Evaluation of Talazoparib, a PARP Inhibitor, in Patients With Somatic BRCA Mutant Metastatic Breast Cancer: Genotyping Based Clinical Trial

Open to females ages 18 years and up

• Metastatic breast cancer with deleterious somatic BRCA 1 or 2 mutations detectable by cell-free circulating tumor DNA, by CLIA certified clinical assay (including but not restricted to MGH-Snapshot cfDNA assay, Guardant360, Foundation One). The eligibility of a given assay and/or BRCA mutation could be discussed with the primary investigator (Dr. Vidula) and senior investigator (Dr. Bardia), who will provide the final discretion.
• Patients with germline BRCA 1 or 2 mutations will not be eligible.
• Patients with only a VUS (Variant of Unknown Significance), or non-functional BRCA mutation, without a deleterious somatic BRCA 1 or 2 mutation will not be eligible.
• The following disease subtypes are eligible:
  • Triple negative breast cancer (defined as ER < 1%, PR < 1%, HER2 negative, as per ASCO CAP guidelines), with disease progression on at least one prior chemotherapy regimen in the metastatic setting.
  • Hormone receptor positive, HER2 negative disease with disease progression on at least one prior endocrine therapy in the metastatic setting or be considered inappropriate for endocrine therapy
• Patients must have evaluable or measurable disease.
• Any number of prior lines of therapy are allowed
• Patients may have received prior platinum based chemotherapy (0-1 prior platinum based therapy). However, the patient must not have progressed while on platinum treatment (any setting), or within 6 months after end of treatment (neoadjuvant and/or adjuvant).
• At least two weeks from last systemic therapy for breast cancer, with recovery of all treatment related toxicity to grade 1 or less. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion.

• At least two weeks from last radiation therapy, with recovery of all treatment related toxicity to grade 1 or less.

  -≥ 18 years of age on day of signing informed consent.

• ECOG performance status of ≤2.
• Adequate organ function as defined in Table 1 within 10 days prior to treatment initiation.
• Adequate Organ Function Laboratory Values
• SYSTEM LABORATORY VALUE
• Hematological
  • Absolute neutrophil count (ANC) ≥1,500 /mcL
  • Platelets ≥100,000 / mcL
  • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)

• Renal

  --Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN

• Hepatic
  • Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels > 1.5 ULN
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN for subjects with liver metastases
• Prior CNS disease is allowed if stable for at least one month since whole brain radiation therapy in patients who received whole brain radiation, or 2 weeks since stereotactic radiotherapy in patients who received stereotactic radiotherapy. Patients should not be requiring steroids. Patients whose CNS disease was surgically treated may be enrolled if stable for at least one month after surgery, and not requiring steroids.
• Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential must use an acceptable form of birth control per treating physician discretion or be surgically sterile, or abstain from heterosexual activity for the course of the study through 7 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. Additionally, male patients may not donate sperm during the duration of the study and through 7 months after the last dose of study therapy.
• Willing and able to provide written informed consent.

• Treatment with an investigational agent within 4 weeks of the first dose of treatment.
• Patients must not have received prior treatment with a PARP inhibitor
• Patients must not have a germline BRCA 1 or 2 mutation

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion.

  --If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known, untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 7 months after the last dose of trial treatment.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has known active Hepatitis B or Hepatitis C.
• Patients should not be on strong P-glycoprotein inhibitors.
• Patients should not be on any other anti-cancer therapy (chemotherapy, hormone therapy, immunotherapy, or alternate investigational therapy).