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

TL;DR

This study tested a new dosing strategy combining a targeted topoisomerase I inhibitor with a PARP inhibitor to reduce toxicity and improve treatment in advanced solid tumors.

Contribution

A novel gapped dosing schedule combining tumor-targeted TOP1 inhibition with PARP inhibition was tested in a phase I trial.

Findings

The maximum tolerated dose was determined for CRLX101 and olaparib with the gapped schedule.

Combination treatment showed elevated DNA damage and acceptable safety in patients.

Partial responses and stable disease were observed in some patients with promising survival metrics.

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.

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