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

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

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.

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.

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.