title: A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors.
abstract: BACKGROUND
  E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids).
  
  
  METHODS
  In a phase 1 study, E7974 was given intravenously over a 2- to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT).
  
  
  RESULTS
  Twenty-eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m(2) , 0.27 mg/m(2) , 0.36 mg/m(2) , 0.45 mg/m(2) , and 0.56 mg/m(2) ) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m(2) , where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours).
  
  
  CONCLUSIONS
  This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m(2).
authors.affiliation: Department of Medical Oncology, University of Miami and Sylvester Comprehensive Cancer Center, Miami, Florida, USA. crocha@med.miami.edu
authors.forename: Caio M
authors.initials: CM
authors.lastname: Rocha-Lima
authors.forename: Soley
authors.initials: S
authors.lastname: Bayraktar
authors.forename: Jessica
authors.initials: J
authors.lastname: Macintyre
authors.forename: Luis
authors.initials: L
authors.lastname: Raez
authors.forename: Aurea M
authors.initials: AM
authors.lastname: Flores
authors.forename: Annapoorna
authors.initials: A
authors.lastname: Ferrell
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Poplin
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Tan
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucarelli
authors.forename: Naseem
authors.initials: N
authors.lastname: Zojwalla
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050256:Antimitotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D050256:Antimitotic Agents; C546192:E 7974; D009842:Oligopeptides; D010880:Piperidines