Phase I Dose-escalation and Pharmacokinetic Trial of Lapatinib (GW572016), a Selective Oral Dual Inhibitor of ErbB-1 and -2 Tyrosine Kinases, in Japanese Patients with Solid Tumors

Objective: The Phase I dose-escalation study was conducted to evaluate the safety and pharmacokinetics of lapatinib (GW572016), a dual ErbB-1 and -2 inhibitor, in Japanese patients with solid tumors that generally express ErbB-1 and/or overexpress ErbB-2. Methods: Patients received oral lapatinib once daily until disease progression or in an event of unacceptable toxicity. Results: Twenty-four patients received lapatinib at dose levels of 900, 1200, 1600 and 1800 mg/day; six subjects enrolled to each dose level. The majority of drug-related adverse events was mild (Grade 1–2); the most common events were diarrhea (16 of 24; 67%), rash (13 of 24; 54%) and dry skin (8 of 24; 33%). No Grade 4 adverse event was observed. There were four Grade 3 drug-related adverse events in three patients (i.e. two events of diarrhea at 1600 and 1800 mg/day each and g-glutamyl transpeptidase increase at 1800 mg/day). The maximum tolerated dose was 1800 mg/day. The pharmacokinetic profile of lapatinib in Japanese patients was comparable to that of western subjects. Conclusions: Lapatinib was well tolerated at doses of 900–1600 mg/day in Japanese solid tumor patients. Overall, our findings were similar to those of overseas studies.