title: Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemonaïve patients with stage IIIB/IV non-small cell lung cancer: Hoosier Oncology Group LUN06-116.
abstract: BACKGROUND
  : Bevacizumab is approved in combination with chemotherapy as first-line treatment for non-small cell lung cancer (NSCLC). Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis.
  
  
  METHODS
  :
  
  
  METHODS
  ≥18 years of age, chemonaïve, stage IIIB/IV nonsquamous NSCLC, and Eastern Cooperative Oncology Group performance status 0 to 1. Patients were randomized to placebo or enzastaurin 500 mg orally daily (after a loading dose), plus pemetrexed 500 mg/m, carboplatin area under the curve 6, and bevacizumab 15 mg/kg, intravenously, every 21 days for four cycles. Patients without progression received maintenance therapy with bevacizumab and placebo or enzastaurin. The primary objective was progression-free survival (PFS). Planned sample size was 90 patients, one-sided alpha of 0.20, with two interim analyses: one for safety and the second for futility, with a PFS hazard ratio of 0.8857.
  
  
  RESULTS
  : Forty patients were randomized. No unique safety concerns were noted at the first interim analysis. The early stopping rule for futility was met at the second interim analysis. Median PFS was 3.5 months and 4.3 months (hazard ratio: 1.04, 95% confidence interval: 0.49-2.21), and response rates were 20% and 30% (p = 0.462) for enzastaurin and placebo, respectively. Grade 3 or 4 toxicity was similar between the two arms. Two patients died on study because of respiratory arrest and pulmonary embolism. An additional patient died of sepsis secondary to a gastrointestinal perforation >30 days after study treatment discontinuation.
  
  
  CONCLUSIONS
  : Enzastaurin does not improve efficacy when combined with pemetrexed, carboplatin, and bevacizumab. This combination does not warrant further study in NSCLC.
authors.affiliation: Indiana University, Indianapolis, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Casey
authors.forename: Wael
authors.initials: W
authors.lastname: Harb
authors.forename: Daniel
authors.initials: D
authors.lastname: Bradford
authors.forename: Jose
authors.initials: J
authors.lastname: Bufill
authors.forename: Sreenivasa
authors.initials: S
authors.lastname: Nattam
authors.forename: Jyoti
authors.initials: J
authors.lastname: Patel
authors.forename: William
authors.initials: W
authors.lastname: Fisher
authors.forename: Jane E
authors.initials: JE
authors.lastname: Latz
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Jingwei
authors.initials: J
authors.lastname: Wu
authors.forename: Nasser
authors.initials: N
authors.lastname: Hanna
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000556:secondary; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D016190:Carboplatin / Q000008:administration & dosage; D004311:Double-Blind Method; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D010919:Placebos; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000556:secondary; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005971:Glutamates; D007211:Indoles; D010919:Placebos; D000068437:Pemetrexed; D000068258:Bevacizumab; D006147:Guanine; D016190:Carboplatin; C504878:enzastaurin