Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis

Inclusion criteria

• for both Phase Ib and Phase II:
• Hormone receptor-positive, HER2-negative metastatic breast cancer.
• Measurable or non-measurable but evaluable disease by RECIST v1.1.
• Candidate for capecitabine treatment per physician decision. See below phase-specific eligibility criteria for further guidance.
• 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 C1D1.
• At least 18 years of age.
• ECOG performance status 0, 1, or 2
• Life expectancy of at least 12 weeks.
• Adequate bone marrow and organ function as defined below:
• Leukocytes ≥ 3 K/cumm
• Absolute neutrophil count (ANC) ≥ 1.5 K/cumm
• Platelets ≥ 100 K/cumm
• Total bilirubin ≤ 1.5 x IULN (or total bilirubin ≤ 3 mg/dL if patient has known Gilbert Syndrome)
• AST(SGOT)/ALT(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 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 PI approval.
• Inclusion Criteria for both Phase Ib:
• Presence of bone metastasis is not required.
• 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 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.
• Inclusion Criteria for Phase II:
• 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

• for both Phase Ib and Phase II:
• 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 Cycle 1 Day 1. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
• Screening resting QTcF above 470 msec.
• Exclusion Criteria for Phase Ib:
• 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.
• Exclusion Criteria for Phase II:
• Prior capecitabine in the metastatic setting.
• History of other malignancy, unless all treatment was completed and patient had no evidence of disease within 2 years of C1D1.