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This is an open-label, single arm, multi-stage, phase II trial of Trifluridine/tipiracil as a palliative treatment for patients with metastatic triple negative breast cancer who have failed both a taxane and anthracycline or have contraindications to these agents.

This is an open-label, single arm, multi-stage, phase II trial of Trifluridine/tipiracil (TAS-102) as a palliative treatment for patients with metastatic triple negative breast cancer who have failed both a taxane and anthracycline or have contraindications to these agents.

The trial will begin with a safety run-in of 10 patients treated as follows:

Cycle 1: Trifluridine/tipiracil administered at 30 mg/m2 orally bid, 5 days per week, with 2 days of rest, for 2 weeks, followed by 14 day rest. Intra-patient dose escalation to 35 mg/m2 orally bid, 5 days per week, with 2 days of rest, for 2 weeks, followed by 14 day rest for subsequent cycles in the absence of dose limiting toxicities. As long as at least 80% of patients tolerate dose escalation, the trial will proceed to the next stage.

Patients enrolled in stages I and II will start Trifluridine/tipiracil at 35 mg/m2 orally bid, 5 days per week, with 2 days of rest, for 2 weeks, followed by 14 day rest.

Inclusion Criteria:

• Age ≥ 18 years

• Life expectancy of ≥ 3 months

• Histologically or cytologically confirmed locally recurrent or metastatic breast cancer that is Estrogen receptor negative, Progesterone receptor negative, and HER2 normal on local testing

• Up to three prior chemotherapy regimens for advanced and/or metastatic disease

• Prior therapy with an anthracycline and a taxane in the adjuvant or metastatic setting or documented unsuitability

• Patients who developed advanced or metastatic disease within 6 months of completing adjuvant therapy are eligible with no prior therapy for advanced disease.

• Resolution of all chemotherapy- or radiation-related toxicities to ≤ grade 1 (except for stable sensory neuropathy ≤ grade 2 and alopecia) prior to commencement of study participation

• Eastern Cooperative Oncology Group performance status of 0 to 2

• Adequate renal function: creatinine clearance ≥ 40 mL/min Cockcroft and Gault formula

• Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, hemoglobin ≥ 10.0 g/dL (a hemoglobin <10.0 g/dL is acceptable if it is corrected by growth factor or transfusion), and platelet count ≥ 100 x 10^9/L

• Adequate liver function: bilirubin ≤ 1.5 times the upper limits of normal (ULN), alanine aminotransferase (ALT ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN)

• Measurable disease (RECIST 1.1)

• Patients with known BRCA or ATM mutations or abnormalities (based on genomic profiling of tumor or germline genetic testing) are eligible if they meet all other inclusion criteria and have none of the exclusion criteria. The trial will not perform tumor genomic profiling or genetic testing but will document this information if available at study enrolment.

• Patients with known central nervous system (CNS) disease are eligible provided all of the following criteria are met:

  • Measurable disease outside the CNS
  • Metastases are limited solely to cerebellar and supratentorial lesions (i.e., no metastases to midbrain, pons, medulla, or spinal cord)
  • If corticosteroids are required, the patient must be on a stable dose or tapering dose of corticosteroids for 4 weeks prior to enrolment as therapy for CNS disease
  • Anticonvulsants at a stable dose are allowed as long as the patient has been seizure free for 3 weeks prior to enrolment
  • No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization
  • No evidence of progression or haemorrhage after completion of CNS directed therapy
  • 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, if all other criteria above are met.

• Women of child-bearing potential and males with female partners with child bearing potential must use highly effective contraceptive measures while taking Trifluridine/tipiracil and for 6 months after stopping treatment. Trifluridine/tipiracil may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier contraceptive method.

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

• Ability to take and retain oral medications

Exclusion Criteria:

• Radiation therapy encompassing more than 30% of marrow
• 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 at least 2 weeks prior to randomization.
• Leptomeningeal disease
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Trifluridine/tipiracil .
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because Trifluridine/tipiracil is an agent with the potential for teratogenic or abortifacient effects.