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

Area of Science:

• Oncology
• Pharmacology
• Nanomedicine

Background:

• Mechanistic rationale supports combining PARP inhibitors and topoisomerase I inhibitors for cancer therapy.
• Clinical application of this combination is limited by dose-limiting toxicities.
• Novel strategies are needed to improve the therapeutic window of DNA-damage response inhibitors.

Purpose of the Study:

• To evaluate the safety and efficacy of combining a nanoparticle topoisomerase I inhibitor (CRLX101) with olaparib.
• To determine the maximum tolerated dose (MTD) of the combination therapy.
• To assess pharmacokinetics, pharmacodynamics, and survival outcomes in patients with advanced solid tumors.

Main Methods:

• Phase I clinical trial (NCT02769962) involving 24 patients with advanced solid tumors.
• Combination of CRLX101 (nanoparticle topoisomerase I inhibitor) with olaparib using a gapped dosing schedule.
• Evaluation of MTD, pharmacokinetics, pharmacodynamics (γH2AX), and survival endpoints (OS, PFS, DOR).

Main Results:

• The MTD for CRLX101 was 12 mg/m² every two weeks, and olaparib was 250 mg twice daily on days 3-13 and 17-26.
• Pharmacokinetics were consistent with monotherapy; elevated DNA damage (γH2AX) was observed with the combination.
• Among 19 evaluable patients, 2 achieved partial responses, 6 had stable disease, with median OS of 6.06 months and PFS of 2.34 months.

Conclusions:

• Targeted delivery of CRLX101 combined with gapped olaparib scheduling demonstrated acceptable safety and promising activity.
• This strategy potentially widens the therapeutic window for DNA-damage response inhibitors by enabling higher olaparib doses.
• The findings support the potential of this approach to improve outcomes for patients with advanced solid tumors.