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Investigator(s):
Elise C. Kohn, M.D. Principal Investigator Phone: 301-402-2726 kohne@mail.nih.gov	Christina M. Annunziata, M.D., Ph.D. Protocol Chair Phone: 301-402-7189 Fax: 301-480-6255 annunzic@mail.nih.gov
Referral Contact(s):
Laura D. Otten, R.N., B.S.N., O.C.N. Medical Oncology Referral Coordinator Phone: 301-451-1228 1-866-611-6310 (Toll Free) Fax: 301-451-5433 ottenl@mail.nih.gov	Nicole Houston, B.S.N., R.N. Research Nurse Phone: 301-443-6431 houstonnd@mail.nih.gov

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Primary Eligibility:

• Histologically or cytologically confirmed breast and/or ovarian epithelial cancer
• Metastatic or unresectable disease for which standard curative measures do not exist or are no longer effective
• Patients with locally advanced, unresectable breast cancer must have been previously treated with standard therapy
• Patients with locally advanced breast cancer presenting for initial therapy are not eligible
• No local (i.e., only in breast or chest wall) recurrence only
• Documented evidence of one of the following:
• Deleterious BRCA1/BRCA2 germline mutation or BRCAPRO score of ≥ 30%
• Non-high risk serous ovarian cancer (negative family history, BRCAPRO score of ≤ 20%, or negative BRCA1/BRCA2 mutation test)
• ER negative, PR negative, Her2neu negative breast cancer (negative family history and/or BRCAPRO score ≤ 10%, or negative BRCA1/BRCA2 mutation test)
• Measurable and/or evaluable disease, defined as disease > 1 cm, pleural or pericardial effusions and/or ascites (cohort 1)
• Disease can be safely biopsied, as determined by an interventional radiologist (cohort 2)
• No diagnosis of brain metastases within the past year
• Patients with brain metastases diagnosed > 1 year ago are eligible provided the patient has undergone resection or radiotherapy for the brain metastases and has had no CNS recurrence for a full year
• Hormone receptor status not specified
• Recovered from prior cancer therapy (≤ CTC grade 1)
• Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapy may be allowed at the discretion of the principal investigator
• At least 6 months since prior platinum drugs
• Patients with platinum-resistant disease are eligible
• No prior PARP inhibitors
• No concurrent combination antiretroviral therapy for HIV-positive patients
• Male or female
• ECOG performance status (PS) 0–2 or Karnofsky PS 60–100%
• Hemoglobin ≥ 10 g/dL
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin normal (in the absence of Gilbert’s syndrome)
• AST/ALT ≤ 2.5 x upper limit of normal (ULN)
• Creatinine clearance ≥ 60 mL/min OR serum creatinine ≤ 1.5 x ULN
• Corrected or ionized calcium normal
• Potassium normal
• Not pregnant or nursing; fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
• Able to swallow pills
• Agrees to undergo mandatory biopsy at baseline (cohort 2)
• No functional impairment due to neuropathy
• No history of severe allergic reactions
• Patients with a severe allergic reaction to platinums who have undergone desensitization therapy and have received subsequent doses of platinums without event are eligible
• No clinically significant bleeding
• No medical condition that would preclude study participation

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Study 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 Day 1 -28 and carboplatin IV over 15–60 minutes on Day 8 of course 1
• For all subsequent courses, patients receive oral AZD2281 on Days 1–21 and carboplatin IV over 15–60 minutes on Day 1
• Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity
• 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
• Patients in cohort 2 also undergo tumor tissue sample collection at baseline
• After completion of study treatment, patients are followed periodically

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Additional Information:

• This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
• There is no charge for medical care received at NIH Clinical Center.
• FAQs about this study - provides information for patients about the trial such as frequency and duration of visits, costs, how to enroll, treatment plan.
• PDQ (Physicians Data Query) - provides additional details about this study for health care providers.

Reviewed: 1/15/09
Updated: 10/30/09