Abstract
Purpose
The epothilones are a novel class of microtubule-stabilizing agents. UTD1 is an epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This phase I study was designed to evaluate the safety and pharmacokinetic(PK) profiles of UTD1 in patients with advanced solid tumors.
Patients and methods
This was an open-label, single-arm, one site, phase I, dose-escalation study. Patients were treated with escalating doses of UTD1 as a 3-h intravenous infusion every 3 weeks.
Results
Twenty-one patients were enrolled and received UTD1 at six dose levels ranging from 25 to 225 mg/m2. Dose-limiting toxicity (DLT) was ataxia, and other frequent non-haematological toxicities were peripheral neuropathy, gastrointestinal disorders, fatigue, and myalgia/arthralgia. Myelosuppression was rare, with no grade 3 and 4 neutropenia, in contrast to paclitaxel and ixabepilone. The maximum-tolerated dose was established as 170 mg/m2. Preliminary results showed linear pharmacokinetics along the range of doses tested. Prolonged disease stabilization was observed in patients with breast cancer, non-small lung cancer, and other cancers.
Conclusions
The recommended phase II dose of UTD1 is 170 mg/m2 as a 3-h infusion every 3 weeks. Ataxia was the DLT. UTD1 showed advantages over paclitaxel and Ixapebilone in relation to safety profile, especially myelosuppression. The acceptable tolerability warrants further phase II study.
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Acknowledgments
We thank the patients for their participation and the study coordinators, nurses, physicians, and laboratory technicians for their assistance. This study was partly supported by a State Innovation Fund for Small and Medium Enterprise of China to R. Qiu and National HighTechnology Project Grant (2004AA2Z3T63) to B. Xu.
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Pin Zhang and Mingyuan Sun contributed equally to this work.
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Zhang, P., Sun, M., Qiu, R. et al. Phase I clinical and pharmacokinetic study of UTD1, a genetically engineered epothilone analog in patients with advanced solid tumors. Cancer Chemother Pharmacol 68, 971–978 (2011). https://doi.org/10.1007/s00280-011-1571-6
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DOI: https://doi.org/10.1007/s00280-011-1571-6