1. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
2. Has had major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization.
3. Has known CNS metastases and/or carcinomatous meningitis.
4. Has received prior radiotherapy within 2 weeks prior to first dose of study intervention. 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.
5. 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.
6. Has clinically significant cardiac 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 associated with hemodynamic instability. Medically controlled arrhythmia stable on medication is permitted.
7. Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO).
8. Prolongation of QTc interval to >480 ms.
9. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) within 28 days prior to the first dose of study intervention.
10. Has a history of interstitial lung disease.
11. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
12. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption).
13. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
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 treatment.
15. Has urine protein ≥1 g/24 hours.
16. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
17. Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug.
18. 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.
19. Has a history of hypersensitivity reaction to any of the investigational agent(s) included in this study.
20. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids 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.
21. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
22. Has an active infection requiring systemic therapy.
23. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
24. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
25. 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 in the best interest of the participant to participate, in the opinion of the treating investigator.
26. Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel.
27. Note: the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
28. 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 prior to randomization.
29. Has had an allogenic tissue/solid organ transplant. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
2. Overall Survival (OS)
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 46 months
2. Up to approximately 66 months
|
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) Per (RECIST 1.1) as Assessed by BICR
2. Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
3. Number of Participants Who Experienced At least One Adverse Event (AE)
4. Number of Participants Who Discontinue Study Treatment Due to an AE
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 46 months
2. Up to approximately 66 months
3. Up to approximately 66 months
4. Up to approximately 66 months
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Guatemala |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Philippines |
| Russian Federation |
| Serbia |
| South Africa |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United States |
| Croatia |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Norway |
| Poland |
| Romania |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
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| 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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