title: A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies.
abstract: OBJECTIVE
  BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s).
  
  
  METHODS
  This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m(2)/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days.
  
  
  RESULTS
  Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m(2)/day to 18 mg/m(2)/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m(2)/day and 18 mg/m(2)/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m(2). Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis.
  
  
  CONCLUSIONS
  BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.
authors.affiliation: Wayne State University/Karmanos Cancer Institute, Detroit, MI 48201, USA. heathe@karmanos.org
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Heath
authors.forename: Patricia
authors.initials: P
authors.lastname: Lorusso
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Tatiana
authors.initials: T
authors.lastname: Besse-Hamer
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
authors.forename: Manuel
authors.initials: M
authors.lastname: Valdivieso
authors.forename: Teresa
authors.initials: T
authors.lastname: Has
authors.forename: Leila
authors.initials: L
authors.lastname: Alland
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D018805:Sepsis / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C437188:BMS-275183; D001952:Bridged-Ring Compounds