First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors.

U3-1565 is a monoclonal antibody directed against heparin-binding epidermal growth factor-like growth factor (HB-EGF), which mediates angiogenesis via induction of vascular endothelial growth factor (VEGF-A). This first-in-human study characterized the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of U3-1565 in subjects with advanced solid tumors. In Part 1 (dose escalation following a modified 3 + 3 design), Cohorts 1-4, U3-1565 was administered at 2, 8, 16, and 24 mg/kg every 3 weeks for Cycle 1 and every 2 weeks thereafter. In Part 1, Cohort 5, and in Part 2 (dose expansion), U3-1565 was administered at 24 mg/kg every week. Thirty-six subjects were enrolled and treated (15 in Part 1; 21 in Part 2). No subject experienced dose limiting toxicity and maximum tolerated dose was not reached. All drug-related events were Grade 1 or 2 in severity, with fatigue and rash predominating. Following treatment with U3-1565, 1 subject with metastatic colorectal cancer experienced partial response and 6 subjects achieved stable disease. Four subjects completed the study main phase (first 12 cycles) and entered the extension phase. Of the 6/36 subjects with high (> 1500 pg/ml) baseline VEGF-A levels, all showed a decrease in VEGF-A (median - 60% [-22% to -97%]). Of the remaining subjects, only 19/30 showed a decrease (median - 18% [-2% to -82%]). Subjects with high VEGF-A baseline levels remained on treatment longer (3/6 entered study extension phase versus 1/30), and were more likely to show disease control (3/6 versus 4/30). In conclusion, U3-1565 demonstrates both proof of mechanism and clinical activity across different tumor types.