A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs)

Abstract

3041 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor (VEGF) family receptor tyrosine kinase (RTK). PDGFRβ, KIT, FLT3, and Tie-2 are also inhibited at low nM concentrations in vitro. XL880 is the 1st orally bioavailable small molecule Met inhibitor to enter the clinic. Methods: Pts with advanced STs were enrolled in successive cohorts to receive XL880 orally as a single dose on Day (D) 1 with pharmacokinetic (PK) sampling, followed by 5 consecutive daily doses (DD) starting on D 4 with additional PK sampling. Pts then continued to receive XL880 for 5 consecutive days, repeated every 14 days. Results: Nineteen pts have been treated across 5 dose levels: 0.1, 0.2, 0.4, 0.8, and 1.6 mg/kg. No dose-limiting toxicities have been observed. Two pts have demonstrated grade 2 hypertension, at 0.8 and 1.6 mg/kg respectively. PK analysis indicated that systemic drug exposure (AUC) and peak plasma levels (Cmax) increased approximately dose-proportionally (r2 values = .89 and .87 respectively) with increasing XL880 dose (0.1–1.6 mg/kg). Following 5 consecutive DD, AUC values were 175–304% higher and Cmax values were 30–203% higher than following a single XL880 dose, suggesting possible drug accumulation with repeat dosing. Terminal half-life values were ∼60 hours (hrs) following 5 consecutive DD (D 8 range: 40–66 hrs), were more variable following a single dose (D 1 range: 26–87 hrs), and appeared to be unaffected by dose. A pt with papillary renal cell carcinoma has a partial response (DD = 0.2 mg/kg) and pts with carcinoid and melanoma have had minor responses. Conclusions: XL880 is a RTK inhibitor with a novel spectrum of activity that targets both tumor cells and tumor-associated vasculature. XL880 is well tolerated up to the 1.6 mg/kg dose, with continued dose escalation ongoing. XL880 demonstrates biologic activity through hypertension and antitumor activity. [Table: see text]