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

Official title

The BELIEVE-VHL Trial: A Real-world Longitudinal Study on Belzutifan's Effectiveness, Pharmacogenetics, and Pharmacoeconomics in Von Hippel-Lindau (VHL) Syndrome Using the HIF2α Inhibitor Belzutifan

Overview

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.

Interventions

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

Primary outcome measures

• Objective Tumor Response per RECIST 1.1 [Time frame: 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 outcome measures (7)

• Incidence of Anemia (per CTCAE v5.0) [Time frame: Baseline to 104 weeks]
• Mean Hemoglobin Level Over Time [Time frame: Baseline to 104 weeks.]
• Erythropoietin Levels Over Time [Time frame: Time Frame: Baseline to 104 weeks]
• Requirement for Erythropoietin Supplementation [Time frame: Baseline to 104 weeks]
• Blood Transfusion Requirement [Time frame: Baseline to 104 weeks]
• Patient-Reported Quality of Life (EORTC QLQ-C30) [Time frame: Baseline to 24 months]
• Pharmacoeconomic Evaluation of Belzutifan Therapy in Individuals with von Hippel-Lindau Syndrome [Time frame: Retrospective analysis of the 5 years prior to belzutifan initiation and prospective follow-up for up to 2 years after treatment initiation.]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 1 center

• AC Camargo Cancer Center — São Paulo

Publications

• 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. PMID 38393723
• 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. PMID 15911640
• 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. PMID 29754016
• 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
• 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
• 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
• 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
• 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):292 PMID 37337409

Identifiers

NCT: NCT07167329 · ACCamargoCC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗