Testing Binimetinib as a Potential Targeted Treatment in Cancers With NRAS Genetic Changes (MATCH-Subprotocol Z1A)
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- 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:
-
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.
-
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.
-
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
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:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
- 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
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.- NCI-2020-03374
- NCI-2020-03374
- EAY131-Z1A
- EAY131-Z1A
- U10CA180820
- U24CA196172
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
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%
|
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%
|
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
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 |
eatrials@jimmy.harvard.edu |
- NCI-2020-03374
- NCI-2020-03374
- EAY131-Z1A
- EAY131-Z1A
- U10CA180820
- U24CA196172