title: A phase I evaluation of oral CI-1033 in combination with paclitaxel and carboplatin as first-line chemotherapy in patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  In the United States, lung cancer represents the third most common cancer, causing the most cancer-related deaths, with treatment advances minimally affecting 5-year survivals. Erb-B family receptor elevations are found in many non-small cell lung cancer tumors, making this receptor family a drug target with potential for improving survival.
  
  
  METHODS
  Chemotherapy-naive patients with advanced non-small cell lung cancer were enrolled who had at least one elevated tumor-expressed member of the erb-B family receptors. This dose-finding, multicenter, open-label, phase I study combined chemotherapy with paclitaxel and carboplatin, adding the tyrosine kinase inhibitor CI-1033. Patients were evaluated for toxicity, response, survival, and pharmacokinetics.
  
  
  RESULTS
  All 39 patients enrolled were assessable for safety and efficacy. Dose-limiting toxicities (diarrhea, rash, asthenia, and hypotension) occurred at the 200- and 150-mg dose levels of CI-1033; the maximum tolerated dose was 100 mg. Most toxicities were mild to moderate. Pharmacokinetics studies showed that paclitaxel levels were unaffected by CI-1033 and that CI-1033 plasma concentrations were consistent with historical controls. Ten patients (25.6%) achieved partial responses and another 11 (28.2%) had stable disease. In the recommended phase II dose cohort (n = 23), six patients (26%) had partial responses and six (26%) had stable disease. Median survival time was 12.4 months; median progression-free survival was 5.1 months.
  
  
  CONCLUSIONS
  Paclitaxel-carboplatin, combined with CI-1033 at 100 mg/day, was safe and well tolerated. Efficacy and survival results were comparable to those of similar studies in advanced non-small cell lung cancer and therefore warrant additional phase II testing.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. chiappaa@moffitt.usf.edu
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Chiappori
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ellis
authors.forename: John Turner
authors.initials: JT
authors.lastname: Hamm
authors.forename: Jacob David
authors.initials: JD
authors.lastname: Bitran
authors.forename: Irene
authors.initials: I
authors.lastname: Eiseman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lovalvo
authors.forename: Diana
authors.initials: D
authors.lastname: Burnett
authors.forename: Stephen
authors.initials: S
authors.lastname: Olson
authors.forename: Peter
authors.initials: P
authors.lastname: Lenehan
authors.forename: Ralph Goldman
authors.initials: RG
authors.lastname: Zinner
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D018579:Patient Selection; D011336:Probability; D011379:Prognosis; D018570:Risk Assessment; D016037:Single-Blind Method; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States
chemical_list: D009025:Morpholines; D016190:Carboplatin; C420268:Canertinib; D017239:Paclitaxel