title: Phase I clinical and pharmacokinetic study of UTD1, a genetically engineered epothilone analog in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  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.affiliation: Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, People's Republic of China.
authors.forename: Pin
authors.initials: P
authors.lastname: Zhang
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Sun
authors.forename: Rongguo
authors.initials: R
authors.lastname: Qiu
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Guifang
authors.initials: G
authors.lastname: Dou
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001259:Ataxia / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone; D017239:Paclitaxel