An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors
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Background This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. Methods Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300–400 μg/mL) every 28 days plus 1,000 mg/m2 gemcitabine HCl (days 1 and 15), 60 mg/m2 docetaxel, 200 mg/m2/day temozolomide, 75 mg/m2 cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*μg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*μg/mL for gemcitabine and erlotinib). Results A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. Conclusions The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.
KeywordsTasisulam LY573636 Phase Ib Dose-escalation Gemcitabine HCl Docetaxel Temozolomide Cisplatin Erlotinib
The authors wish to thank the Study JZAK investigators for their participation in the study: Drs Stephen Anthony, Thaddeus Beck, Thomas Boyd, Gabriela Chiorean, Maria Flores, Beth Hellerstedt, Pam Kaiser, Robert Raju, Rachel Sanborn, and Hillary Wu. We also thank Cindy C. Taylor of ClinGenuity LLC for assistance with the preparation of the manuscript, Dinesh P. De Alwis formerly of Eli Lilly and Company for assistance with the pharmacokinetics analyses, and Baha Alkuzweny of Inventiv for statistical analyses. We are grateful to the patients who participated in this trial.
This study was funded by Eli Lilly and Company.
Drs Chen, Turner, Chow, Tai, and Ilaria Jr. are employees and minor stockholders of Eli Lilly and Company. Drs Smith and Jotte were on the speaker’s bureau for Eli Lilly and Company when the current study was conducted. Dr Von Hoff has received institutional funding for ongoing clinical trials on hedgehog pathway inhibitor Eli Lilly and Company. The other authors have no conflicts of interest to report.
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