A Phase II Study of Binimetinib in Combination With Encorafenib in Adults With Recurrent BRAF V600-Mutated High-Grade Astrocytoma or Other Primary Brain Tumor
Overview
- Phase
- Phase 2
- Intervention
- Research Bloods
- Conditions
- High Grade Glioma
- Sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Enrollment
- 5
- Locations
- 3
- Primary Endpoint
- Tumor Radiographic Response Per RANO for 3 Treatment Cohorts
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients receiving any other standard or investigational agents are ineligible.
- •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.
- •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.
- •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.)
Exclusion Criteria
- •Patients receiving any other standard or investigational agents are ineligible.
- •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.
- •Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients
- •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.
- •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.
- •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;
Arms & Interventions
Treatment Cohort 2 anaplastic PXAs
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Research Bloods
Treatment Cohort 2 anaplastic PXAs
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Tumor Tissue
Treatment Cohort 1 AA & GBM
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Encorafenib
Treatment Cohort 1 AA & GBM
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Binimetinib
Treatment Cohort 1 AA & GBM
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Research Bloods
Treatment Cohort 1 AA & GBM
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Tumor Tissue
Treatment Cohort 2 anaplastic PXAs
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Encorafenib
Treatment Cohort 2 anaplastic PXAs
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Binimetinib
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
Intervention: Encorafenib
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
Intervention: Binimetinib
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
Intervention: Research Bloods
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
Intervention: Tumor Tissue
Treatment Cohort 3 Other Tumors
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Encorafenib
Treatment Cohort 3 Other Tumors
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Binimetinib
Treatment Cohort 3 Other Tumors
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Research Bloods
Treatment Cohort 3 Other Tumors
Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Intervention: Tumor Tissue
Outcomes
Primary Outcomes
Tumor Radiographic Response Per RANO for 3 Treatment Cohorts
Time Frame: Up to 1 year
Number of participants from each treatment cohort with response as defined by Response Assessment in Neuro-oncology (RANO) criteria: 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.
Secondary Outcomes
- Number of Participants With Adverse Events as Defined by Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)(up to 3 years)
- Overall Survival(up to 3 years)
- Duration of Response - Complete and Partial(up to 3 year)
- Progression Free Survival for 3 Treatment Cohorts(up to 3 years)