An Open-label, Randomized Phase 3 Study of MK-6482 versus Everolimus in Participants with Advanced Renal Cell Carcinoma that has Progressed After Prior Therapy
- Conditions
- Advanced Renal Cell CarcinomaMedDRA version: 21.1Level: PTClassification code 10067946Term: Renal cell carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-003444-72-NO
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 736
1. Has unresectable, locally advanced or metastatic clear cell RCC
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 had disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with both: PD-1/L1 checkpoint inhibitor and VEGF-TKI in sequence or in combination.
• PD-1/L1 checkpoint inhibitor 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 demonstrated radiographic PD during or after an anti- PD-1/L1 mAb
• VEGF-TKI treatment progression is defined by meeting the following criteria:
o Has demonstrated radiographic PD during or after a treatment with a VEGF-TKI
4. Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC
5. For the most recently received regimen, has demonstrated radiographic disease progression
6. Is male or female, who is at least 18 years of age at the time of signing the informed consent
7. Has a KPS score of at least 70% assessed within 10 days prior to randomization.
8. 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 study intervention:
• 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:
o 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. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penilevaginal intercourse or use a male condom during each episode of penilevaginal penetration.
9. 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 30 days after the last dose of study intervention for those randomized to the belzutifan study intervention and for at least 8 weeks after last dose of study intervention for those randomized to the everolimus arm. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine) as required by local regulations within 24 hours before the first dose ofstudy 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
test is positive.
• Additional requirements for pregnancy testing during and after study intervention are in the Schedule of Activities.
• The investigator is responsible for review of
1. A WOCBP who has a positive urine pregnancy test within 24 hours
prior to randomization. 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 as defined by 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 cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study medication administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted
6. Has poorly controlled hypertension defined as SBP =150 mm Hg and/or DBP =90 mm Hg
7. Has moderate to severe hepatic impairment (Child-Pugh B or C)
8. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) within 28 days prior to randomization
9. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
10. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
11. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan or everolimus) formulations
12. Has received prior treatment with belzutifan or another HIF-2a inhibitor
13. Has received prior treatment with everolimus or any other specific or selective TORC1/PI3K/AKT inhibitor (eg, temsirolimus) in the advanced disease setting
14. Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization
15. Has received any type of systemic anticancer antibody (including investigational antibody) within 4 weeks before randomization
16. Has received prior radiotherapy within 2 weeks prior to 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
17. Has had major surgery within 3 weeks prior to randomization
18. Has received a live vaccine within 30 days prior to randomization of study medication. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
19. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of CYP3A4 that cannot be discontinued for the duration of the study
20. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: 1. To compare belzutifan (MK-6482) to everolimus with respect to PFS per RECIST 1.1 as assessed by BICR<br>2. To compare belzutifan (MK-6482) to everolimus with respect to OS;Secondary Objective: 1. To compare belzutifan to everolimus with respect to ORR based on RECIST 1.1 as assessed by BICR<br>2. To evaluate the DOR as assessed by BICR according to RECIST 1.1<br>3. To evaluate the safety and tolerability of belzutifan compared to everolimus<br>4. To evaluate TTD and change from baseline in HRQoL using the EORTC QLQ-C30 and the FKSI-DRS<br>5. To characterize health utility as measured using the EuroQoL EQ-5D-5L<br>;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)<br>2. Overall Survival (OS);Timepoint(s) of evaluation of this end point: 1. Up to approximately 39 months<br>2. Up to approximately 39 months
- Secondary Outcome Measures
Name Time Method