A Pilot Study of Talazoparib as a Neoadjuvant Study in Patients With a Diagnosis of Invasive Breast Cancer and a Deleterious BRCA Mutation
Overview
- Phase
- Phase 2
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Breast Adenocarcinoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Number of Participants With Overall Pathological Complete Response (pCR)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Treatment (talazoparib)
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.
Intervention: Laboratory Biomarker Analysis
Treatment (talazoparib)
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.
Intervention: Talazoparib
Outcomes
Primary Outcomes
Number of Participants With Overall Pathological Complete Response (pCR)
Time Frame: Up to 6 months
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.
Number of Participants With Grade 4 Toxicities
Time Frame: up to 6 months
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.
Secondary Outcomes
- Median Clinical Response to Single Agent Talazoparib(2 months)