• Progression free survival for 3 treatment cohorts [ Time Frame: up to 1 year ]
  Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status
• Overall Survival [ Time Frame: up to 2 years ]
  median overall survival
• Duration of response [ Time Frame: up to 1 year ]
  Time from response to progression. Response is defined by RANO: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.
• Number of participants with adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [ Time Frame: 1 year ]

Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs).

Secondary Objectives

1. Estimate efficacy as measured by progression-free survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug.
2. Evaluate duration of response in subjects who have a partial or complete response.
3. Quantify the time-to-response among subjects who have a radiologic response.
4. Estimate efficacy as measured by overall survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug.
5. Characterize the toxicity profile of the combination of encorafenib and binimetinib in this patient population.

There are two arms: medical and surgical. Subjects on the surgical arm must have a high-grade glioma or a known BRAF-mutated low-grade glioma with high clinical suspicion for progression to high-grade.

Medical: Following enrollment, patients will receive encorafenib and binimetinib at the FDA-approved dose of 450 mg of encorafenib once daily and the FDA-approved dose of 45 mg of binimetinib twice daily separated by 12 hours, continuously in 28-day cycles until progression or unacceptable toxicity. Patients will be followed by routine blood work, and general and neurological examination. A brain MRI will be performed prior to every odd-numbered cycle (every 8 weeks). Response will be assessed by RANO criteria. Patients may remain on study and receive treatment until progression or other reason.

Surgical: These subjects will take encorafenib and binimetinib in combination at their FDA-approved doses for 10-14 days prior to surgery. The last dose of both drugs will be administered two hours prior to surgery. Specimens will be collected during surgery. After surgery, the subjects will not take further encorafenib or binimetinib until a study visit to assess their neurological exam, physical exam, and performance status, at 2-6 weeks post-operatively. At time of restarting combination treatment, subjects will follow the schedule for the medical cohort, and will continue treatment until progression.

• High Grade Glioma
• BRAF V600E
• BRAF V600K
• Anaplastic Astrocytoma
• Anaplastic Pleomorphic Xanthoastrocytoma
• Gliosarcoma
• Glioblastoma

• Drug: Encorafenib
  450mg QD 28 day cycle
• Drug: Binimetinib
  45mg BID 28 day cycle
• Biological: Research Bloods
  Baseline; pre-cycle 3; Pre-cycle 7; off Treatment
  Other Name: Circulating Tumor DNA
• Biological: Tumor Tissue
  at time of surgery contrast enhancing and non enhancing tumor; 20 unstained slides

• Experimental: Treatment Cohort 1 AA & GBM

  Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

  Research Bloods

  Interventions:

  • Drug: Encorafenib
  • Drug: Binimetinib
  • Biological: Research Bloods
• Experimental: Treatment Cohort 2 anaplastic PXAs

  Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

  Research Bloods

  Interventions:

  • Drug: Encorafenib
  • Drug: Binimetinib
  • Biological: Research Bloods
• Experimental: Surgical Arm

  Pre-op -14 days: Encorafenib 450mg QD and Binimetinib 45mg BID last dose of both drugs 2hrs prior to surgery

  Tumor; research blood; CSF samples

  post surgery: Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

  Interventions:

  • Drug: Encorafenib
  • Drug: Binimetinib
  • Biological: Research Bloods
  • Biological: Tumor Tissue
• Experimental: Treatment Cohort 3 Other Tumors

  Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

  Research Bloods

  Interventions:

  • Drug: Encorafenib
  • Drug: Binimetinib
  • Biological: Research Bloods

Inclusion Criteria:

1. Patients receiving any other standard or investigational agents are ineligible.
2. Patients with history or current evidence of the following conditions are excluded: neuromuscular disorder with associated elevated CK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy), pancreatitis, retinal vein occlusion, uncontrolled HIV, or Hepatitis B/C. An exception will be made for (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and for subjects with cleared HBV and HCV infections, who may enroll in the study.
3. Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing disease by MRI imaging within 30 days of starting treatment.

4. The following intervals from previous treatments are required to be eligible:

   • 12 weeks from the completion of radiation.
   • 16 weeks from an anti-VEGF therapy
   • 4 weeks from a nitrosourea chemotherapy
   • 3 weeks from a non-nitrosourea chemotherapy
   • 2 weeks or 5 half-lives from any investigational (not FDA-approved) agents
   • 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)
5. Patients must be 18 years of age or older.
6. Patients must have a Karnofsky Performance (KPS) Status ≥ 60%
7. Patients must have adequate organ and marrow function within 30 days of starting treatment.
8. Patients must be able to provide written informed consent.
9. Women of childbearing potential must have a negative serum pregnancy test prior to study start. Women of childbearing potential must agree to use adequate contraception (intrauterine device, barrier, or other non-hormonal method of birth control; or abstinence) and not to donate ova from screening through 30 days after the last dose of study drug. Male participants must also agree to use adequate contraception and not to donate sperm from screening until 90 days after the last dose of study drug.
10. Patients must be maintained on a stable or decreasing dose of systemic corticosteroid regimen (no increase for 5 days) prior to baseline MRI. Topical and inhaled steroid treatment is allowed.
11. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with other malignancies must be disease-free for ≥ 2 years.
12. Patients must be able to swallow tablets and capsules.
13. Patients must have a tumor tissue form completed and signed by a pathologist (see Section 9.6.4). The tumor tissue form must indicate availability of archived tissue. The archived tissue should be from the most recent tumor resection, demonstrating active tumor when sufficient tissue is available. If sufficient tissue is not available from the most recent surgery, then tissue from an earlier surgery is acceptable, if available, including from the initial resection at diagnosis.

Exclusion Criteria:

1. Patients receiving any other standard or investigational agents are ineligible.
2. Patients with history or current evidence of the following conditions are excluded: neuromuscular disorder with associated elevated CK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy), pancreatitis, retinal vein occlusion, uncontrolled HIV, or Hepatitis B/C. An exception will be made for (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and for subjects with cleared HBV and HCV infections, who may enroll in the study.
3. Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients
4. Current use of a prohibited medication (including herbal medications, supplements, or foods), or use of a prohibited medication ≤ 7 days prior to the start of study treatment.
5. Patient has not recovered to ≤ Grade 1 non-hematologic toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and may enroll.

6. Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following:

   • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) ≤ 180 days prior to start date;
   • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
   • Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO;
   • Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;
   • History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
   • Triplicate average baseline QTc interval ≥ 480 ms.
7. Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (≤ 90 days) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs.
8. History of recent (≤ 90 days) thromboembolic or cerebrovascular event such as transient ischemic attack, cerebrovascular accident, or hemodynamically significant (massive or sub-massive) deep vein thrombosis or pulmonary emboli (DVT/PE). Note: Patients with DVT/PE that does not result in hemodynamic instability may enroll as long as they are anticoagulated for at least 4 weeks. Note: Patients with DVT/PE related to indwelling catheters or other procedures may enroll.
9. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
10. Pregnant women are excluded from this study because the effects of encorafenib and/or binimetinib on a fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with encorafenib or binimetinib, breastfeeding should be discontinued if the mother is treated with encorafenib and/or binimetinib.
11. Patients who previously received BRAF or MEK inhibitors are excluded (including but not limited to dabrafenib, vemurafenib, encorafenib, sorafenib, trametinib, binimetinib, cobimetinib, or selumetinib).
12. Patients will be excluded if their tumor harbors a known RAS activating mutation. This does not need to be specifically tested for eligibility.

3.4 Additional Inclusion Criteria for Surgical Arm

Patients must meet the above inclusion / exclusion criteria for consideration with one exception. Patients with a BRAF-V600 E or K mutated low-grade glioma for whom there is a strong clinical suspicion of progression to high-grade would also be eligible for this arm. Additionally:

1. Patients must have a clinical indication for a tumor surgery.
2. No a priori contraindication to biospecimen collection (blood, tumor, CSF).

• National Cancer Institute (NCI)
• Pfizer