E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pheochromocytoma/Paraganglioma or Pancreatic Neuroendocrine Tumor |
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E.1.1.1 | Medical condition in easily understood language |
Pheochromocytoma, Paraganglioma or Pancreatic Neuroendocrine Tumors |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034876 |
E.1.2 | Term | Pheochromocytoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10073860 |
E.1.2 | Term | Paraganglioma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067518 |
E.1.2 | Term | Pancreatic neuroendocrine tumor |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate the objective response rate (ORR) of belzutifan/MK-6482 per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR) |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the duration of response (DOR) of belzutifan/MK-6482 in participants with a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR 2. To evaluate the time to response (TTR) of belzutifan/MK-6482 in participants with a confirmed CR or PR per RECIST 1.1 by BICR 3. To evaluate disease control rate (DCR) of belzutifan/MK-6482 per RECIST 1.1 by BICR 4. To evaluate progression-free survival (PFS) per RECIST 1.1 by BICR in participants receiving belzutifan/MK-6482 5. To evaluate the overall survival (OS) of participants receiving belzutifan/MK-6482 6. To evaluate the safety of belzutifan/MK-6482
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Cohort A1: Pheochromocytoma/Paraganglioma (PPGL) 1. Has documented histopathological diagnosis (local report) of pheochromocytoma or paraganglioma 2. Has locally advanced or metastatic disease that is not amenable to surgery or curative intent treatment 3. Adequately controlled blood pressure defined as blood pressure ≤150/90 mm Hg (≤135/85 mm Hg for adolescents) and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment Cohort A2: Pancreatic Neuroendocrine Tumor (pNET) 4. Has documented histopathological or cytopathological diagnosis (local report) of well-differentiated, low or intermediate grade (G1 or G2 pNET per 2017 WHO classification and grading) pNET 5. Has locally advanced disease or metastatic disease that is: a. Not amenable for surgery, radiation, locoregional therapies or combination modality of such treatments with curative intent b. Experienced disease progression on or after at least 1 line of prior systemic therapy that includes an approved targeted agent such as everolimus (mTOR inhibitor) or sunitinib (antiVEGF targeted agent). Participants who have received >3 prior systemic therapies will be capped to ≤20% of the cohort Cohorts A1 and A2 6. Has disease progression within the past 12 months from screening 7. Has measurable disease per RECIST v1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified in real time by BICR. BICR must confirm the presence of radiologically measurable disease per RECIST 1.1 for the participant to be eligible for the study a. Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth since completion of radiation b. Metastatic lesions situated in the brain are not considered measurable and should be considered nontarget lesions c. Only lesions of the primary indication for the cohort may be evaluated for measurability; other neoplastic lesions will be documented by the investigator and this information provided to the independent reviewers to ensure that such lesions are not included in the RECIST assessment 8. Is male or female, 12 years of age inclusive (≥40 kg for adolescents [12-17 years of age]), at the time of signing the informed consent 9. 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: - 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 10. 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, during the intervention period and for at least 30 days after the last dose of study intervention • A WOCBP must have a negative highly sensitive pregnancy test within 24 hours for urine or 72 hours for serum before the first dose of study intervention • If a urine test cannot be confirmed as negative, a serum pregnancy test is required • 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 11. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR 12. Submit 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 if the lesion is accessible and a biopsy is not clinically contraindicated 13. Has an ECOG performance status of either 0 or 1, as assessed within 7 days of treatment initiation 14. Has adequate organ function |
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E.4 | Principal exclusion criteria |
1. Is unable to swallow orally administered medication or has a disorder that might affect the absorption of belzutifan 2. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years with the following exceptions: a) Participants with history of VHL disease will be permitted provided concurrent lesions (other than PPGL for Cohort A1 and pNET for Cohort A2) are localized without immediate need for intervention b) Prior history of surgical resection(s) for concurrent localized VHL disease-associated tumors is allowed provided there is no history of metastatic disease from concurrent tumors; history of systemic therapy for concurrent tumors will be exclusionary c) Participants with history of other genetic syndromes will be allowed provided concurrent tumors (outside of the organ affected in Cohort A1 and Cohort A2, respectively) are localized and do not require immediate intervention; history of metastatic disease in concurrent tumors or history of systemic therapy for concurrent tumors will be exclusionary 3. Has known CNS metastases and/or carcinomatous meningitis 4. Has any of the following: • Hypoxia as defined by a pulse oximeter reading <92% at rest, or • Requires intermittent supplemental oxygen, or • Requires chronic supplemental oxygen 5. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction, or arterial bypass (CABG) or PTCA ≤6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Concurrent uncontrolled hypertension defined as blood pressure >150/90 mm Hg despite optimal antihypertensive medications within 2 weeks prior to the first dose of study treatment 6. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study 7. Has had major surgery ≤4 weeks prior to first dose of study intervention 8. Has received prior treatment (except somatostatin analogs) with chemotherapy, targeted therapy, or other investigational therapy within the past 4 weeks of study entry, or prior biologics or immunotherapy within the past 6 weeks of study entry 9. Has received prior locoregional therapies or radiation within the past 4 weeks of study entry 10. Has received prior treatment with PRRT/radionuclide therapy or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with pNET 11. Has received meta-iodobenzylguanidine (MIBG) therapy or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with PPGL 12. Has received prior treatment with any HIF-2α inhibitor (including belzutifan) 13. Has a known hypersensitivity to the study treatment and/or any of its excipients 14. Has toxicities from prior locoregional or systemic or any other therapies that is not recovered to baseline or CTCAE ≤Grade 1 (with the exception of alopecia) 15. Has received colony-stimulating factors ≤28 days prior to the first dose of study intervention 16. Is currently receiving strong inhibitors of CYP3A4 that cannot be discontinued for the duration of the study 17. 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 CYP3A4 that cannot be discontinued for the duration of the study 18. Is currently enrolled in and receiving study therapy, was enrolled in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks (28 days) of the first dose of study intervention 19. Has an active infection requiring systemic therapy 20. Has a known history of HIV infection 21. Has a known history of hepatitis B (defined as HBsAg reactive) or known active HCV (defined as detection of HCV RNA [qualitative]) infection 22. Participant has resting electrocardiogram (ECG) indicating uncontrolled cardiac conditions, as judged by the investigator, or participant has congenital long QT syndrome 23. For Cohort A2, has a tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or NET of nonpancreatic origin 24. For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at study entry 25. In the judgment of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study 26. 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 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. Objective Response (OR): a confirmed complete response (CR) or partial response (PR)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 4 years |
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E.5.2 | Secondary end point(s) |
1. Duration of response: the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first 2. Time to response, defined as the time from first dose of belzutifan/MK-6482 to first documented evidence of CR or PR 3. Disease control: a confirmed CR, PR, or stable disease (SD) 4. Progression-free survival: the time from first dose of belzutifan/MK-6482 to the first documented progressive disease (PD) or death from any cause, whichever occurs first 5. Overall survival: the time from first dose of belzutifan/MK-6482 until death from any cause 6. Number of Participants Who Experienced One or More Adverse Events (AEs) 7. Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 4 years 2. Up to approximately 4 years 3. Up to approximately 4 years 4. Up to approximately 4 years 5. Up to approximately 4 years 6. Up to approximately 4 years 7. Up to approximately 4 years |
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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 | 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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Canada |
Russian Federation |
Turkey |
United States |
Denmark |
France |
Germany |
Hungary |
Italy |
Spain |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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 |