The authors 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), CRLX101, poly-CD-PEG-camptothecin, a nanoparticle topoisomerase I inhibitor, (discovered by M.R. Davis, WO200033885) was combined 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 small cell lung 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.
Thomas A, Takahashi N, Oplustil O’Connor L, Redon CE, Mohindroo C, Sciuto L, Pongor L, Schmidt KT, Steinberg SM, Aladjem MI, Figg WD, O’Connor MJ, Pommier Y. Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling. Nat Commun. 2025 Oct 27;16(1):9457. doi: 10.1038/s41467-025-64509-5.