Journal article
Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling
Nature communications, Vol.16(1), pp.9457-11
10/27/2025
DOI: 10.1038/s41467-025-64509-5
PMID: 41145467
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.
There is compelling mechanistic rationale for combining PARP inhibitors with topoisomerase I (TOP1) inhibitors but hindered by dose-limiting toxicities. Here this group proposes a dose-escalation strategy integrating tumor-targeted TOP1 inhibitor with optimized PARP inhibitor scheduling, and evaluate the safety and efficacy in a phase 1 trial of 24 patients with advanced solid tumors.
Details
- Title: Subtitle
- Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling
- Creators
- Anish Thomas - National Institutes of HealthNobuyuki Takahashi - National Institutes of HealthLenka Oplustil O’Connor - AstraZenecaChristophe E. Redon - National Institutes of HealthChirayu Mohindroo - National Institutes of HealthLinda Sciuto - National Institutes of HealthLorinc Pongor - National Institutes of HealthKeith T. Schmidt - National Institutes of HealthSeth M. Steinberg - National Cancer InstituteMirit I. Aladjem - National Institutes of HealthWilliam Douglas Figg - National Cancer InstituteMark J. O’Connor - AstraZeneca (United Kingdom)Yves Pommier - National Institutes of Health
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), pp.9457-11
- DOI
- 10.1038/s41467-025-64509-5
- PMID
- 41145467
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK
- Grant note
- ZIA BC 011793 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (https://doi.org/10.13039/100000054)
- Language
- English
- Date published
- 10/27/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985178657302771
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