187: Gapped PARP + Tumor‑Targeted TOP1 in Advanced Tumors

️ Episode 187: Gapped PARP + Tumor‑Targeted TOP1 in Advanced Tumors In this episode of PaperCast Base by Base, we explore a phase I dose‑escalation trial that pairs a tumor‑targeted topoisomerase I inhibitor (CRLX101, a nanoparticle camptothecin) with optimized, gapped scheduling of the PARP inhibitor olaparib to reduce toxicity while preserving efficacy in advanced solid tumors. Study Highlights:Twenty‑four adults with advanced solid tumors received CRLX101 every two weeks with olaparib started 48 hours later; the maximum tolerated and recommended phase 2 dose was CRLX101 12 mg/m² plus olaparib 250 mg twice daily on days 3–13 and 17–26 of each 28‑day cycle. Pharmacokinetics for both agents were consistent with their single‑agent profiles, and γH2AX pharmacodynamic assays in hair follicles showed higher DNA damage after adding olaparib compared with CRLX101 alone, supporting the mechanistic rationale. Among nineteen evaluable patients, two achieved confirmed partial responses and six had stable disease, with median overall survival of 6.06 months and progression‑free survival of 2.34 months; a patient with myxofibrosarcoma harboring a PALB2 truncation experienced a deep, durable response. Toxicities were manageable and mainly hematologic—leukopenia, anemia, neutropenia, and thrombocytopenia—while the gapped schedule mitigated dose‑limiting myelosuppression seen in prior PARP–TOP1 combinations and enabled higher olaparib dosing. Conclusion:Tumor‑targeted TOP1 delivery combined with gapped PARP inhibition appears to widen the therapeutic window for DDR‑chemotherapy combinations and merits biomarker‑informed expansion studies. Reference:Thomas A, Takahashi N, O’Connor LO, Redon CE, Mohindroo C, Sciuto L, Pongor L, Schmidt KT, Steinberg SM, Aladjem MI, Figg WD, O’Connor MJ, Pommier Y. Tumor‑targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling. Nature Communications. 2025;16:9457. https://doi.org/10.1038/s41467-025-64509-5 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

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