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.
OBJECTIVE
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.


METHODS
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 β-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. Clin Cancer Res; 21(12); 2695-703. ©2015 AACR.
University of Washington, Seattle, Washington. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. gchiorea@uw.edu antonio.jimeno@ucdenver.edu.
Elena Gabriela
EG
Chiorean
Yale University, New Haven, Connecticut.
Patricia
P
LoRusso
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
Robert Matthew
RM
Strother
University of Colorado School of Medicine, Denver, Colorado.
Jennifer R
JR
Diamond
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
Anne
A
Younger
University of Colorado School of Medicine, Denver, Colorado.
Wells A
WA
Messersmith
Regeneron Pharmaceuticals Inc. Tarrytown, NY.
Lieve
L
Adriaens
Regeneron Pharmaceuticals Inc. Tarrytown, NY.
Liming
L
Liu
Regeneron Pharmaceuticals Inc. Tarrytown, NY.
Richard J
RJ
Kao
Regeneron Pharmaceuticals Inc. Tarrytown, NY.
Albert Thomas
AT
DiCioccio
Regeneron Pharmaceuticals Inc. Tarrytown, NY.
Ana
A
Kostic
University of Oxford, Oxford, United Kingdom.
Russell
R
Leek
University of Oxford, Oxford, United Kingdom.
Adrian
A
Harris
University of Colorado School of Medicine, Denver, Colorado. gchiorea@uw.edu antonio.jimeno@ucdenver.edu.
Antonio
A
Jimeno
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D049690:History, Ancient; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein; C000600154:enoticumab