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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04924075




Registration number
NCT04924075
Ethics application status
Date submitted
8/06/2021
Date registered
11/06/2021

Titles & IDs
Public title
Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2a Related Genetic Alterations (MK-6482-015)
Scientific title
A Phase 2 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-2a Related Genetic Alterations
Secondary ID [1] 0 0
MK-6482-015
Secondary ID [2] 0 0
6482-015
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pheochromocytoma/Paraganglioma 0 0
Pancreatic Neuroendocrine Tumor 0 0
Von Hippel-Lindau Disease 0 0
Advanced Gastrointestinal Stromal Tumor 0 0
HIF-2a Mutated Cancers 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Stomach
Cancer 0 0 0 0
Bowel - Small bowel (duodenum and ileum)
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 0 0 0 0
Pancreatic
Metabolic and Endocrine 0 0 0 0
Other endocrine disorders
Neurological 0 0 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Belzutifan

Experimental: Belzutifan - Belzutifan, 120 mg, oral, once daily (QD) until progressive disease or discontinuation.


Treatment: Drugs: Belzutifan
Belzutifan, 120 mg, oral, once daily (QD) until progressive disease or discontinuation.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)
Timepoint [1] 0 0
Up to approximately 5.5 years
Secondary outcome [1] 0 0
Duration of Response (DOR) as Assessed by BICR
Timepoint [1] 0 0
Up to approximately 5.5 years
Secondary outcome [2] 0 0
Time to Response (TTR) as Assessed by BICR
Timepoint [2] 0 0
Up to approximately 5.5 years
Secondary outcome [3] 0 0
Disease Control Rate (DCR) as Assessed by BICR
Timepoint [3] 0 0
Up to approximately 5.5 years
Secondary outcome [4] 0 0
Progressive Free Survival (PFS) as Assessed by BICR
Timepoint [4] 0 0
Up to approximately 5.5 years
Secondary outcome [5] 0 0
Overall Survival (OS)
Timepoint [5] 0 0
Up to approximately 5.5 years
Secondary outcome [6] 0 0
Number of Participants Experiencing Adverse Events (AEs)
Timepoint [6] 0 0
Up to approximately 5.5 years
Secondary outcome [7] 0 0
Number of Participants Discontinuing Study Drug due to an AE
Timepoint [7] 0 0
Up to approximately 5.5 years
Secondary outcome [8] 0 0
Time to Surgery (TTS)
Timepoint [8] 0 0
Up to approximately 5.5 years

Eligibility
Key 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

* Has locally advanced or metastatic disease that is not amenable to surgery or curative intent treatment
* 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)

* 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.
* Has locally advanced disease or metastatic disease that is:

1. Not amenable for surgery, radiation, locoregional therapies or combination modality of such treatments with curative intent.
2. 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, A2 and PPGL/pNET participants from Cohort D

* Has disease progression within the past 12 months from Screening.
* 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.

1. Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth since completion of radiation.
2. Metastatic lesions situated in the brain are not considered measurable and should be considered nontarget lesions.
3. 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.
4. 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

* Have a diagnosis of VHL disease as determined by a germline test (documented germline VHL gene alteration) locally and/or clinical diagnosis.
* 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.
* 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.
* Must be =18 years of age.

For Cohort B1 participants with PPGL

* Must not have pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate surgery.
* 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.
* Must not have Metastatic or locally advanced, unresectable PPGL.
* 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:

* Must not have lesion(s) located in the head of the pancreas must be >2 cm that requires immediate surgery.
* Must not have lesion(s) located in the body or tail of the pancreas must be >3 cm that requires immediate surgery.
* Must not have locally advanced, unresectable or metastatic pNET.
* 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):

* Must not have lesion(s) >3 cm that requires immediate surgery.
* Must not have metastatic RCC.
* Presence of concomitant VHL disease-associated tumors is permitted as long as they do not require immediate surgery or intervention.

For Cohort C participants with GIST (wt):

* Has documented histopathological diagnosis of GIST.
* Local test report documenting the absence of sensitizing mutations in both platelet derived growth factor receptor alpha (PDGFRA) and receptor tyrosine kinase (c-KIT).
* Has locally advanced or metastatic disease that is not amenable to surgery or curative intent treatment.

For Cohort D participants with advanced solid tumors with HIF-2a related genetic alterations:

* Local test report documenting germline or somatic mutations in at least one of the HIF-2a related genes.
* Has locally advanced or metastatic solid tumor that is not amenable to surgery or curative intent treatment.
* Has progressed on/after standard therapy for advanced/metastatic disease.
* 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:

1. 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
2. Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause as detailed below:

i. 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:

1. Is not a WOCBP OR
2. 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.

* Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 7 days of treatment initiation.
* Has adequate organ function.
* Has a life expectancy of at least 3 months.
Minimum age
12 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Is unable to swallow orally administered medication or has a disorder that might affect the absorption of belzutifan.
* 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.

* 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 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.
* 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.
* 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, 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.
* 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.
* Cohort B1 participants with concomitant retinal angiomas/retinal hemangioblastomas must not require immediate intervention.
* Cohort B1 participants with any concomitant tumors must not require immediate surgery or intervention.
* 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.
* Has known CNS metastases and/or carcinomatous meningitis.
* 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.

* Has any of the following: A pulse oximeter reading <92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen.
* Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
* Has had major surgery =4 weeks prior to first dose of study intervention.
* Has received prior treatment (except somatostatin analogs for pNET participants) with chemotherapy, targeted therapy, biologics or other investigational therapy within the past 4 weeks of first dose of study intervention.
* Has received prior locoregional therapies or radiation within the past 4 weeks of first dose of study intervention.
* 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.
* Has received meta-iodobenzylguanidine (MIBG) therapy or other radiopharmaceutical therapy within the past 12 weeks from Screening for participants with PPGL.
* Has received prior treatment with any HIF-2a inhibitor (including belzutifan).
* Has a known hypersensitivity to the study treatment and/or any of its excipients.
* 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).
* 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.
* Is currently receiving strong inhibitors of Cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study.
* Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.
* 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.
* Has an active infection requiring systemic therapy.
* Has a known history of human immunodeficiency virus (HIV) infection.
* Has a known history of hepatitis B or known active hepatitis C (HCV) infection.
* For Cohort A2, has a tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or neuroendocrine tumor (NET) of nonpancreatic origin.

1. 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.
2. 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.
* For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at study entry.
* Has had an allogenic tissue/solid organ transplant.
* For Cohort B1 participants, metastatic disease identified at Screening.
* For Cohort C and GIST participants, clinically significant active bleeding (such as gastrointestinal [GI] bleeding), perforation, obstruction, and other disease-related complications, requiring emergency surgery.
* For Cohort D participants, VHL disease is exclusionary.

Study design
Purpose of the study
Treatment
Allocation to intervention
NA
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/08/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
26/02/2027
Actual
Sample size
Target
322
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Prince of Wales Hospital-Medical Oncology ( Site 1601) - Randwick
Recruitment hospital [2] 0 0
The Royal Melbourne Hospital ( Site 1602) - Parkville
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Iowa
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Michigan
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Tennessee
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
Canada
State/province [11] 0 0
Alberta
Country [12] 0 0
Canada
State/province [12] 0 0
Ontario
Country [13] 0 0
China
State/province [13] 0 0
Beijing
Country [14] 0 0
China
State/province [14] 0 0
Guangdong
Country [15] 0 0
China
State/province [15] 0 0
Shanghai
Country [16] 0 0
China
State/province [16] 0 0
Sichuan
Country [17] 0 0
Denmark
State/province [17] 0 0
Hovedstaden
Country [18] 0 0
Denmark
State/province [18] 0 0
Syddanmark
Country [19] 0 0
France
State/province [19] 0 0
Alsace
Country [20] 0 0
France
State/province [20] 0 0
Bouches-du-Rhone
Country [21] 0 0
France
State/province [21] 0 0
Ile-de-France
Country [22] 0 0
France
State/province [22] 0 0
Paris
Country [23] 0 0
France
State/province [23] 0 0
Rhone-Alpes
Country [24] 0 0
Germany
State/province [24] 0 0
Baden-Wurttemberg
Country [25] 0 0
Germany
State/province [25] 0 0
Bayern
Country [26] 0 0
Germany
State/province [26] 0 0
Nordrhein-Westfalen
Country [27] 0 0
Germany
State/province [27] 0 0
Berlin
Country [28] 0 0
Hungary
State/province [28] 0 0
Budapest
Country [29] 0 0
Israel
State/province [29] 0 0
Ramat Gan
Country [30] 0 0
Israel
State/province [30] 0 0
Tel Aviv
Country [31] 0 0
Italy
State/province [31] 0 0
Campania
Country [32] 0 0
Italy
State/province [32] 0 0
Lombardia
Country [33] 0 0
Italy
State/province [33] 0 0
Brescia
Country [34] 0 0
Italy
State/province [34] 0 0
Milano
Country [35] 0 0
Italy
State/province [35] 0 0
Verona
Country [36] 0 0
Japan
State/province [36] 0 0
Hokkaido
Country [37] 0 0
Japan
State/province [37] 0 0
Kanagawa
Country [38] 0 0
Japan
State/province [38] 0 0
Kochi
Country [39] 0 0
Japan
State/province [39] 0 0
Tokyo
Country [40] 0 0
Japan
State/province [40] 0 0
Kyoto
Country [41] 0 0
Netherlands
State/province [41] 0 0
Utrecht
Country [42] 0 0
Russian Federation
State/province [42] 0 0
Baskortostan, Respublika
Country [43] 0 0
Russian Federation
State/province [43] 0 0
Leningradskaya Oblast
Country [44] 0 0
Russian Federation
State/province [44] 0 0
Moskva
Country [45] 0 0
Singapore
State/province [45] 0 0
Central Singapore
Country [46] 0 0
Spain
State/province [46] 0 0
Asturias
Country [47] 0 0
Spain
State/province [47] 0 0
Madrid, Comunidad De
Country [48] 0 0
Spain
State/province [48] 0 0
Barcelona
Country [49] 0 0
Sweden
State/province [49] 0 0
Skane Lan
Country [50] 0 0
Sweden
State/province [50] 0 0
Stockholms Lan
Country [51] 0 0
Sweden
State/province [51] 0 0
Uppsala Lan
Country [52] 0 0
Sweden
State/province [52] 0 0
Vastra Gotalands Lan
Country [53] 0 0
Turkey
State/province [53] 0 0
Izmir
Country [54] 0 0
Turkey
State/province [54] 0 0
Ankara
Country [55] 0 0
Turkey
State/province [55] 0 0
Istanbul
Country [56] 0 0
United Kingdom
State/province [56] 0 0
Cambridgeshire
Country [57] 0 0
United Kingdom
State/province [57] 0 0
England
Country [58] 0 0
United Kingdom
State/province [58] 0 0
Glasgow City
Country [59] 0 0
United Kingdom
State/province [59] 0 0
London, City Of

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://engagezone.msd.com/ds_documentation.php


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04924075