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

Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatmentassignment to ComboMATCH to EAY191-N2 based on the presence of an actionablemutation 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 ComboMATCHRegistration Trial EAY191 at the time of registration to EAY191-N2. Thisincludes submission of next-generation sequencing (NGS) data from one of theNational Cancer Institute (NCI) credentialed designated laboratories for allpotential patients prior to treatment trial assignment. Copy number and allelefrequency cutoff as per the Registration protocol

• Patients must have disease that can be safely biopsied and agree to a pre-treatmentbiopsy or, if disease cannot be safely biopsied, have archival tissue available fromwithin 12 months prior to the date of registration on the ComboMATCH registrationtrial (EAY191)

• Please note the current actionable marker of interest (aMOI)/actionablealteration list for this treatment trial can be found on the Cancer TrialSupport Unit (CTSU) ComboMATCH Registration protocol page

• Please note novel/Dynamic aMOI can be submitted for review per the processdescribed in the ComboMATCH Registration protocol

• A COMBOMATCH TREATMENT TRIAL EAY191-N2 ELIGIBILITY CRITERIA:

• The patient or a legally authorized representative must provide study-specificinformed 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 andone additional lesion that can be biopsied (primary, metastatic both allowed)

• Patients must have inactivating or inferred inactivating NF1 alterations detected intumor as determined by the ComboMATCH screening assessment

• The tumor must have been determined to be estrogen receptor (ER) and/or progesteronereceptor (PgR) positive assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for hormonereceptor 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/CAPguidelines

• Prior use of CDK4/6 inhibitor(i) is required

• Prior use of fulvestrant regardless of duration is allowed and will determinetreatment 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 xULN

• For patients who will be assigned to Cohort 2 (fulvestrant-resistant), a leftventricular ejection fraction (LVEF) assessment must be performed within 12 weeksprior to registration. The LVEF must be >= 50% regardless of the cardiac imagingfacility's lower limit of normal. (LVEF assessment performed by echocardiogram ispreferred; however, MUGA scan may be substituted based on institutional/situationalpreferences)

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months of registration are eligiblefor this trial

• ELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO MIGRATE TOCOHORT 2: Cohort migration: Patients treated with control treatment fulvestrant whoexperience disease progression may be eligible to migrate to Cohort 2 and receivecombination treatment with binimetinib and fulvestrant. Patients who choose to do somust meet laboratory values and performance status requirements below and shouldbegin treatment within 28 days

• PATIENTS WHO MIGRATE TO COHORT 2: Patient's willingness to migrate to Cohort 2affirmed

• PATIENTS WHO MIGRATE TO COHORT 2: The patient must have an ECOG performance statusof 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 limitof 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 theCockcroft-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 (LVEFassessment performed by echocardiogram is preferred; however, MUGA scan may besubstituted based on institutional/situational preferences)

• PATIENTS WHO MIGRATE TO COHORT 2: Pregnancy test according to institutionalstandards 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 thatrequires systemic steroids or immunosuppressive agents

• Active brain metastasis. Brain metastases that have been stable for at least 1 monthafter completion of treatment are not an exclusion criterion

• History of or evidence of retinal pathology on ophthalmologic examination that isconsidered a risk factor for neurosensory retinal detachment/central serous,chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular maculardegeneration

• Patients will be excluded if they currently have the following risk factors for RVOthat 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 bymedication or congenital long QT syndrome will be excluded due to known side effectsof binimetinib

• Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheralsensory neuropathy) >= grade 2

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplications

• Other conditions that, in the opinion of the investigator, would preclude thepatient from meeting the study requirements or interfere with interpretation ofstudy results

• Pregnancy or lactation at the time of registration or intention to become pregnantduring the study (Note: Pregnancy testing according to institutional standards forpatients of childbearing potential)

• For binimetinib, highly effective contraception should be used for at least 30days after the last dose, and patients should not breastfeed for 3 days afterthe last dose

• For fulvestrant, highly effective contraception should be used for 1 year afterthe last dose, and patients should not breastfeed for 1 year after the lastdose

• Use of any investigational product within 30 days prior to study entry

• INELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO MIGRATE TOCOHORT 2

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