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High Grade GliomaPhase 2BRAFNCT03973918

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

A Phase 2 study testing Encorafenib, Binimetinib and Research Bloods in people with High Grade Glioma and BRAF V600E, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
High Grade Glioma, BRAF V600E, BRAF V600K
What is being tested?
Encorafenib, Binimetinib and Research Bloods
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
3 sitesUnited States
Study dates
29 Jul 2019to 1 Oct 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.)
  • 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.
  • 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.
  • 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.
  • Patients must be able to swallow tablets and capsules.
  • 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.

Who cannot join

  • 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:
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  • 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.
  • 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.
  • Patients who previously received BRAF or MEK inhibitors are excluded (including but not limited to dabrafenib, vemurafenib, encorafenib, sorafenib, trametinib, binimetinib, cobimetinib, or selumetinib).
  • 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:
  • Patients must have a clinical indication for a tumor surgery.
  • No a priori contraindication to biospecimen collection (blood, tumor, CSF).

Trial locations and contacts

3 sites in 1 country.

United States3 sites
  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21231

  • UAB Comprehensive Cancer Center

    Birmingham, Alabama, 35294-3410

  • Wake Forest University Comprehensive Cancer Center

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Encorafenib, Binimetinib, Research Bloods, Tumor Tissue
Keywords
BRAF V600E/K, High Grade Primary Brain Tumor, High Grade Glioma, Glioblastoma
Medical subject headings
Glioma, Astrocytoma, Gliosarcoma, Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EncorafenibDrug

    Also called Braftovi

    450mg QD 28 day cycle

  • BinimetinibDrug

    Also called Mektovi

    45mg BID 28 day cycle

  • Research BloodsBiological

    Also called Circulating Tumor DNA

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

  • Tumor TissueBiological

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

Study groups in NCT03973918
Study groupRoleWhat they receive
Treatment Cohort 1 AA & GBMExperimentalEncorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Receives: Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue
Treatment Cohort 2 anaplastic PXAsExperimentalEncorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Receives: Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue
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
Receives: Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue
Treatment Cohort 3 Other TumorsExperimentalEncorafenib 450mg QD Binimetinib 45mg BID 28 day cycle Research Bloods
Receives: Drug: Encorafenib; Drug: Binimetinib; Biological: Research Bloods; Biological: Tumor Tissue

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 1 year

Secondary outcomes (4)
  1. Progression Free Survival for 3 Treatment Cohorts

    Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status

    Measured: up to 3 years

  2. Overall Survival

    overall survival in months. Specific survival for each patient due to early termination

    Measured: up to 3 years

  3. Duration of Response - Complete and Partial

    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.

    Measured: up to 3 year

  4. Number of Participants With Adverse Events as Defined by Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)

    time from first dose to 30 days post last dose

    Measured: up to 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2019
  2. Study start29 Jul 2019
  3. Primary completion30 Apr 2022
  4. Study completion1 Oct 2023

Why it stopped: NCI decided to terminate ABTC Consortium due to NCI moving in different direction for Brain Cancer

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03973918
Sponsor's protocol ID
ABTC 1802
Other IDs
UM1CA137443
Acronym
BRAF
Status last verified
Oct 2024
First submitted
31 May 2019
Last updated
31 Oct 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Encorafenib, Binimetinib and Research Bloods in people with High Grade Glioma and BRAF V600E, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 31 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Tumor Radiographic Response Per RANO for 3 Treatment Cohorts (time frame: Up to 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Oct 2024.

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