This phase II ComboMATCH treatment trial compares the usual treatment alone (fulvestrant) to using binimetinib plus the usual treatment in patients with hormone receptor positive breast cancer that has spread from where it first started to other places in the body (metastatic) and has an NF1 genetic change. Fulvestrant is a hormonal therapy that binds to estrogen receptors in tumor cells, resulting in estrogen receptor destruction and decreased estrogen binding, which may inhibit the growth of estrogen-sensitive tumor cells. Binimetinib is a targeted therapy that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The addition of binimetinib to fulvestrant in breast cancers with an NF1 genetic change could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression) as compared to fulvestrant alone.
PRIMARY OBJECTIVES: I. To determine whether the combination of fulvestrant and binimetinib improves progression-free survival (PFS) compared to treatment with fulvestrant alone in patients not previously treated with fulvestrant. (Cohort 1) II. To determine whether overall response rate (ORR) within 4 months in patients who have previously progressed on a fulvestrant-containing regimen is greater than 10%, as a historical comparison, when these patients receive combination fulvestrant and binimetinib therapy. (Cohort 2) SECONDARY OBJECTIVES: I. To estimate ORR at any time after the start of the treatment for Cohort 2 and separately for the two arms in Cohort 1. II. To estimate PFS distribution in Cohort 2. III. To estimate clinical benefit rate separately for the two arms in Cohort 1 and Cohort 2. IV. To determine the safety and toxicity profile in both cohorts. V. To estimate the overall survival (OS) in both cohorts. VI. Collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (DNA) (ctDNA) mutation profile from plasma, as described in ComboMATCH Registration Protocol. For this treatment substudy, the outcome objective will be to report the proportion of cases providing sufficient tissue for that integrated scientific activity in the ComboMATCH Registration Protocol. EXPLORATORY BIOMARKER OBJECTIVES: I. To analyze the cell-free (cf)DNA at progression to determine the changes in cfDNA profile in order to understand blood-based mutation dynamics. II. To analyze RNAseq at progression to determine potential pathways that are altered that may contribute to the sensitivity/resistance. III. To discover/detect novel biomarkers using microscaled proteogenomics by analyzing the proteins and phosphor-proteins along with genomics to determine potential pathways that may correlate with the response to the combination treatment. IV. To detect the loss of NF1, using immunohistochemistry staining to precisely measure the level of the NF1 protein. V. To determine the variant allele frequency (VAF) of mutant NF1 measuring by using droplet digital polymerase chain reaction (ddPCR) for the targeted NF1 gene level. OUTLINE: Patients who are fulvestrant naive are assigned to Cohort I, while patients who are fulvestrant resistant are assigned to Cohort II. COHORT I: Patients are randomized to 1 of 2 arms. ARM I: Patients receive fulvestrant intramuscularly (IM) on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles and binimetinib orally (PO) twice daily (BID) on days 15 to 28 of cycle 1 and day 1 through 28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a computed tomography (CT), magnetic resonance imaging (MRI), or bone scan, echocardiography (ECHO) or multi-gated acqusition scan (MUGA), and tumor biopsy, as well as possible blood sample collection during screening and on study. ARM II: Patients receive fulvestrant IM on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who progress on fulvestrant alone may migrate to cohort II if they meet the migration eligibility criteria. Patients not willing to migrate to cohort II will have further therapy at the investigator's discretion. Patients undergo a CT, MRI, or bone scan and tumor biopsy, as well as ECHO or MUGA and possible blood sample collection during screening and on study. COHORT II: Patients receive fulvestrant IM on day 1 of each cycle and binimetinib PO BID on days 15-28 of cycle 1 and day 1 through 28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT, MRI, or bone scan, ECHO or MUGA and tumor biopsy, as well as possible blood sample collection during screening and on study. Upon completion of study treatment patients are followed up every 6 months for 5 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Given PO
Undergo tumor biopsy
Undergo blood sample collection
Undergo bone scan
Undergo CT scan
Undergo ECHO
Given IM
Undergo MRI
Undergo MUGA
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Kingman Regional Medical Center
Kingman, Arizona, United States
PCR Oncology
Arroyo Grande, California, United States
Epic Care-Dublin
Dublin, California, United States
Epic Care Partners in Cancer Care
Emeryville, California, United States
Progression Free Survival (PFS) (Cohort I)
PFS of the two study arms will be compared by log-rank test (1-sided, alpha=0.1). Kaplan-Meier plot will be provided. Hazard ratio (HR) and the corresponding 95% confidence interval (CI) will be estimated by Cox proportional model using treatment as covariate.
Time frame: The duration between randomization and progression or death from all cause, whichever happens first, assessed up to 5 years
Objective Response Rate (ORR) (Cohort II)
ORR is the percentage of patients who reaches a complete or partial response (defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] version\[v\]1.1) within 4 months of the start of the treatment. ORR will be calculated as the proportion of patients achieved partial response (PR) or complete response (CR) within 4 months after the initiation of the treatment. ORR will be reported with corresponding 95% exact CI. Patients who have withdrawn from the study before any efficacy follow up are considered non-evaluable for clinical response and will be replaced.
Time frame: Within 4 months of the start of treatment
ORR for Each Study Arm (Cohort I)
ORR is the percentage of patients who reach a complete or partial response (defined by RECIST v1.1) any time after the start of the treatment. ORR for each study arm will be calculated with corresponding 95% exact CI. Fisher exact test will be used to compare the ORR of the two study arms.
Time frame: Any time after the start of the treatment, assessed up to 5 years
ORR (Cohort II)
ORR is the percentage of patients who reach a complete or partial response (defined by RECIST v1.1) any time after the start of the treatment.
Time frame: Any time after the start of the treatment, assessed up to 5 years
Clinical Benefit Rate
Defined as proportion of patients who achieved a CR, PR, or stable disease defined by RECIST criteria any time after the start of the treatment. Clinical benefit rate will be analyzed for each arm of cohort I and cohort II as described for ORR. ORR for each study arm will be calculated with corresponding 95% exact CI. Fisher exact test will be used to compare the ORR of the two study arms.
Time frame: Any time after the start of the treatment, assessed up to 5 years
PFS (Cohort II)
PFS for cohort II will be summarized using the Kaplan-Meier's method. Median PFS with corresponding 95% CI will be provided.
Time frame: The duration between randomization and progression or death from all cause, whichever happens first, assessed up to 5 years
Overall Survival (OS)
OS for cohort I will be analyzed as described for PFS in cohort I and OS for cohort II will be analyzed as described for PFS in cohort II. PFS of the two study arms will be compared by log-rank test (1-sided, alpha=0.1). Kaplan-Meir plot will be provided. HR and the corresponding 95% CI will be estimated by Cox proportional model using treatment as covariate. PFS for Cohort 2 will be summarized using the Kaplan-Meir's method. Median PFS with corresponding 95% CI will be provided.
Time frame: The duration between randomization and death of all causes, assessed up to 5 years
Incidence of Adverse Events
The grade of toxicity measurement will follow Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The distribution by treatment group of the highest grade of each CTCAEs experienced by each patient categorized will be tabulated. The tabulations will also be reviewed on a semi-annual basis by the Data Monitoring Committee. These tabulations will include summaries by system organ class and summaries by term under each system organ class.
Time frame: Up to 5 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Contra Costa Regional Medical Center
Martinez, California, United States
Saint Joseph Hospital - Orange
Orange, California, United States
Saint John's Cancer Institute
Santa Monica, California, United States
Epic Care Cyberknife Center
Walnut Creek, California, United States
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, United States
...and 186 more locations