Belzutifan/MK-6482 for the treatment of PPGL or pNET or VHL disease

JRCT ID: jRCT2011220024

Registered date:04/11/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Pheochromocytoma/Paraganglioma, Pancreatic Neuroendocrine Tumor, VHL Disease-Associated Tumors
• Date of first enrollment: 30/11/2022
• Target sample size: 18
• Countries of recruitment: United States,Japan,Canada,Japan,Denmark,Japan,France,Japan,Germany,Japan,Hungary,Japan,Israel,Japan,Italy,Japan,Netherlands,Japan,Russia,Japan,Spain,Japan,Sweden,Japan,Turkey,Japan,United Kingdom,Japan,Australia,Japan,New Zealand,Japan,Singapore,Japan,China,Japan
• Study type: Interventional
• Intervention(s): Belzutifan 120 mg, oral, once daily (QD) until progressive disease or discontinuation

Outcome(s)

• Primary Outcome: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)

Secondary Outcome

1. Duration of Response (DOR) as Assessed by BICR
2. Time to Response (TTR) as Assessed by BICR
3. Disease Control Rate (DCR) as Assessed by BICR
4. Progressive Free Survival (PFS) as Assessed by BICR
5. Overall Survival (OS)
6. Safety
7. Time to Surgery (TTS)

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

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.
-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.

Exclude 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 PPGL for Cohort A1 and pNET for Cohort A2) are localized without immediate need for intervention.
-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 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.
-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 locoregional therapies or radiation within the past 4 weeks of first dose of study intervention.
-Has received prior treatment with any HIF-2alpha 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.
-Has had an allogenic tissue/solid organ transplant.
-For Cohort B1 participants, metastatic disease identified at Screening.

Related Information

• Primary Sponsor: Hoki Toshifumi
• Secondary ID(s): NCT04924075