Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC)

Abstract

5032 Background: AV-951 is a potent inhibitor of VEGFR-1, 2 & 3 kinases (IC50 0.21, 0.16 and 0.24 nM respectively), and inhibits cKit and PDGFR at 10-times higher concentrations (IC50 1.63 and 1.72 nM respectively). In a phase II RDT of AV-951 (1.5 mg/day; 3 wks on, 1 wk off) in RCC, preliminary ORR at wk 16 was 28% (ASCO GU. 2008; abstract #283). Methods: Pts with locally advanced or metastatic RCC (any histology) and no prior VEGF-targeted therapy received AV-951 for 16 wks, after which further treatment was assigned based on response. Pts with ≥ 25% tumor shrinkage continued treatment with AV-951, while pts with < 25% change from baseline were randomly assigned to receive AV-951 or placebo for 12 wks (double-blinded). The primary end points were (1) objective response rate (ORR) at 16 wks, (2) percentage of randomly assigned pts remaining progression free at 12 wks following randomization, (3) safety profile. Results: 272 pts were enrolled: 70% male, 93% white, median age 56 yrs. 53% pts were treatement naïve, 72% had undergone nephrectomy and 83% had RCC with clear cell component. With a median duration of treatment of 5 mo (range 0–12 mo), the investigator assessed ORR (CR+PR) is 27.2% (30% in clear cell RCC), SD 60.5% and Disease Control Rate (CR/PR + SD) 88%. 118 (43%) pts were randomized to AV-951 or placebo. The most common treatment-related AEs (all grades) were hypertension (HTN, 42%) and dysphonia (16%). Guidelines for management of HTN were provided to investigators, and 52% pts received anti-hypertensives. Minimal (all grades) diarrhea (9%), fatigue (8%), stomatitis (3%) and hand-foot syndrome (2%) were observed. Laboratory abnormalities (all grades) were notable for minimal neutropenia (8%) and elevations of AST (21%) and ALT (21%). AEs led to dose reduction in 4% and treatment discontinuation in 5.5% of pts. Conclusions: Interim results of this phase II study demonstrate that AV-951 is active in RCC. The AE profile of AV-951 is consistent with that of a selective VEGFR inhibitor, with minimal off-target toxicities. Updated results of ORR (including independent radiology assessment), safety, percentage of randomly assigned pts remaining progression free at 12 wks, and overall PFS will be presented. [Table: see text]