Phase Ib/II study to evaluate the efficacy and tolerability of PM01183 (lurbinectedin) in combination with olaparib in patients with advanced solid tumors

Abstract

Background: PM01183 is a new anticancer drug that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Recently a significant activity in platinum-resistant ovarian cancer patients in terms of Response Rates (RR), has been reported (Poveda A et al. ASCO 2014.abstr #5505). PM01183 is currently being studied in different solid tumors. Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5'diphosphoribose [ poly (ADP ribose] polymerisation (PARP) inhibitor (PARP-1,-2 and-3) with proven antitumoral activity in homologous recombination deficient (HRD) tumors. Olaparib is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anti-cancer agents. The combination of PM01183 and Olaparib has shown synergistic activity in cell-lines independent of HRD status. Trial design: This first-in-human phase I-II study evaluates the safety and tolerability of PM1183 in combination with short course of Olaparib through a 3 + 3 dose escalation design Selection of patients: Phase-I patients with advanced or metastatic solid tumors without established standard therapeutic alternatives. Phase-II expansion cohort: platinum-resistant ovarian cancer patients (epithelial non-mucinous), triple negative breast and endometrial cancer patients. For patients included in the phase-II part of the study, evidence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will be required. Primary endpoints are Phase-I: safety (MTD, DLT and RP2D); Phase-II: overall response rate. Secondary enpoints: Progression Free survival, Overall survival, PK and pharmacodynamic profiles, safety profile. Additional translational research to analyze predictive factors to further select potential candidates will be explored. The trial is in progress; 13 of up to 48 planned pts in the phase-I part have been recruited at the end of April 2016 (enrollment started Nov 2015).