title: Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.
abstract: BACKGROUND
  We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study.
  
  
  METHODS
  Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study.
  
  
  RESULTS
  The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related.
  
  
  CONCLUSIONS
  The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Alberto.Chiappori@moffitt.org
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bearz
authors.forename: Fernando
authors.initials: F
authors.lastname: Barata
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.forename: Asavari
authors.initials: A
authors.lastname: Wagle
authors.forename: Astra M
authors.initials: AM
authors.lastname: Liepa
authors.forename: Yan Daniel
authors.initials: YD
authors.lastname: Zhao
authors.forename: Nadia
authors.initials: N
authors.lastname: Chouaki
authors.forename: Neill
authors.initials: N
authors.lastname: Iscoe
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D014805:Vitamin B 12 / Q000008:administration & dosage
chemical_list: D005971:Glutamates; D007211:Indoles; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D014805:Vitamin B 12; C504878:enzastaurin