A Phase II Study to Evaluate the Efficacy and Safety of Belzutifan (MK-6482, Formerly PT2977) Monotherapy in Participants With Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Advanced Solid Tumors With HIF-2α Related Genetic Alterations
Study Identifier:
MK-6482-015
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
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Study Summary
This is a study to evaluate the efficacy and safety of belzutifan monotherapy in participants with advanced pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET), von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Advanced Solid Tumors With hypoxia inducible factor-2 alpha (HIF-2α) related genetic alterations.
To evaluate the efficacy and safety of Belzutifan monotherapy in participants with advanced pheochromocytoma/paraganglioma (PPGL) or pancreatic neuroendocrine tumor (pNET).
To evaluate belzutifan in participants (pts) with advanced panNETs.
To evaluate the HIF-2α inhibitor, belzutifan, in advanced PPGL.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
II
Sex
Female & Male
Age
12+ years
Study Drug
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Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
Inclusion criteria
- The main inclusion criteria include but are not limited to the following: Male and female participants at least 12 years of age (at least 18 years of age for Cohort B1) Diagnosis of one of the following: Advanced/metastatic pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumors (pNET), von Hippel-Lindau (VHL) disease associated localized tumors, or advanced wild-type gastrointestinal stromal tumor (wt GIST) or advanced solid tumors with Hypoxia Inducible Factor- 2 alpha subunit (HIF-2α) related genetic alterations Cohort BI: VHL Disease-associated tumors: Have a diagnosis of VHL disease as determined by a germline test locally and/or clinical diagnosis Must be ≥18 years of age Has a life expectancy of at least 3 months.
- CFDA:
- 1Male or female, aged 12 years or older at the time of signing the informed consent form (adolescents [12-17 years] weighing ≥40 kg). Only adult subjects (≥18 years) are eligible to participate in the B1 cohort (VHL-associated tumors).2Male participants may participate in this study if they agree to follow the contraceptive methods described in protocol 5.1.8 during treatment and for at least 7 days after the last dose of study treatment, and comply with local regulations regarding contraceptive methods for clinical study participants.3Female participants may participate in this study if they are not pregnant or breastfeeding and follow the contraceptive methods described in protocol 5.1.8 and meet the local regulations for contraceptive methods for clinical study participants.4Submit a preserved tumor tissue sample (that has not previously received radiotherapy) or a freshly obtained core needle biopsy or excision biopsy sample.5The ECOG performance status assessed within 7 days prior to the start of treatment is 0 or 1.6According to the definition in Table 1 of scheme 5.1.12, prove that it has sufficient organ function.7Cohort A2: Pancreatic Neuroendocrine Tumors (pNETs) a) A well-differentiated, low- or intermediate-grade (G1 or G2 pNET according to the 2017 WHO classification and grading) pNET with a documented histopathological or cytopathological diagnosis (locally reported). b) Locally advanced or metastatic disease, i.e., not suitable for surgery, radiotherapy, local therapy, or a combination of these therapies with radical therapy; disease progression during or after at least one prior systemic treatment.8Cohort A2 a) Disease progression within the past 12 months of screening. b) Assessed by a local research center investigator/radiologist with measurable lesions via CT or MRI according to RECIST v1.1 and validated by BICR.9Cohort B1: Patients diagnosed with VHL disease by local genetic testing (with confirmed germline VHL gene alterations) and/or with a clinical diagnosis in the following circumstances: a) a family history of VHL disease and at least one VHL-related tumor feature; b) the presence of two or more retinal or CNS HBs; c) the presence of one retinal or CNS HB, plus at least one VHL-characteristic visceral tumor.10Cohort B1: Participants must be assessed by a local research center investigator/radiologist according to RECIST 1.1 as having at least one measurable lesion of RCC, PPGL, or pNET, and verified by BICR. BICR must confirm the presence of a measurable lesion of RCC, PPGL, or pNET on the imaging of Chinese subjects according to RECIST 1.1 to determine their eligibility.11For PPGL subjects in cohort B1: a) No pheochromocytoma >5 cm or paraganglioma >4 cm requiring immediate surgery. b) Subjects should have adequately controlled blood pressure, defined as blood pressure ≤150/90 mmHg, with no change in antihypertensive medication use for at least 2 weeks prior to starting study treatment. c) Metastatic or locally advanced, unresectable PPGL will be excluded. d) Concurrent VHL-related tumors are permissible on a case-by-case basis, provided immediate surgery or intervention is not required.12For pNET subjects in cohort B1: a) No lesions >2 cm in the pancreatic head requiring immediate surgery. b) No lesions >3 cm in the pancreatic body or tail requiring immediate surgery. c) Locally advanced, unresectable, or metastatic pNET will be excluded. d) Concurrent VHL-related tumors are permitted on a case-by-case basis, provided they do not require immediate surgery or intervention.13For RCC subjects in cohort B1: a) No lesions >3 cm requiring immediate surgery. b) Metastatic RCC will be excluded. c) Concurrent VHL-related tumors are permitted on a case-by-case basis, provided that immediate surgery or intervention is not required.14For GIST subjects in cohort C (wt): a) a documented histopathological diagnosis of GIST (locally reported); b) a documented local trial report of no sensitizing mutations in PDGFRA and c-KIT; c) locally advanced or metastatic disease unsuitable for surgery or radical treatment.15For subjects with advanced solid tumors and HIF-2α-related gene alterations in cohort D: a) a local trial has documented a germline or somatic mutation in at least one HIF-2α-related gene (HIF-2α/EPAS1, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, EGLN1, EGLN2, MDH2, ELOC/TCEB1); b) they have locally advanced or metastatic disease that is not suitable for surgery or radical treatment; c) the subject must have progressed during/after standard treatment for advanced/metastatic disease. In the context of advanced/metastatic disease, this cohort is not permitted to have received more than three lines of prior therapy.
Exclusion criteria
- The main exclusion criteria include but are not limited to the following: Unable to swallow orally administered medication or has a disorder that might affect the absorption of belzutifan History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years Any of the following: A pulse oximeter reading <92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen Clinically significant cardiac disease, including unstable angina, acute myocardial infarction, or arterial bypass (CABG) or Percutaneous transluminal coronary angioplasty (PTCA) ≤6 months from study entry, or New York Heart Association Class III or IV congestive heart failure Received prior treatment (except somatostatin analogs) with chemotherapy, targeted therapy, biologics, or other investigational therapy within the past 4 weeks of first dose of study intervention.
- CFDA:
- 1Those who are unable to swallow oral medications or have a condition that affects the absorption of belzutifan.2A history of a second malignant tumor is not required unless a potentially curative treatment has been completed and there is no evidence of malignancy within the past two years.3Known CNS metastases and/or carcinomatous meningitis.4If any of the following conditions exist: resting pulse oximeter reading < 92%, or intermittent oxygen therapy is required, or long-term oxygen therapy is required.5Patients with clinically significant heart disease, including unstable angina, acute myocardial infarction, or who have undergone arterial bypass (CABG) or PTCA within 6 months prior to day 1 of administration of the study drug, or who have New York Heart Association class III or IV congestive heart failure.6A history of mental illness or substance abuse may affect compliance with trial requirements.7The study intervention was initiated if the patient had undergone major surgery within ≤4 weeks prior to the first dose.8Prior treatment (excluding somatostatin analogues) including chemotherapy, targeted therapy or other investigational treatments received within 4 weeks prior to the start of the study, or biologics or immunotherapy received within 6 weeks prior to the first dose of the study intervention.9Those who received local treatment or radiation therapy within 4 weeks prior to the first dose of the study intervention.10pNET participants had received PRRT/radionoid therapy (such as 177Lu-Dotatate) or other radiopharmaceutical therapy within 12 weeks prior to the screening period.11He has received any HIF-2α inhibitors (including belzutifan).12Hypersensitivity reactions are known to occur with the investigational treatment and/or any of its excipients.13Toxicity that occurred after previous local or systemic or any other treatment and has not recovered to CTCAE ≤ 1 (excluding alopecia).14Received colony-stimulating factors (e.g., G-CSF, GM-CSF, or recombinant EPO) ≤28 days prior to the first dose of the study intervention.15We are currently using a potent inhibitor of CYP3A4 and cannot discontinue the medication during the study.16We are currently using potent and intermediate-potency inducers of CYP3A4 and cannot discontinue them during the study.17Currently enrolled in other studies, or having participated in studies of the investigational drug or device within 4 weeks (28 days) prior to the start of treatment in this study.18There is an active infection that requires systemic treatment.19Known history of HIV infection.20A known history of hepatitis B or a known history of active hepatitis C virus infection.twenty oneThe researchers determined that the subject's resting electrocardiogram showed uncontrolled heart disease, or that the subject had congenital long QT syndrome.twenty twoResearchers determined that participants were unlikely to comply with research procedures, restrictions, and requirements.twenty threeThe investigator determines that there is prior or current evidence of any disease, treatment, or laboratory abnormality that may affect the study results, prevent the subject from participating in the study throughout the course of the study, or is not in the best interests of the subject.twenty fourHas received allogeneic tissue/solid organ transplantation.25Cohort A2: a) Tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or NET of non-pancreatic origin. b) Subjects in Cohort A2 whose functional pNET symptoms were uncontrolled at the start of the study.26Cohort B1: Subjects in Cohort B1 will be excluded if they have a history of any systemic antitumor therapy (including investigational drugs) for any VHL-related tumors, or a history of metastasis of any VHL-related tumors or other non-VHL-related tumors.27For cohort C and GIST subjects, clinically significant active bleeding (such as GI bleeding), perforation, obstruction, and other disease-related complications requiring emergency surgery are considered.28For subjects in cohort D, subjects with VHL disease were excluded.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Lisbon
Lisbon, Portugal, 1649-035
Investigator
Andre Mansinho
Status
Recruiting
Condition(s) Treated at Site
Neuroendocrine
Pancreas
Von Hippel-Lindau Disease
Gastrointestinal stromal tumor
Gene Mutations