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 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
- 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
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.
Masking: Open Label, Primary Purpose: Treatment
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
Northern Centre for Cancer Treatment at Newcastle General Hospital
United Kingdom: Medicines and Healthcare Products Regulatory Agency