Phase I clinical, biology & pharmacokinetic study of the combination of GW 572016 and capecitabine in patients with advanced solid tumors

Abstract

3070 Background. GW572016 (GW), a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, which induces growth arrest and/or apoptosis in ErbB1 or ErbB2 expressing tumor cell lines. Capecitabine (C), an orally administered fluoropyrimidine, is preferentially converted to 5-FU by thymidine phosphorylase (TP) in tumor cells. Inhibition of EGFR may upregulate TP and downregulate thymidylate synthase (TS), leading to synergistic antitumor effect when combined with C. Methods. A 2-part Phase I study combining GW with C was conducted in 45 patients (pts) with advanced solid tumors: (A) dose-escalation phase (24 pts) and (B) pharmacokinetic phase at the optimally tolerated regimen (OTR) (21 pts): M/F (23:22), median age 57 yrs (34–78), ECOG (0/1/2:29/13/3), heavily:lightly pretreated (23:22), tumor types (HN breast (8), colorectal (7), lung (6), others (16)) and median cycle 3 (1–9). Pts were treated with 14 days of C (1500–2500 mg/m2) and daily GW (1250–1500 mg) every 3 weeks. Results. Dose-limiting tox...