A safety, tolerability, and pharmacokinetic (PK) study of GW572016 in patients with solid tumors

Abstract

3179 Background: GW572106 is a reversible inhibitor of ErbB1/ErbB2 tyrosine kinases. This phase I monotherapy study evaluated safety, tolerability, and PK in patients with advanced solid tumors at once (QD) and twice daily (BID) dosing schedules. Methods: Patients (pts) were administered GW572106 on a QD or BID continuous schedule. QD doses ranged from 175 to 1800 mg and BID doses were 500, 750, and 900 mg per dose. In addition to standard evaluations, serial MUGAs were obtained. PK on days 1 and 14 and disease assessments every 8 weeks (RECIST criteria) were obtained. Results: 81 pts with various carcinomas were enrolled; 64 pts (39 QD, 25 BID) included in safety and disease assessment; 57 included in PK. Median age was 62 yrs; 39 males/25 females. The majority of drug-related AEs were grade I (75% of pts QD, 71% pts BID). Diarrhea was the most frequent AE (17% QD, 29% BID of pts). Two pts had grade 3 diarrhea at 900 mg BID. Other AEs were fatigue (16%), nausea (16%) and rash (9%) on QD and nausea (11%) and rash (11%) on BID dosing. While serial MUGAs revealed no significant median change in LVEF, only 1 of the 81 pts experienced cardiac toxicity; a grade 2, asymptomatic decline in LVEF was observed. There were no clinically significant changes in the other safety evaluations. The severity of diarrhea and rash were not correlated with dose; severity of rash but not diarrhea appeared to correlate with serum concentration. Conclusion: Administration of GW572106 on a QD schedule was well-tolerated at all doses while 500 and 750 mg BID were better tolerated than 900 mg BID. The majority of AEs were grade 1 or 2 skin and/or GI toxicities, manageable with symptomatic treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline; Pharmacia GlaxoSmithKline Bristol-Myers Squibb; GlaxoSmithKline GlaxoSmithKline