Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG
Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG
The goal of this study is to estimate the efficacy of encorafenib and binimetinib as measured
 by radiographic response in recurrent high-grade primary brain tumors.
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.
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).