Pheochromocytoma/Paraganglioma or Pancreatic Neuroendocrine Tumor or von Hippel-Lindau (VHL) Disease-Associated Tumors or Gastrointestinal Stromal Tumor (wt GIST), or Advanced Solid Tumors with HIF-2a related Genetic Alterations MedDRA version: 20.1 Level: LLT Classification code 10034876 Term: Pheochromocytoma System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10073860 Term: Paraganglioma System Organ Class: 100000004864 MedDRA version: 21.0 Level: LLT Class
Conditions
Interventions
Product Name: Belzutifan
Product Code: MK-6482
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Belzutifan
Current Sponsor code: MK-6482
Concentration unit: mg milligram(s)
Concentration t
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Cohort A1: 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: 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 6. Has disease progression within the past 12 months from Screening (Cohorts A1, A2 and PPGL/pNET participants from Cohort D) 7. Has measurable disease per RECIST v1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified by BICR. 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. This criterion does not apply to Cohort B1 participants. 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 providing the informed consent. Only adult participants (=18 years of age) are eligible to participate for Cohort B1. 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
Exclusion criteria
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 the tumor type being assessed such as PPGL for Cohort A1 and pNET for Cohort A2) are localized without immediate need for intervention. Cohort D participants with VHL disease will not be eligible 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, C and D 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. d. Refer to exclusion criterion protocol section 5.2 for Cohort B1 participants 3. Has known CNS metastases and/or carcinomatous meningitis 4. Has any of the following: • A pulse oximeter reading 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 for pNET participants) with chemotherapy, targeted therapy, biologics or other inv. therapy within the past 4 weeks of first dose of study intervention. 9. Has received prior locoregional therapies or radiation within the past 4 weeks of first dose of study intervention. 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 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-2a inhibitor 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 CTCAE =Grade 1 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 or moderate 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 inv. agent and received study therapy or used an in
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To evaluate the objective response rate (ORR) of belzutifan per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR). 2. Cohort B1: To evaluate the ORR of belzutifan per RECIST 1.1 by BICR in VHL disease-associated PPGL 3. Cohort B1: To evaluate the ORR of belzutifan per RECIST 1.1 by BICR in VHL disease-associated pNET 4. Cohort B1: To evaluate the ORR of belzutifan per RECIST 1.1 by BICR in VHL disease-associated RCC among China/Japan participants ;Secondary Objective: 1. To evaluate the duration of response (DOR) of belzutifan 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 in participants with a confirmed CR or PR per RECIST 1.1 by BICR 3. To evaluate disease control rate (DCR) of belzutifan per RECIST 1.1 by BICR 4. To evaluate progression-free survival (PFS) per RECIST 1.1 by BICR in participants receiving belzutifan 5. To evaluate the overall survival (OS) of participants receiving belzutifan 6. To evaluate the safety of belzutifan 7. Cohort B1: To evaluate the tumor specific DOR, TTR, DCR, PFS of belzutifan per RECIST 1.1 by BICR and time to surgery (TTS) in VHL disease-associated a.) PPGL, b.) pNET 8. Cohort B1: To evaluate the DOR, TTR, DCR, and PFS of belzutifan per RECIST 1.1 by BICR and TTS in VHL disease-associated RCC among China/Japan participants;Primary end point(s): 1. Objective Response (OR): a confirmed complete response (CR) or partial response (PR) ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 5 years | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 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 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 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) 8. Time to Surgery: TTS is defined as the time from the first dose of belzutifan to the first documented surgical intervention or tumor reduction procedure;Timepoint(s) of evaluation of this end point: 1. Up to approximately 5 years 2. Up to approximately 5 years 3. Up to approximately 5 years 4. Up to approximately 5 years 5. Up to approximately 5 years 6. Up to approximately 5 years 7. Up to approximately 5 years 8. Up to approximately 5 years | — |
Countries
Australia, Canada, China, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, New Zealand, Russian Federation, Singapore, Spain, Sweden, Turkey, United Kingdom, United States
Outcome results
None listed