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).
