Safety and Preliminary Efficacy Results of a Phase I First-in-Human Study of the Novel Notch-1 Targeting Antibody Brontictuzumab (OMP-52M51) Administered Intravenously to Patients with Hematologic Malignancies
Authors: Casulo Carla , Ruan Jia , Dang Nam H. , Gore Lia , Diefenbach Catherine , Beaven Anne W , Castro Januario E. , Porcu Pierluigi , Faoro Leonardo , Dupont Jakob , Kapoun Ann , Wang Min , McGuire Kristin , Flinn Ian W. 
Published: October 2019

Abstract
Background: The Notch pathway plays a key role in embryonic development and regulation of stem and progenitor cells, and is implicated in human cancer. Notch1 (N1) signaling is activated by various mechanisms including N1 activating mutations in certain hematologic tumors such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL). Brontictuzumab (BRON) is a humanized IgG2 antibody that inhibits the signaling function of N1. As such, BRON is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including cancer stem cells, and tumor angiogenesis.
Materials and methods: A phase I dose escalation and expansion study was initiated in patients (pts) with previously treated CLL, MCL, DLBCL, anaplastic large cell lymphoma (ALCL), transformed mycosis fungoides (TMF), Sezary Syndrome (SS), T-cell acute lymphoblastic leukemia (T-ALL), or other hematologic malignancies with known N1 activating mutation. BRON was administered intravenously to study safety, pharmacokinetics (PK), pharmacodynamics, preliminary efficacy, and to determine the maximum tolerated dose (MTD). Clinical trial information: NCT01778439.
Results: Twenty-four pts were enrolled and 23 pts have been treated in 4 dose escalation cohorts at doses of 0.25 mg/kg every 4 weeks (Q4W), 0.5 mg/kg Q4W, 1 mg/kg Q4W, and 1 mg/kg every 2 weeks (Q2W). Tumor types included DLBCL (6 pts), CLL (5 pts), TMF (5 pts), MCL (4 pts), and one each with T-ALL, T-cell prolymphocytic leukemia (T-PLL), and follicular lymphoma (FL). Two pts experienced dose-limiting toxicity (DLTs) adverse events at the 1.0 mg/kg Q2W dose cohort: one pt had gr 5 acute renal failure in the setting of tumor lysis (1 mg/kg Q2W) and 1 pt had gr 3 diarrhea and gr3 acute on chronic renal failure (1 mg/kg Q2W). The most frequent treatment-related adverse events (AE) of any grade were: diarrhea (22%), fatigue (17%), anemia (13%), abdominal pain (9%), nausea (9%), vomiting (9%), peripheral edema (9%), increased bilirubin (9%), decreased appetite (9%), hypokalemia (9%), and acute renal failure (9%). One pt with TMF had partial response to treatment, after receiving 1 mg/kg Q2W. Two additional pts had stable disease as best overall response (1 with MCL, and 1 with TMF). Five of the 24 pts had N1 mutations that were predicted to be deleterious and 3 pts had unknown N1 mutation status. Of the 5 patients with N1 mutations, 3 had classical frame shift mutations in the N1 PEST domain and are validated to be activating mutations and 2 had mutations in EGF-like domain where the mutation significance is unknown. Of the three patients with known N1 activating mutations, 1 pt was treated at 0.25 mg/kg Q4W and had progressive disease at first assessment, 1 pt never received study drug, and 1 pt treated at 1 mg/kg Q2W had stable disease as best response and was on study 101 days.
Conclusions: BRON is generally well tolerated and had moderate anti-tumor activity. Diarrhea is the primary toxicity of this antibody. The MTD has not been established. Updated efficacy, safety, N1 intracellular domain expression status, and PK results will be presented.

Disclosures
Casulo: Infinity: Consultancy, Honoraria; Celgene: Research Funding. Dang:Pharmacyclics LLC, an AbbVie Company: Research Funding; Seattle Genetics: Research Funding; Novartis: Honoraria; Eisai: Research Funding; Valor: Research Funding; Oncomed Pharmaceuticals Inc: Research Funding. Diefenbach:Gillead: Equity Ownership; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Faoro:OncoMed Pharmaceuticals: Employment, Equity Ownership. Dupont:OncoMed Pharmaceuticals: Employment, Equity Ownership. Kapoun:OncoMed Pharmaceuticals: Employment, Equity Ownership. Wang:OncoMed Pharmaceuticals: Employment, Equity Ownership. McGuire:OncoMed Pharmaceuticals: Employment, Equity Ownership. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership.