title: Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer.
abstract: BACKGROUND
  Preclinical studies have suggested that the oral antifungal agent itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer.
  
  
  METHODS
  The study enrolled patients with progressive nonsquamous non-small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m2 on day 1, with or without itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity.
  
  
  RESULTS
  A total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone (p = 0.11). Median progression-free survivals were 5.5 months (itraconazole) versus 2.8 months (control) (hazard ratio = 0.399, p = 0.089). Overall survival was longer in patients receiving itraconazole (median 32 months) versus control (8 months) (hazard ratio = 0.194, p = 0.012). There were no evident differences in toxicity between the study arms.
  
  
  CONCLUSIONS
  Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1550 Orleans Street, Baltimore, MD 21231, USA. rudin@jhmi.edu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Julie R
authors.initials: JR
authors.lastname: Brahmer
authors.forename: Rosalyn A
authors.initials: RA
authors.lastname: Juergens
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.forename: David S
authors.initials: DS
authors.lastname: Ettinger
authors.forename: Rosa
authors.initials: R
authors.lastname: Sebree
authors.forename: Ruth
authors.initials: R
authors.lastname: Smith
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary*; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D017964:Itraconazole; D006147:Guanine
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