An Exploratory Phase 2 Study for Evaluating CNS Efficacy of Belvarafenib in Patients With BRAF-Altered Solid Tumors
This is a Phase 2, open-label, single-arm clinical study designed to evaluate the efficacy and safety of Belvarafenib in patients with BRAF-altered primary brain tumors (Cohort 1) and metastatic brain tumors (Cohort 2). Eligible patients are those with a confirmed BRAF alteration identified by next-generation sequencing (NGS). Patients who meet the eligibility criteria will receive a detailed explanation of the study, including its purpose, procedures, potential benefits, and risks. Only patients who voluntarily provide written informed consent will be enrolled. All enrolled patients will receive Belvarafenib monotherapy at a dose of 450 mg twice daily (BID). The study drug will be taken orally within 30 minutes after meals with at least 200 mL of water, preferably at approximately 12-hour intervals each day. One treatment cycle is defined as 28 consecutive days of continuous dosing without a planned treatment break. Patients will receive treatment for six cycles (approximately six months) as the initial treatment period. Treatment may be extended or discontinued earlier at the investigator's discretion based on clinical benefit, disease status, and tolerability. During the study, patients will undergo regular clinical evaluations, including physical examinations, vital sign assessments, laboratory tests, and monitoring for adverse events. Radiologic assessments using MRI and/or CT will be performed at scheduled intervals to evaluate tumor response and disease progression. The study aims to determine whether Belvarafenib can control tumor growth, delay disease progression, and improve clinical outcomes in patients with BRAF-altered brain tumors. If treatment-related toxicities occur, dose reductions are permitted according to the protocol. The dose may be reduced from 450 mg BID to 300 mg BID, and subsequently to 200 mg BID, if clinically indicated. Temporary treatment interruption may also be implemented until toxicity resolves. If unacceptable toxicity persists despite dose modification, treatment will be permanently discontinued. Study treatment may be discontinued if any of the following occurs: confirmed disease progression, unacceptable toxicity, withdrawal of informed consent, inability to comply with the study protocol, receipt of other anticancer therapies that may interfere with study outcomes, or if the investigator determines that continued treatment is no longer in the patient's best interest. However, if radiologic disease progression is observed but the investigator determines that the patient continues to derive clinical benefit, treatment beyond progression may be considered after discussion with the sponsor, with appropriate documentation of the rationale. After discontinuation of study treatment, patients will receive the most appropriate subsequent management, including best supportive care (BSC) or other anticancer therapies, as determined by the treating investigator. Follow-up assessments will continue according to the study protocol. The primary objective of this study is to evaluate the efficacy of Belvarafenib in patients with BRAF-altered primary and metastatic brain tumors, while also assessing its safety profile. The results of this study are expected to provide important clinical evidence supporting the development of new treatment strategies for patients with BRAF-altered brain tumors.
• Male or female patients aged 19 years or older.
• Histologically confirmed primary brain tumor or metastatic brain tumor.
• Documented BRAF mutation, including point mutations (e.g., V600E) or BRAF fusion mutations.
• Willing and able to provide written informed consent prior to participation in the study.
• Estimated life expectancy of at least 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Adequate organ function demonstrated by laboratory assessments performed within 14 days prior to the first dose of study treatment, meeting all of the following criteria:
‣ Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
⁃ Hemoglobin ≥ 9 g/dL
⁃ Platelet count ≥ 100 × 10⁹/L
⁃ PT/INR and aPTT ≤ 1.5 × upper limit of normal (ULN)
⁃ Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients with Gilbert syndrome)
⁃ AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN in patients with liver metastases)
⁃ Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 × ULN in patients with liver or bone metastases)
⁃ Albumin ≥ 2.5 g/dL
⁃ Amylase ≤ 1.5 × ULN
⁃ Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) \> 50 mL/min using the Cockcroft-Gault formula
• Women of childbearing potential (defined as women from menarche until 1 year after menopause unless permanently sterile) and men with partners of childbearing potential must agree to use highly effective contraception throughout the study and for 3 months after the last dose of Belvarafenib.
• Women of childbearing potential must have a negative pregnancy test during screening unless surgically sterile.
• Acceptable contraceptive methods include:
⁃ Hormonal contraception
⁃ Intrauterine device (IUD) or intrauterine system (IUS)
⁃ Vasectomy or bilateral tubal occlusion
⁃ Complete abstinence Barrier methods (e.g., male or female condoms); if barrier methods are used alone, the use of two complementary barrier methods is recommended.
• Additional Inclusion Criteria for Cohort 1 (Primary Brain Tumors) 1) Patients with BRAF-mutant primary brain tumors who meet at least one of the following conditions:
• \- No available or appropriate local treatment options (e.g., surgery or radiotherapy);
⁃ Radiographic evidence of disease recurrence or progression following standard therapy (including surgery and/or chemoradiotherapy \[CCRT\]), with no further suitable standard treatment available;
⁃ Standard treatment is considered inappropriate or unavailable in the investigator's judgment.
⁃ Additional Inclusion Criteria for Cohort 2 (Metastatic Brain Tumors)
∙ <!-- -->
• Patients with brain metastases from BRAF-mutant solid tumors.
• Patients with radiographic evidence of disease progression after receiving the standard treatment for the primary malignancy, or whose disease is refractory to conventional therapy, regardless of prior exposure to BRAF-targeted therapy, and who have no available or appropriate local treatment options (e.g., surgery or radiotherapy).
• At least one measurable intracranial lesion, with a maximum of five target lesions, as defined by the Response Assessment in Neuro-Oncology (RANO) criteria.