ACCURACY: A phase II trial of AL101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notchmut): Results of 6-mg cohort

Abstract

Background Notch signaling plays a key role in ACC tumorigenesis. Notchmut are found in ?20% of ACC tumors, which are aggressive with a poor prognosis (Ferrarotto 2016, Ho 2019). No therapies are approved for R/M ACC. AL101, an investigational ?-secretase inhibitor, blocks Notch signaling and inhibits tumors in ACC patient-derived xenograft models with Notchmut (AACR �19, Abstr 4885). AL101 has clinical activity at 4 mg once weekly (QW) with a disease control rate of 68% (15% partial response) and appears to be well tolerated (Ferrarotto ESMO �20, #919MO). Based on the safety and activity in the 4-mg cohort, a cohort of 42 additional subjects was added to evaluate treatment with 6 mg QW. Methods ACCURACY is an open-label, multicenter phase II study of AL101 (4 and 6 mg intravenous QW) in subjects with R/M ACC and known Notch1-4mut (ASCO �19, Abstr TPS6098). Subjects require evidence of disease progression within 6 months of entry or newly diagnosed metastatic disease and an ECOG performance status of 0-1. Primary end point was overall response rate (ORR) by RECIST v1.1 (or modified MD Anderson bone criteria), as assessed by investigators. Secondary end points were ORR by central review, duration of response, and safety. The study provides ?80% power to detect an increase of the ORR from 8% to 25% using a type I error of 5%. Results A total of 37 subjects were enrolled in the 6-mg QW cohort. Most common (?20%) treatment-related adverse events of all grades in the 6-mg cohort were diarrhea (73%; grade 3 (gr3) 11%), fatigue (49%; gr3 5%), nausea (41%; gr3 3%), hypophosphatemia (27%; gr3 0%), vomiting (27%; gr3 0%), decreased appetite (22%; gr3 3%), and rash (22%; gr3 0%). Conclusions AL101 6 mg QW appears to be well tolerated in Notchmut R/M ACC. Efficacy and pharmacokinetic data will be presented. Accrual and follow-up to the 6-mg cohort is ongoing.