Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling

Abstract

Despite mechanistic rationale for combining PARP inhibitors with topoisomerase I inhibitors, clinical use has been hindered by dose-limiting toxicities. We hypothesized that integrating tumor-targeted topoisomerase I inhibitor delivery with optimized PARP inhibitor scheduling could enable effective combination therapy while reducing toxicity. In this trial (NCT02769962), we combined CRLX101, a nanoparticle topoisomerase I inhibitor, with olaparib using a gapped dosing schedule. The primary objective was to determine the maximum tolerated dose. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics, overall and progression-free survival. Twenty-four patients with advanced solid tumors were enrolled. The maximum tolerated dose for CRLX101 was 12 mg/m² every two weeks and olaparib 250 mg twice daily on days 3-13 and 17-26. Pharmacokinetics were consistent with monotherapy of each agent, and γH2AX kinetics revealed elevated DNA damage with the combination treatment compared to CRLX101 alone, supporting mechanistic efficacy. Among 19 evaluable patients, 2 patients had partial responses, and 6 had stable disease. Median overall survival was 6.06 months, progression-free survival 2.34 months, and duration of response 7.95 months. The combination showed acceptable safety across dose levels. Targeted delivery of a topoisomerase I inhibitor and gapped scheduling allowed higher olaparib dosing, showing promising activity and supporting the strategy’s potential to widen the therapeutic window of DNA-damage response inhibitors while reducing toxicity.