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

Inclusion Criteria:

• Metastatic breast cancer with deleterious somatic BRCA 1 or 2 mutations detectableby cell-free circulating tumor DNA, by CLIA certified clinical assay (including butnot restricted to MGH-Snapshot cfDNA assay, Guardant360, Foundation One). Theeligibility of a given assay and/or BRCA mutation could be discussed with theprimary investigator (Dr. Vidula) and senior investigator (Dr. Bardia), who willprovide 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 BRCAmutation, 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, asper ASCO CAP guidelines), with disease progression on at least one priorchemotherapy regimen in the metastatic setting.

• Hormone receptor positive, HER2 negative disease with disease progression on atleast one prior endocrine therapy in the metastatic setting or be consideredinappropriate 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 platinumbased therapy). However, the patient must not have progressed while on platinumtreatment (any setting), or within 6 months after end of treatment (neoadjuvantand/or adjuvant).

• At least two weeks from last systemic therapy for breast cancer, with recovery ofall treatment related toxicity to grade 1 or less. Subjects with ≤ Grade 2neuropathy are an exception to this criterion.

• At least two weeks from last radiation therapy, with recovery of all treatmentrelated 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 treatmentinitiation.

• 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 beused 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 ULNfor subjects with liver metastases

• Prior CNS disease is allowed if stable for at least one month since whole brainradiation therapy in patients who received whole brain radiation, or 2 weeks sincestereotactic radiotherapy in patients who received stereotactic radiotherapy.Patients should not be requiring steroids. Patients whose CNS disease was surgicallytreated may be enrolled if stable for at least one month after surgery, and notrequiring steroids.

• Female subjects of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.

• Female subjects of childbearing potential must use an acceptable form of birthcontrol per treating physician discretion or be surgically sterile, or abstain fromheterosexual activity for the course of the study through 7 months after the lastdose of study medication. Subjects of childbearing potential are those who have notbeen surgically sterilized or have not been free from menses for > 1 year.

• Male subjects should agree to use an adequate method of contraception starting withthe first dose of study therapy through 7 months after the last dose of studytherapy. Additionally, male patients may not donate sperm during the duration of thestudy and through 7 months after the last dose of study therapy.

• Willing and able to provide written informed consent.

Exclusion Criteria:

• Treatment with an investigational agent within 4 weeks of the first dose oftreatment.

• 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 therapywithin 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or atbaseline) from adverse events due to a previously administered agent. Note: Subjectswith ≤ Grade 2 neuropathy are an exception to this criterion.

--If subject received major surgery, they must have recovered adequately from thetoxicity 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 ofthe skin that has undergone potentially curative therapy or in situ cervical cancer.

• Has known, untreated central nervous system (CNS) metastases and/or carcinomatousmeningitis.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the screening visit through 7 monthsafter 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, hormonetherapy, immunotherapy, or alternate investigational therapy).