Olaparib (AZD2281, KU-0059436) is a poly ADP ribose polymerase (PARP) inhibitor. Previous studies have shown relevant clinical activity as single agent in ovarian, breast and prostate cancers with BRCA1/2 mutations. However, little is known about the activity of PARP inhibitors in EC. The aim of this study is to identify pharmacodynamic and pharmacogenetic biomarkers associated with a short term exposure to olaparib in type I primary EC patients (pts).
Phase 0, multicenter, single arm, window of opportunity trial in women with type I primary EC candidate to surgery. They receive a 28 days course of olaparib tablets, 300 mg twice daily before surgery. The study was approved by the IRB from 5 participating sites in Spain. Major eligibility criteria are (1) pts aged ≥18 years with histologically confirmed type I primary EC; (2) who have not received prior anticancer therapies for current disease and (3) adequate organ function and performance status. The trial uses an exact single stage design. The primary endpoints are the significant inhibition of cyclin D1, Ki67 and active caspase 3 activity in post-treatment against pre-treatment. We define significant inhibition in a patient if he shows ≥50% histoscore reduction, with a 95% confidence that it is not due to chance compared to the variation among the baseline values in all the sample. These pts are considered responders. The inhibition rate below which the treatment is considered inactive is 5%. The inhibition rate above which the treatment warrants further exploration is 35%; with type I and II errors of 5%, the sample size is 36 pts, with ≥6 responders as threshold. The secondary objectives include the measurement of the correlation between PARP inhibition and mitosis, angiogenesis and apoptosis tumor-tissue biomarkers, and to estimate the potential predictive role of microsatellite instability and PTEN loss in clinical tumor changes and PARP inhibition. Four women have been recruited for the trial since study start on March 2016. The expected end of accrual will be on November 2016.
Clinical trial identification
NCT02506816; EudraCT 2015-001156-30
Legal entity responsible for the study
Medica Scientia Innovation, MedSIR-ARO
I. Romero: advisory board: Astra Zeneca, Roche Speaker's bureau: Astra Zeneca, Roche, Pharmamar Accomodation travel expenses: Astra Zeneca, Roche, Pharmamar. A. Llombart-Cussac: has received honoraria lectures and advisory boards from Roche, GlaxoSmithKline, Novartis, Celgene, Eisai and AstraZeneca and research funding from GlaxoSmithKline, Sanofi and Puma Biotechnology. All other authors have declared no conflicts of interest.