title: Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN).
abstract: OBJECTIVE
  This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel.
  
  
  METHODS
  Twenty-eight patients with head and neck cancer were enrolled. Patients were orally given erlotinib (50 mg) daily plus 35 mg/m² of docetaxel intravenously weekly × 3 every 4 weeks. Dose escalation of erlotinib was in 50-mg increments until toxicity. Pharmacokinetics were studied with LC-MS/MS, standard, and population pharmacokinetic methods.
  
  
  RESULTS
  Ninety-five courses were successfully given (median 3, range 1-6). The most frequent side effects were diarrhea, fatigue, skin rash, anemia, and hypoalbuminemia. Dose de-escalation for both erlotinib and docetaxel was due to skin rash, neutropenia and/or severe infection with docetaxel to 25 mg/m² and erlotinib to starting dose of 50 mg and re-escalation of docetaxel to 35 mg/m². Responses were observed in 4/26 evaluable patients (100 mg erlotinib). In 24 patients, the mean Cmax and AUC erlotinib values increased with dose and following cumulative dosing (days 7 and 8 vs. day 1, p < 0.05). The CL/F (~7 L/h), V/F (~140 L), and t1/2 (~20 h) for erlotinib were similar to the reported. The mean AUC ratio of metabolite OSI-420 to erlotinib following repetitive dosing at 100 mg (+ or - docetaxel) showed a ~50% increase (p < 0.02), possibly suggesting self-enzyme induction. Population pharmacokinetic studies showed no significant covariate affecting erlotinib pharmacokinetics.
  
  
  CONCLUSIONS
  The combination of erlotinib and docetaxel was associated with significant toxicity, which limited the amount of administered erlotinib. Dosing for phase II trials was docetaxel 35 mg/m² and erlotinib 50 mg. The reason for excessive toxicity is not clear, but not due to change in pharmacokinetics.
authors.affiliation: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, College of Medicine and The Ohio State University Medical Center, Columbus, OH, USA. Eric.Kraut@osumc.edu
authors.forename: Eric H
authors.initials: EH
authors.lastname: Kraut
authors.forename: Christopher
authors.initials: C
authors.lastname: Rhoades
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Josephine
authors.initials: J
authors.lastname: Aimiumu
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: James
authors.initials: J
authors.lastname: Lang
authors.forename: Donn C
authors.initials: DC
authors.lastname: Young
authors.forename: Amit
authors.initials: A
authors.lastname: Agrawal
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002853:Chromatography, Liquid; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D053719:Tandem Mass Spectrometry; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride