Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors.

3012 Background: GW786034 is a tyrosine kinase inhibitor of VEGFR-1,-2 and -3, PDGFR-α and -β, and c-kit. Plasma trough concentrations above ∼ 18 μg/mL were required for optimal anti-tumor and anti-angiogenic activity in animal models.,Pts with solid tumors were enrolled in an ongoing Phase I study. Safety (including daily BP monitoring), single- and multiple-dose PK, biomarkers, and clinical activity were evaluated. Response was assessed by RECIST.,43 pts were enrolled in the dose escalation phase at doses ranging from 50 mg 3 times weekly to 2000 mg daily (qd) in 11 cohorts. Mean half-life was ∼ 35 hrs. Accumulation of 1.5 - 3 fold and Cmax/Cmin of ∼ 2 were observed at steady-state. Maximal exposure with trough concentrations (C24) > 18 μg/mL were observed after doses ≥ 800 mg qd. MTD was not achieved. The most frequent drug related AEs were NCI CTC2, Gr 1 and 2: nausea (Gr 1/2 n=15, Gr 3 n=1), diarrhea (Gr 1/2 n=15), fatigue (Gr 1/2 n=12, Gr 3 n=1), HTN (Gr 1/2 n=6, Gr 3 n=6), anorexia (Gr 1/2 n=12), and vomiting (Gr 1/2 n=9, Gr 3 n=1). Hair depigmentation was observed (n=6/14) at doses of ≥ 800 mg. The greatest magnitude in BP change was observed at 800 mg and correlated with C24 of > 20 μg/mL. HTN was amenable to treatment and was reversible upon cessation of GW786034. No pts were withdrawn from study solely due to HTN. One of 3 pts treated at 2000 mg qd developed Gr 3 fatigue (DLT). Tumor shrinkage (minimal response) was observed in all 3 pts with renal cell cancer treated at ≥ 800 mg qd and in one pt with Hurthel cell tumor. Six additional pts (melanoma n=1, sarcoma n=3, lung n=1, neuroendocrine n=1) remained on study for ≥ 6 mos with SD.,GW786034 was generally well tolerated with preliminary evidence of anti-tumor activity in cancer patients. HTN and hair depigmentation were indicative of VEGFR and c-kit modulation. Two dose cohorts (800 mg qd and 300 mg bid) are being expanded. [Table: see text].