title: Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer.
abstract: BACKGROUND
  Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment.
  
  
  METHODS
  Eligibility criteria included histologically confirmed NSCLC, age range of 20-74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m(-2) and was escalated in patients by 25 mg m(-2) increments up to a maximum dose of 150 mg m(-2).
  
  
  RESULTS
  Twenty-seven patients were enrolled: male/female=14/13; median age=60 (45-75); histology, adenocarcinoma/non-adenocarcinoma=25/2; performance status 0-1/2=19/8; previous response to gefitinib, partial response/stable disease/PD=21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32-82 days); median overall survival, 244 days (95% CI, 185-303 days); and 1-year survival rate, 32.6%.
  
  
  CONCLUSIONS
  The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy.
authors.affiliation: Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ward, Tokyo 135-8550, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Horiike
authors.forename: K
authors.initials: K
authors.lastname: Kudo
authors.forename: E
authors.initials: E
authors.lastname: Miyauchi
authors.forename: F
authors.initials: F
authors.lastname: Ohyanagi
authors.forename: K
authors.initials: K
authors.lastname: Kasahara
authors.forename: T
authors.initials: T
authors.lastname: Horai
authors.forename: M
authors.initials: M
authors.lastname: Nishio
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D000077146:Irinotecan; D066246:ErbB Receptors; D000077156:Gefitinib; D002166:Camptothecin