Talazoparib and Avelumab for the Treatment of Advanced Breast Cancer, the TALAVE study

Inclusion Criteria

• Histologically confirmed advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, that is amenable to biopsy. Patients will be enrolled in one of two cohorts: cohort 1 - BRCA1/2 mutant cohort: pre-identified presence of somatic or germline BRCA1/2 deleterious mutation with HER2-negative breast cancers (HER2 definition by current American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines); cohort 2 - BRCA1/2 wild status cohort: patients with triple negative breast cancer (TNBC) (defined as estrogen [ER], progesterone [PR] and HER2 negative i.e. ER < 1%, PR < 1% and HER2 negativity by current ASCO/CAP guidelines) without a known germline or somatic BRCA1/2 mutation. Variants of unknown significance will not be eligible. Patients with germline deleterious mutations may have been identified at any time point prior to inclusion in the protocol and do NOT need to have this genetic testing repeated regardless of time frame and intervening therapy
• Life expectancy of more than 3 months
• Age >= 18 years
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (tumor >= 1 cm in longest diameter on axial image on computed tomography [CT] or magnetic resonance imaging [MRI] and/or lymph node[s] >= 1.5 cm in short axis on CT or MRI) on baseline imaging
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
• Patients with TNBC and no BRCA mutation who have progressed on a “taxane” based regimen in prior lines of therapy. Patients who refuse standard therapy would also be eligible, as long as their refusal is documented. Note: If a taxane is not an appropriate option for the patient then they will also be eligible to participate as long as it is documented by the treating physician
• Patients with a standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs): * Corrected QT (QTc) interval at screening < 481 msec * Resting heart rate 50-100 beats per minute (bpm)
• Absolute neutrophil count (ANC) >= 1,500/mm^3. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 2 weeks before obtaining sample
• Platelets >= 100,000/mm^3. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 2 weeks before obtaining sample
• Hemoglobin >= 9.0 g/dL. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample
• Creatinine clearance >= 60 mL/min based on Cockcroft-Gault equation
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x the upper normal limit of institution's normal range. For subjects with liver metastases, AST and ALT =< 5 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
• Total bilirubin =< 1.5 x 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, 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
• 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 cycle 1, day 1 (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 Institutional Review Board (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 PARP inhibitor-based therapy
• Known or suspected central nervous system (CNS) metastases, unless at least one month has passed since last local CNS therapy and there is no evidence for recurrent or progressive CNS disease on follow up imaging. Participants may remain on steroids for CNS disease if they are taking a stable dose that is less than 10 mg of prednisone per day, or the equivalent
• Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and TNFalpha antagonists) within 7 days prior to the first dose of study treatment * Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the study principal investigators (PIs) * The use of inhaled, intranasal, ophthalmic or topical corticosteroids is allowed * The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension is allowed * Physiologic doses of systemic corticosteroids at doses which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid is allowed * High dose steroid pre-treatment for CT contrast dye allergy is allowed, provided the dose(s) of steroids is(are) given at least 1 week prior to starting the study medications
• Known chronic infection with human immunodeficiency virus (HIV) or hepatitis B virus (testing not required prior to enrollment) * Patients with chronic hepatitis C virus may be enrolled if there is no clinical/laboratory evidence of cirrhosis AND the patient’s liver function tests fall within the parameters set
• Active tuberculosis OR known history of previous clinical diagnosis of tuberculosis
• Severe infections within 4 weeks prior to day 1 of study therapy, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia * Any course of oral or IV antibiotics must have been completed at least 2 weeks prior to the first dose of study medications
• Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation
• Patient has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, auto-immune Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis with the following caveats: * Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment * Patients with Grave’s disease, vitiligo, autoimmune alopecia, or psoriasis not requiring systemic treatment (within the past 2 years) are eligible upon consultation with the study PIs * Patients with questionable diagnosis of autoimmune disease who have never been treated with immunosuppressive regimen and have no ongoing symptoms at the time of enrollment may be eligible after discussion with medical monitor and PI
• 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 * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months. Additionally, patients must not have QT prolongation greater than or equal to 481 milliseconds
• 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 (e.g. chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patient has received a live vaccine within 30 days of planned start of study therapy
• Presence of a psychiatric illness or social situation that would limit compliance with study requirements
• Women who are pregnant or breastfeeding
• The subject must not have had diagnosis, detection, or treatment of another type of cancer =< 2 years prior to randomization (except basal or squamous cell carcinoma of the skin that has been definitively treated). Questions regarding the inclusion of individual subjects should be directed to the principal investigators, Dr. Isaacs
• Patients must not have had investigational therapy administered =< 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
• Patients must not have had radiotherapy encompassing > 20% of the bone marrow
• Patients must not have a known hypersensitivity to the components of talazoparib, avelumab or the excipients
• 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. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome
• Current use of potent P-glycoprotein (gp) inhibitors within 7 days prior to randomization