AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer

Background: AZD2281 (KU-0059436) is an oral PARP-1 and PART-2 inhibitor that affects tumor growth by impairing the ability of the cell to repair damaged DNA. Carboplatin causes covalent cross-linking of DNA with stalled replication forks that would usually be repaired through nucleotide excision repair and homologous recombination (HR). Sporadic breast (triple negative) and ovarian cancers have been shown to exhibit a BRCA1-like phenotype. BRCA1/2 proteins have a critical function in the homologous DNA repair pathway. BRCA1/2 mutation carriers are at high risk for breast and ovarian cancer, and increased risk of pancreatic cancer and prostate cancer. Mutation carriers have been shown to have increased susceptibility to DNA damaging agents, such as the platinums. BRCA1/2 deficient cells have been shown to be sensitive to PARP inhibition alone and in combination with DNA damaging agents. Combining these two agents in a background of impaired HR in BRCA1/2 mutation potitive malignancies may result in synergistic anti-tumor effect. Objectives: Determine the safety and toxicity of the combination of AZD2281 and carboplatin in BRCA1/2-associated or familial recurrent breast and ovarian cancer patients (cohort 1, Group A), non-high risk serous ovarian cancer patients (Group B), and non-high risk triple negative breast cancer patients (Group C). Determine pharmacodynamics, estimates of biochemical changes in the apoptosis and PARP signal transduction pathways in tumor and stromal cells in response to treatment of an expansion cohort (cohort 2) at the MTD in a pilot fashion. Eligibility: Adults with breast or ovarian CA that is metastatic or unresectable and for which standard curativetherapies do not exist or are no longer effective. Documented deleterious BRCA1/2 mutation or a BRCAPRO score of greater than or equal to 30%. Non-high risk serous ovarian cancer (negative family history, BRCAPRO score of less than or equal to 20% or negative BRCA1/2 mutation test). Documented ER negative, PR negative, Her2neu negative breast cancer (negative family history and/or BRCAPRO score less than or equal to 10% (or negative BRCA1/2 mutation test). Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy. ECOG performance status 0-2 and adequate organ and marrow function. Design: Patients will receive AZD2281 for days 1-7 of each 21 day cycle to maximize PARP inhibition with carboplatin administration on day 2. Carboplatin will then be administered q3weeks and with continuation AZD2281 BID on days 1-7 of each 21 day cycle. AZD2281 or carboplatin will be escalated sequentially in Cohort 1 (Groups A, B, and C), and after the maximum tolerated dose is determined, Cohort 2 will be enrolled for assessment of translational endpoints. Patients will be evaluated for toxicity in clinic every 3 weeks and every other cycle for response using RECIST criteria. The clinic visit will be changed to every 4 weeks when patients continue to stay on the study longer than two years with no or minimal disease. Imaging studies will be obtained every 3 cycles for patients who stay on the study longer than four years. The clinic visit will be changed to every two months (+/- 7 days) and the imaging studies will be obtained every four months (+/- 7 days) for patients who stay on the study longer than five years. Tumor biopsies and plasma and serum samples will be obtained from patients in Cohort 2 before treatment (biopsy mandatory), prior to treatment on cycle 2, day 1, and at time of disease progression (biopsies optional). Tumor biopsies (optional) will also be taken from "super responders" in Cohort 1 who have had a durable response longer than two years. A minimum of 84 and a maximum of 101 patients will be needed to achieve the objectives of the trial.