Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN)

Abstract

Purpose This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel. Patients and 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. day1, 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.

Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naïve Prostate Cancer: A Systematic Review and Network Meta-analysis

“…Снижение клиренса доцетаксела зарегистрировано в исследованиях, оценивавших результаты его сочета-ния с топотеканом, -на 50 %, что привело к повы-шению частоты развития нейтропении [47], и с па-зопанибом [48]. В то же время при сочетании с эрлотинибом не отмечено ухудшения фармакокине-тики, однако частота осложнений возрастала [49]. Среди поддерживающей терапии одними из наиболее часто используемых являются препараты, действие которых направлено на профилактику тошноты и рво-ты.…”

Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial

“…15 The combination of erlotinib and docetaxel resulted in significant toxicities in a phase I trial in patients with SCCHN necessitating reduction of the erlotinib dose to 50 mg daily. 16 This prompted us to study gefitinib as the EGFR-TKI of choice. Our hypothesis was that the addition of gefitinib to docetaxel will be synergistic and improve the outcome of previously treated and/or compromised performance status patients with recurrent or metastatic SCCHN.…”

Inter-patient variability in docetaxel pharmacokinetics: A review

“…The combination docetaxel-erlotinib was associated with severe toxicity, without a significant change in PK [47]. In contrast, in a phase I and PK study on the combination of docetaxel and pazopanib, a lower docetaxel CL was found due to pazopanib co-treatment [52].…”