title: Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naïve patients with advanced non-small-cell lung cancer.
abstract: BACKGROUND
  Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naïve patients with advanced NSCLC.
  
  
  METHODS
  Escalating doses of GEM (800-2000 mg/m2) and TAX (60-100 mg/m2) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels.
  
  
  RESULTS
  Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m2 plus GEM 1750 and, respectively, 2000 mg/m2). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hematological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of Cmax and AUC. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients.
  
  
  CONCLUSIONS
  The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m2 of GEM and 100 mg/m2 of TAX are recommended for phase II studies.
authors.affiliation: Division of Medical Oncology, European Institute of Oncology, Milano, Italy. tommaso.de-pas@ieo.it
authors.forename: T
authors.initials: T
authors.lastname: De Pas
authors.forename: F
authors.initials: F
authors.lastname: de Braud
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.forename: C
authors.initials: C
authors.lastname: Catania
authors.forename: G
authors.initials: G
authors.lastname: Curigliano
authors.forename: S
authors.initials: S
authors.lastname: Fogli
authors.forename: M
authors.initials: M
authors.lastname: del Tacca
authors.forename: G
authors.initials: G
authors.lastname: Zampino
authors.forename: A
authors.initials: A
authors.lastname: Sbanotto
authors.forename: A
authors.initials: A
authors.lastname: Rocca
authors.forename: S
authors.initials: S
authors.lastname: Cinieri
authors.forename: E
authors.initials: E
authors.lastname: Marrocco
authors.forename: A
authors.initials: A
authors.lastname: Milani
authors.forename: A
authors.initials: A
authors.lastname: Goldhirsch
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine