PhII Randomized CAPecitabine + ELAcestrant vs. Capecitabine Alone in ER+ Breast Cancer (CAPELA)

Inclusion Criteria:

• Participants must have histologically confirmed estrogen receptor-positive (ER+),HER2- negative metastatic or locally recurrent unresectable (advanced) invasivebreast cancer.

ER and HER2 measurements should be performed according to institutional guidelines in a CLIA-approved setting. ER must be ≥ 10% on the most recent biopsy in which receptor testing was performed. Cutoff values for positive/negative HER2 staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines

• Participants must have standard of care testing documenting ESR1 mutation status. Inpatients without ESR1 mutation, this result must be from within 2 months.

• qualifying ESR1 mutations: E380Q, V422del, S436P, L536H, L536P, L536R, Y537C,Y537D, Y537N, Y537S, D538G

• Women or men age ≥ 18 years. Because no dosing or adverse event data are currentlyavailable on the use of capecitabine in combination with elacestrant participants <18 years of age are excluded from this study

• Women must be postmenopausal, which is defined as any of the following:

• Age ≥ 60 years

• Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy,tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in thepostmenopausal range per local normal range

• Premenopausal women who have been on a GnRH agonist for at least threeconsecutive months prior to study entry are eligible. Women in this group MUSTremain on the GnRH agonist for the duration of protocol treatment.

• Status-post bilateral oophorectomy or total hysterectomy after adequate healingpost-surgery

• Must have measurable or evaluable disease by RECIST 1.1. Must have progressed on atleast one line of endocrine therapy in the metastatic setting or recurred on orwithin one year of adjuvant endocrine therapy

• Up to two prior endocrine therapies (with or without targeted treatment) are allowedin the advanced disease setting. If a patient recurred on or within one year ofadjuvant endocrine therapy, it would be counted as one line of treatment.

• Prior CDK4/6 inhibition is required (in adjuvant or metastatic disease), unless aCDK4/6 inhibitor is contraindicated (CDK4/6 inhibitor in combination with endocrinetreatment is considered as one line of endocrine treatment).

• Participants must have remained on a prior endocrine treatment alone or incombination with a CDK4/6 inhibitor in the metastatic setting without progressionfor at least 6 months prior to study entry. This regimen does not need to be themost recent regimen prior to study entry. If patients have progressed on adjuvantendocrine treatment and have not received treatment in the metastatic setting, theymust have progressed after at least two years of adjuvant endocrine treatments.

• Prior alpelisib with endocrine treatment is allowed (considered as a line ofendocrine treatment).

• Prior everolimus with endocrine treatment is allowed (considered a line of endocrinetreatment).

• Prior capivasertib with endocrine treatment is allowed (considered a line ofendocrine treatment)

• Prior fulvestrant is permitted. Prior elacestrant is NOT permitted, but prior otheroral SERD is permitted.

• No prior chemotherapy regimen is allowed in the metastatic setting.

• Participants may have received radiotherapy for palliative purposes but must not beexperiencing grade >1 treatment-related toxicities at study entry and must havecompleted treatment > 14 days prior to registration.

• ECOG PS 0-1

• Adequate hematological, liver, and kidney function, as defined below:

• Absolute neutrophil count > 1,500/µL

• Platelets > 100,000/µL

• Hemoglobin > 9 g/dL (transfusion is allowed to meet this criterion) Totalbilirubin < 1.5 x institutional upper limit or normal (ULN) or < 3institutional ULN in the presence of documented Gilbert's syndrome

• AST (SGOT)/ALT (SGPT) < 2.5 x institutional ULN, or ≤ 5 institutional ULN forsubjects with documented metastatic disease to the liver

• Creatinine clearance > 30 mL/min/1.73 m2 for subjects with creatinine levelsabove institutional ULN

• Women of childbearing age, women who are made postmenopausal through use of GNRHagonists, and men must agree to use adequate contraception for the duration ofprotocol treatment and for at least 6 months after the last dose of capecitabine.

• Premenopausal women must have a negative serum or urine pregnancy test. Pregnancytesting does not need to be pursued in female participants who are:

• Age > 60 years; or

• Age < 60 with intact uterus and amenorrhea for 12 consecutive months or moreAND estrogen (estradiol) and FSH levels are within postmenopausal range; or

• Status-post bilateral oophorectomy, total hysterectomy, or bilateral tuballigation

• Participants must be able to swallow and retain oral medication.

• Ability to understand and the willingness to sign a written informed consentdocument.

• HIV-infected participants must have well-controlled HIV on ART, defined as:

1. Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time ofscreening.

2. Participants on ART must have achieved and maintained virologic suppressiondefined as confirmed HIV RNA level below 50 or the LLOQ (below the limit ofdetection) using the locally available assay at the time of screening and forat least 12 weeks before screening.

3. It is advised that participants must not have had any AIDS-definingopportunistic infections within the past 12 months.

4. Participants on ART must have been on a stable regimen, without changes indrugs or dose modification, for at least 4 weeks before study entry (Day 1) andagree to continue ART throughout the study. The combination ART regimen mustnot contain any antiretroviral medications that interact with CYP3A4inhibitors/inducers/substrates.

Note: No HIV testing is required at screening unless mandated by local health Authority.

• Participants who are HBsAg positive are eligible if they have received HBV antiviraltherapy for at least 4 weeks, and have undetectable HBV viral load beforeallocation.

Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

Hepatitis B screening tests are not required unless:

• Known history of HBV infection

• As mandated by local health authority Participants with history of HCV infection areeligible if HCV viral load is undetectable at screening. Note: Participants musthave completed curative antiviral therapy at least 4 weeks before allocation.

Hepatitis C screening tests are not required unless:

• Known history of HCV infection

• As mandated by local health authority

Exclusion Criteria:

• Participants who have had endocrine and/or biologic therapy < 14 days prior toentering the study or those who have not recovered from any prior treatment-relatedtoxicities (must recover to no more than grade 1; alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 toxicity not constituting a safety risk based oninvestigator's judgment are acceptable). This is to minimize risk of drug-druginteractions and clarify etiology of future toxicities.

• Participants who are receiving concurrent therapy with other investigational agents.This is to minimize risk of drug-drug interactions and clarify etiology of futuretoxicities.

• Rapidly progressive, symptomatic, visceral spread of disease placing participant atrisk of life- threatening complications in the short term. It is likely that thesepatients will not benefit from this regimen.

• History of dihydropyrimidine dehydrogenase (DPD) deficiency. Patients with thisdeficiency are prone to significant toxicity from capecitabine.

• Participants with active brain metastases. Treated brain metastases that areasymptomatic and do not require systemic steroids for management of symptoms areallowed if they have received SRS (7-day washout) or WBRT (14-day washout) orasymptomatic untreated brain metastases measuring <1cm. Patients with leptomeningealdisease are not eligible. It is unlikely that these patients will benefit from thisregimen.

• Uncontrolled intercurrent illness including, but not limited to: ongoing or activeinfection requiring systemic therapy, clinically significant cardiovascular diseaseincluding: cerebral vascular accident/stroke (< 6 months prior to enrollment),myocardial infarction (< 6 months prior to enrollment), unstable angina, congestiveheart failure (≥ New York Heart Association Classification Class II), or seriouscardiac arrhythmia requiring medication, uncontrolled diabetes mellitus,gastrointestinal disorders potentially affecting the absorption of elacestrant,inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or totalgastric resection, or psychiatric illness/social situations that would limitcompliance with study requirements. Active hepatitis B or active hepatitis Cinfection. Ability to comply with study requirements is to be assessed by eachinvestigator at the time of screening for study participation. This could increaserisk of toxicity from treatment and potentially decrease adherence to studyprotocol.

• Individuals with a history of a different malignancy are ineligible except for thefollowing circumstances: (1) Individuals with a history of other malignancies areeligible if they have been disease-free for at least 3 years and are deemed by theinvestigator to be at low risk for recurrence of that malignancy. (2) Individualswith the following cancers are eligible if diagnosed and treated within the past 5years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basalcell or squamous cell carcinoma of the skin. History of prior malignancy putspatients at risk of recurrence from their prior malignancy or progression of asecond malignancy which would complicate interpretation of the end points of thistrial.

• Ongoing treatment with drugs that are sensitive substrates of P-glycoprotein (dabigatran, digoxin, fexofenadine) or BRCP (rosuvastatin, sulfasalazine). Thesedrugs have potential drug-drug interactions with the study agents.

• Treatment with strong CYP3A inhibitors within 2 weeks before first study treatmentadministration or five elimination half-lives, whichever is longest and cannot bereplaced.

• Medical conditions requiring concomitant administration of medications with a narrowtherapeutic window metabolized by CYP3A and for which a dose reduction cannot beconsidered. See Appendix D for a list of medications that are CYP3A substrates.These drugs have potential drug-drug interactions with the study agents.

• Female participants lactating or nursing. The safety of these medications inpregnancy or breast feeding patients is unknown.