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

NCT03973918

Last updated date
Study Location
UAB Comprehensive Cancer Center
Birmingham, Alabama, 35294-3410, United States
Contact
410-955-8837

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
High Grade Glioma, BRAF V600E, BRAF V600K, Anaplastic Astrocytoma, Anaplastic Pleomorphic Xanthoastrocytoma, Gliosarcoma, Glioblastoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


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).

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High Grade Glioma, BRAF V600E, BRAF V600K, Anaplastic Astrocytoma, Anaplastic Pleomorphic Xanthoastrocytoma, Gliosarcoma, GlioblastomaStudy of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG
NCT03973918
  1. Birmingham, Alabama
  2. Los Angeles, California
  3. Baltimore, Maryland
  4. Boston, Massachusetts
  5. Detroit, Michigan
  6. New York, New York
  7. Winston-Salem, North Carolina
  8. Cleveland, Ohio
  9. Philadelphia, Pennsylvania
  10. Pittsburgh, Pennsylvania
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • High Grade Glioma
  • BRAF V600E
  • BRAF V600K
  • Anaplastic Astrocytoma
  • Anaplastic Pleomorphic Xanthoastrocytoma
  • Gliosarcoma
  • Glioblastoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Treatment Cohort 1 AA & GBM

    Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

    Research Bloods

    Interventions:
    • Drug: Encorafenib
    • Drug: Binimetinib
    • Biological: Research Bloods
  • Experimental: Treatment Cohort 2 anaplastic PXAs

    Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

    Research Bloods

    Interventions:
    • Drug: Encorafenib
    • Drug: Binimetinib
    • Biological: Research Bloods
  • 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

    Interventions:
    • Drug: Encorafenib
    • Drug: Binimetinib
    • Biological: Research Bloods
    • Biological: Tumor Tissue
  • Experimental: Treatment Cohort 3 Other Tumors

    Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

    Research Bloods

    Interventions:
    • Drug: Encorafenib
    • Drug: Binimetinib
    • Biological: Research Bloods
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 31, 2019)
62
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2023
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Schreck, MD410-955-8837[email protected]
Contact: Michaella Iacoboni, RN410-955-4009[email protected]
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03973918
Other Study ID Numbers  ICMJE ABTC 1802
UM1CA137443 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Pfizer
Investigators  ICMJE
Study Director:Stuart A Grossman, MDABTC
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP