Abstract LB-201: Updated results from a Phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and -3 tyrosine kinase inhibitor, in patients with advanced solid tumors

Background: AV-951 inhibits phosphorylation of VEGF receptors (VEGFR)-1, -2, and -3 at picomolar concentrations (IC50 of 0.21, 0.16, and 0.24 nM, respectively) and inhibits c-Kit and PDGFR at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM, respectively). In a dose-escalation study of AV-951 given orally on a 4 week on, 2 week off schedule, the maximum tolerated dose (MTD) was determined to be 1.5 mg/day and clinical activity was observed in renal (RCC), colon, and lung cancers [Proc ASCO 2006;24(18S):2034]. Thereafter, the study was amended to enroll an additional 10 patients at 1.0 mg/day in order to compare the safety profile, pharmacokinetics (PK), effects on tumor blood flow, and antitumor activity across all dose levels. Results: 40 patients (26M/14F), were enrolled at AV-951 doses of 1 (n=16), 1.5 (n=16), and 2.0 mg (n=8). At 2 mg DLTs consisting of grade 3 proteinuria, grade 3 ataxia, and grade 4 intracranial hemorrhage were seen in one patient each. The primary toxicity across all dose levels was hypertension (HTN), as listed in Table 1. HTN was dose-dependent, and could be controlled with standard anti-hypertensive agents. Only two patients, both at 1.5 mg, required dose reduction to 1.0 mg for control of HTN. PK analysis revealed dose dependent drug exposure and peak plasma concentrations. DCE-MRI analysis indicated a decrease in tumor perfusion in selected patients. Among 9 patients with RCC, there were 2 confirmed partial responses at 2.0 mg (n=1) and 1.5 mg (n=1) lasting 128 weeks and 42 weeks, respectively, and 7 patients with stable disease (lasting >12 wks) at 1.0 mg (n=5), 1.5 mg (n=1), and 2.0 mg (n=1). Clinical activity was observed in multiple tumor types. Conclusions: AV-951 could be safely administered at 1.0 and 1.5 mg doses. The primary toxicity was dose-dependent HTN, a biomarker of VEGFR inhibition. Clinical activity was observed across all dose levels. In future combination studies, AV-951 may be administered at a dose of either 1.0 mg or 1.5 mg.