Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN).
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.
Kraut
Eric H
EH
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
Rhoades
Christopher
C
Zhang
Yilong
Y
Cheng
Hao
H
Aimiumu
Josephine
J
Chen
Ping
P
Lang
James
J
Young
Donn C
DC
Agrawal
Amit
A
Dancey
Janet
J
Chan
Kenneth K
KK
Grever
Michael R
MR
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
D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride