• 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 measured 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 enzymes, 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 and analysis for DNA repair [ Designated as safety issue: No ]
  
• To determine the optimal oral dosing regimen, based on the assessment of antitumor activity and the safety profile [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• To determine the response rate to PARP-1 inhibitor rucaparib 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.
• To determine a tolerable and effective dosing regimen of the oral formulation.

OUTLINE: This is a dose-escalation study followed by an open label multicenter study. The study was originally set up with an IV formulation. An oral formulation of the PARP-1 inhibitor rucaparib will be used from now on. Patients are stratified according to tumor type (breast vs ovarian) and mutation status ( BRCA 1 vs BRCA 2). In addition, patient with high-grade serous ovarian cancer can be enrolled into Stage 1 of the study. All patients enrolled will receive PARP-1 inhibitor rucaparib oral formulation once daily for either 7, 14, or 21 days of each cycle, (two possible dosages for 21 days treatment). 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 and/or CA 15.3) measurements, rucaparib 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.