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The Desmoid Tumor Research Foundation

June 2018

A phase I study of AL101, a pan-NOTCH inhibitor, in patients with locally advanced or metastatic solid tumors

Author Information

A El-Khoue iry, JDesai, S Iyer, S Gadgeel, S Ramalingam, L Horn, P LoRusso, G Bajaj, G Kollia, Z Qi, S Basak, B Fischer, M Davis, P Bedard

University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Peter MacCallum Cancer Centre & Royal Melbourne Hospital, Melbourne, Australia; The Methodist Cancer Center Weill Cornell Medical School, Houston, TX; University of Michigan, Ann Arbor, MI; Winship Cancer Institute, Emory University, Atlanta, GA; Vanderbilt University Medical Center, Nashville, TN; Yale University School of Medicine Yale Cancer Center, New Haven, CT; Bristol-Myers Squibb, Princeton, NJ; Bristol-Myers Squibb, Pennington, NJ, US; Aurigene Discovery Technologies Ltd, Bangalore, India; Ayala Pharmaceuticals, Rehovot, Israel; Princess Margaret Cancer Centre, Toronto, ON, Canada.

Publication

J Clin Onc

Summary

Notch signaling can be deregulated in human cancer. AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits all Notch receptors, was evaluated. The primary objective was safety and tolerability of multiple IV doses of AL101 and to establish a RP2D. Pts with advanced tumors refractory to standard therapies were included. Primary and secondary endpoints included safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Cohorts were administered escalating doses of AL101 IV weekly (QW) or q 2 weeks (Q2W) using a 3+3 design, with expansion at the MTD in TNBC, NSCLC, and selected other tumors with reported Notch activation. There were dose related increases in exposures over 0.3 to 8.4 mg, and the mean plasma half-life following 4 doses QW was 67 - 148 hours, supporting QW dosing. AL101 at the RP2D was generally well-tolerated and demonstrated sustained Notch inhibition as well as clinical activity across different tumor types. Future trials will evaluate AL101 in tumors with Notch activating mutations.

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