title: A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC).
abstract: OBJECTIVE
  To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin.
  
  
  METHODS
  Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m(2) and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration.
  
  
  RESULTS
  Seventy patients were enrolled and 68 patients were treated, 37 in phase 1 and 31 in phase 2 (14 with the combination and 17 with chemotherapy alone). Dose-limiting toxicity of CP-547,632 250 mg by mouth daily in combination with paclitaxel and carboplatin was grade 3 rash and grade 3 diarrhea despite medical intervention. CP-547,632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. No subject had CR. In phase I, seven subjects (22.6%) had a confirmed partial response. In phase II, four subjects (28.6%) receiving CP-547,632 plus chemotherapy had a confirmed partial response. In the phase II chemotherapy alone group, four subjects (25%) had a confirmed partial response.
  
  
  CONCLUSIONS
  The combination of CP-547,632 and paclitaxel and carboplatin was well-tolerated at doses up to 200 mg by mouth daily. Dose-limiting toxicity of CP-547,632 at 250 mg consisted of diarrhea and rash. CP-547,632 did not increase the objective response rate to chemotherapy alone in patients with advanced non-small cell lung cancer.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, USA. roger.cohen@fccc.edu
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: George Rajan
authors.initials: GR
authors.lastname: Simon
authors.forename: Peter David
authors.initials: PD
authors.lastname: Eisenberg
authors.forename: John Daniel
authors.initials: JD
authors.lastname: Hainsworth
authors.forename: Stefan
authors.initials: S
authors.lastname: Madajewicz
authors.forename: Thomas Michael
authors.initials: TM
authors.lastname: Cosgriff
authors.forename: Kristen
authors.initials: K
authors.lastname: Pierce
authors.forename: Huiping
authors.initials: H
authors.lastname: Xu
authors.forename: Katherine
authors.initials: K
authors.lastname: Liau
authors.forename: Diane
authors.initials: D
authors.lastname: Healey
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011379:Prognosis; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: C480540:3-(4-bromo-2,6-difluorobenzyloxy)-5-(3-(4-pyrrolidin-1-ylbutyl)ureido)isothiazole-4-carboxylic acid amide; D013844:Thiazoles; D014508:Urea; D016190:Carboplatin; D017239:Paclitaxel