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Testing the Use of Fulvestrant and Binimetinib Targeted Treatment for NF1 Mutation in Hormone Receptor-Positive Metastatic Breast Cancer, A ComboMATCH Treatment Trial

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ClinicalTrials.gov Identifier: NCT05554354
Recruitment Status : Recruiting
First Posted : September 26, 2022
Last Update Posted : April 5, 2024
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This ComboMATCH phase II 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.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Metastatic HER2-Negative Breast Carcinoma Metastatic Hormone Receptor-Positive Breast Carcinoma Drug: Binimetinib Procedure: Biopsy Procedure: Bone Scan Procedure: Computed Tomography Drug: Fulvestrant Procedure: Magnetic Resonance Imaging Phase 2

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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 95 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of Fulvestrant and Binimetinib in Patients With Hormone Receptor-Positive Metastatic Breast Cancer With a Frameshift or Nonsense Mutation or Genomic Deletion in NF1: A ComboMATCH Treatment Trial
Estimated Study Start Date : May 29, 2024
Estimated Primary Completion Date : November 1, 2026
Estimated Study Completion Date : November 1, 2026


Arm Intervention/treatment
Experimental: Cohort I (Arm I) (fulvestrant, binimetinib)
Patients receive fulvestrant IM on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles and binimetinib PO 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 CT, MRI, or bone scan and tumor biopsy during screening and on study.
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162
  • Mektovi

Procedure: Biopsy
Undergo tumor biopsy
Other Names:
  • BIOPSY_TYPE
  • Bx

Procedure: Bone Scan
Undergo bone scan
Other Name: Bone Scintigraphy

Procedure: Computed Tomography
Undergo CT scan
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography

Drug: Fulvestrant
Given IM
Other Names:
  • Faslodex
  • Faslodex(ICI 182,780)
  • ICI 182,780
  • ICI 182780
  • ZD9238

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI

Active Comparator: Cohort I (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 are asked to reaffirm their willingness to enroll in cohort II. Patients not willing to transition to cohort II continue further therapy as clinically indicated. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study.
Procedure: Biopsy
Undergo tumor biopsy
Other Names:
  • BIOPSY_TYPE
  • Bx

Procedure: Bone Scan
Undergo bone scan
Other Name: Bone Scintigraphy

Procedure: Computed Tomography
Undergo CT scan
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography

Drug: Fulvestrant
Given IM
Other Names:
  • Faslodex
  • Faslodex(ICI 182,780)
  • ICI 182,780
  • ICI 182780
  • ZD9238

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI

Experimental: Cohort II (fulvestrant, binimetinib)
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 and tumor biopsy during screening and on study.
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162
  • Mektovi

Procedure: Biopsy
Undergo tumor biopsy
Other Names:
  • BIOPSY_TYPE
  • Bx

Procedure: Bone Scan
Undergo bone scan
Other Name: Bone Scintigraphy

Procedure: Computed Tomography
Undergo CT scan
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography

Drug: Fulvestrant
Given IM
Other Names:
  • Faslodex
  • Faslodex(ICI 182,780)
  • ICI 182,780
  • ICI 182780
  • ZD9238

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI




Primary Outcome Measures :
  1. Progression free survival (PFS) (Cohort I) [ Time Frame: The duration between randomization and progression or death from all cause, whichever happens first, assessed up to 5 years ]
    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.

  2. Objective response rate (ORR) (Cohort II) [ Time Frame: Within 4 months of the start of treatment ]
    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.


Secondary Outcome Measures :
  1. ORR for each study arm (Cohort I) [ Time Frame: Any time after the start of the treatment, assessed up to 5 years ]
    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.

  2. ORR (Cohort II) [ Time Frame: Any time after the start of the treatment, assessed up to 5 years ]
    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.

  3. Clinical benefit rate [ Time Frame: Any time after the start of the treatment, assessed up to 5 years ]
    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.

  4. PFS (Cohort II) [ Time Frame: The duration between randomization and progression or death from all cause, whichever happens first, assessed up to 5 years ]
    PFS for cohort II will be summarized using the Kaplan-Meier's method. Median PFS with corresponding 95% CI will be provided.

  5. Overall survival (OS) [ Time Frame: The duration between randomization and death of all causes, assessed up to 5 years ]
    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.

  6. Incidence of adverse events [ Time Frame: Up to 5 years ]
    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.


Other Outcome Measures:
  1. Analysis of integrated and exploratory biomarkers [ Time Frame: Up to 5 years ]
    A separate statistical analysis plan will be developed for the integrated and exploratory biomarker analysis. Concordance of diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid mutation profile will be assessed. Details are provided in the statistical plan of the ComboMATCH Registration protocol.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A COMBOMATCH TREATMENT TRIAL EAY191 ELIGIBILITY CRITERIA:
  • The patient must be enrolled on the ComboMATCH Master Registration Trial EAY191

    • Note: Patients must fulfill all eligibility criteria outlined in the ComboMATCH Registration Trial EAY191 at the time of registration to EAY191-N2. This includes submission of next-generation sequencing (NGS) data from one of the National Cancer Institute (NCI) credentialed designated laboratories for all potential patients prior to treatment trial assignment. Copy number and allele frequency cutoff as per the Registration protocol
  • Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or, if disease cannot be safely biopsied, have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH registration trial (EAY191)

    • Please note the current actionable marker of interest (aMOI)/actionable alteration list for this treatment trial can be found on the Cancer Trial Support Unit (CTSU) ComboMATCH Registration protocol page
    • Please note novel/Dynamic aMOI can be submitted for review per the process described in the ComboMATCH Registration protocol
  • A COMBOMATCH TREATMENT TRIAL EAY191-N2 ELIGIBILITY CRITERIA:
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
  • Age >= 18
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 14 days prior to registration
  • Histologically or cytologically confirmed invasive breast carcinoma
  • Confirmed metastatic disease by either imaging or tissue diagnosis
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and one additional lesion that can be biopsied (primary, metastatic both allowed)
  • Patients must have NF1 nonsense or frameshift mutation, or NF1 whole gene deletion detected in tumor as determined by the ComboMATCH screening assessment
  • The tumor must have been determined to be estrogen receptor (ER) and/or progesterone receptor (PgR) positive assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for hormone receptor testing. Patients with >= 1% ER or PgR staining by immunohistochemistry (IHC) are considered positive
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines
  • Prior use of CDK4/6 inhibitor(i) is required
  • Prior use of fulvestrant regardless of duration is allowed and will determine treatment assignment
  • Up to one line of chemotherapy in metastatic setting is allowed
  • Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to registration)
  • Platelet count >= 100,000/ mm^3 (within 14 days prior to registration)
  • Hemoglobin level >= 10 g/dL (within 14 days prior to registration)
  • Measured or calculated creatinine clearance > 30 mL/min (within 14 days prior to registration)
  • Total bilirubin level =< institutional upper limit of normal (within 14 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 5.0 x ULN
  • Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks prior to registration (LVEF assessment performed by echocardiogram is preferred; however, multi-gated acquisition scan [MUGA] scan may be substituted based on institutional/situational preferences). The LVEF must be >= 50% regardless of the cardiac imaging facility's lower limit of normal
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
  • ELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO TRANSITION TO COHORT 2:
  • Patient's willingness to transition to Cohort 2 affirmed
  • The patient must have an ECOG performance status of 0-2
  • Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to second registration)
  • Platelet count >= 100,000/ mm^3 (within 14 days prior to second registration)
  • Hemoglobin level >= 10 g/dL (within 14 days prior to second registration)
  • Total bilirubin level =< institutional upper limit of normal (ULN) (within 14 days prior to second registration)
  • AST and ALT must be =< 5.0 x ULN
  • Measured or calculated creatinine clearance > 30 mL/min (within 14 days prior to second registration)
  • The LVEF performed within the last 3 months must be >= 50% regardless of the cardiac imaging facility's lower limit of normal (LVEF assessment performed by echocardiogram is preferred; however, MUGA scan may be substituted based on institutional/situational preferences)
  • Pregnancy test according to institutional standards done within 14 days before second registration must be negative (for patients of childbearing potential only)

Exclusion Criteria:

  • Concurrent anticancer therapy
  • Active autoimmune disease requiring systemic treatment within the past 3 months, documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
  • Active brain metastasis. Brain metastases that have been stable for at least 1 month after completion of treatment are not an exclusion criterion
  • History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous, chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
  • Patients will be excluded if they currently have the following risk factors for RVO that are documented prior to the enrollment:

    • Uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg
    • Serum cholesterol >= grade 2.
    • Hypertriglyceridemia >= grade 2
    • Hyperglycemia (fasting) >= grade 2
  • Patients with baseline QT corrected for heart rate (QTc) > 500 ms, either induced by medication or congenital long QT syndrome will be excluded due to known side effects of binimetinib
  • Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2 within 14 days prior to registration. Patients with nervous system disorders that resolve to =< Grade 1 prior to registration are eligible
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results
  • Pregnancy or lactation at the time of registration or intention to become pregnant during the study (Note: Pregnancy testing according to institutional standards for patients of childbearing potential must be performed within 14 days prior to registration)

    • For binimetinib, highly effective contraception should be used for at least 30 days after the last dose, and patients should not breastfeed for 3 days after the last dose
    • For fulvestrant, highly effective contraception should be used for 1 year after the last dose, and patients should not breastfeed for 1 year after the last dose
  • Use of any investigational product within 30 days prior to study entry
  • INELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO TRANSITION TO COHORT 2
  • Not a candidate for binimetinib in the opinion of the treating investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05554354


Locations
Show Show 174 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
NRG Oncology
Investigators
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Principal Investigator: Bora Lim NRG Oncology
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05554354    
Other Study ID Numbers: NCI-2022-07265
NCI-2022-07265 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EAY191-N2 ( Other Identifier: NRG Oncology )
EAY191-N2 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: September 26, 2022    Key Record Dates
Last Update Posted: April 5, 2024
Last Verified: February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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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.: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs