Last updated on September 2011

AZD2281 and Carboplatin in Treating Patients With BRCA1/BRCA2-Associated Hereditary or Triple Negative Metastatic or Unresectable Breast Cancer or Ovarian Epithelial Cancer


Brief description of study

RATIONALE: AZD2281 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving AZD2281 together with carboplatin may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of AZD2281 when given together with carboplatin in treating patients with BRCA1/BRCA2-associated, hereditary, or triple negative metastatic or unresectable breast cancer or ovarian epithelial cancer.

Detailed Study Description

OBJECTIVES: Primary - Determine the safety and toxicity of AZD2281 and carboplatin in patients with BRCA1/BRCA2-associated or familial breast or ovarian epithelial cancer, low genetic risk sporadic ovarian serous epithelial cancer, or low genetic risk triple negative breast cancer. - Determine the biochemical changes in poly (ADP-ribose) polymerase (PARP) activity and γ-H2AX levels in mononuclear cells and in tumor tissue in response to treatment with this regimen in these patients. Secondary - Assess the clinical activity of this regimen. - Evaluate and correlate differences in PARP and XRCC1 polymorphisms with clinical activity and toxicity of this regimen. - Evaluate the induction of apoptosis in tumor tissue. - Evaluate the pharmacodynamics of this regimen. OUTLINE: This is a dose-escalation study of AZD2281. Patients are initially enrolled in cohort 1. Once the maximum tolerated dose (MTD) of AZD2281 is determined, additional patients are enrolled in cohort 2 and treated at the MTD. - Cohort 1 (dose-escalation cohort): Patients receive oral AZD2281 twice daily on days 1-7 and carboplatin* IV over 15-60 minutes on day 2. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: *Patients who experience a partial response or stable disease may receive 8-10 courses of carboplatin (more than 10 courses will be at the investigator's discretion); patients with complete response (CR) may receive no more than 2 courses of carboplatin past CR. - Cohort 2 (expansion cohort): Patients receive AZD2281 (at the MTD determined in cohort 1) and carboplatin as in cohort 1. Patients in both cohorts undergo blood sample collection periodically for analysis of PARP inhibition by ELISA. Blood samples from patients in cohort 2 are also analyzed for PARP/XRCC1 polymorphism, γ-H2AX determination by immunofluorescence assay, and pharmacogenomics. Patients in cohort 2 also undergo tumor tissue sample collection at baseline for analysis of apoptosis by TUNEL assay, PARP inhibition by ELISA, γ-H2AX determination by immunofluorescence assay, and tissue proteomics. After completion of study treatment, patients are followed periodically for 4 weeks.

Clinical Study Identifier: NCT00647062

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Recruitment Status: Open


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