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

Not Applicable

Recruiting

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

• Registration Number: NCT07167329
• Lead Sponsor: José Claudio Casali da Rocha

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.

Study Timeline

• Study Start: 2024-01-01
• Study First Submitted: 2025-01-25
• Status Verified: 2025-09
• Study First Submitted QC: 2025-09-09
• Last Update Submitted: 2025-09-09
• Study First Posted: 2025-09-11
• Last Update Posted: 2025-09-11
• Primary Completion: 2026-02-01
• Study Completion: 2030-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Objective Tumor Response per RECIST 1.1	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.	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.

Secondary Outcome Measures

Name	Time	Method
Incidence of Anemia (per CTCAE v5.0)	Baseline to 104 weeks	Number of participants developing grade ≥2 anemia during treatment with belzutifan, evaluated according to CTCAE version 5.0.; Correlate hematologic outcomes with tumor response (RECIST 1.1) and lesion dynamics to identify potential predictive biomarkers.; Unit of Measure: Percentage of participants.
Mean Hemoglobin Level Over Time	Baseline to 104 weeks.	Longitudinal change in hemoglobin levels (g/dL) at months 1, 3, 6, 12, and annually thereafter.; Unit of Measure: g/dL.
Patient-Reported Quality of Life (EORTC QLQ-C30)	Baseline to 24 months	Change in health-related quality of life scores measured by the EORTC QLQ-C30: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, version 3.0, at baseline, months 1, 3, 6, 12, and annually thereafter.; It consists of 28 items evaluating symptom burden and functional status, each scored on a 4-point Likert scale (1 = "Not at all," 2 = "A little," 3 = "Quite a bit," 4 = "Very much"). In addition, two items assess overall health and overall quality of life, each rated on a 7-point scale (1 = "Very poor" to 7 = "Excellent") All treatment modifications-including interruptions, dose reductions, or discontinuations-will be recorded throughout the study.; Unit of Measure: Score from 0 to 100 (higher score indicates better quality of life).
Erythropoietin Levels Over Time	Time Frame: Baseline to 104 weeks	Longitudinal change in endogenous erythropoietin levels (mIU/mL) at months 1, 3, 6, 12, and annually thereafter.; Unit of Measure: mIU/mL.
Requirement for Erythropoietin Supplementation	Baseline to 104 weeks	Proportion of participants requiring subcutaneous erythropoietin supplementation for symptomatic or grade ≥3 anemia, including dose, frequency, and duration.; Unit of Measure: Percentage of participants.
Blood Transfusion Requirement	Baseline to 104 weeks	Number of participants requiring at least one blood transfusion during treatment with belzutifan.; Unit of Measure: Percentage of participants.
Pharmacoeconomic Evaluation of Belzutifan Therapy in Individuals with von Hippel-Lindau Syndrome	Retrospective analysis of the 5 years prior to belzutifan initiation and prospective follow-up for up to 2 years after treatment initiation.	The pharmacoeconomic analysis will be conducted in the same cohort of participants treated with belzutifan. Retrospective data on direct medical costs, expressed in Brazilian Reais (R$), will be collected, including expenses related to medications, surgical procedures, and hospital admissions. Indirect costs, particularly those related to productivity losses, will also be assessed and quantified as a percentage reduction compared with healthy employees or as hours/days lost due to illness or treatment-related absenteeism during the preceding five years. All cost data will be analyzed on a per-patient-per-month (PPPM) basis, stratified by defined time intervals. Cost-effectiveness will be evaluated by comparing healthcare costs before and after belzutifan initiation, accounting for changes in procedure frequency and overall resource utilization. Unit of Measure: Brazilian Reais (R$) per PPPM.

Trial Locations

Locations (1)

AC Camargo Cancer Center; 🇧🇷 São Paulo, São Paulo, Brazil