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

Anish Thomas (), Nobuyuki Takahashi, Lenka Oplustil O’Connor, Christophe E. Redon, Chirayu Mohindroo, Linda Sciuto, Lorinc Pongor, Keith T. Schmidt, Seth M. Steinberg, Mirit I. Aladjem, William Douglas Figg, Mark J. O’Connor and Yves Pommier
Additional contact information
Anish Thomas: National Institutes of Health
Nobuyuki Takahashi: National Institutes of Health
Lenka Oplustil O’Connor: AstraZeneca
Christophe E. Redon: National Institutes of Health
Chirayu Mohindroo: National Institutes of Health
Linda Sciuto: National Institutes of Health
Lorinc Pongor: National Institutes of Health
Keith T. Schmidt: National Institutes of Health
Seth M. Steinberg: National Institutes of Health
Mirit I. Aladjem: National Institutes of Health
William Douglas Figg: National Institutes of Health
Mark J. O’Connor: AstraZeneca
Yves Pommier: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64509-5

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