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

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/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.

• Authors: Pin Zhang, Mingyuan Sun, Rongguo Qiu, Li Tang, Guifang Dou, Binghe Xu
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 68 Issue 4 Pg. 971-8 (Oct 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 21305287 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Epothilones
• ixabepilone
• Paclitaxel

Topics

• Adult
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Ataxia (chemically induced)
• Dose-Response Relationship, Drug
• Epothilones (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Female
• Genetic Engineering
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Paclitaxel (adverse effects, therapeutic use)
• Treatment Outcome