Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), or Von Hippel-Lindau (VHL) Disease-Associated Tumors (MK-6482-015)
Study Details
Study Description
Brief 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) or von Hippel-Lindau (VHL) Disease-Associated Tumors. The primary objective of the study is 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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Belzutifan Belzutifan, 120 mg, oral, once daily (QD) until progressive disease or discontinuation. |
Drug: Belzutifan
Belzutifan, 120 mg, oral, once daily (QD) until progressive disease or discontinuation.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) [Up to approximately 5 years]
ORR is the percentage of participants with complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression) or death due to any cause, whichever occurs first.
Secondary Outcome Measures
- Duration of Response (DOR) as Assessed by BICR [Up to approximately 5 years]
DOR is the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
- Time to Response (TTR) as Assessed by BICR [Up to approximately 5 years]
TTR is defined as the time from first dose of belzutifan to first documented evidence of CR or PR.
- Disease Control Rate (DCR) as Assessed by BICR [Up to approximately 5 years]
Disease control is a confirmed CR, PR, or stable disease (SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study).
- Progressive Free Survival (PFS) as Assessed by BICR [Up to approximately 5 years]
PFS is the time from first dose of belzutifan to the first documented PD or death from any cause, whichever occurs first.
- Overall Survival (OS) [Up to approximately 5 years]
OS is the time from first dose of belzutifan until death from any cause.
- Number of Participants Experiencing Adverse Events (AEs) [Up to approximately 5 years]
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
- Number of Participants Discontinuing Study Drug due to an AE [Up to approximately 5 years]
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinue study treatment due to an AE will be presented.
- Time to Surgery (TTS) [Up to approximately 5 years]
TTS is defined as the time from the first dose of belzutifan to the first documented surgical intervention or tumor reduction procedure.
Eligibility Criteria
Criteria
Inclusion Criteria:
Cohort A1: Pheochromocytoma/Paraganglioma (PPGL)
- Has documented histopathological diagnosis (local report) of pheochromocytoma or paraganglioma.
Note: Participants are allowed to receive therapy in first line where a satisfactory treatment option does not exist and if participants are not candidates for systemic chemotherapy or have refused such therapy. There is no limit on number of prior systemic therapies. Locoregional therapies or adjuvant/neoadjuvant therapies are not considered a line of prior systemic therapy.
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Has locally advanced or metastatic disease that is not amenable to surgery or curative intent treatment.
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Has 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)
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Has documented histopathological or cytopathological diagnosis (local report) of well-differentiated, low, or intermediate grade (G1 or G2 pNET per 2017 World Health Organization (WHO) classification and grading) pNET.
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Has locally advanced disease or metastatic disease that is:
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Not amenable for surgery, radiation, locoregional therapies or combination modality of such treatments with curative intent.
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Experienced disease progression on or after at least 1 line of prior systemic therapy that includes an approved targeted agent such as everolimus or sunitinib. Participants who have received >3 prior systemic therapies will be capped to ≤20% of the cohort.
Note: Chemoembolization/radiofrequency ablation/locoregional therapies, neoadjuvant/adjuvant treatments, or somatostatin analog monotherapy or interferon monotherapy will not count as 1 line of prior systemic therapy.
Cohorts A1 and A2
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Has disease progression within the past 12 months from Screening.
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Has measurable disease per RECIST 1.1 by computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by local site investigator/radiology assessment and verified by BICR.
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Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth since completion of radiation.
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Metastatic lesions situated in the brain are not considered measurable and should be considered nontarget lesions.
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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.
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Participants who are adolescents (12-17 years of age) need to have a body weight of 40 kilograms (kg) or more.
Cohort B1: von Hippel-Lindau (VHL) Disease-Associated Tumors
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Have a diagnosis of VHL disease as determined by a germline test (documented germline VHL gene alteration) locally and/or clinical diagnosis.
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Have at least 1 measurable PPGL or pNET per RECIST 1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified by BICR.
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Participants from China or Japan defined as participants of Chinese or Japanese origin residing in mainland China or Japan respectively at the time of Screening, must have at least 1 measurable RCC or PPGL or pNET per RECIST 1.1 as assessed by local site investigator/radiology assessment and verified by BICR.
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Must be ≥18 years of age.
For Cohort B1 participants with PPGL
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Must not have pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate surgery.
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Have adequately controlled blood pressure defined as blood pressure =150/90 mm Hg and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment.
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Must not have Metastatic or locally advanced, unresectable PPGL.
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Presence of concomitant VHL disease-associated tumors is permitted as long as they do not require immediate surgery or intervention.
For Cohort B1 participants with pNET:
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Must not have lesion(s) located in the head of the pancreas must be >2 cm that requires immediate surgery.
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Must not have lesion(s) located in the body or tail of the pancreas must be >3 cm that requires immediate surgery.
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Must not have locally advanced, unresectable or metastatic pNET.
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Presence of concomitant VHL disease-associated tumors is permitted as long as they do not require immediate surgery or intervention.
For Cohort B1 participants with renal cell carcinoma (RCC):
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Must not have lesion(s) >3 cm that requires immediate surgery.
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Must not have metastatic RCC.
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Presence of concomitant VHL disease-associated tumors is permitted as long as they do not require immediate surgery or intervention.
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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:
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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
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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 woman/women of childbearing potential (WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
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Is not a WOCBP). OR
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Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), for at least 30 days after the last dose of study intervention.
- Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (not previously irradiated). Formalin-fixed, paraffin embedded (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.
Note: If participant has only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from a nontarget lesion or archival tissue. Bone biopsies should not be submitted.
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Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 7 days of treatment initiation.
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Has adequate organ function.
Exclusion Criteria:
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Is unable to swallow orally administered medication or has a disorder that might affect the absorption of belzutifan.
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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:
Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
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Participants with history of VHL disease (germline VHL mutation documented by a local test report or with clinical diagnosis) will be permitted provided concurrent lesions (other than PPGL for Cohort A1 and pNET for Cohort A2) are localized without immediate need for intervention.
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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.
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Participants with history of other genetic syndromes (such as those with succinate dehydrogenase subunit genes (SDHx) germline mutation or multiple endocrine neoplasia/MEN) 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.
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Cohort B1 participants with concomitant central nervous system (CNS) hemangioblastoma must not require immediate surgery or intervention and must not be at risk of imminent neurological complications.
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Cohort B1 participants with concomitant retinal angiomas/retinal hemangioblastomas must not require immediate intervention.
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Cohort B1 participants with any concomitant tumors must not require immediate surgery or intervention.
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For Cohort B1 participants, history of any anticancer systemic therapy (including investigational agents) for any VHL disease-associated tumor or history of metastatic disease from any VHL disease-associated tumor or other non-VHL disease-related tumor(s) will be exclusionary.
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Has known CNS metastases and/or carcinomatous meningitis.
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Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction, or arterial bypass (CABG) or percutaneous transluminal coronary angioplasty (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 mercury (Hg) despite optimal antihypertensive medications within 2 weeks prior to the first dose of study treatment.
Note: Medically controlled arrhythmia stable on medication is permitted.
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Has any of the following: A pulse oximeter reading <92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen.
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Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
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Has had major surgery ≤4 weeks prior to first dose of study intervention.
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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 first dose of study intervention.
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Has received prior locoregional therapies or radiation within the past 4 weeks of first dose of study intervention.
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Has received prior treatment with Peptide Receptor Radionuclide Therapy (PRRT)/radionuclide therapy (such as 177Lu-Dotatate) or other radiopharmaceutical therapy within the past 12 weeks from Screening for participants with pNET.
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Has received meta-iodobenzylguanidine (MIBG) therapy or other radiopharmaceutical therapy within the past 12 weeks from Screening for participants with PPGL.
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Has received prior treatment with any HIF-2α inhibitor (including belzutifan).
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Has a known hypersensitivity to the study treatment and/or any of its excipients.
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Has toxicities from prior locoregional or systemic or any other therapies that is not recovered to Common Terminology Criteria for Adverse Events (CTCAE) ≤Grade 1 (with the exception of alopecia).
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Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), or recombinant Erythropoietin (EPO) ≤28 days prior to the first dose of study intervention.
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Is currently receiving strong inhibitors of Cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study.
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Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.
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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.
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Has an active infection requiring systemic therapy.
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Has a known history of human immunodeficiency virus (HIV) infection.
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Has a known history of hepatitis B or known active hepatitis C (HCV) infection.
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For Cohort A2, has a tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or neuroendocrine tumor (NET) of nonpancreatic origin.
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Poorly differentiated or high grade pancreatic pNET or pancreatic neuroendocrine carcinoma; mixed adenoneuroendocrine carcinoma of the pancreas or concurrent pancreatic ductal adenocarcinoma will not be allowed.
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Neuroendocrine tumor of nonpancreatic origin such as gastrointestinal, lung/thoracic, unknown primary, or other organs (including adenocarcinoid/goblet cell carcinoid/small cell carcinoma/large cell carcinoma). Note: Neuroendocrine carcinoma of any origin is exclusionary.
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For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at study entry.
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Has had an allogenic tissue/solid organ transplant.
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For Cohort B1 participants, metastatic disease identified at Screening.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cedars-Sinai Medical Center ( Site 0110) | Los Angeles | California | United States | 90048 |
| 2 | University of Iowa ( Site 0104) | Iowa City | Iowa | United States | 52242 |
| 3 | Johns Hopkins Hospital-Sidney Kimmel Comprehensive Cancer Center - Developmental Therapeutics ( Site | Baltimore | Maryland | United States | 21287 |
| 4 | University of Michigan ( Site 0126) | Ann Arbor | Michigan | United States | 48109 |
| 5 | Washington University-Internal Medicine/Oncology ( Site 0124) | Saint Louis | Missouri | United States | 63110 |
| 6 | Icahn School of Medicine at Mount Sinai ( Site 0123) | New York | New York | United States | 10029 |
| 7 | Vanderbilt University Medical Center ( Site 0107) | Nashville | Tennessee | United States | 37232 |
| 8 | University of Texas MD Anderson Cancer Center ( Site 0112) | Houston | Texas | United States | 77030 |
| 9 | Tom Baker Cancer Center-Clinical Research Unit ( Site 0203) | Calgary | Alberta | Canada | T2N 4N2 |
| 10 | Princess Margaret Cancer Centre ( Site 0202) | Toronto | Ontario | Canada | M5G 2M9 |
| 11 | Rigshospitalet-Department of Endocrinology ( Site 0303) | Copenhagen | Hovedstaden | Denmark | 2100 |
| 12 | Odense Universitetshospital ( Site 0302) | Odense | Syddanmark | Denmark | 5000 |
| 13 | CHU Strasbourg-Hautepierre-Medecine Interne, Endocrinologie et Nutrition ( Site 0402) | Strasbourg | Alsace | France | 67098 |
| 14 | Institut Paoli-Calmettes-Oncology ( Site 0406) | Marseille | Bouches-du-Rhone | France | 13009 |
| 15 | Hôpital Edouard Herriot-oncologie ( Site 0405) | Lyon | Rhone-Alpes | France | 69003 |
| 16 | Gustave Roussy ( Site 0403) | Villejuif | Val-de-Marne | France | 94800 |
| 17 | Hopitaux Universitaires Paris Centre-Hopital Cochin ( Site 0404) | Paris | France | 75679 | |
| 18 | Universitaetsklinikum Freiburg ( Site 0504) | Freiburg | Baden-Wurttemberg | Germany | 79106 |
| 19 | Klinikum der Ludwig-Maximilians-Universitaet Muenchen-Department of Internal Medicine IV, Division ( | München | Bayern | Germany | 80336 |
| 20 | Comprehensive Cancer Center Mainfranken-Div. of Endocrinology and Diabetes ( Site 0500) | Würzburg | Bayern | Germany | 97080 |
| 21 | Charité Universitaetsmedizin Berlin - Campus Mitte-Department of Endocrinology and Metabolism ( Site | Berlin | Germany | 10117 | |
| 22 | Semmelweis University-Belgyógyászati és Onkológiai Klinika Hematológia Osztály ( Site 0600) | Budapest | Hungary | 1083 | |
| 23 | University of Naples Federico II-Dipartimento di Medicina Clinica e Chirurgia ( Site 0704) | Naples | Campania | Italy | 80100 |
| 24 | Azienda Ospedaliera Spedali Civili di Brescia-Oncology ( Site 0701) | Brescia | Italy | 25123 | |
| 25 | Istituto Europeo di Oncologia IRCCS-Divisione di Oncologia Medica Gastrointestinale e Tumori Neuroe | Milano | Italy | 20141 | |
| 26 | Azienda Ospedaliera Universitaria Integrata Verona - Ospedale Borgo Roma ( Site 0703) | Verona | Italy | 37134 | |
| 27 | GBUZ Republican Clinical Oncological Dispensary ( Site 0804) | Ufa | Baskortostan, Respublika | Russian Federation | 450054 |
| 28 | Saint Petersburg State University-Clinic of advanced medical technologies n. a. Nicolay I. Pirogov ( | Saint Petersburg | Leningradskaya Oblast | Russian Federation | 190020 |
| 29 | Saint-Petersburg City Clinical Oncology Dispensary-Department of chemotherapy ( Site 0803) | Saint Petersburg | Leningradskaya Oblast | Russian Federation | 198255 |
| 30 | Fed State Budgetary Inst N.N. Blokhin Med Center of Oncology MHRF ( Site 0801) | Moscow | Moskva | Russian Federation | 115478 |
| 31 | Endocrinology Research Center of Rosmedtechnologies-Surgery ( Site 0809) | Moscow | Moskva | Russian Federation | 117036 |
| 32 | Hospital Universitario Central de Asturias-Medical Oncology ( Site 1101) | Oviedo | Asturias | Spain | 33011 |
| 33 | MD Anderson Cancer Center-Oncology ( Site 1102) | Madrid | Madrid, Comunidad De | Spain | 28033 |
| 34 | Hospital Universitario 12 de Octubre-Medical Oncology ( Site 1103) | Madrid | Madrid, Comunidad De | Spain | 28041 |
| 35 | Hospital Universitari Vall d'Hebron ( Site 1100) | Barcelona | Spain | 08035 | |
| 36 | Skanes University Hospital Lund ( Site 1200) | Lund | Skane Lan | Sweden | 22185 |
| 37 | Karolinska Universitetssjukhuset Solna ( Site 1202) | Stockholm | Stockholms Lan | Sweden | 171 76 |
| 38 | Akademiska sjukhuset-Blod- och tumörsjukdomar ( Site 1201) | Uppsala | Uppsala Lan | Sweden | 751 85 |
| 39 | Sahlgrenska Universitetssjukhuset-Department of Oncology CTU Clinical Trial Unit ( Site 1204) | Gothenburg | Vastra Gotalands Lan | Sweden | 413 45 |
| 40 | Ege University Medicine of Faculty ( Site 0900) | Bornova | Izmir | Turkey | 35100 |
| 41 | Hacettepe Universitesi-oncology hospital ( Site 0901) | Ankara | Turkey | 06230 | |
| 42 | Istanbul Universitesi Cerrahpasa-Medical Oncology ( Site 0902) | Istanbul | Turkey | 34668 | |
| 43 | Addenbrooke's Hospital ( Site 1309) | Cambridge | Cambridgeshire | United Kingdom | CB2 2QQ |
| 44 | Royal Free Hospital ( Site 1302) | London | England | United Kingdom | NW32QG |
| 45 | The Beatson West of Scotland Cancer Centre ( Site 1308) | Glasgow | Glasgow City | United Kingdom | G12 0YN |
| 46 | Hammersmith Hospital-Medical Oncology ( Site 1304) | London | London, City Of | United Kingdom | W12 0HS |
Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 6482-015
- MK-6482-015
- PT2977
- 2020-005028-13