Phase i clinical and pharmacokinetic study of UTD1, a genetically engineered epothilone analog in patients with advanced solid tumors

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/m ². 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/m ². 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/m ² 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.