A phase II clinical trial of veliparib and topotecan in patients with platinum resistant ovarian cancer

Abstract

Background: Preclinical observations indicate that addition of PARP inhibitors to topoisomerase I-directed agents such as topotecan results in increased antitumor efficacy in vitro and in vivo. However, when veliparib or olaparib were combined with conventional 5 day topotecan in patients, the regimens were quite myelosuppressive. In contrast, a phase I trial of veliparib in combination with weekly topotecan, a less myelosuppressive but routinely used regimen, demonstrated a manageable safety profile and early signs of activity. This was manifested by responses or disease stability for >=4 months in 52% of patients, particularly in ovarian cancer patients with deleterious germline repair pathway mutations. Therefore, a phase 2 clinical trial is now underway. Trial design: This single arm, multi-center clinical trial is open and available at Experimental Therapeutics Clinical Trials Network (ETCTN) sites in the US. The primary endpoint is response rate and the secondary endpoint is progression free survival. Correlative goals include assessing differences in toxicity and efficacy based on BRCA1/ 2 mutation status as well as evaluating the association between pretreatment tumor cell levels of topoisomerase 1, PARP, XRCC1 or P-glycoprotein and response. Eligible patients must have platinum resistant ovarian, primary peritoneal or fallopian tube cancer and have received 2 or fewer prior chemotherapy regimens. ECOG performance status of 0, 1, or 2 and adequate bone marrow, renal and hepatic function are also required. No prior PARP inhibitor therapy is allowed.