• Age

• a) Patients must be less than or equal to 25 years of age at the time of enrollment.

• Study Group

• a) Progressive/Recurrent LGG (non-NF1) with documented BRAF or CRAF alteration as identified through molecular assays as routinely performed at CLIA or other similar certified laboratories.

• Diagnosis

‣ All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.

⁃ Patient must have progressive or recurrent LGG.

⁃ Must have at least 1 measurable lesion, as defined by RANO-LGG criteria.

⁃ Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO grade I and II) by WHO classification of Tumors of the Central Nervous system -5th edition revised with exception of subependymal giant cell astrocytoma.

• Prior Therapy

‣ Must have received at least 1 line of systemic therapy prior (at least a vinca alkaloid and/or single agent carboplatin and/or a MEK or BRAF inhibitor) and have documented evidence of radiographic progression.

⁃ Patients must have fully recovered from the acute toxic effects (≤ Grade I) of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable.

• i. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) ii. Radiation therapy (XRT): Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of combination therapy. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more measurable lesions are eligible. At least 2 weeks after the last dose fraction of XRT to the non-target lesion.

• iii. Investigational agent or any other anticancer therapy not defined above: At least four weeks prior to planned start of combination therapy, or five half-lives, whichever is shorter.

• iv. Patients must have recovered from acute effects of any prior surgery. v. Chronic toxicities from prior anticancer therapy must be stable as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 2, except ongoing retinopathy which must be ≤ Grade 1.

• Performance Level

• a) Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Tumor Tissue Sample Confirmation that an archival tumor tissue sample is available. If an archival tumor tissue sample is not available, a fresh biopsy should be performed at baseline. Submission of tumor tissue and a blood sample are mandatory and must be submitted within 14 days from enrollment onto the study and prior to initiation of treatment. Biopsy may be either at initial diagnosis or recurrence.

• Organ function

• a) Adequate bone marrow function defined as: i. Absolute neutrophil count ≥ 1000/mm3 ii. Platelet count (unsupported) ≥ 100 x 109/L (transfusions allowed per institutional guidelines; last transfusion \> 2 weeks prior to enrollment) iii. Hemoglobin (unsupported)≥ 10.0 g/dL (transfusions allowed per institutional guidelines; last transfusion \> 4 weeks prior to enrollment) iv. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor.

• b) Adequate hepatic and renal function defined as: i. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (patients with documented Gilbert's disease may be enrolled with sponsor approval and total bilirubin ≤ 2 x ULN) ii. Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 x ULN iii. Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) ≤ 2.5 x ULN iv. Serum creatinine within normal limits or estimated glomerular filtration rate

• ≥ 60 ml/min/1.73 m2 based on local institutional practice for determination. c) Thyroid functions tests within institutional normal range. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting therapy are eligible.

• d) Adequate cardiac function defined as: i. Left ventricular ejection fraction (LVEF) of ≥ 50% as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional shortening (FS) ≥ 25% (Tissot et al., 2018) as measured by ECHO, within 14 days before enrollment (while not receiving medications for cardiac function). If normal practice at the institution is to provide the LVEF result as a range of values, then the upper value of the range will be used to determine the result.

• ii. QTc (by Fridericia's formula) \< 470ms as measured by electrocardiogram (ECG) within 14 days before enrollment (while not receiving medications for cardiac function).

• e) Adequate central nervous system (CNS) function defined as: i. Patients with seizures should be stable and not have experienced a significant increase in seizure frequency within 14 days prior to enrollment.

• ii. Patients with neurologic deficits should have deficits that are stable for a minimum of 14 days prior to enrollment.

• iii. Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose, no increase or decrease) for 14 days prior to enrollment.

• Study specific

‣ Baseline ophthalmology assessment within 28 days of study enrollment.

⁃ MRI assessment within 28 days of study enrollment. MRI done for clinical indication but within the window for study would be permitted as baseline.

⁃ Ability to comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation.

⁃ Willingness of male and female patients with reproductive potential to use double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Effective birth control methods are described in Appendix H.

⁃ Ability to swallow tablets or liquid, or gastric access via a nasal or gastric tube.

⁃ Patient is able to start treatment within 14 working days of screening.

⁃ Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study ICF and applicable pediatric assent form before initiation of any protocol related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.