Zunsemetinib in Combination with Capecitabine for the Treatment of Patients with Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer

Inclusion Criteria

• Hormone receptor-positive, HER2-negative metastatic breast cancer
• Measurable or non-measurable but evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Candidate for capecitabine treatment per physician decision
• No more than one prior chemotherapy for metastatic disease
• Patient must have received prior endocrine therapy with CDK4/6 inhibitor
• If patient is on denosumab or zoledronic acid prior to enrollment, patient must have been on the regimen for at least 6 months prior to study. However, a washout of 3 weeks is required prior to cycle 1 day 1 (C1D1)
• At least 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Life expectancy of at least 12 weeks
• Leukocytes ≥ 3 K/cumm
• Absolute neutrophil count (ANC) ≥ 1.5 K/cumm
• Platelets ≥ 100 K/cumm
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (or total bilirubin ≤ 3 mg/dL if patient has known Gilbert syndrome)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 x IULN
• Creatinine clearance > 60 mL/min by Cockcroft-Gault
• Calcium within normal limits
• Women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. Contraception should continue for 6 months (for women) or 3 months (for men) after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately
• Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document
• Patients must have archival tissue sample available from prior metastatic biopsy. If no tissue is available, patient may still be able to enroll with principal investigator (PI) approval
• PHASE IB ONLY: Presence of bone metastasis is not required
• PHASE IB ONLY: Candidate for, or currently on stable doses of capecitabine, defined as capecitabine: 1000 mg/m^2 BID, 14 days on and 7 days off. A stable dose of capecitabine is defined as no more than grade 1 adverse events (AEs) related to capecitabine on the 1000 mg/m^2 BID, 14 days on and 7 days off dose for at least 1 cycle. Capecitabine is not counted as a prior chemotherapy regimen in these patients
• PHASE II ONLY: Progressive bone metastasis per the most recent tumor imaging studies by RECIST 1.1 or clinical progression (such as worsening bone pain, elevation of tumor marker) per treating physician

Exclusion Criteria

• Patients may not have received the following investigational or SOC therapies within the below specified time frames prior to C1D1: * Radiation therapy within 1 week * Systemic chemotherapy, including antibody drug conjugates with chemotherapy payload, within 3 weeks * Immunotherapy within 3 weeks * Oral chemotherapy or molecularly targeted therapy within 5 half-lives of the agent * Endocrine therapies do not have a required washout and may be continued until C1D1 * Strong and moderate CYP3A4 and CYP2C8 inhibitors (including grapefruit), strong and moderate CYP3A and CYP2C8 inducers, and drugs with QT prolonging potential within 5 half-lives of the agent
• Untreated brain metastases. Patients with treated brain metastases are eligible if they show no evidence of progression and are off steroids
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to zunsemetinib or other agents used in the study
• History of acute, untreated skeletal related events (SRE) or active untreated SRE or a change or an anticipated change in the SOC anti-resorptive agents after entering the study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of C1D1
• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to C1D1. Concurrent treatment with effective anti-retroviral therapy (ART) according to Department of Health and Human Services (DHHS) treatment guidelines is recommended
• Screening resting Fridericia’s formula–corrected QT interval (QTcF) above 470 msec
• PHASE IB ONLY: Capecitabine within 2 weeks prior to C1D1. Patients may be currently taking capecitabine, but must not have dosed within 2 weeks prior to C1D1 for study correlative purposes
• PHASE II ONLY: Prior capecitabine in the metastatic setting
• PHASE II ONLY: History of other malignancy, unless all treatment was completed and patient had no evidence of disease within 2 years of C1D1