Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial

NCT07167329 | Recruiting Phase 2 DMC

• 1 other identifier: ACCamargoCC
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The BELIEVE-VHL Trial is a prospective real-life study designed to evaluate the therapeutic effects, benefits, and adverse effects of belzutifan, as well as the timing of treatment response and disease progression in patients with von Hippel-Lindau (VHL) syndrome.

Conditions

Von Hippel Lindau; Von Hippel Lindau Disease; Von Hippel Lindau-Deficient Clear Cell Renal Cell Carcinoma; Hemangioblastoma (HB) of the Central Nervous System (CNS); PNET; Retinal Angiomatous Proliferation; Pheochromocytoma/Paraganglioma; Endolymphatic Sac Tumor

Keywords

Belzutifan; von Hippel-Lindau; Renal Cell Clear Carcinoma; Hemangioblastoma of Central Nervous System; Pharmacogenetics

Outcome Measures

Primary Outcomes (1)

• Objective Tumor Response per RECIST 1.1

  Evaluation of target lesion size according to RECIST 1.1 criteria at baseline, weeks 12, 24, 52, and annually, up to 104 weeks. Imaging modalities will include MRI for solid tumors, 68Ga-DOTATATE PET for pancreatic neuroendocrine tumors (PNET), and retinal fluorescein angiography (FA) for retinal lesions. Unit of Measure: Percentage of participants with objective response.

  From enrollment and initiation of treatment until the earliest of either documented disease progression or death from any cause, with follow-up of up to 104 weeks.

Secondary Outcomes (7)

• Incidence of Anemia (per CTCAE v5.0)

  Baseline to 104 weeks

• Mean Hemoglobin Level Over Time

  Baseline to 104 weeks.

• Erythropoietin Levels Over Time

  Time Frame: Baseline to 104 weeks

• Requirement for Erythropoietin Supplementation

  Baseline to 104 weeks

• Blood Transfusion Requirement

  Baseline to 104 weeks

Study Arms (1)

Oral Belzutifan (WELIREG™)

EXPERIMENTAL

Patients with von Hippel-Lindau Syndrome presenting with lesions or neoplasms requiring treatment with oral Belzutifan (WELIREG™)

Drug: Belzutifan

Interventions

Belzutifan DRUG

Patients with Von Hippel-Lindau Syndrome presenting with lesions or neoplasms requiring treatment with oral Belzutifan.

Oral Belzutifan (WELIREG™)

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 14 years.
• Clinical or genetic confirmation of von Hippel-Lindau (VHL) syndrome.
• Presence of measurable or progressive VHL-associated tumors, as defined by RECIST 1.1 or disease-specific imaging criteria.
• ECOG performance status of 0-2.
• Adequate bone marrow, hepatic, and renal function as defined by laboratory reference values.
• Ability to swallow oral medication.
• Provision of written informed consent prior to enrollment.

You may not qualify if:

• Age \< 14 years.
• Absence of a confirmed diagnosis of von Hippel-Lindau (VHL) syndrome.
• Presence of an active malignancy outside the VHL tumor spectrum within the past 3 years, except for adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or other malignancies considered cured for \>2 years.
• Known hypersensitivity or allergic reaction to belzutifan or any excipient in the formulation.
• History of severe or uncontrolled cardiovascular disease, including but not limited to unstable angina, myocardial infarction within the past 6 months, congestive heart failure requiring treatment, or uncontrolled hypertension.
• Active infectious diseases, including HIV, hepatitis B, or hepatitis C.
• Immunosuppressed status, whether due to underlying disease or ongoing therapy.
• History of significant bleeding disorders, including bleeding diathesis, thrombocytopenia, or coagulopathy.
• Radiotherapy administered within 4 weeks prior to study enrollment.
• Major surgical procedure, including for VHL-related tumors, within 4 weeks prior to study enrollment, or immediate need for surgical intervention for tumor management.
• Malabsorption secondary to prior gastrointestinal surgery or active gastrointestinal disease.
• Current use of concomitant medications known to interact with belzutifan and significantly alter its bioavailability.
• Anticipated low adherence to or planned interruption of belzutifan therapy.

Sponsors & Collaborators

• José Claudio Casali da Rocha: lead
• AC Camargo Cancer Center: collaborator

Study Sites (1)

AC Camargo Cancer Center

São Paulo, São Paulo, 01509900, Brazil

RECRUITING

Related Publications (16)

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• Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R; MK-6482-004 Investigators. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425.

  PMID: 34818478 BACKGROUND

• Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E. Inhibition of hypoxia-inducible factor-2alpha in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021 May;27(5):802-805. doi: 10.1038/s41591-021-01324-7. Epub 2021 Apr 22.

  PMID: 33888901 BACKGROUND

• Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JS. A Review of Von Hippel-Lindau Syndrome. J Kidney Cancer VHL. 2017 Aug 2;4(3):20-29. doi: 10.15586/jkcvhl.2017.88. eCollection 2017.

  PMID: 28785532 BACKGROUND

• Priesemann M, Davies KM, Perry LA, Drake WM, Chew SL, Monson JP, Savage MO, Johnston LB. Benefits of screening in von Hippel-Lindau disease--comparison of morbidity associated with initial tumours in affected parents and children. Horm Res. 2006;66(1):1-5. doi: 10.1159/000093008. Epub 2006 Apr 27.

  PMID: 16651847 BACKGROUND

• Daniels AB, Tirosh A, Huntoon K, Mehta GU, Spiess PE, Friedman DL, Waguespack SG, Kilkelly JE, Rednam S, Pruthi S, Jonasch EA, Baum L, Chahoud J; International VHL Surveillance Guidelines Consortium. Guidelines for surveillance of patients with von Hippel-Lindau disease: Consensus statement of the International VHL Surveillance Guidelines Consortium and VHL Alliance. Cancer. 2023 Oct 1;129(19):2927-2940. doi: 10.1002/cncr.34896. Epub 2023 Jun 19. No abstract available.

  PMID: 37337409 BACKGROUND

• Krauss T, Ferrara AM, Links TP, Wellner U, Bancos I, Kvachenyuk A, Villar Gomez de Las Heras K, Yukina MY, Petrov R, Bullivant G, von Duecker L, Jadhav S, Ploeckinger U, Welin S, Schalin-Jantti C, Gimm O, Pfeifer M, Ngeow J, Hasse-Lazar K, Sanso G, Qi X, Ugurlu MU, Diaz RE, Wohllk N, Peczkowska M, Aberle J, Lourenco DM Jr, Pereira MAA, Fragoso MCBV, Hoff AO, Almeida MQ, Violante AHD, Quidute ARP, Zhang Z, Recasens M, Diaz LR, Kunavisarut T, Wannachalee T, Sirinvaravong S, Jonasch E, Grozinsky-Glasberg S, Fraenkel M, Beltsevich D, Egorov VI, Bausch D, Schott M, Tiling N, Pennelli G, Zschiedrich S, Darr R, Ruf J, Denecke T, Link KH, Zovato S, von Dobschuetz E, Yaremchuk S, Amthauer H, Makay O, Patocs A, Walz MK, Huber TB, Seufert J, Hellman P, Kim RH, Kuchinskaya E, Schiavi F, Malinoc A, Reisch N, Jarzab B, Barontini M, Januszewicz A, Shah N, Young WF Jr, Opocher G, Eng C, Neumann HPH, Bausch B. Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2018 Sep;25(9):783-793. doi: 10.1530/ERC-18-0100. Epub 2018 May 10.

  PMID: 29748190 BACKGROUND

• Dallagnol TN, Da Cas E, Junior OR, Casali-da-Rocha JC. Comprehensive characterization and building of National Registry of von Hippel-Lindau disease in Brazil. Mol Genet Genomic Med. 2023 Apr;11(4):e2136. doi: 10.1002/mgg3.2136. Epub 2023 Jan 10.

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• Gomy I, Molfetta GA, de Andrade Barreto E, Ferreira CA, Zanette DL, Casali-da-Rocha JC, Silva WA Jr. Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation. Fam Cancer. 2010 Dec;9(4):635-42. doi: 10.1007/s10689-010-9357-2.

  PMID: 20567917 BACKGROUND

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  PMID: 15611513 BACKGROUND

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  PMID: 12624160 BACKGROUND

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MeSH Terms

Conditions

von Hippel-Lindau Disease; Hemangioblastoma; Neuroectodermal Tumors, Primitive; Pheochromocytoma; Paraganglioma; Carcinoma, Renal Cell

Interventions

belzutifan

Condition Hierarchy (Ancestors)

Neurocutaneous Syndromes; Nervous System Diseases; Angiomatosis; Vascular Diseases; Cardiovascular Diseases; Ciliopathies; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Hemangioma, Capillary; Hemangioma; Neoplasms, Vascular Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Adenocarcinoma; Carcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Central Study Contacts

José Claudio Casali da Rocha, Head of Oncogenetics

CONTACT

+55 41 98505 8585; casali.rocha@accamargo.org.br

José Reinaldo De Oliveira Junior

CONTACT

+55 31 99549 3678; j.junior@accamargo.org.br

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Department of Oncogenetics

Model Details: The BELIEVE-VHL Trial is a prospective cohort study designed to evaluate the effectiveness and adverse effects of belzutifan in 100 patients with von Hippel-Lindau syndrome enrolled in a single intervention arm. The trial is structured as a basket trial, including all VHL-associated tumors, in patients aged 14 years or older and at any disease stage. The intervention consists of oral administration of belzutifan (Welireg) 120 mg once daily in patients with clinically or genetically confirmed VHL who are symptomatic or present with progressive tumors.

Study Record Dates

• First Submitted: January 25, 2025
• First Posted: September 11, 2025
• Study Start: January 1, 2024
• Primary Completion: February 1, 2026
• Study Completion (Estimated): January 1, 2030
• Last Updated: September 11, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: At any time of the study as the results are analyzed, publicly presented and published
• Access Criteria: Data will be shared after Transfer Data Agreement between Principal Investigators and institutions, based on new bilateral approval on Ethics and Research Committees of both involved oncology centers.

Locations

BR (1)