Clinical Trials /

Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG

NCT03973918

Description:

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.

Related Conditions:
  • Anaplastic Pleomorphic Xanthoastrocytoma
  • Low Grade Glioma
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: ABTC 1802
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT03973918

Conditions

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

Interventions

DrugSynonymsArms
EncorafenibTreatment Cohort 1 AA & GBM
BinimetinibTreatment Cohort 1 AA & GBM
Research BloodsCirculating Tumor DNATreatment Cohort 1 AA & GBM
Tumor TissueSurgical Arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment Cohort 1 AA & GBMExperimentalEncorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
  • Encorafenib
  • Binimetinib
  • Research Bloods
Treatment Cohort 2 anaplastic PXAsExperimentalEncorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
  • Encorafenib
  • Binimetinib
  • Research Bloods
Surgical ArmExperimentalPre-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
  • Encorafenib
  • Binimetinib
  • Research Bloods
  • Tumor Tissue
Treatment Cohort 3 Other TumorsExperimentalEncorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
  • Encorafenib
  • Binimetinib
  • Research Bloods

Eligibility Criteria

        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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor radiographic response per RANO for 3 treatment cohorts
Time Frame:1 year
Safety Issue:
Description: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 Outcome Measures

Measure:Progression free survival for 3 treatment cohorts
Time Frame:up to 1 year
Safety Issue:
Description:Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status
Measure:Overall Survival
Time Frame:up to 2 years
Safety Issue:
Description:median overall survival
Measure:Duration of response
Time Frame:up to 1 year
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • BRAF V600E/K
  • High Grade Primary Brain Tumor
  • High Grade Glioma
  • Glioblastoma

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