A phase I escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with...

Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy.

Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m(2), for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1-4 of the non-standard regimens).

No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93% of patients), including acneiform dermatitis (83% of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C (max) and AUC(0-infinity) after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of >or=400 mg/m(2), CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8%) achieved partial response (at 100/100 mg/m(2)). The overall disease control rate (partial response + stable disease) was 58%.

The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m(2) followed thereafter by weekly 1-h infusions of 250 mg/m(2) for non-Japanese patients is feasible for future clinical studies in Japanese patients.