Testing Binimetinib as a Potential Targeted Treatment in Cancers With NRAS Genetic Changes (MATCH-Subprotocol Z1A)

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT04439344
Collaborator
(none)
53
1
1

Study Details

Study Description

Brief Summary

This phase II MATCH treatment trial investigates the good and bad effects of binimetinib in patients whose cancer has a genetic change called NRAS mutation. Binimetinib blocks proteins called MEK1 and MEK2, which may be needed for cancer cell growth when an NRAS mutation is present. Researchers hope to learn if binimetinib will shrink this type of cancer or stop its growth.

Detailed Description

PRIMARY OBJECTIVE:
  1. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.
SECONDARY OBJECTIVES:
  1. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.

  2. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.

  3. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.

OUTLINE:

Patients receive binimetinib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, and then every 6 months for year 3 from study entry.

Study Design

Study Type:
Interventional
Actual Enrollment :
53 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
MATCH Treatment Subprotocol Z1A: Binimetinib in Patients With Tumors (Other Than Melanoma) With NRAS Mutations
Actual Study Start Date :
May 31, 2016
Actual Primary Completion Date :
May 3, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (binimetinib)

Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162
  • Mektovi
  • Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) [Tumor assessments occurred at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration]

      ORR is defined as the percentage of patients whose tumors have a complete or partial response to treatment among eligible and treated patients. Objective response rate is defined consistent with Response Evaluation Criteria in Solid Tumors version 1.1 criteria for solid tumors, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. For each treatment arm, 90% two-sided binomial exact confidence interval will be calculated for ORR.

    Secondary Outcome Measures

    1. 6-Month Progression-free Survival (PFS) Rate [Tumor assessments occurred at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration, from which 6-month PFS is determined]

      Progression free survival is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. 6 month PFS rate was estimated using the Kaplan-Meier method, which can provide a point estimate for any specific time point.

    2. Progression Free Survival (PFS) [Assessed at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration]

      Progression free survival is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. Median PFS was estimated using the Kaplan-Meier method.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol

    • Patients must have NRAS mutation in codon 12, 13, 61 as determined via the MATCH Master Protocol

    • Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must have no clinically significant abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block)

    • Creatinine =< 1.5 mg/dL, or calculated creatinine clearance (determined as per Cockcroft-Gault) >= 50mL/min

    • Patients must have adequate cardiac function:

    • Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram,

    • QTc interval =< 480 ms

    Exclusion Criteria:
    • Patients must not have known hypersensitivity to binimetinib or compounds of similar chemical or biologic composition

    • Patients with melanoma are excluded

    • Patients must not have any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions) and/or leptomeningeal metastases

    • NOTE: Patients treated with stereotactic radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease progression >= 3 months. Patients must be off corticosteroid therapy for >= 3 weeks

    • Patients must not have a history or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)

    • Patients must not have a history of retinal degenerative disease

    • Patients must not have a history of Gilbert's syndrome

    • Patients must not have uncontrolled arterial hypertension despite medical treatment

    • Patients must not have active hepatitis B, and/or active hepatitis C infection

    • Patients must not have neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)

    • Patients must not have impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)

    • Patients who have received prior MEK inhibitors are excluded

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 ECOG-ACRIN Cancer Research Group Philadelphia Pennsylvania United States 19103

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: James M Cleary, ECOG-ACRIN Cancer Research Group

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT04439344
    Other Study ID Numbers:
    • NCI-2020-03374
    • NCI-2020-03374
    • EAY131-Z1A
    • EAY131-Z1A
    • U10CA180820
    • U24CA196172
    First Posted:
    Jun 19, 2020
    Last Update Posted:
    Jul 19, 2022
    Last Verified:
    Feb 1, 2022
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Subprotocol Z1A was activated on May 31, 2016. A total of 114 patients were assigned to this arm after screening, all from screening cohort. Of the 114 patients, 53 patients were enrolled to arm Z1A in the period from May 31, 2016 and June 7, 2018.
    Pre-assignment Detail To be assigned to a specific MATCH subprotocol, patients needed to submit a tumor biopsy for molecular characterization and those with molecular variants addressed by treatments included in the trial entered corresponding MATCH subprotocol. For the subprotocol Z1A, patients had to have a tumor harboring a codon 12, 13, or 61 NRAS-mutation.
    Arm/Group Title Treatment (Binimetinib)
    Arm/Group Description Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Binimetinib: Given PO
    Period Title: Overall Study
    STARTED 53
    Started Protocol Therapy 50
    Eligible 47
    COMPLETED 0
    NOT COMPLETED 53

    Baseline Characteristics

    Arm/Group Title Treatment (Binimetinib)
    Arm/Group Description Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Binimetinib: Given PO
    Overall Participants 47
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    60
    Sex: Female, Male (Count of Participants)
    Female
    29
    61.7%
    Male
    18
    38.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    5
    10.6%
    Not Hispanic or Latino
    40
    85.1%
    Unknown or Not Reported
    2
    4.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    2
    4.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    3
    6.4%
    White
    40
    85.1%
    More than one race
    0
    0%
    Unknown or Not Reported
    2
    4.3%

    Outcome Measures

    1. Primary Outcome
    Title Objective Response Rate (ORR)
    Description ORR is defined as the percentage of patients whose tumors have a complete or partial response to treatment among eligible and treated patients. Objective response rate is defined consistent with Response Evaluation Criteria in Solid Tumors version 1.1 criteria for solid tumors, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. For each treatment arm, 90% two-sided binomial exact confidence interval will be calculated for ORR.
    Time Frame Tumor assessments occurred at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration

    Outcome Measure Data

    Analysis Population Description
    Patients who were eligible and received protocol treatment
    Arm/Group Title Treatment (Binimetinib)
    Arm/Group Description Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Binimetinib: Given PO
    Measure Participants 47
    Number (90% Confidence Interval) [percentage of participants]
    0.021
    0%
    2. Secondary Outcome
    Title 6-Month Progression-free Survival (PFS) Rate
    Description Progression free survival is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. 6 month PFS rate was estimated using the Kaplan-Meier method, which can provide a point estimate for any specific time point.
    Time Frame Tumor assessments occurred at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration, from which 6-month PFS is determined

    Outcome Measure Data

    Analysis Population Description
    Patients who were eligible and received protocol treatment
    Arm/Group Title Treatment (Binimetinib)
    Arm/Group Description Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Binimetinib: Given PO
    Measure Participants 47
    Number (90% Confidence Interval) [percentage of participants]
    0.292
    0.6%
    3. Secondary Outcome
    Title Progression Free Survival (PFS)
    Description Progression free survival is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. Median PFS was estimated using the Kaplan-Meier method.
    Time Frame Assessed at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration

    Outcome Measure Data

    Analysis Population Description
    Patients who were eligible and received protocol treatment
    Arm/Group Title Treatment (Binimetinib)
    Arm/Group Description Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Binimetinib: Given PO
    Measure Participants 47
    Median (90% Confidence Interval) [months]
    3.5

    Adverse Events

    Time Frame Assessed every 28 days while on treatment and for 30 days after the end of treatment, up to 3 years post registration.
    Adverse Event Reporting Description All 53 patients enrolled to the trial were monitored for mortality, the 50 treated patients were monitored for adverse events.
    Arm/Group Title Treatment (Binimetinib)
    Arm/Group Description Patients receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Binimetinib: Given PO
    All Cause Mortality
    Treatment (Binimetinib)
    Affected / at Risk (%) # Events
    Total 43/53 (81.1%)
    Serious Adverse Events
    Treatment (Binimetinib)
    Affected / at Risk (%) # Events
    Total 24/50 (48%)
    Cardiac disorders
    Heart failure 1/50 (2%)
    Myocardial infarction 1/50 (2%)
    Eye disorders
    Eye disorders - Other, specify 1/50 (2%)
    Gastrointestinal disorders
    Mucositis oral 1/50 (2%)
    Nausea 1/50 (2%)
    Small intestinal obstruction 1/50 (2%)
    General disorders
    Edema limbs 1/50 (2%)
    Fatigue 1/50 (2%)
    Multi-organ failure 1/50 (2%)
    Infections and infestations
    Urinary tract infection 1/50 (2%)
    Investigations
    Alanine aminotransferase increased 1/50 (2%)
    Alkaline phosphatase increased 1/50 (2%)
    Aspartate aminotransferase increased 1/50 (2%)
    CPK increased 2/50 (4%)
    Ejection fraction decreased 1/50 (2%)
    Lymphocyte count decreased 2/50 (4%)
    White blood cell decreased 1/50 (2%)
    Metabolism and nutrition disorders
    Anorexia 1/50 (2%)
    Dehydration 1/50 (2%)
    Hypoalbuminemia 1/50 (2%)
    Hyponatremia 1/50 (2%)
    Hypophosphatemia 1/50 (2%)
    Musculoskeletal and connective tissue disorders
    Muscle weakness lower limb 1/50 (2%)
    Muscle weakness upper limb 1/50 (2%)
    Nervous system disorders
    Syncope 1/50 (2%)
    Skin and subcutaneous tissue disorders
    Rash acneiform 3/50 (6%)
    Skin and subcutaneous tissue disorders - Other, specify 1/50 (2%)
    Vascular disorders
    Hypertension 6/50 (12%)
    Other (Not Including Serious) Adverse Events
    Treatment (Binimetinib)
    Affected / at Risk (%) # Events
    Total 44/50 (88%)
    Blood and lymphatic system disorders
    Anemia 7/50 (14%)
    Eye disorders
    Blurred vision 9/50 (18%)
    Retinal detachment 3/50 (6%)
    Eye disorders - Other, specify 7/50 (14%)
    Gastrointestinal disorders
    Constipation 6/50 (12%)
    Diarrhea 26/50 (52%)
    Mucositis oral 7/50 (14%)
    Nausea 15/50 (30%)
    Vomiting 9/50 (18%)
    General disorders
    Edema face 5/50 (10%)
    Edema limbs 17/50 (34%)
    Fatigue 18/50 (36%)
    General disorders and administration site conditions - Other 3/50 (6%)
    Investigations
    Alanine aminotransferase increased 8/50 (16%)
    Alkaline phosphatase increased 9/50 (18%)
    Aspartate aminotransferase increased 17/50 (34%)
    CPK increased 16/50 (32%)
    Creatinine increased 4/50 (8%)
    Lymphocyte count decreased 4/50 (8%)
    Neutrophil count decreased 3/50 (6%)
    Platelet count decreased 6/50 (12%)
    White blood cell decreased 3/50 (6%)
    Metabolism and nutrition disorders
    Anorexia 5/50 (10%)
    Hyperglycemia 3/50 (6%)
    Hypoalbuminemia 7/50 (14%)
    Hypocalcemia 3/50 (6%)
    Hypomagnesemia 6/50 (12%)
    Musculoskeletal and connective tissue disorders
    Myalgia 3/50 (6%)
    Respiratory, thoracic and mediastinal disorders
    Cough 3/50 (6%)
    Dyspnea 3/50 (6%)
    Skin and subcutaneous tissue disorders
    Alopecia 4/50 (8%)
    Dry skin 6/50 (12%)
    Pruritus 8/50 (16%)
    Rash acneiform 27/50 (54%)
    Rash maculo-papular 9/50 (18%)
    Skin and subcutaneous tissue disorders - Other, specify 4/50 (8%)
    Vascular disorders
    Hypertension 5/50 (10%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Study Statistician
    Organization ECOG-ACRIN Statistical Office
    Phone 617-632-3012
    Email eatrials@jimmy.harvard.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT04439344
    Other Study ID Numbers:
    • NCI-2020-03374
    • NCI-2020-03374
    • EAY131-Z1A
    • EAY131-Z1A
    • U10CA180820
    • U24CA196172
    First Posted:
    Jun 19, 2020
    Last Update Posted:
    Jul 19, 2022
    Last Verified:
    Feb 1, 2022