Study of ASTX727 Plus Talazoparib in Patients With Triple Negative or Hormone Resistant/HER2-negative Metastatic Breast Cancer

Prior treatment

• Prior treatment with decitabine, guadecitabine or other known DNA Methyltransferase inhibitors (DNMTis)
• Prior treatment with talazoparib or other known PARPi (poly(ADP-ribose polymeras inhibitor)
• Chemotherapy within 3 weeks of registration
• Radiation therapy within 2 weeks of registration
• Hormone therapy within 2 weeks of registration
• Patients requiring ongoing therapy with strong P-gp inhibitors

Other illness

• Known deleterious breast cancer susceptibility gene (BRCA) mutation. Patients with BRCA variants of unknown significance (VUS) or who have not had germline genetic testing may participate.
• Active or symptomatic CNS disease
• Patients with HER2+ disease
  • HER2 will be considered positive if scored 3+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of \> 2.0 or \> 6 total HER2 gene copies per cell.
• Patients with active malignancy other than breast cancer. Patients with prior malignancies without recurrence after standard treatment will not be excluded

• ≥ 18 years old at the time of informed consent
• Ability to provide written informed consent and HIPAA authorization
• Locally recurrent (not amenable to local therapy with curative intent) or metastatic breast cancer
  • Patients with triple negative breast cancer must have received at least one prior chemotherapy regimen for metastatic disease.
  • Patients with hormone-positive, HER2-negative disease must have received treatment with and progressed on at least one prior endocrine therapy including a CDK4/6 inhibitor in the metastatic setting.
• Measurable or evaluable disease based on RECIST 1.1 criteria.
• Only subjects who have disease amenable to biopsy will be asked to consent to serial tumor biopsies. Consent for biopsy is not required for participation.
  • NOTE: If no amendable disease is present at the time of biopsy, subjects may continue participation in the study and further study specific biopsies will not be required.
• Eastern Cooperative Oncology Group Performance Status 0 or 1
• Patients with treated, asymptomatic central nervous system (CNS) disease may participate if the patient is \> 4 weeks from completion of CNS therapy (radiation and/or surgery), is clinically stable at the time of study entry, and is receiving a stable or decreasing dose of corticosteroid therapy. Brain MRI or head CT is required at screening for patients with known brain metastases.
• Adequate organ function as indicated by:
  • Total bilirubin \</= ULN (upper limit of normal) (except in patients with documented Gilbert's disease, who must have a total bilirubin \</= 3.0 mg/dL)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \</= 3.0 x ULN (\</= 1.5-3.0 x baseline if baseline is abnormal)
  • Calculated creatinine clearance of \>/= 60 mL/min using the Cockcroft-Gault formula
  • Absolute neutrophil count (ANC) \>/= 1.5 K/mm3
  • Platelets \>/= 100 K/mm3
  • Hemoglobin (Hgb) \>/= 9.0 g/dL
• Women of childbearing potential must have a negative pregnancy test within 14 days of protocol registration. Women are considered to have childbearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) unless they meet one of the following criteria:
  • Has undergone a hysterectomy or bilateral oophorectomy; or
  • Has been naturally amenorrheic for at least 24 consecutive months.
• Women of childbearing potential and men must agree to use effective contraception throughout the study and for 7 months after the last study treatment. Note: Acceptable methods of birth control include abstinence, partner with previous vasectomy, placement of an intrauterine device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control (pills or injections).