Show Notes
Nature Communications (2025) 16:9457 et al., Nature Communications - Phase I dose-escalation trial combining CRLX101 (nanoparticle camptothecin) with olaparib using a 48-hour gapped schedule in 24 patients with advanced solid tumors to determine MTD and assess pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy. Key terms: CRLX101, olaparib, PARP inhibitor, topoisomerase I, gapped scheduling.
Study Highlights:
This phase I study combined tumor-targeted CRLX101 with gapped olaparib dosing in 24 heavily pretreated patients to identify a tolerable regimen and probe PD effects. The MTD/RP2D was CRLX101 12 mg/m² every two weeks with olaparib 250 mg twice daily on days 3–13 and 17–26. Pharmacokinetics were consistent with single-agent profiles and γH2AX in hair follicles and PBMCs increased after olaparib, indicating augmented DNA damage. Among 19 evaluable patients there were two confirmed partial responses and six stable diseases with manageable myelosuppression.
Conclusion:
Tumor-targeted TOP1 delivery paired with a 48-hour gapped olaparib schedule established a recommended Phase 2 dose (CRLX101 12 mg/m² + olaparib 250 mg BID on specified days), produced additive DNA-damage pharmacodynamics, showed preliminary antitumor activity, and was tolerable with expected hematologic toxicity, supporting further evaluation.
Music:
Enjoy the music based on this article at the end of the episode.
Article title:
Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling
First author:
Nature Communications (2025) 16:9457
Journal:
Nature Communications
DOI:
10.1038/s41467-025-64509-5
Reference:
Nature Communications (2025) 16:9457; https://doi.org/10.1038/s41467-025-64509-5
License:
CC BY 4.0 (Creative Commons Attribution 4.0 International License)
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Episode link: https://basebybase.com/episodes/gapped-scheduling-crlx101-olaparib-phase1
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-03.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections cover: DDR rationale, TOP1 and PARP inhibitors, CRLX101 nanoparticle delivery, gapped 48-hour scheduling, phase I trial design and dosing, pharmacodynamics (γH2AX) in surrogate tissues, pharmacokinetics, safety/toxicity, clinical efficacy signals (PR/SD), and exploratory genomic analyses.
- transcript topics: DNA damage response and PARP/TOP1 inhibitor synergy; CRLX101 nanoparticle delivery and tumor targeting via EPR; Gapped scheduling strategy with a 48-hour interval; Phase I trial design, dosing levels, and RP2D; Pharmacokinetics of CRLX101 and olaparib with no major interaction; Pharmacodynamics: γH2AX as a biomarker in hair follicles and PBMCs
QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0
Metadata Audited:
- article_doi
- article_title
- article_journal
- license
- episode_title
- episode_number
- season
Factual Items Audited:
- MTD for CRLX101 and olaparib (RP2D) reported as 12 mg/m2 q2w and 250 mg BID on days 3–13 and 17–26
- 31-dose escalation with RP2D determined at DL4R
- 19 evaluable patients; 2 partial responses; 6 stable disease; median OS 6.06 months; median PFS 2.34 months
- γH2AX pharmacodynamics detected in hair follicles and PBMCs, increasing with combination treatment
- PK data show CRLX101 and olaparib with no major drug–drug interaction; CRLX101 half-life ~47 hours
- Gap scheduling mitigates bone marrow toxicity while allowing higher olaparib dosing
QC result: Pass.
