ACCURACY a phase (P) II trial of AL101, a pan-Notch inhibitor, in recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) patients (pts) with Notch activating mutations (Notch act mut): Preliminary safety and efficacy data

Abstract

Abstract Background Notch signaling plays a key role in tumorigenesis. AL101 is a γ-secretase inhibitor that potently inhibits signaling through Notch receptors 1-4. AL101 has robust antitumor activity in ACC patient-derived xenograft models with Notchact mut (AACR ‘19, Abstr 4885). In P1 testing, AL101 was well tolerated, with manageable AEs and a recommended P2 dose of 4\xa0mg IV QW (ASCO ‘18, Abstr 2515). One of the 4 responders in P1 had ACC with Notchact mut. ACC is a rare chemotherapy-refractory cancer of the secretory glands. Notchact mut are found in ∼20% of ACC pts, characterized by a particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC. Methods ACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4\xa0mg IV QW) in R/M ACC pts (bone-exclusive disease allowed) with known Notch1-4act mut (ASCO ‘19, Abstr TPS6098). Pts with disease progression ≤6 months of enrollment or newly diagnosed metastatic disease are allowed. Primary endpoint: ORR by RECIST v1.1 (or modified MD Anderson bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per Simon optimal design, 12 pts are enrolled in stage 1; if\xa0≥\xa02 pts respond, 24 additional pts are enrolled in stage 2. If\xa0≥\xa06 pts of 36 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. Results In stage 1, 12 pts are being treated (median of 1.5 cycles, as of May ‘19). Most pts are males, with ECOG PS of 0, and with Notch mutations in the PEST domain (Table). Table: 1148P . Disposition and Baseline characteristics of patients treated with the investigational new drug AL101 Screened/Enrolled (signed consent), n 18 Screen failures, n 6 Treated, n 12 Median number of cycles, n 1.5 Gender, n Male Female 8 4 Median age, years 56.5 Race, n White Black Asian Other Not Reported N/A 6 1 0 1 2 2 ECOG performance status, n 0 1 N/A 6 4 2 Disease status, n With nodal or visceral metastases With bone-exclusive metastases 10 2 Type of mutations, n In the NRR region In the PEST domain In the NRR and PEST regions 3 6 3 N/A=not available Conclusions In the stage 1 of the ACCURACY trial, 12 pts with Notch1-4act mut are being treated with the pan-Notch inhibitor AL101. The trial will advance to stage 2 if\xa0≥\xa02 pts respond. Efficacy/safety data on these first 12 pts will be presented at the meeting. Accrual to stage 2 is ongoing. Clinical trial identification NCT03691207. Editorial acknowledgement Francesca Balordi, PhD, of The Lockwood Group (Stamford, CT, USA), in accordance with Good Publication Practice (GPP3) guidelines, funded by Ayala Pharmaceuticals, Inc. Legal entity responsible for the study Ayala Pharmaceuticals, Inc. Funding Ayala Pharmaceuticals, Inc. Disclosure R. Ferrarotto: Honoraria (self), Advisory / Consultancy: Ayala Pharmaceuticals; Honoraria (self): Regeneron. A. Ho: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Ayala Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Research grant / Funding (self): Celldex Therapeutics; Research grant / Funding (self): Bayer; Research grant / Funding (self): Eli Lilly and Company; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Allos Therapeutics; Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Sanofi Genzyme; Honoraria (self), Advisory / Consultancy: Sun Pharma; Honoraria (self), Advisory / Consultancy: Regeneron; Honoraria (self), Advisory / Consultancy: TRM Oncology; Research grant / Funding (self), Travel / Accommodation / Expenses: Kura Oncology; Travel / Accommodation / Expenses: Ignyta. L.J. Wirth: Honoraria (self), Advisory / Consultancy: Ayala Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Eisai. C. Rodriguez: Honoraria (self), Advisory / Consultancy: Cue Biopharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck. E. Dekel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. R.M. Walker: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. C. Nadri-Shay: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. A. Vergara-Silva: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. All other authors have declared no conflicts of interest.