Abstract B48: A first-in-human Phase I study of the novel cancer stem cell (CSC) targeting antibody OMP-52M51 (anti-Notch1) administered intravenously to patients with certain advanced solid tumors.
Authors: Davis S. Lindsey , LoRusso Patricia , Xu Lu , Kapoun Ann M. , Dupont Jakob , Munster Pamela , Eckhardt S. Gail , Patnaik Amita 
Published: August 2014

Abstract
Background: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many forms of human cancer. Notch1 is known to be frequently activated in certain solid tumor types. OMP-52M51 is a humanized IgG2 antibody that inhibits the signaling function of the Notch1 receptor. Mouse xenograft studies using minimally-passaged, patient-derived xenografts have shown that OMP-52M51 impedes tumor growth and selectively eliminates CSCs in a range of tumor types particularly in tumors with activated Notch1 signaling. In these models, anti-Notch1 antibody also has anti-angiogenic effects leading to tumor growth inhibition. As such, OMP-52M51 is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects on tumor angiogenesis.
Methods: A phase I dose escalation and expansion study was initiated in patients with certain advanced solid tumor indications (cholangiocarcinoma, breast, colorectal, esophageal, gastric, and small cell lung cancers) that have frequencies of Notch1 activation of 12-29% (AACR 2013; #3728). OMP-52M51 was administered intravenously to study safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and to determine the maximum tolerated dose (MTD). The trial has a Notch1 IHC biomarker selected expansion cohort to test for single-agent response rate.
Results: Ten patients have been enrolled in 4 dose-escalation cohorts at doses of 0.25, 0.5, 1, and 2.5mg/kg administered every 4 weeks (Q4W). The most frequently reported drug-related adverse events were: mild to moderate diarrhea (56%), rash (22%), and nausea (22%). One patient developed grade 3 diarrhea for 24 hours controlled with Imodium. No dose-limiting toxicities (DLTs) have occurred and dose escalation continues. The PK of OMP-52M51 in patients is characterized by dose-dependent clearance. One patient with colorectal cancer has prolonged stable disease for &gt;100 days with a decline in CEA tumor marker. Biomarker analyses for Notch pathway modulation and activation are ongoing.
Conclusions: OMP-52M51 is generally well tolerated. Dose escalation continues and updated results will be presented.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B48.
Citation Format: S. Lindsey Davis, Patricia LoRusso, Lu Xu, Ann M. Kapoun, Jakob Dupont, Pamela Munster, S. Gail Eckhardt, Amita Patnaik. A first-in-human Phase I study of the novel cancer stem cell (CSC) targeting antibody OMP-52M51 (anti-Notch1) administered intravenously to patients with certain advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B48.