Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer.

Abstract

Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B). Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory). A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15% of all patients were: nausea (41%), fatigue (32%), vomiting (30%), decreased appetite (27%), pyrexia (25%), peripheral edema (23%), and urinary tract infection (UTI, 20%). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7% each). No radiographic responses were noted. Median progression-free survival in part B was 6.3weeks (95% confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0%). LY3022856 was well tolerated up to a dose of 30mg/kgqwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS. NCT01288989.