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

2515 Background: 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 occurred at 8.4 mg QW (Gr 3 infusion reaction, Gr 3 vomiting, Gr 5 liver failure) and 6 mg in de-escalation (Gr 3 vomiting/lipase elevation, Gr 3 diarrhea [n = 3]). The MTD for Q2W was 6 mg, with 1 DLT in 6 evaluable pts (Gr 3 diarrhea). In escalation/expansion at the QW MTD (n = 43), Gr 3 or higher related AEs were: hypophosphatemia (42%), diarrhea (16%), hypokalemia (7%), and anaphylaxis, anemia, AST increase, nausea, pruritus, and vomiting (2% each). 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. Dose related reduction of HES1 mRNA was seen with > 80% peak inhibition and > 50% inhibition sustained over several days at QW doses of 4 mg and higher. Objective responses were seen in 4 pts (RECIST v1.1): gastroesophageal junction adenocarcinoma (n = 1, 1 cCR ongoing > 1 y), desmoid tumor (n = 3, 2 cPR, ongoing > 1 y, > 3 y), adenoid cystic carcinoma (n = 2, 1 cPR with PD at 8 m). SD was best response in 9 pts (9.6%). Conclusions: 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. Clinical trial information: NCT01292655.