title: Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design.
abstract: OBJECTIVE
  BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated titration "2B" design, of BMS-247550 given as a 1-hour infusion every 3 weeks.
  
  
  METHODS
  Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles (1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m2. All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists.
  
  
  RESULTS
  First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m2. Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m2. Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot syndrome, and mucositis. AUC and C(max) seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug exposure above a threshold.
  
  
  CONCLUSIONS
  The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration "2B" design may help in determining MTD with fewer patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten the study duration.
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
authors.forename: Antoinette
authors.initials: A
authors.lastname: Wozniak
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Boinpally
authors.forename: Richard
authors.initials: R
authors.lastname: Wiegand
authors.forename: Lance K
authors.initials: LK
authors.lastname: Heilbrun
authors.forename: Vikas
authors.initials: V
authors.lastname: Jain
authors.forename: Ralph
authors.initials: R
authors.lastname: Parchment
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Colevas
authors.forename: Marvin B
authors.initials: MB
authors.lastname: Cohen
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D034261:Epothilones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone