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 (H&N (8); 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 toxicities (DLT) were: Gr 3 mucositis, fatigue and anorexia- 1250 GW/2000 C (n=1); Gr 3 rash (n=1), Gr 3 diarrhea (n=1)- 1500 GW/2000 C & Gr 2 bleeding stomatitis (n=1), Gr 3 diarrhea (n=1)- 1250 GW/2500 C. Other toxicities included stomatitis (36%), nausea/vomiting (30%), diarrhea (45%), unconjugated hyperbilirubinemia (14%), fatigue (19%), rash (38%) and hand foot syndrome (29%). OTR was 1250 GW/2000 C. Responses (RECIST criteria) included 1 CR in a woman with inflammatory breast cancer refractory to trastuzimab-and chemotherapy. Her tumor overexpressed ErbB2 (3+) with low TS. In addition, 4 PRs (1 @ erlotinib-resistant H&N; taxane refractory-H&N; breast; gastric) and 6 SD >12 weeks were observed. Conclusions. GW (1250 mg)/C (2000 mg) was active and tolerable. Use of biomarkers (e.g., ErbB2, TS) may identify potential responders. Complete PK data will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline