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.

The purpose of this study is to evaluate the efficacy and safety of Belvarafenib, an oral pan-RAF inhibitor, in patients with BRAF-altered primary brain tumors and BRAF-altered metastatic brain tumors.

The study includes two groups of patients:

Cohort 1: Patients with primary brain tumors harboring BRAF alterations. Cohort 2: Patients with metastatic brain tumors harboring BRAF alterations.

The study will evaluate whether Belvarafenib can:

Reduce or control tumor growth. Delay disease progression. Improve survival outcomes. Demonstrate treatment activity in brain lesions as well as in tumors outside the brain (for patients with metastatic disease).

In addition, the study will assess changes in neurological symptoms, physical function, and overall health-related quality of life using the PROMIS Global Health Scale (PROMIS-GH) to better understand the relationship between treatment response and patients' clinical outcomes.

The results of this study are expected to provide important evidence regarding the potential role of Belvarafenib as a treatment option for patients with BRAF-altered primary and metastatic brain tumors.

Inclusion Criteria: (Applicable to Both Cohorts)

1. Male or female patients aged 19 years or older.

2. Histologically confirmed primary brain tumor or metastatic brain tumor.

3. Documented BRAF mutation, including point mutations (e.g., V600E) or BRAF fusion mutations.

4. Willing and able to provide written informed consent prior to participation in the study.

5. Estimated life expectancy of at least 3 months.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

7. 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

8. 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.

9. 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.

10. Additional Inclusion Criteria for Cohort 2 (Metastatic Brain Tumors)

1. Patients with brain metastases from BRAF-mutant solid tumors.
2. 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).
3. At least one measurable intracranial lesion, with a maximum of five target lesions, as defined by the Response Assessment in Neuro-Oncology (RANO) criteria.

Exclusion Criteria: (Applicable to Both Cohorts)

1. History of hypersensitivity to BRAF inhibitors or related compounds. Prior treatment with a BRAF inhibitor is permitted.

2. Presence of hematologic malignancy or double primary malignancies at screening. The following second primary malignancies are permitted:

   • Carcinoma in situ of the cervix successfully treated at least 1 year before enrollment;
   • Papillary thyroid carcinoma treated with curative surgical resection;
   • Completely resected cutaneous squamous cell carcinoma.

3. Any of the following:

   - Receipt of an investigational medicinal product within 28 days or within five half-lives (whichever is longer) before the first dose of study treatment;

   - Major surgery within 28 days before the first dose of study treatment;

   • Newly initiated or recently increased systemic corticosteroid therapy equivalent to ≥10 mg/day of prednisolone within 28 days before the first dose.
   • Patients receiving a stable dose for at least 2 weeks or requiring continued corticosteroid treatment after surgery may be enrolled at the investigator's discretion;
   • Current treatment with systemic immunosuppressive agents or anticipated need for continuous systemic immunosuppression during the study. Topical preparations, inhaled corticosteroids, ophthalmic preparations, and local injections are permitted;
   • More than five prior systemic anticancer treatment regimens.

4. Unresolved adverse events of CTCAE Grade ≥2 from previous anticancer therapy at screening, except alopecia.

5. Any of the following cardiovascular conditions:

   • Mean QTcF >440 msec;
   • New York Heart Association (NYHA) Class III or IV heart failure;
   • Cardiac metastasis;
   • Uncontrolled electrolyte abnormalities (hyponatremia, hypokalemia, hypocalcemia, or hypomagnesemia);
   • Within 6 months before the first dose: unstable angina, acute coronary syndrome (including myocardial infarction), uncontrolled arrhythmia (except sinus arrhythmia or adequately controlled atrial fibrillation for at least 30 days), symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack;
   • Coronary angioplasty, coronary/peripheral artery bypass graft surgery, or coronary stent placement within 6 months before the first dose;
   • History of congenital long QT syndrome or clinically significant CTCAE Grade ≥2 ventricular or atrial dysrhythmias.

6. Any of the following ophthalmologic disorders:

   - History or evidence at screening of retinal vein occlusion (RVO), central serous retinopathy (CSR), or neovascular macular degeneration;

   - Intraocular pressure ≥21 mmHg with glaucoma.

7. Current or prior interstitial lung disease (ILD), drug-induced ILD, or radiation pneumonitis requiring corticosteroid treatment.

8. Uncontrolled hypertension.

9. Uncontrolled infectious or neurologic disease, active infection requiring intravenous antibiotics, known human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) infection, or active hepatitis C virus (HCV) infection.

10. Inability to swallow oral tablets or any gastrointestinal condition that may interfere with the administration, absorption, or metabolism of Belvarafenib, including refractory nausea or vomiting, malabsorption syndrome, external biliary shunt, significant small bowel resection, clinically significant gastrointestinal bleeding, acute pancreatitis within 28 days before the first dose, or diverticulitis.

11. Requirement for continuous treatment with CYP2C8 substrate medications (e.g., amodiaquine) or rifampin.

12. Known or suspected substance abuse or alcohol abuse.

13. Psychological, social, geographic, psychiatric, or congenital conditions that, in the investigator's judgment, would interfere with compliance with the study protocol or follow-up.

14. Pregnant or breastfeeding women, or women of childbearing potential planning to become pregnant during the study.

15. Any other medical condition, laboratory abnormality, or circumstance that, in the investigator's judgment, would make the participant unsuitable for study treatment.

16. Additional Exclusion Criteria for Cohort 1 (Primary Brain Tumors) 1) New intracranial lesions identified within 12 weeks after prior brain radiotherapy when radiation necrosis cannot be reliably distinguished from tumor progression.

17. Additional Exclusion Criteria for Cohort 2 (Metastatic Brain Tumors) 1) Clinically unstable disease due to uncontrolled primary malignancy. 2) Requirement for concurrent systemic anticancer therapy (e.g., chemotherapy, targeted therapy, or other systemic anticancer treatment) for extracranial disease during the study.

Individual participant data (IPD) will not be shared because there is no plan for public data sharing under the current study protocol. Data will be used solely for the purposes of this study and managed in accordance with applicable regulations, institutional policies, and participant confidentiality requirements.