A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors

Purpose: Enoticumab (REGN421) is a fully human IgG(1) monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. Experimental Design: Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W). Results: Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non-small cell lung cancer bronchoalveolar-type with a beta-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3 > 6 months). Conclusions: Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. (C)2015 AACR.