Olaparib in Combination With Carboplatin for Refractory or Recurrent Women s Cancers

Background: * Olaparib (AZD2281) is an oral PARP-1/2 inhibitor (PARPi) that affects tumors by impairing repair of single stranded DNA and causing double strand breaks. Carboplatin covalently crosslinks DNA causing stalled replication forks repaired through nucleotide excision repair and homologous recombination (HR). * There is no published data on sequence-specificity of PARPi with platinums. Our preclinical data indicate sequence may be important in growth inhibition and DNA damage and repair. * We have demonstrated activity and safety with concomitant administration of olaparib and carboplatin. * We hypothesize that elucidation of sequence specificity may improve upon that clinical benefit by optimizing drug administration and potentially safety. Objectives: * To determine safe dose of olaparib tablet with carboplatin. * To estimate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of two schedules of olaparib and carboplatin using peripheral blood mononuclear cells (PBMCs). * To determine the schedule-associated safety of olaparib and carboplatin in women s cancers. Eligibility: * Adult women with recurrent/refractory epithelial ovarian cancer, fallopian, primary peritoneal, uterine papillary serous cancer, or malignant mixed mullerian tumors, or recurrent/refractory breast cancer that is metastatic or unresectable and for which standard therapies do not exist or are no longer effective. BRCA1/2 mutation carriers will be eligible with any metastatic disease. * Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. * ECOG performance status 0-2 and adequate organ and marrow function. Design: * A phase I 3 plus 3 safety run-in will optimize tablet olaparib dose (d1-7) in combination with carboplatin on day 1. The carboplatin dose through the trial will be AUC4. * Subsequent accrual will randomize patients to one of 2 schedules on cycle 1 with the other schedule on cycle 2. A: olaparib d1-7 \> carbo d8; B: carbo d1 \> olaparib d2-8. * Cycle 3-8 will be schedule B. After 8 cycles of carboplatin, olaparib will be administered alone on a daily basis. * Research samples will be obtained for PD endpoints prior to and approximately 24 hours after carboplatin infusion and prior to the 1st and 3rd of olaparib. * Blood samples for olaparib PK will be obtained in all patients after the first dose of olaparib in cycles 1 and 2. * Patients will be evaluated for toxicity in clinic every 3 weeks and every two cycles for response using RECIST criteria. Imaging studies will be obtained every 3 cycles for patients who stay on the study longer than four years.