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

NCT ID: NCT07167329

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-01
• Study Completion Date: 2030-01-01

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.

Detailed Description

PRIMARY OBJECTIVE:

To evaluate the therapeutic effects, benefits, and adverse effects associated with belzutifan treatment, as well as the timing of treatment response and/or disease progression.

SECONDARY OBJECTIVES

1. To evaluate the association of host intrinsic factors with toxicity and treatment response in a Brazilian cohort of patients with von Hippel-Lindau syndrome treated with belzutifan.

2. To assess hemoglobin and erythropoietin levels during the first six months of treatment, and to document the need for subcutaneous erythropoietin supplementation in patients who develop grade 2-3 anemia, fatigue, or hypoxia.

3. To evaluate the potential impact of erythropoietin supplementation on tumor growth during belzutifan treatment.

4. To assess health-related quality of life and patient perceptions regarding VHL syndrome using validated questionnaires and instruments.

5. To conduct a pharmacoeconomic analysis in the cohort of patients with access to belzutifan, assessing its impact on healthcare costs compared to the natural history of the disease.

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Oral Belzutifan (WELIREG™)

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

Group Type: EXPERIMENTAL

Belzutifan

Intervention Type: DRUG

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

Interventions

Belzutifan

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.

• Minimum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AC Camargo Cancer Center

OTHER

Sponsor Role: collaborator

José Claudio Casali da Rocha

OTHER

Sponsor Role: lead

Responsible Party

José Claudio Casali da Rocha

Head of Department of Oncogenetics

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

AC Camargo Cancer Center

São Paulo, São Paulo, Brazil

Site Status: RECRUITING

Countries

Brazil

Central Contacts

José Claudio Casali da Rocha, Head of Oncogenetics

Role: CONTACT

casali.rocha@accamargo.org.br

+55 41 98505 8585

José Reinaldo De Oliveira Junior

Role: CONTACT

j.junior@accamargo.org.br

+55 31 99549 3678

Facility Contacts

Giovana Tardin Torrezan, Research Coordinator

Role: primary

cep_accamargo@accamargo.org.br

+55 11 2189 5020 ext. 5020

Sandra Almeida, Administrative CEP

Role: backup

cep_accamargo@accamargo.org.br

+55 11 2189 5020 ext. 5020

References

Else T, Jonasch E, Iliopoulos O, Beckermann KE, Narayan V, Maughan BL, Oudard S, Maranchie JK, Iversen AB, Goldberg CM, Fu W, Perini RF, Liu Y, Linehan WM, Srinivasan R. Belzutifan for von Hippel-Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study. Clin Cancer Res. 2024 May 1;30(9):1750-1757. doi: 10.1158/1078-0432.CCR-23-2592.

Reference Type: BACKGROUND

PMID: 38393723 (View on PubMed)

Eriksson M, Lindstrom B. Validity of Antonovsky's sense of coherence scale: a systematic review. J Epidemiol Community Health. 2005 Jun;59(6):460-6. doi: 10.1136/jech.2003.018085.

Reference Type: BACKGROUND

PMID: 15911640 (View on PubMed)

Bagattini AM, Camey SA, Miguel SR, Andrade MV, de Souza Noronha KVM, de C Teixeira MA, Lima AF, Santos M, Polanczyk CA, Cruz LN. Electronic Version of the EQ-5D Quality-of-Life Questionnaire: Adaptation to a Brazilian Population Sample. Value Health Reg Issues. 2018 Dec;17:88-93. doi: 10.1016/j.vhri.2017.11.002. Epub 2018 May 11.

Reference Type: BACKGROUND

PMID: 29754016 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34818478 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33888901 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28785532 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16651847 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 37337409 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29748190 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 36625343 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20567917 (View on PubMed)

Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990 Nov;77(283):1151-63. doi: 10.1093/qjmed/77.2.1151.

Reference Type: BACKGROUND

PMID: 2274658 (View on PubMed)

Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004 Dec 15;22(24):4991-5004. doi: 10.1200/JCO.2004.05.061.

Reference Type: BACKGROUND

PMID: 15611513 (View on PubMed)

Rocha JC, Silva RL, Mendonca BB, Marui S, Simpson AJ, Camargo AA. High frequency of novel germline mutations in the VHL gene in the heterogeneous population of Brazil. J Med Genet. 2003 Mar;40(3):e31. doi: 10.1136/jmg.40.3.e31. No abstract available.

Reference Type: BACKGROUND

PMID: 12624160 (View on PubMed)

Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology. 1995 Mar;194(3):629-42. doi: 10.1148/radiology.194.3.7862955.

Reference Type: BACKGROUND

PMID: 7862955 (View on PubMed)

Chittiboina P, Lonser RR. Von Hippel-Lindau disease. Handb Clin Neurol. 2015;132:139-56. doi: 10.1016/B978-0-444-62702-5.00010-X.

Reference Type: BACKGROUND

PMID: 26564077 (View on PubMed)

Other Identifiers

ACCamargoCC

Identifier Type: -

Identifier Source: org_study_id