Pharmacokinetics (PK) and tolerability of GW786034, a VEGFR tyrosine kinase inhibitor, after daily oral administration to patients with solid tumors

Abstract

3054 Background: GW786034 is a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity in vitro and in vivo. Preclinical models suggest that plasma GW786034 concentrations above ∼18μg/mL throughout the dosing interval were associated with optimal activity. Methods: Patients (pts) with solid tumors were enrolled into an ongoing Phase I, dose-escalation study. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicity. Serial plasma GW786034 concentrations and circulating VEGF, d-dimer, VCAM-1, E-selectin, thrombin, and Factor VIII were evaluated . Wound healing assays and dynamic MRI's were obtained before and during GW786034 dosing. Results: Twenty-eight patients were enrolled at dose levels up to 400mg daily. Selected mean PK results are: Drug-related adverse events by grade (G) included: hypertension (n=2; G1, G3); GI hemorrhage (n=2; G1, G4); emesis (n=2; G1); diarrhea (n=2; G1); myoclonus (n=1; G3); ecchymoses (n=1; G1); increased alkaline phosphatase (n=1; G1), SGPT (n=1; G1), SGOT (n=1; G1), and bilirubin (n=1, G1). Six patients have remained on study for greater than 3 months. Dose escalation is continuing. Conclusions: Daily oral doses of GW786034 can achieve plasma concentrations similar to those that show anti-tumor and anti-angiogenic activity in preclinical models. Doses of up to 400mg daily were well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline; Merck GlaxoSmithKline; Merck GlaxoSmithKline