OncoMed Pharmaceuticals, a clinical-stage company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, has announced dosing of the first patient in a phase Ib clinical trial of brontictuzumab (anti-Notch1, OMP-52M51) plus chemotherapy in patients with metastatic colorectal cancer.

The phase Ib trial is intended to determine the maximum-tolerated dose of brontictuzumab in combination with trifluridine/tipiracil (Lonsurf). The phase Ib trial is designed to assess safety, preliminary efficacy and immunogenicity, as well as predictive and pharmacodynamics biomarkers. Metastatic colorectal cancer patients who have received at least two prior lines of therapy will be enrolled in the dose-escalation portion of the trial, and once a maximum tolerated dose is identified, additional patients whose tumors test high for the activated form of Notch1 will be enrolled in an expansion cohort. 

“Brontictuzumab targets Notch1, a key receptor in the Notch pathway, and preclinical data suggest that elevated Notch1 gene expression appears to be an oncogenic driver in a number of tumor types, including colorectal cancer,” said Robert Stagg, Pharm.D., OncoMed’s senior vice president, Clinical Research and Development. “In this Phase 1b trial, we expect to determine the safety and optimal therapeutic index of brontictuzumab in combination with chemotherapy, assess preliminary efficacy and explore the correlation of biomarker status and anti-tumor responses.”

Brontictuzumab (anti-Notch1, OMP-52M51) blocks signaling of Notch, an important cancer stem cell pathway implicated in chemoresistance, tumor angiogenesis and stem cell self-renewal, proliferation and differentiation. Notch1 signaling is prevalent in several solid tumor types, including certain breast, esophageal, colorectal, gastric, pancreatic and small cell lung cancers, as well as adenoid cystic carcinoma and cholangiocarcinoma. Single-agent anti-tumor activity was observed in OncoMed’s phase Ia dose escalation study of brontictuzumab in patients with certain advanced solid tumors, particularly in biomarker-defined patients whose tumors tested positive for overexpression of the activated form of Notch1. Brontictuzumab was generally well-tolerated, with the most common adverse event being manageable diarrhea.

OncoMed retains the worldwide rights to develop brontictuzumab.