Phase I study of REGN421 (R)/SAR153192, a fully-human delta-like ligand 4 (Dll4) monoclonal antibody (mAb), in patients with advanced solid tumors.

• DOI: 10.1200/jco.2013.31.15_suppl.2502
• Publication Date: 2020-03-11T19:29:27Z
• Authors: Antonio Jimeno; Patricia LoRusso; Robert Matthew St...; Jennifer Robinson...; Leah Plato; Anne Younger; Wells A. Messersmith; Muaiad Kittaneh; Doug Sawyer; Lieve Adriaens; Liming Liu; Richard J. Kao; A Thomas DiCioccio; Carrie M. Brownstein; Israel Lowy; Pamela Trail; E. Gabriela Chiorean
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

2502 Background: Dll4, a Notch receptor ligand, may have role in tumor angiogenesis and is an emerging anticancer target. REGN421 (R) fully human IgG 1 mAb that binds Dll4 disrupts Notch-mediated signaling. Methods: Primary objectives of the dose escalation (3+3 design) trial were to determine safety recommended phase II (RP2D) R patients (pts) with advanced cancer. was given IV at doses 0.25, 0.5, 1, 2 4mg/kg every 3 weeks (Q3W) or 0.75, 1.5, 3mg/kg (Q2W). Secondary PK, immunogenicity, antitumor activity. Results: 53 pts (M/F=22/31, ECOG 0/1=18/35) enrolled; 31 treated Q3W 0.25 - 4 mg/kg; 22 Q2W 0.75 mg/kg. Two DLTs occurred: Grade (Gr3) nausea (0.5mg/kg Q3W) Gr3 abdominal pain (1 mg/kg Q2W). A maximum tolerated not reached on either schedule. 3/4 AEs occurred 29 pts; nausea, pain, dyspnea, hypoxia, hypertension (HTN) reported ≥ 5%. Most frequent treatment related fatigue (30%), headache (26%), HTN (15%). Six SAEs (all reversed off treatment) patients: BNP increase (0.25mg/kg, Gr1), troponin I (4mg/kg, Gr3), right ventricular dysfunction (1.5mg/kg, left (3mg/kg, Gr3) events pulmonary Gr 3, Gr3). Laboratory abnormalities (≥ neutropenia (3) anemia (2), elevated ALP (7), ALT (3), bilirubin AST decreased albumin (1). Anti-tumor activity included PRs (NSCLC BAL-type beta-catenin mutation ovarian cancer [OvCa]), 16 SD (3 had > 6 months). 8 OvCa CA125 responses. non-linear target-mediated PK without accumulation. The half-life 7 days. No immunogenicity observed. Conclusions: acceptable profile, RP2Ds Q2W. Responses prolonged noted other solid tumors. Dose has concluded disease specific expansion cohorts are ongoing. Clinical information: NCT00871559.