title: A phase I trial and in vitro studies combining ABT-751 with carboplatin in previously treated non-small cell lung cancer patients.
abstract: BACKGROUND
  ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs.
  
  
  METHODS
  Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs.
  
  
  RESULTS
  Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9-27.0). Time to tumor progression was 2.8 months (95% CI 2.0-2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs.
  
  
  CONCLUSIONS
  Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Ma
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Fuld
authors.forename: James R
authors.initials: JR
authors.lastname: Rigas
authors.forename: Anne E
authors.initials: AE
authors.lastname: Hagey
authors.forename: Gary B
authors.initials: GB
authors.lastname: Gordon
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
authors.forename: Konstantin H
authors.initials: KH
authors.lastname: Dragnev
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D045823:Ileus / Q000209:etiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D011014:Pneumonia / Q000209:etiology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: C490492:ABT751; D000970:Antineoplastic Agents; D013449:Sulfonamides; D019938:Cyclin D1; D016190:Carboplatin