• Assessment of antitumor activity according to RECIST using tumor size measured clinically or radiologically with CT scan, MRI, plain x-ray, or other imaging techniques [ Designated as safety issue: No ]
  
• Safety profile [ Designated as safety issue: Yes ]
  

• Time to progression and overall survival [ Designated as safety issue: No ]
  
• Plasma levels by Liquid Chromatography/Mass Spectrometry/Mass Spectrometry [ Designated as safety issue: No ]
  
• Poly(ADP-ribose) polymerase (PARP) activity measured ex vivo using validated assays [ Designated as safety issue: No ]
  
• PARP expression using quantitative Western blotting immuno-assays [ Designated as safety issue: No ]
  
• Pharmacogenomics including CYP2D6 and CYP3A5, drug transport proteins, as well as polymorphisms in the genes coding for the PARP enzymes themselves [ Designated as safety issue: No ]
  
• BRCA mutation status, PARP activity, and PARP expression in tumor biopsy samples (when possible) [ Designated as safety issue: No ]
  
• DNA repair enzyme status using immunohistochemical techniques in paraffin sections from original diagnostic biopsies/operative procedures (where available) [ Designated as safety issue: No ]
  
• DNA double strand break repair pathway function in cells obtained from ascitic or pleural fluid (where available) for primary cell culture [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine the response rate to PARP-1 inhibitor AG014699 in patients with locally advanced or metastatic breast or advanced ovarian cancer shown to express the BRCA 1 or 2 mutations.
• To evaluate the toxicity of this drug in these patients.

Secondary

• To evaluate the time to progression and overall survival in patients treated with this drug.
• To study pharmacokinetics of this drug in these patients.
• To evaluate the Poly(ADP-ribose) polymerase (PARP) activity in peripheral blood lymphocytes from BRCA 1 and 2 heterozygotic patients.

Tertiary

• To evaluate PARP expression using quantitative western blotting immuno-assays.
• To investigate pharmacogenomics, including CYP2D6 and CYP3A5, drug transport proteins, as well as polymorphisms in the genes coding for the PARP enzymes themselves.
• To analyze tumor biopsy samples (when possible) for BRCA mutation status, PARP activity, and PARP expression.
• To analyze paraffin sections from original diagnostic biopsies/operative procedures (when available) for DNA repair enzyme status using immunohistochemical techniques.
• To analyze cells obtained from ascitic or pleural fluid (where available) for primary cell culture for DNA double strand break repair pathway function.

OUTLINE: This is a dose-escalation study followed by an open label multicenter study. Patients are stratified according to tumor type (breast vs ovarian) and mutation status ( BRCA 1 vs BRCA 2).

Patients receive PARP-1 inhibitor AG014699 IV (at one of several possible dosages) over 30 minutes once daily on days 1-5. Treatment repeats every 21 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stable or responding disease may receive additional courses of treatment at the discretion of the chief investigator or Drug Development Office (DDO).

Patients undergo blood sample collection periodically for pharmacokinetic and pharmacodynamic studies. Samples are analyzed for tumor marker (CA 125 or CA 15.3) measurements, AG-014699 plasma levels via liquid chromatography/mass spectrometry/mass spectrometry, PARP activity, and PARP protein expression via western blotting immunoassays. Paraffin embedded sections from original diagnostic biopsy are also collected and analyzed for PARP protein expression via immunohistochemical technique. Pleural and ascitic fluid may be collected and analyzed for DNA DS break repair proficiency via immunohistochemical technique. Some patients also undergo biopsy of tumors and samples are analyzed for BRCA 2 mutation as well as PARP activity via validated PARP immunoblotting assay.

After completion of study treatment, patients are followed for 28 days.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

DISEASE CHARACTERISTICS:

• Histologically confirmed locally advanced or metastatic breast cancer or advanced ovarian cancer

• Must meet 1 of the following criteria:

  • Proven a carrier of a known mutation of BRCA 1 or BRCA 2
  • Considered highly likely a carrier of BRCA 1 or 2 mutation (score of ≥ 20 per Manchester criteria)

• No more than 3 prior chemotherapy regimens for patients with breast or ovarian cancer

  • More than 2 months since prior carboplatin- or cisplatin-containing chemotherapy for ovarian cancer

• Measurable disease, as defined by RECIST criteria and measured by x-ray, CT scan, or MRI

  • Patients with bone disease must have other measurable disease for evaluation
  • Previously irradiated lesions cannot be used for measurable disease
• No known brain metastases
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Life expectancy ≥ 12 weeks
• Menopausal status not specified
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophils ≥ 1,500/mm ^3
• Platelets ≥ 100,000/mm ^3
• Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT or AST ≤ 2.5 times ULN (≤ 5 times ULN if due to tumor)
• Glomerular filtration rate (GFR) ≥ 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use two highly effective forms of contraception (i.e., oral, injected, or implanted hormonal contraception, intrauterine device, barrier method of condom plus spermicide, or are surgically sterile) 4 weeks prior to (females), during, and for 6 months after (males and females) completion of study therapy
• Able to cooperate with treatment and follow-up
• No non-malignant systemic disease, including active uncontrolled infection

• No other concurrent malignancy, except adequately treated cone-biopsied carcinoma in situ of the uterine cervix, basal cell or squamous cell carcinoma of the skin, or breast and ovarian carcinoma

  • Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years, and are deemed at low risk for recurrence are eligible

• No active or unstable cardiac disease or history of myocardial infarction within the past 6 months

  • Patients with cardiovascular signs or symptoms should have a MUGA scan or echocardiogram, and those with a left ventricular ejection fraction (LVEF) below the institutional limit of normal should be excluded
• No other condition which, in the investigator's opinion, would not make the patient a good candidate for this study

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy (6 weeks for nitrosoureas and mitomycin C)
• At least 4 weeks since prior major thoracic and/or abdominal surgery and recovered
• Concurrent radiotherapy for the control of bone pain or skin lesions allowed, but not within 5 days of the last dose of study drug
• Concurrent bisphosphonates allowed provided the dose is stable and treatment was started at least 2 weeks prior to recruitment
• No unresolved toxicities (CTCAE ≥ grade 1) from prior treatments (except for alopecia)
• No concurrent anticancer therapy or investigational drugs
• No concurrent tetracycline antibiotic therapy for prolonged periods (short courses [5-7 days] for treatment of infection are allowed)