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

NCT03973918 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: ABTC 1802UM1CA137443
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 3

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Tumor Radiographic Response Per RANO for 3 Treatment Cohorts

  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.

  Up to 1 year

Secondary Outcomes (4)

• Progression Free Survival for 3 Treatment Cohorts

  up to 3 years

• Overall Survival

  up to 3 years

• Duration of Response - Complete and Partial

  up to 3 year

• 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

Study Arms (4)

Treatment Cohort 1 AA & GBM

EXPERIMENTAL

Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods

Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue

Treatment Cohort 2 anaplastic PXAs

EXPERIMENTAL

Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods

Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue

Surgical Arm

EXPERIMENTAL

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; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue

Treatment Cohort 3 Other Tumors

EXPERIMENTAL

Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods

Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue

Interventions

Encorafenib DRUG

450mg QD 28 day cycle

Also known as: Braftovi

Surgical Arm; Treatment Cohort 1 AA & GBM; Treatment Cohort 2 anaplastic PXAs; Treatment Cohort 3 Other Tumors

Binimetinib DRUG

45mg BID 28 day cycle

Also known as: Mektovi

Surgical Arm; Treatment Cohort 1 AA & GBM; Treatment Cohort 2 anaplastic PXAs; Treatment Cohort 3 Other Tumors

Research Bloods BIOLOGICAL

Baseline; pre-cycle 3; Pre-cycle 7; off Treatment

Also known as: Circulating Tumor DNA

Surgical Arm; Treatment Cohort 1 AA & GBM; Treatment Cohort 2 anaplastic PXAs; Treatment Cohort 3 Other Tumors

Tumor Tissue BIOLOGICAL

at time of surgery contrast enhancing and non enhancing tumor; 20 unstained slides

Surgical Arm; Treatment Cohort 1 AA & GBM; Treatment Cohort 2 anaplastic PXAs; Treatment Cohort 3 Other Tumors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• weeks from the completion of radiation.
• weeks from an anti-VEGF therapy
• weeks from a nitrosourea chemotherapy
• weeks from a non-nitrosourea chemotherapy
• weeks or 5 half-lives from any investigational (not FDA-approved) agents
• weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)
• Patients must be 18 years of age or older.
• Patients must have a Karnofsky Performance (KPS) Status ≥ 60%
• Patients must have adequate organ and marrow function within 30 days of starting treatment.
• Patients must be able to provide written informed consent.
• 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.

You may not qualify if:

• 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;
• 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.
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator
• Pfizer: collaborator

Study Sites (3)

UAB Comprehensive Cancer Center

Birmingham, Alabama, 35294-3410, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157, United States

Location

MeSH Terms

Conditions

Glioma; Astrocytoma; Gliosarcoma; Glioblastoma

Interventions

encorafenib; binimetinib; Circulating Tumor DNA

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Cell-Free Nucleic Acids; Nucleic Acids; Nucleic Acids, Nucleotides, and Nucleosides; DNA, Neoplasm; DNA

Limitations and Caveats

Due to early termination, results are given per cohort per patient, as the data is meaningless otherwise due to small numbers. The NCI/CTEP mandated the closure of ABTC Consortium and hence why this study was terminated early

Results Point of Contact

• Title: Director of ABTC Consortium
• Organization: ABTC Consortium

jfisher@jhmi.edu

410-955-8837

Study Officials

• Karisa C Schreck, MD

  ABTC

  PRINCIPAL INVESTIGATOR

• Stuart A Grossman, MD

  ABTC

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2019
• First Posted: June 4, 2019
• Study Start: July 29, 2019
• Primary Completion: April 30, 2022
• Study Completion: October 1, 2023
• Last Updated: October 31, 2024
• Results First Posted: March 6, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)