title: A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.
abstract: BACKGROUND
  The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small-cell lung cancer.
  
  
  METHODS
  A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome.
  
  
  RESULTS
  On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095).
  
  
  CONCLUSIONS
  The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Garth D
authors.initials: GD
authors.lastname: Nelson
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Meyers
authors.forename: Araba A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ross
authors.forename: Rafat H
authors.initials: RH
authors.lastname: Ansari
authors.forename: Alan P
authors.initials: AP
authors.lastname: Lyss
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stella
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000855:Anorexia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004417:Dyspnea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D013280:Stomatitis / Q000139:chemically induced; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics; D000093542:Gemcitabine; D007211:Indoles
chemical_list: D016190:Carboplatin; D003841:Deoxycytidine; D011799:Quinazolines; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D040321:Vascular Endothelial Growth Factor Receptor-3; D000093542:Gemcitabine; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C500926:cediranib; D007211:Indoles