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

February 17, 2026 updated by: National Cancer Institute (NCI)

Phase 2 Trial of Fulvestrant and Binimetinib in Patients With Hormone Receptor-Positive Metastatic Breast Cancer With Inactivating or Inferred Inactivating NF1 Alterations: A ComboMATCH Treatment Trial

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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

Enrollment (Actual)

1

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • Bayamón, Puerto Rico, 00961
        • Puerto Rico Hematology Oncology Group
      • Manatí, Puerto Rico, 00674
        • Doctors Cancer Center
      • San Juan, Puerto Rico, 00927
        • Centro Comprensivo de Cancer de UPR
      • San Juan, Puerto Rico, 00927
        • PROncology
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama at Birmingham Cancer Center
    • Arizona
      • Kingman, Arizona, United States, 86401
        • Kingman Regional Medical Center
    • California
      • Arroyo Grande, California, United States, 93420
        • PCR Oncology
      • Dublin, California, United States, 94568
        • Epic Care-Dublin
      • Emeryville, California, United States, 94608
        • Epic Care Partners in Cancer Care
      • Martinez, California, United States, 94553-3156
        • Contra Costa Regional Medical Center
      • Orange, California, United States, 92868
        • Saint Joseph Hospital - Orange
      • Santa Monica, California, United States, 90404
        • Saint John's Cancer Institute
      • Walnut Creek, California, United States, 94597
        • Epic Care Cyberknife Center
    • Florida
      • Aventura, Florida, United States, 33180
        • UM Sylvester Comprehensive Cancer Center at Aventura
      • Coral Gables, Florida, United States, 33146
        • UM Sylvester Comprehensive Cancer Center at Coral Gables
      • Deerfield Beach, Florida, United States, 33442
        • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
      • Jacksonville, Florida, United States, 32224-9980
        • Mayo Clinic in Florida
      • Miami, Florida, United States, 33136
        • University of Miami Miller School of Medicine-Sylvester Cancer Center
      • Miami, Florida, United States, 33176
        • UM Sylvester Comprehensive Cancer Center at Kendall
      • Plantation, Florida, United States, 33324
        • UM Sylvester Comprehensive Cancer Center at Plantation
    • Idaho
      • Boise, Idaho, United States, 83706
        • Saint Alphonsus Cancer Care Center-Boise
      • Boise, Idaho, United States, 83712
        • Saint Luke's Cancer Institute - Boise
      • Caldwell, Idaho, United States, 83605
        • Saint Alphonsus Cancer Care Center-Caldwell
      • Coeur d'Alene, Idaho, United States, 83814
        • Kootenai Health - Coeur d'Alene
      • Fruitland, Idaho, United States, 83619
        • Saint Luke's Cancer Institute - Fruitland
      • Meridian, Idaho, United States, 83642
        • Saint Luke's Cancer Institute - Meridian
      • Nampa, Idaho, United States, 83687
        • Saint Alphonsus Cancer Care Center-Nampa
      • Nampa, Idaho, United States, 83687
        • Saint Luke's Cancer Institute - Nampa
      • Post Falls, Idaho, United States, 83854
        • Kootenai Clinic Cancer Services - Post Falls
      • Sandpoint, Idaho, United States, 83864
        • Kootenai Clinic Cancer Services - Sandpoint
      • Twin Falls, Idaho, United States, 83301
        • Saint Luke's Cancer Institute - Twin Falls
    • Illinois
      • Barrington, Illinois, United States, 60010
        • Advocate Good Shepherd Hospital
      • Chicago, Illinois, United States, 60611
        • Northwestern University
      • Chicago, Illinois, United States, 60612
        • John H Stroger Jr Hospital of Cook County
      • Chicago, Illinois, United States, 60657
        • Advocate Illinois Masonic Medical Center
      • Crystal Lake, Illinois, United States, 60014
        • AMG Crystal Lake - Oncology
      • Danville, Illinois, United States, 61832
        • Carle at The Riverfront
      • DeKalb, Illinois, United States, 60115
        • Northwestern Medicine Cancer Center Kishwaukee
      • Effingham, Illinois, United States, 62401
        • Carle Physician Group-Effingham
      • Elgin, Illinois, United States, 60123
        • Advocate Sherman Hospital
      • Geneva, Illinois, United States, 60134
        • Northwestern Medicine Cancer Center Delnor
      • Hazel Crest, Illinois, United States, 60429
        • Advocate South Suburban Hospital
      • Lake Forest, Illinois, United States, 60045
        • Northwestern Medicine Lake Forest Hospital
      • Libertyville, Illinois, United States, 60048
        • Condell Memorial Hospital
      • Libertyville, Illinois, United States, 60048
        • AMG Libertyville - Oncology
      • Mattoon, Illinois, United States, 61938
        • Carle Physician Group-Mattoon/Charleston
      • Oak Lawn, Illinois, United States, 60453-2699
        • Advocate Christ Medical Center
      • Orland Park, Illinois, United States, 60462
        • Northwestern Medicine Orland Park
      • Park Ridge, Illinois, United States, 60068
        • Advocate Lutheran General Hospital
      • Shiloh, Illinois, United States, 62269
        • Memorial Hospital East
      • Urbana, Illinois, United States, 61801
        • Carle Cancer Center
      • Warrenville, Illinois, United States, 60555
        • Northwestern Medicine Cancer Center Warrenville
    • Iowa
      • Ankeny, Iowa, United States, 50023
        • UI Health Care Mission Cancer and Blood - Ankeny Clinic
      • Des Moines, Iowa, United States, 50314
        • Mercy Medical Center - Des Moines
      • Des Moines, Iowa, United States, 50309
        • UI Health Care Mission Cancer and Blood - Des Moines Clinic
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • University of Kentucky/Markey Cancer Center
    • Maine
      • Brewer, Maine, United States, 04412
        • Lafayette Family Cancer Center-EMMC
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland/Greenebaum Cancer Center
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center
      • Cumberland, Maryland, United States, 21502
        • UPMC Western Maryland
    • Massachusetts
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States, 48106
        • Trinity Health Saint Joseph Mercy Hospital Ann Arbor
      • Brighton, Michigan, United States, 48114
        • Trinity Health IHA Medical Group Hematology Oncology - Brighton
      • Brighton, Michigan, United States, 48114
        • Trinity Health Medical Center - Brighton
      • Canton, Michigan, United States, 48188
        • Trinity Health IHA Medical Group Hematology Oncology - Canton
      • Canton, Michigan, United States, 48188
        • Trinity Health Medical Center - Canton
      • Chelsea, Michigan, United States, 48118
        • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
      • Chelsea, Michigan, United States, 48118
        • Chelsea Hospital
      • Dearborn, Michigan, United States, 48124
        • Corewell Health Dearborn Hospital
      • Farmington Hills, Michigan, United States, 48336
        • Corewell Health Farmington Hills Hospital
      • Flint, Michigan, United States, 48503
        • Hurley Medical Center
      • Flint, Michigan, United States, 48503
        • Genesee Hematology Oncology PC
      • Flint, Michigan, United States, 48503
        • Genesys Hurley Cancer Institute
      • Flint, Michigan, United States, 48503
        • Cancer Hematology Centers - Flint
      • Lansing, Michigan, United States, 48912
        • University of Michigan Health - Sparrow Lansing
      • Livonia, Michigan, United States, 48154
        • Trinity Health Saint Mary Mercy Livonia Hospital
      • Macomb, Michigan, United States, 48044
        • Henry Ford Saint John Hospital - Macomb Medical
      • Royal Oak, Michigan, United States, 48073
        • Corewell Health William Beaumont University Hospital
      • Saginaw, Michigan, United States, 48604
        • Oncology Hematology Associates of Saginaw Valley PC
      • Saginaw, Michigan, United States, 48601
        • MyMichigan Medical Center Saginaw
      • Tawas City, Michigan, United States, 48764
        • MyMichigan Medical Center Tawas
      • Troy, Michigan, United States, 48085
        • Corewell Health Beaumont Troy Hospital
      • West Branch, Michigan, United States, 48661
        • Saint Mary's Oncology/Hematology Associates of West Branch
      • Ypsilanti, Michigan, United States, 48197
        • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
      • Ypsilanti, Michigan, United States, 48106
        • Huron Gastroenterology PC
    • Minnesota
      • Bemidji, Minnesota, United States, 56601
        • Sanford Joe Lueken Cancer Center
      • Coon Rapids, Minnesota, United States, 55433
        • Mercy Hospital
      • Deer River, Minnesota, United States, 56636
        • Essentia Health - Deer River Clinic
      • Duluth, Minnesota, United States, 55805
        • Essentia Health Cancer Center
      • Edina, Minnesota, United States, 55435
        • Fairview Southdale Hospital
      • Hibbing, Minnesota, United States, 55746
        • Essentia Health Hibbing Clinic
      • Maplewood, Minnesota, United States, 55109
        • Saint John's Hospital - Healtheast
      • Minneapolis, Minnesota, United States, 55407
        • Abbott-Northwestern Hospital
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic in Rochester
      • Saint Louis Park, Minnesota, United States, 55416
        • Park Nicollet Clinic - Saint Louis Park
      • Saint Paul, Minnesota, United States, 55101
        • Regions Hospital
      • Saint Paul, Minnesota, United States, 55102
        • United Hospital
      • Sandstone, Minnesota, United States, 55072
        • Essentia Health Sandstone
      • Virginia, Minnesota, United States, 55792
        • Essentia Health Virginia Clinic
    • Mississippi
      • Gulfport, Mississippi, United States, 39502
        • Gulfport Memorial Hospital
    • Missouri
      • City of Saint Peters, Missouri, United States, 63376
        • Siteman Cancer Center at Saint Peters Hospital
      • Creve Coeur, Missouri, United States, 63141
        • Siteman Cancer Center at West County Hospital
      • St Louis, Missouri, United States, 63110
        • Washington University School of Medicine
      • St Louis, Missouri, United States, 63129
        • Siteman Cancer Center-South County
      • St Louis, Missouri, United States, 63136
        • Siteman Cancer Center at Christian Hospital
    • Montana
      • Anaconda, Montana, United States, 59711
        • Community Hospital of Anaconda
      • Billings, Montana, United States, 59101
        • Billings Clinic Cancer Center
      • Bozeman, Montana, United States, 59715
        • Bozeman Health Deaconess Hospital
      • Great Falls, Montana, United States, 59405
        • Benefis Sletten Cancer Institute
      • Kalispell, Montana, United States, 59901
        • Logan Health Medical Center
      • Missoula, Montana, United States, 59804
        • Community Medical Center
    • Nevada
      • Henderson, Nevada, United States, 89052
        • OptumCare Cancer Care at Seven Hills
      • Las Vegas, Nevada, United States, 89102
        • OptumCare Cancer Care at Charleston
      • Las Vegas, Nevada, United States, 89148
        • OptumCare Cancer Care at Fort Apache
    • New York
      • The Bronx, New York, United States, 10461
        • Montefiore Medical Center-Einstein Campus
    • North Dakota
      • Bismarck, North Dakota, United States, 58501
        • Sanford Bismarck Medical Center
      • Fargo, North Dakota, United States, 58122
        • Sanford Roger Maris Cancer Center
      • Fargo, North Dakota, United States, 58122
        • Sanford Broadway Medical Center
    • Ohio
      • Belpre, Ohio, United States, 45714
        • Strecker Cancer Center-Belpre
      • Canton, Ohio, United States, 44710
        • Aultman Health Foundation
      • Centerville, Ohio, United States, 45459
        • Miami Valley Hospital South
      • Chillicothe, Ohio, United States, 45601
        • Adena Regional Medical Center
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer Center
      • Columbus, Ohio, United States, 43219
        • The Mark H Zangmeister Center
      • Columbus, Ohio, United States, 43213
        • Mount Carmel East Hospital
      • Dayton, Ohio, United States, 45409
        • Miami Valley Hospital
      • Dayton, Ohio, United States, 45415
        • Miami Valley Hospital North
      • Dayton, Ohio, United States, 45415
        • Dayton Physician LLC - Englewood
      • Dayton, Ohio, United States, 45409
        • Premier Blood and Cancer Center
      • Franklin, Ohio, United States, 45005-1066
        • Atrium Medical Center-Middletown Regional Hospital
      • Greenville, Ohio, United States, 45331
        • Miami Valley Cancer Care and Infusion
      • Kettering, Ohio, United States, 45429
        • Kettering Medical Center
      • Lancaster, Ohio, United States, 43130
        • Fairfield Medical Center
      • Marietta, Ohio, United States, 45750
        • Marietta Memorial Hospital
      • Marysville, Ohio, United States, 43040
        • Memorial Hospital
      • Mount Vernon, Ohio, United States, 43050
        • Knox Community Hospital
      • Newark, Ohio, United States, 43055
        • Licking Memorial Hospital
      • Perrysburg, Ohio, United States, 43551
        • Mercy Health - Perrysburg Hospital
      • Portsmouth, Ohio, United States, 45662
        • Southern Ohio Medical Center
      • Springfield, Ohio, United States, 45504
        • Springfield Regional Cancer Center
      • Springfield, Ohio, United States, 45504
        • Springfield Regional Medical Center
      • Toledo, Ohio, United States, 43623
        • Mercy Health - Saint Anne Hospital
      • Troy, Ohio, United States, 45373
        • Upper Valley Medical Center
      • Westerville, Ohio, United States, 43081
        • Saint Ann's Hospital
      • Zanesville, Ohio, United States, 43701
        • Genesis Healthcare System Cancer Care Center
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • University of Oklahoma Health Sciences Center
    • Oregon
      • Newberg, Oregon, United States, 97132
        • Providence Newberg Medical Center
      • Ontario, Oregon, United States, 97914
        • Saint Alphonsus Cancer Care Center-Ontario
      • Oregon City, Oregon, United States, 97045
        • Providence Willamette Falls Medical Center
      • Portland, Oregon, United States, 97213
        • Providence Portland Medical Center
      • Portland, Oregon, United States, 97225
        • Providence Saint Vincent Medical Center
    • Pennsylvania
      • Altoona, Pennsylvania, United States, 16601
        • UPMC Altoona
      • Bryn Mawr, Pennsylvania, United States, 19010
        • Bryn Mawr Hospital
      • Erie, Pennsylvania, United States, 16505
        • UPMC Hillman Cancer Center Erie
      • Greensburg, Pennsylvania, United States, 15601
        • UPMC Cancer Centers - Arnold Palmer Pavilion
      • Mechanicsburg, Pennsylvania, United States, 17050
        • UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion
      • Media, Pennsylvania, United States, 19063
        • Riddle Memorial Hospital
      • Monroeville, Pennsylvania, United States, 15146
        • UPMC Hillman Cancer Center - Monroeville
      • Paoli, Pennsylvania, United States, 19301
        • Paoli Memorial Hospital
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University Hospital
      • Pittsburgh, Pennsylvania, United States, 15232
        • University of Pittsburgh Cancer Institute (UPCI)
      • Pittsburgh, Pennsylvania, United States, 15237
        • UPMC-Passavant Hospital
      • Willow Grove, Pennsylvania, United States, 19090
        • Asplundh Cancer Pavilion
      • Wynnewood, Pennsylvania, United States, 19096
        • Lankenau Medical Center
    • South Dakota
      • Sioux Falls, South Dakota, United States, 57117-5134
        • Sanford USD Medical Center - Sioux Falls
      • Sioux Falls, South Dakota, United States, 57104
        • Sanford Cancer Center Oncology Clinic
    • Texas
      • Houston, Texas, United States, 77030
        • M D Anderson Cancer Center
    • Virginia
      • Richmond, Virginia, United States, 23235
        • VCU Massey Cancer Center at Stony Point
      • Richmond, Virginia, United States, 23298
        • Virginia Commonwealth University/Massey Cancer Center
      • Richmond, Virginia, United States, 23229
        • Virginia Cancer Institute
      • South Hill, Virginia, United States, 23970
        • VCU Community Memorial Health Center
    • Washington
      • Edmonds, Washington, United States, 98026
        • Swedish Cancer Institute-Edmonds
      • Issaquah, Washington, United States, 98029
        • Swedish Cancer Institute-Issaquah
      • Renton, Washington, United States, 98055
        • Valley Medical Center
      • Yakima, Washington, United States, 98902
        • North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
    • Wisconsin
      • Ashland, Wisconsin, United States, 54806
        • Duluth Clinic Ashland
      • Burlington, Wisconsin, United States, 53105
        • Aurora Cancer Care-Southern Lakes VLCC
      • Cudahy, Wisconsin, United States, 53110
        • Aurora Saint Luke's South Shore
      • Germantown, Wisconsin, United States, 53022
        • Aurora Health Care Germantown Health Center
      • Grafton, Wisconsin, United States, 53024
        • Aurora Cancer Care-Grafton
      • Green Bay, Wisconsin, United States, 54311
        • Aurora BayCare Medical Center
      • Kenosha, Wisconsin, United States, 53142
        • Aurora Cancer Care-Kenosha South
      • La Crosse, Wisconsin, United States, 54601
        • Gundersen Lutheran Medical Center
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin Carbone Cancer Center - University Hospital
      • Madison, Wisconsin, United States, 53718
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
      • Marinette, Wisconsin, United States, 54143
        • Aurora Bay Area Medical Group-Marinette
      • Milwaukee, Wisconsin, United States, 53209
        • Aurora Cancer Care-Milwaukee
      • Milwaukee, Wisconsin, United States, 53215
        • Aurora Saint Luke's Medical Center
      • Milwaukee, Wisconsin, United States, 53233
        • Aurora Sinai Medical Center
      • Oshkosh, Wisconsin, United States, 54904
        • Vince Lombardi Cancer Clinic - Oshkosh
      • Racine, Wisconsin, United States, 53406
        • Aurora Cancer Care-Racine
      • Sheboygan, Wisconsin, United States, 53081
        • Vince Lombardi Cancer Clinic-Sheboygan
      • Summit, Wisconsin, United States, 53066
        • Aurora Medical Center in Summit
      • Two Rivers, Wisconsin, United States, 54241
        • Vince Lombardi Cancer Clinic-Two Rivers
      • Wauwatosa, Wisconsin, United States, 53226
        • Aurora Cancer Care-Milwaukee West
      • West Allis, Wisconsin, United States, 53227
        • Aurora West Allis Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-N2 based on the presence of an actionable mutation as defined in EAY191

  • 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
  • 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 inactivating or inferred inactivating NF1 alterations 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
  • Platelet count >= 100,000/ mm^3
  • Hemoglobin level >= 10 g/dL
  • Creatinine clearance (CrCL) of ≥ 30 mL/min by the Cockcroft-Gault formula
  • Total bilirubin level =< institutional upper limit of normal
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 5.0 x ULN
  • For patients who will be assigned to Cohort 2 (fulvestrant-resistant), a left ventricular ejection fraction (LVEF) assessment must be performed within 12 weeks prior to registration. The LVEF 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)
  • 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 MIGRATE TO COHORT 2: Cohort migration: Patients treated with control treatment fulvestrant who experience disease progression may be eligible to migrate to Cohort 2 and receive combination treatment with binimetinib and fulvestrant. Patients who choose to do so must meet laboratory values and performance status requirements below and should begin treatment within 28 days
  • PATIENTS WHO MIGRATE TO COHORT 2: Patient's willingness to migrate to Cohort 2 affirmed
  • PATIENTS WHO MIGRATE TO COHORT 2: The patient must have an ECOG performance status of 0-2
  • PATIENTS WHO MIGRATE TO COHORT 2: Absolute neutrophil count >= 1,500/mm^3
  • PATIENTS WHO MIGRATE TO COHORT 2: Platelet count >= 100,000/ mm^3
  • PATIENTS WHO MIGRATE TO COHORT 2: Hemoglobin level >= 10 g/dL
  • PATIENTS WHO MIGRATE TO COHORT 2: Total bilirubin level =< institutional upper limit of normal (ULN)
  • PATIENTS WHO MIGRATE TO COHORT 2: AST and ALT must be =< 5.0 x ULN
  • PATIENTS WHO MIGRATE TO COHORT 2: Creatinine clearance (CrCL) of ≥30 mL/min by the Cockcroft-Gault formula
  • PATIENTS WHO MIGRATE TO COHORT 2: A 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)
  • PATIENTS WHO MIGRATE TO COHORT 2: Pregnancy test according to institutional standards 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:

    • Known uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg
    • Known serum cholesterol >= grade 2.
    • Known hypertriglyceridemia >= grade 2
    • Known 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
  • 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
  • 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)

    • 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 MIGRATE TO COHORT 2
  • PATIENTS WHO MIGRATE TO COHORT 2: Not a candidate for binimetinib in the opinion of the treating investigator

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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, ECHO or MUGA, and tumor biopsy, as well as possible blood sample collection during screening and on study.
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162
  • Mektovi
  • ARRY 438162
  • ARRY 162
  • ARRY162
  • ARRY438162
  • MEK 162
  • MEK-162
Procedure: Computed Tomography
Undergo CT scan
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
Procedure: Multigated Acquisition Scan
Undergo MUGA
Other Names:
  • Blood Pool Scan
  • Equilibrium Radionuclide Angiography
  • Gated Blood Pool Imaging
  • MUGA
  • Radionuclide Ventriculography
  • RNVG
  • SYMA Scanning
  • Synchronized Multigated Acquisition Scanning
  • MUGA Scan
  • Multi-Gated Acquisition Scan
  • Radionuclide Ventriculogram Scan
  • Gated Heart Pool Scan
  • RNV Scan
Drug: Fulvestrant
Given IM
Other Names:
  • Faslodex
  • Faslodex(ICI 182,780)
  • ICI 182,780
  • ICI 182780
  • ZD9238
  • ICI-182780
  • ICI182780
  • ZD 9238
  • ZD-9238
Procedure: Bone Scan
Undergo bone scan
Other Names:
  • Bone Scintigraphy
Procedure: Echocardiography Test
Undergo ECHO
Other Names:
  • Echocardiography
  • EC
Procedure: Biopsy Procedure
Undergo tumor biopsy
Other Names:
  • Bx
  • BIOPSY_TYPE
  • Biopsy
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 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.
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
Procedure: Computed Tomography
Undergo CT scan
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
Procedure: Multigated Acquisition Scan
Undergo MUGA
Other Names:
  • Blood Pool Scan
  • Equilibrium Radionuclide Angiography
  • Gated Blood Pool Imaging
  • MUGA
  • Radionuclide Ventriculography
  • RNVG
  • SYMA Scanning
  • Synchronized Multigated Acquisition Scanning
  • MUGA Scan
  • Multi-Gated Acquisition Scan
  • Radionuclide Ventriculogram Scan
  • Gated Heart Pool Scan
  • RNV Scan
Drug: Fulvestrant
Given IM
Other Names:
  • Faslodex
  • Faslodex(ICI 182,780)
  • ICI 182,780
  • ICI 182780
  • ZD9238
  • ICI-182780
  • ICI182780
  • ZD 9238
  • ZD-9238
Procedure: Bone Scan
Undergo bone scan
Other Names:
  • Bone Scintigraphy
Procedure: Echocardiography Test
Undergo ECHO
Other Names:
  • Echocardiography
  • EC
Procedure: Biopsy Procedure
Undergo tumor biopsy
Other Names:
  • Bx
  • BIOPSY_TYPE
  • Biopsy
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, ECHO or MUGA and tumor biopsy, as well as possible blood sample collection during screening and on study.
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162
  • Mektovi
  • ARRY 438162
  • ARRY 162
  • ARRY162
  • ARRY438162
  • MEK 162
  • MEK-162
Procedure: Computed Tomography
Undergo CT scan
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
Procedure: Multigated Acquisition Scan
Undergo MUGA
Other Names:
  • Blood Pool Scan
  • Equilibrium Radionuclide Angiography
  • Gated Blood Pool Imaging
  • MUGA
  • Radionuclide Ventriculography
  • RNVG
  • SYMA Scanning
  • Synchronized Multigated Acquisition Scanning
  • MUGA Scan
  • Multi-Gated Acquisition Scan
  • Radionuclide Ventriculogram Scan
  • Gated Heart Pool Scan
  • RNV Scan
Drug: Fulvestrant
Given IM
Other Names:
  • Faslodex
  • Faslodex(ICI 182,780)
  • ICI 182,780
  • ICI 182780
  • ZD9238
  • ICI-182780
  • ICI182780
  • ZD 9238
  • ZD-9238
Procedure: Bone Scan
Undergo bone scan
Other Names:
  • Bone Scintigraphy
Procedure: Echocardiography Test
Undergo ECHO
Other Names:
  • Echocardiography
  • EC
Procedure: Biopsy Procedure
Undergo tumor biopsy
Other Names:
  • Bx
  • BIOPSY_TYPE
  • Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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)
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.
Within 4 months of the start of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Any time after the start of the treatment, assessed up to 5 years
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.
The duration between randomization and progression or death from all cause, whichever happens first, assessed up to 5 years
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.
Any time after the start of the treatment, assessed up to 5 years
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.
Any time after the start of the treatment, assessed up to 5 years
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.
The duration between randomization and death of all causes, assessed up to 5 years
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.
Up to 5 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Collaborators

NRG Oncology

Investigators

  • Principal Investigator: Bora Lim, CenterThe University of Texas MD Anderson Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 13, 2024

Primary Completion (Actual)

April 4, 2025

Study Completion (Actual)

April 4, 2025

Study Registration Dates

First Submitted

September 22, 2022

First Submitted That Met QC Criteria

September 22, 2022

First Posted (Actual)

September 26, 2022

Study Record Updates

Last Update Posted (Actual)

March 3, 2026

Last Update Submitted That Met QC Criteria

February 17, 2026

Last Verified

August 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2022-07265 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • U10CA180868 (U.S. NIH Grant/Contract)
  • EAY191-N2 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD 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.

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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