TALAVE: Induction Talazoparib Followed by Combination of Talazoparib and Avelumab in Advanced Breast Cancer

Inclusion Criteria:

Histologically confirmed advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, that is amenable to biopsy
Radiographically measurable disease by RECIST v1.1
Age ≥ 18 years
Life expectancy of more than 3 months
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
Signed informed consent form

Patients with a standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs):

QTc interval at screening < 481 msec
Resting heart rate 50-100bpm

Adequate hepatic, bone marrow, and renal function at the time of enrollment:

Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin ≥ 9.0 g/dL. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 2 weeks before obtaining sample
Creatinine clearance ≥ 60 mL/min based on Cockcroft-Gault equation
Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 × the upper normal limit of institution's normal range, except for subjects with documented history of Gilbert's syndrome who may enroll at Investigator discretion. For subjects with liver metastases, AST and ALT < 5 × the upper normal limit of institution's normal range, and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must be ≤ 2 X the upper limit of the institution's normal range and International Normalized Ratio (INR) < 2. Subjects on anticoagulation (such as coumadin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator
Patients may have received an unlimited number of prior therapies. The last dose of systemic therapy must have occurred a minimum of 2 weeks prior to C1D1.
Patients must have fully recovered from all effects of surgery. Patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy. Minor procedures requiring conscious sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator
Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
Patient is capable of swallowing pills whole
Subject, or legally authorized representative (LAR) is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the IRB, prior to the initiation of any screening or study-specific procedures
Patient, or LAR, must consent to multiple biopsies during study.

Exclusion Criteria:

Prior disease progression while receiving anti-PD-1 or anti-PD-L1 therapy within 6 months of use
Prior exposure to PARP inhibitor-based therapy
Patients with known untreated central nervous system (CNS) metastases
Recent severe infection or antibiotic use, or known chronic infection with human immunodeficiency virus (HIV) or hepatitis B virus
Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
Diagnosis of immunodeficiency or is receiving systemic steroid or other immunosuppressive therapy
Active autoimmune disease that has required systemic treatment in the past 2 years
History of tuberculosis
History of allogenic bone marrow transplant or solid organ transplant
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan
Life-threatening visceral disease or other severe concurrent disease that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol
Live vaccine administration within 30 days of planned start of study therapy
Cardiovascular disease problems including unstable angina, therapy for lifethreatening ventricular arrhythmia, or myocardial infarction, stroke within the last 6 months, or a diagnosis of congestive heart failure
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs
Presence of a psychiatric illness or social situation that would limit compliance with study requirements
Women who are pregnant or breastfeeding
Patients with history of another active malignancy within the past 2 years, excluding non-melanoma carcinoma of the skin
Patients receiving any other investigational agents
Patients must not have had radiotherapy encompassing >20% of the bone marrow
Patients must not have current evidence of any condition, therapy, or laboratory abnormality (including active or uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia, thrombocytopenia]) that might confound the results of the study or interfere with the patient's participation for the full duration of the study treatment or that makes it not in the best interest of the patient to participate
Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection.
Current use of potent P-gp inhibitors within 7 days prior to randomization.