INCLUSION CRITERIA:
Patients must have breast and/or epithelial ovarian cancer histologically or cytologically confirmed at the NCI that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective.
All patients in cohort 1 must have measurable and/or evaluable disease, defined as disease greater than or equal to 1 cm, pleural or pericardial effusions, and/or ascots.
Patients in the expansion cohort 2 must have safely biopsible disease as determine by an interventional radiologist and must agree to the first mandatory biopsy (the other two biopsies optional).
Breast cancer patients with locally advanced, unresectable disease must have been previously treated with standard therapy.
There is no limit on number of prior therapy.
Patients must be at least 6 months from their last platinum exposure.
Platinum-resistant patients may participate.
Age greater than or equal to 18 years.
ECOG performance status greater than or equal to 2 (Karnofsky greater than or equal to 60%.
Life expectancy greater than 3 months.
Patients must have normal organ and marrow function as defined below:
hemoglobin greater than or equal to 10g/dL
leukocytesgreater than or equal to 3,000/mcL
absolute neutrophil count greater than or equal to 1,500/mcL
platelets greater than or equal to 100,000/mcL
total bilirubin greater than or equal to upper limit of normal (ULN) in the absence in the Gilbert's syndrome
AST(SGOT)/ALT(SGPT) greater than or equal to 2.5 X ULN
creatinine clearance greater than or equal to 60 mL/min by 24-hour urine
OR
serum creatinine greater than or equal to 1.5 mg/dl
Magnesium within normal limits, replacement is acceptable
Corrected or Ionized Calcium greater than or equal to ULN
Potassium within normal limits
A documented deleterious BRCA 1/2 germline mutation or BRCAPRO score of greater than or equal to 30%.
The effects of AZD on the developing human fetus are unknown. For this reason and because platinum agents are known to be teratogenic, men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately, Patients of child-bearing potential should continue on contraception for at least three months following the last dose of therapy on study.
Toxicities from previous cancer therapies must have recovered to grade 1 (defined by CTC 3.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis by the PI. No patients with functional impairment due to neuropathy will be eligible.
Ability to understand and the willingness to sign a written informed consent document.
Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to the start of the study.
EXCLUSION CRITERIA:
Patients who have had chemotherapy, biological therapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
Patients may not be receiving any other investigational agents or had them in the previous 28 days.
Patients with known brain metastases diagnosed within 1 year should be excluded from this clinical trail because of their poor prognosis and because they often develop progressive neurological dysfunction that would confound the evaluation of neurologic and other adverse events.
Patients with brain metastases diagnosed greater than 1 year prior to study entry are eligible if they received sterilizing therapy to the CNS (resection or radiation) and have been CNS recurrence-free for a full 1-year period.
History of severe allergic reactions.
Patients with a severe allergic reaction to platinum who have undergone desensitivation therapy and have received subsequent doses of platinums without event are still eligible.
Clinically significant bleeding.
Inability to swallow pills.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant and breast-feeding women.
HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD2281. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy such as carboplatin.
Previous treatment with PARP inhibitor.
Major surgery within the past 28 days.
Patients with locally advanced breast tumors presenting for their initial therapy, or patients with local (only in breast or chest wall) recurrence only.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/30/2009