On June 4, 2018 Ayala Pharmaceuticals, a clinical stage precision oncology biopharmaceutical company dedicated to developing novel targeted therapies for genomically defined cancers in patient populations with high unmet medical needs, reported results from the Phase 1b study of AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits signaling downstream of Notch receptors (1, 2, 3 and 4) (Press release, Ayala Pharmaceuticals, JUN 4, 2018, View Source [SID1234527161]). These data were accepted for a poster presentation titled, "A phase I study of AL101, a pan-Notch inhibitor, in patients with locally advanced or metastatic solid tumors," at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. The poster was selected for a discussion session that will take place on Monday, June 4, 2018, from 3:00 p.m.-4:15 p.m. in Hall A, Room S406, McCormick Place.

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The primary objective of the study was to assess the safety and tolerability of multiple IV doses of AL101, and to establish the recommended Phase 2 dose. Secondary objectives were to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of AL101 and its equally active metabolite after the first IV dose and after repeated doses. All study objectives were met.

AL101 is a best-in-class gamma secretase inhibitor that has demonstrated potent and selective inhibition downstream of all four Notch receptors in preclinical models. Based on these encouraging findings, a Phase 1 study was designed in advanced solid tumors to evaluate safety and tolerability as well as PK and PD of the compound.

Ninety-four patients were enrolled in the study and treated with one of two alternative regimens: Arm A (QW, n=83) and Arm B (Q2W, n=11) using a 3+3 design, with expansion at the maximum tolerated dose (MTD). Tumor types included adenoid cystic carcinoma (ACC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC) and selected other tumors with reported Notch activation. The defining dose-limiting toxicity (DLT) period was four weeks (4 doses QW or 2 doses Q2W). PD biomarkers of Notch activity, including HES1 mRNA, were evaluated in serial whole blood.

A MTD of 4 mg QW was established in the escalation phase and used in the expansion phase. The safety profile was consistent with that on target effects of Notch inhibition. The majority of adverse effects were low grade and manageable with protocol guidelines. Grade 3/4 events reported in >15% (all doses, Arm A) included: diarrhea 17 (20%), hypophosphatemia 31(37%), nausea 1 (1%), vomiting 4 (5%), hypokalemia 6 (7%).

Seven DLTs were reported in Arm A: four in patients receiving 6 mg, (Grade 3 vomiting, Grade 3 diarrhea, Grade 3 diarrhea/colonic ulcerations, Grade 3 diarrhea/Grade 4 dehydration) and in three patients receiving 8.4 mg (Recurrent Grade 3 infusion reaction, Grade 3 vomiting, Grade 5 hepatic failure). There were no DLTs in three DLT-evaluable patients at 6 mg QW during escalation, and once 8.4 mg QW was deemed above the MTD, 11 additional patients were enrolled at 6 mg (10 were DLT evaluable). There were no DLTs in seven DLT-evaluable patients receiving 4 mg QW.

Weekly dosing of AL101 led to continuous Notch inhibition as measured by HES 1 transcription at doses 4 mg QW and above. Clinical activity was demonstrated across different solid tumor types at the MTD as defined by RECIST v1.1: one complete response was observed in a patient with a gastroesophageal junction adenocarcinoma with two missense and one splice-site mutation in Notch 1. One partial response was observed in a patient with a desmoid tumor, and one PR was observed in a patient with an ACC, with mutated Notch 1.

"Ayala is dedicated to precision oncology, bringing forward targeted therapies for cancer patients with high unmet needs," said Roni Mamluk, Ph.D., Chief Executive Officer at Ayala Pharmaceuticals. "As we continue our clinical development plans for Ayala’s Phase 2 study in the second half of this year, we are particularly encouraged by AL101’s clinical activity seen to date and look forward to initiating trials in our lead indication, ACC, in patients with activated Notch pathway, an indication with no approved treatment and patients in need for a therapy."