title: Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma.
abstract: OBJECTIVE
  This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).
  
  
  METHODS
  Patients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m(2), day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025.
  
  
  RESULTS
  Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001).
  
  
  CONCLUSIONS
  Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.
authors.affiliation: Department of Neurooncology, University of Heidelberg, Im Neuenheimer Feld, 400 D-69120 Heidelberg. wolfgang.wick@med.uni-heidelberg.de
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Puduvalli
authors.forename: Marc C
authors.initials: MC
authors.lastname: Chamberlain
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Antoine F
authors.initials: AF
authors.lastname: Carpentier
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Cher
authors.forename: Warren
authors.initials: W
authors.lastname: Mason
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Shengyan
authors.initials: S
authors.lastname: Hong
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.forename: Astra M
authors.initials: AM
authors.lastname: Liepa
authors.forename: Donald E
authors.initials: DE
authors.lastname: Thornton
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008130:Lomustine / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*
chemical_list: D007211:Indoles; D008130:Lomustine; C504878:enzastaurin