Repotrectinib with or without Fulvestrant for the Treatment of Patients with Metastatic Invasive Lobular Carcinoma, REPLOT Trial

Inclusion Criteria

• 18 years of age or older
• Confirmed invasive lobular carcinoma (ILC) with negative E-cadherin immunohistochemistry (IHC) staining on pre-treatment biopsy or archival biopsy * Patients with ILC who have a germline CDH1 mutation will be included if the E-cadherin IHC staining is negative
• Estrogen receptor positive (> 1%), progesterone receptor positive or negative, and HER2-negative according to HER2 testing guidelines from the American Society of Clinical Oncology/College of American Pathologists * For cohort 2 only: ER-negative patients who previously had documented ER-positive/HER2-negative disease and subsequently converted to ER-negative status (cTN-ILC) are also eligible
• Patients must be willing to undergo biopsy as required by the study, if the tumor is safely accessible
• Patient must have been exposed to a CDK4/6i prior to enrollment
• Patients who received prior chemotherapy, antibody drug conjugate (ADCs), mTOR inhibitor and/or PI3K are eligible * Patients with ESR1 mutation who received prior elacestrant can still enroll on the study. If they did not receive prior fulvestrant they will be enrolled on Cohort 1. If they received prior fulvestrant they will be enrolled on Cohort 2
• Patients should not have received more than 2 chemotherapeutic agents and/or ADCs in the metastatic setting * The enrollment of patients who received 2 or more prior line of therapy (including endocrine therapy) in the metastatic setting will be limited to 50% of the total accrual in both cohorts
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Patient has either measurable disease per response evaluation criteria in solid tumors (RECIST) version (v) 1.1 criteria OR at least one predominantly lytic bone lesion must be present
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation
• WOCBP must agree to use adequate contraception for the duration of study treatment and 7 months after the last dose of study treatment
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 70,000/mcL
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN
• Creatinine ≤ 1.5 x institutional ULN
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
• 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
• Patients with no current symptoms of cardiac disease
• Ability to understand and the willingness to sign a written informed consent document
• The effects of repotrectinib on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (follicle stimulating hormone and wstradiol in menopausal range, who have received whole pelvic radiation therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. * Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

Exclusion Criteria

• Patients with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment
• Patients who have had chemotherapy, hormonal therapy, biotherapy, immunotherapy or radiotherapy within 2 weeks prior to entering the study
• Systemic small molecule-targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents
• Patients with prior history of pneumonitis/ILD
• Patients with grade ≥ 2 ataxia, muscle weakness, dysgeusia, dizziness, paresthesia and/or peripheral neuropathy
• Patients with untreated or progressing brain metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to repotrectinib, fulvestrant or other agents used in study
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because repotrectinib and fulvestrant have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with repotrectinib, breastfeeding should be discontinued if the mother is treated with repotrectinib. These potential risks may also apply to other agents used in this study