Talazoparib Before Standard Therapy in Treating Patients With Invasive, BRCA-Mutated Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects of talazoparib when given before standard therapy in treating patients with breast cancer that has spread to nearby healthy tissue and has a mutation in a breast cancer, early onset (BRCA) gene. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may be especially effective in patients with BRCA mutations. It is not yet known whether adding talazoparib before standard treatment is safe in treating patients with BRCA mutated breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the feasibility of using talazoparib prior to initiating standard neoadjuvant therapies. II. To evaluate the toxicity profile in women taking talazoparib in the neoadjuvant setting. SECONDARY OBJECTIVES: I. To provide first estimate of clinical response to talazoparib in the neoadjuvant setting in a pilot trial setting. II. To evaluate biomarkers of therapy efficacy as well as initiate patient derived xenograft (PDX) models: targeted or whole exome sequencing for BRCA pathway mutations and other somatic and germline alterations; ribonucleic acid (RNA) sequencing; evaluation of changes in immune response; transcriptional profile to assess triple negative breast cancer (TNBC) subtype, BRCA-ness signature and putative PARP sensitivity predictors; functional proteomics with reverse phase protein array (RPPA); generate PDX models and mammosphere cultures from patient derived tumors; PTEN, gamma-H2A histone family, member x (gamma-H2A.X), Ki-67 and cleaved caspase 3 by immunohistochemistry (IHC). OUTLINE: Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to the standard of care therapy of the treating physician's choice. After completion of study treatment, patients are followed up until the day after definitive breast surgery.

Official Title
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A Pilot Study of Talazoparib as a Neoadjuvant Study in Patients With a Diagnosis of Invasive Breast Cancer and a Deleterious BRCA Mutation

Conditions
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Breast Adenocarcinoma, Deleterious BRCA1 Gene Mutation, Deleterious BRCA2 Gene Mutation, HER2/Neu Negative, Invasive Breast Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Talazoparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Histologically confirmed primary invasive adenocarcinoma of the breast with the size of the primary tumor being at least 1 cm on imaging by either mammography, ultrasound or breast magnetic resonance imaging (MRI) Negative human epidermal growth factor receptor 2 (HER-2)/neu- disease defined as patients with fluorescence in situ hybridization (FISH) ratio < 2.0 or < 6.0 HER2 gene copies per nucleus, and IHC staining scores of 0, 1+, or 2+ No treatment for current primary invasive adenocarcinoma of the breast such as irradiation, chemotherapy, immunotherapy, investigational therapy or surgery; previous treatment for breast and/or ovarian cancer with chemotherapy, endocrine therapy, surgery and radiation are allowed if >= 3 years prior to current diagnosis and there is no clinical evidence of metastatic disease Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Baseline multi gated acquisition scan (MUGA) or echocardiogram scans with left ventricular ejection fraction (LVEF) of > 50% Absolute neutrophil count (ANC) >= 1,500/uL Platelets >= 100,000/uL Hemoglobin (Hgb) >= 9 g/dL Creatinine clearance > 50 ml/min Total bilirubin =< 1.5 X upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN Negative serum or urine pregnancy test for women within 7 days of receiving the first dose of the study medication for women of childbearing potential; women will be considered not of childbearing potential and exempt from pregnancy testing if they are either a) older than 50 and amenorrheic for at least 12 consecutive months following cessation of all exogenous hormonal treatments, or b) have documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product; men on study also must be using contraception Identified deleterious mutation in BRCA 1 or 2 genes (this does not include variants of uncertain significance) Eligible to receive standard of care chemotherapy and/or surgery based upon standard practices or institutional guidelines Exclusion Criteria: Women who are pregnant (including positive pregnancy test at enrollment or prior to study drug administration) or breast-feeding Disease free of prior malignancy for < 3 years with the exception of curatively treated basal carcinoma of the skin or carcinoma in situ of the cervix Any other previous antitumor therapies for the current cancer event Has had major surgery within 21 days before cycle 1 day 1 Gastrointestinal tract disease or defect with associated malabsorption syndrome Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) Myocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication Serious intercurrent infections or non-malignant medical illness that are uncontrolled or the control of which may be jeopardized by this therapy Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocols Unable to take oral medications Known to be human immunodeficiency virus positive Known active hepatitis C virus, or known active hepatitis B virus Concurrent disease or condition that would interfere with study participation or safety, such as any of the following: Active, clinically significant infection either grade > 2 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03 or requiring the use of parenteral anti-microbial agents within 14 days before day 1 of study drug Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders Non-healing wound, ulcer, or bone fracture Known hypersensitivity to any of the components of talazoparib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (talazoparib)<br>Patients receive talazoparib PO QD on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to the standard of care therapy of the treating physician's choice. This arm was concluded early after 13 patients. An expansion arm of 20 patients was opened in August 2016 to include at least 4 and up to 6 cycles of talazoparib, followed by surgery to estimate residual cancer burden after therapy with single-agent talazoparib. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Talazoparib<br>* Given PO<br>* Other names: BMN-673;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Pathological Complete Response (pCR) | Pathologic response was documented using the Residual Cancer Burden (RCB) Calculator. Residual cancer burden by ICR will be reported as a categorical variable with four classes (categories) RCB 0 (pCR) which correlates to no invasive disease in breast and lymph, I (minimal RCB), II (moderate RCB), and III (extensive RCB). Up to two fine needle aspirates (FNAs) will also be obtained at each time point for a total of up to 6 FNA's for the trial, which will be used for the patient derived xenograft models. Pre-study biopsies, as well as biopsies within 7 days prior to the completion of 2 months of talazoparib will be collected via diagnostic imaging. During the expansion phase of this trial, ultrasounds will be obtained every 2 cycles (+/- 1 week). Therapy will be discontinued if the Physician or PI indicates clinically significant progression of disease. | Up to 6 months | 
| Number of Participants With Grade 4 Toxicities | To assess the toxicity profile of women taking single agent Talazoparib prior to surgery. If greater than 33% of the patients enrolled have either a grade 4 toxicity possibly, probably, or definitely related to the treatment as attributed by the Principal Investigator, or requires a delay in treatment for greater than 4 weeks due to toxicity. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Clinical Response to Single Agent Talazoparib | Imaging was the primary measures response with tumor volume shrinkage after 2 months of Talazoparib prior to proceeding with standard chemotherapy for all participants. The clinical response to Talazoparib in the neoadjuvant setting in a pilot trial setting. | 2 months |