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Ref Type Journal Article
PMID (25724527)
Authors Chiorean EG, LoRusso P, Strother RM, Diamond JR, Younger A, Messersmith WA, Adriaens L, Liu L, Kao RJ, DiCioccio AT, Kostic A, Leek R, Harris A, Jimeno A
Title 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.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 21
Issue 12
Date 2015 Jun 15
URL
Abstract Text Enoticumab (REGN421) is a fully human IgG1 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.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).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 β-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3> 6 months).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. Clin Cancer Res; 21(12); 2695-703. ©2015 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Enoticumab Enoticumab 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Enoticumab SAR15319|REGN421 DLL4 Antibody 6 Enoticumab (REGN421) is a monoclonal Dll4 antibody that inhibits Notch signaling, which may prevent Vegf induced angiogenesis (PMID: 26377940, PMID: 25724527).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Enoticumab Phase I Actionable In a Phase I trial, Enoticumab (REGN421) resulted in partial response in 3% (2/53) and stable disease in 30% (16/53) of patients with advanced solid tumors (PMID: 25724527). 25724527
Unknown unknown ovarian cancer not applicable Enoticumab Phase I Actionable In a Phase I study, Enoticumab (REGN421) demonstrated safety and preliminary efficacy in ovarian cancer patients (PMID: 25724527). 25724527