Low Dose Capecitabine for the Treatment of Locally Advanced and Metastatic HER2 Negative Breast Cancer

Inclusion Criteria

• Histologically or cytologically confirmed breast cancer with HER2 negative status. A copy of the pathology report is required at the time of enrollment * HER2 negativity will be determined by in situ hybridization (ISH) non-amplified and immunohistochemistry (IHC) 0 or 1+ or 2+ * Patients with HR (hormone receptor) positive (estrogen receptor [ER] and/ or progesterone receptor [PR] positive ≥ 1%) and triple negative breast cancer (TNBC: ER < 1%, PR < 1%, HER2 negative), according to the American Society of Clinical Oncology/College of American Pathologists guidelines) will be eligible for enrollment
• Metastatic or locally advanced breast cancer, with at least one measurable lesion according to RECIST (v1.1)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Patients must have progressed on at least 1 prior line of therapy in the metastatic setting (hormonal therapy or chemotherapy). Patients have other prior options for standard-of-care treatment associated with clinical benefit such as hormonal therapies, antibody drug conjugates, and chemotherapies
• Absolute neutrophil count (ANC) > 1.5 x 10^9/L (1500/uL) or > 1.3 x 10^9/L (1300/uL) for patients with history of benign ethnic neutropenia
• Platelet count ≥ 100,000/uL (without transfusion within 2 weeks prior to initiation of study treatment [cycle 1, day 1])
• Hemoglobin ≥ 9.0 g/dl. Patients may be transfused or receive erythropoietic treatment to meet this criterion
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN) with following exceptions: * Patients with documented liver metastasis: AST and ALT ≤ 5 x ULN * Patients with documented liver or bone metastasis: alkaline phosphatase ≤ 5 x ULN
• Serum bilirubin ≤ 1.5 x ULN * Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN * This applies only to the patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
• Creatinine clearance > 30 mL/min (measured using Cockcroft-Gault equation or estimated glomerular filtration rate from the Modification of Diet in Renal Disease Study)
• Patients must be able to provide signed informed consent
• Female patients of any ethnic group. Female patients must be surgically sterile, postmenopausal (no menses for at least one year), or using medically approved method of contraception (excluding rhythm, withdraw or abstinence). Men must agree to use a medically approved method of contraception (excluding rhythm, withdraw or abstinence)
• Patients ≥ 60 years old and/or frail patients at any age, defined by the investigator as an individual at greater risk of complications and poorer outcomes with systemic therapy, secondary to a lower physiologic reserve and higher comorbidities and functional deficits
• Complete initial work-up within 2 weeks prior to start of treatment (cycle 1 day 1)
• Patients known to be HIV positive are eligible if they meet the inclusion criteria

Exclusion Criteria

• Any history of treatment with capecitabine in metastatic setting
• Patients who only have non-measurable disease
• Patients with severe hepatic (bilirubin > 3 times upper limit of normal) or renal failure (creatinine clearance [CrCl] < 30 calculated using Cockcroft-Gault formula)
• Patients who are unable to swallow pills
• Patients with HER2 positive breast cancer
• Major surgical procedure within 3 weeks prior to study entry
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to initiation of study treatment (cycle 1, day 1)
• Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met: * No stereotactic radiation within 7 days or whole brain radiation within 14 days prior to initiation of study treatment (cycle 1, day 1) * Note: Patients with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be eligible without the need for an additional brain scan prior to enrollment, if all other criteria are met
• History of leptomeningeal disease
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
• Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency
• Severe infection within 4 weeks prior to initiation of study treatment (cycle 1, day 1), including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia, including COVID-19 or any active infection that could impact patient safety
• Patients with suspected or confirmed COVID-19 may be re-screened for eligibility following physician-prescribed COVID-19 treatment and/or quarantine and following a negative COVID-19 real-time reverse transcription polymerase chain reaction (rRT-PCR) test
• Patients receiving warfarin anti-coagulation therapy, given significant interaction with capecitabine
• Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible
• Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with the following exceptions: * Patients who are HCV Ab positive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution are eligible. Patients with untreated HCV may be enrolled if the HCV is stable, the patient is not at risk for hepatic decompensation, and the intended treatment is not expected to exacerbate the HCV infection * Patients on concurrent HCV treatment may be enrolled if they have HCV below the limit of quantification
• Patients known to have active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test) * Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV deoxyribonucleic acid (DNA)
• Active tuberculosis