Working…
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03973918
Recruitment Status : Recruiting
First Posted : June 4, 2019
Last Update Posted : January 21, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Array BioPharma
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Condition or disease Intervention/treatment Phase
High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Drug: Encorafenib Drug: Binimetinib Biological: Research Bloods Biological: Tumor Tissue Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 29, 2019
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2023


Arm Intervention/treatment
Experimental: Treatment Cohort 1 AA & GBM

Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

Research Bloods

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

Experimental: Treatment Cohort 2 anaplastic PXAs

Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

Research Bloods

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

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

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 3 Other Tumors

Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

Research Bloods

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




Primary Outcome Measures :
  1. Tumor radiographic response per RANO for 3 treatment cohorts [ Time Frame: 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 Outcome Measures :
  1. 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

  2. Overall Survival [ Time Frame: up to 2 years ]
    median overall survival

  3. 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.

  4. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03973918


Contacts
Layout table for location contacts
Contact: Study Chair, MD 410-955-8837 ksolt1@jhmi.edu
Contact: Michaella Iacoboni, RN 410-955-4009 msheeh13@jhmi.edu

Locations
Layout table for location information
United States, Alabama
UAB Comprehensive Cancer Center Not yet recruiting
Birmingham, Alabama, United States, 35294-3410
Contact: Thiru Pillay, RN    205-934-1842    thiru@uab.edu   
Principal Investigator: Burt Nabors, MD         
United States, California
Jonsson Comprehensive Cancer Center at UCLA Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Timothy Cloughesy, MD    310-825-5321    TCloughesy@mednet.ucla.edu   
Principal Investigator: Timothy Cloughesy, MD         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Michaella Iacoboni, RN    410-955-4009    msheeh13@jhmi.edu   
Contact: Aiana Cerezo, BS    443-614-2818    arodri47@jhu.edu   
Sub-Investigator: Matthias Holdhoff, MD         
Principal Investigator: Stuart Grossman, MD         
United States, Massachusetts
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Gina Cach       Gina_Cach@DFCI.HARVARD.EDU   
Principal Investigator: Patrick Wen, MD         
United States, Michigan
Henry Ford Hospital Not yet recruiting
Detroit, Michigan, United States, 48202
Contact: Amy Williamson, RN       awillia12@hfhs.org   
Contact: Emily Krozek, MHSA       ekrozek1@hfhs.org   
Principal Investigator: Tobias Walbert, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10021
Contact: Thomas Kaley, MD    212-639-5122      
Principal Investigator: Thomas Kaley, MD         
United States, North Carolina
Wake Forest University Comprehensive Cancer Center Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Clinical Trials Office    336-713-6771      
Contact: Roy Strowd    336-716-2357      
Principal Investigator: Roy Strowd, MD         
United States, Ohio
Cleveland Clinic Taussig Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Cancer Center-Cares    216-444-7923      
Principal Investigator: David Peereboom, MD         
Sub-Investigator: Manmeet Ahluwalia, MD         
United States, Pennsylvania
Abrams Cancer Center of the University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Clinical Trials Office-Abrams Cancer Center    800-474-9892      
Principal Investigator: Arati Desai, MD         
Hillman Cancer Center at University of Pittsburgh Cancer Institute Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Clinical Trials Office - Hillman Cancer Center    412-647-8073      
Principal Investigator: Frank Lieberman, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Array BioPharma
Investigators
Layout table for investigator information
Study Director: Stuart A Grossman, MD ABTC

Layout table for additonal information
Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03973918    
Other Study ID Numbers: ABTC 1802
UM1CA137443 ( U.S. NIH Grant/Contract )
First Posted: June 4, 2019    Key Record Dates
Last Update Posted: January 21, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
BRAF V600E/K
High Grade Primary Brain Tumor
High Grade Glioma
Glioblastoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Glioblastoma
Astrocytoma
Gliosarcoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue