Rucaparib(CO-338;Formally Called AG-014699 or PF-0136738) in Treating Patients With Locally Advanced or Metastatic Breast Cancer or Advanced Ovarian Cancer
RATIONALE: rucaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase II trial is studying the side effects and best dose of rucaparib and to see how well it works in treating patients with locally advanced or metastatic breast cancer or advanced ovarian cancer.
brca1 Mutation Carrier
brca2 Mutation Carrier
Drug: rucaparib (CO-338; formally AG-014699 or PF-01367338)
Genetic: protein expression analysis
Genetic: western blotting
Other: immunohistochemistry staining method
Other: liquid chromatography
Other: mass spectrometry
Other: pharmacological study
|Study Design:||Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Cancer Research UK Phase II Proof of Principle Trial of the Activity of the PARP-1 Inhibitor, AG-014699, in Known Carriers of a BRCA 1 or BRCA 2 Mutation With Locally Advanced or Metastatic Breast or Advanced Ovarian Cancer|
- 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 ]
- To determine the optimal oral dosing regimen, based on the assessment of antitumor activity and the safety profile [ Designated as safety issue: Yes ]
- TERTIARY OUTCOMES [ Designated as safety issue: No ]PARP expression using quantitative Western blotting immuno-assays
- TERTIARY OUTCOMES [ 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
- TERTIARY OUTCOMES [ Designated as safety issue: No ]BRCA mutation status, PARP activity, and PARP expression in tumor biopsy samples (when possible)
- TERTIARY OUTCOMES [ Designated as safety issue: No ]DNA repair enzyme status using immunohistochemical techniques in paraffin sections from original diagnostic biopsies/operative procedures (where available)
- TERTIARY OUTCOMES [ 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
|Study Start Date:||December 2007|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
- Assessment of Anti tumour activity 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 treatment with Rucaparib in these population's.
- To evaluate the time to progression and overall survival in patients treated with this drug.
- To study pharmacokinetics of this drug in these patient populations.
- 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 Rucaparib 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00664781
|Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust|
|Birmingham, England, United Kingdom, B15 2TT|
|Leeds Cancer Centre at St. James's University Hospital|
|Leeds, England, United Kingdom, LS9 7TF|
|Cancer Research UK and University College London Cancer Trials Centre|
|London, England, United Kingdom, W1T 4TJ|
|Manchester, England, United Kingdom, M20 4BX|
|Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Level 2, Freeman Hospital|
|Newcastle-Upon-Tyne, England, United Kingdom, NE4 6BE|
|Plymouth, England, United Kingdom, PL6 8DH|
|Beatson West of Scotland Cancer Centre|
|Glasgow, Scotland, United Kingdom, G12 0YN|
|Principal Investigator:||Ruth Plummer||Northern Centre for Cancer Treatment at Newcastle General Hospital|