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

2515Background: 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. Methods: 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. The DLT period was 4 weeks (4 doses QW or 2 doses Q2W). PD markers of Notch activity, including HES1 mRNA, were evaluated in serial whole blood. Results: As of 1Feb2018, preliminary data are available on 94 pts dosed at 0.3 mg to 8.4 mg QW, and 4 mg to 6 mg Q2W. The MTD for QW was 4 mg with 0 DLTs in 7 evaluable pts; DLTs...