| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | 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 disease-free survival (DFS) as assessed by investigator for participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab. |
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| E.2.2 | Secondary objectives of the trial |
1.To compare overall survival (OS) for participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab.
2.To compare the safety and tolerability profiles for participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab.
3To compare measures of disease recurrence-specific survival (DRSS) as assessed by the investigator, in participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab.
4. To compare participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab with respect to mean change from baseline in health-related quality of life (HRQoL) and symptoms using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 30 Questionnaire (QLQ-C30) and the Functional Assessment of Cancer Therapy –Kidney Symptom Index Disease-related Symptoms (FKSI-DRS). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
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| E.4 | Principal exclusion criteria |
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1.Disease-Free Survival (DFS) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1.Up to approximately 66 months |
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| E.5.2 | Secondary end point(s) |
1.Overall Survival (OS)
2.Number of Participants Who Experience At Least One Adverse event (AE)
3.Number of Participants Who Discontinue Study Treatment Due to an AE
4.Disease Recurrence-Specific Survival 1 (DRSS1)
5.Disease Recurrence-Specific Survival 2 (DRSS2)
6.Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
7.Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score
8.Change From Baseline in Role Functioning Using the EORTC QLQ-C30 Items 6 and 7 Score
9.Change From Baseline in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Up to approximately 94 months
2.Up to approximately 66 weeks
3.Up to approximately 54 weeks
4.Up to approximately 66 months
5.Up to approximately 66 months
6.Baseline (Day 1) and Up to approximately 66 months
7.Baseline (Day 1) and Up to approximately 66 months
8.Baseline (Day 1) and Up to approximately 66 months
9.Baseline (Day 1) and Up to approximately 66 months
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 97 |
| 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 |
| Chile |
| Colombia |
| Malaysia |
| New Zealand |
| Singapore |
| Ukraine |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Bulgaria |
| Czechia |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Sweden |
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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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| Receipt of the last laboratory test result or LPLV, whichever comes last |
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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 | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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