• 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)

      Ferrarotto, R.; Wirth, L. J.; Muzaffar, J.; Rodriguez, C. P.; Xia, B.; Perez, C. A.; Bowles, D. W.; Winquist, E.; Hotte, S. J.; Metcalf, Robert; et al. (2020)
      Background: Notch signaling plays a key role in ACC tumorigenesis. AL101, an investigational g-secretase inhibitor, blocks Notch signaling and inhibits tumor in ACC patient-derived xenograft models with Notchmut (AACR ‘19, Abstr 4885). Notchmut are found in w20% of ACC tumors these tumors are aggressive with a poor prognosis (Ferrarotto 2016, Ho 2019). No therapies are approved for R/M ACC. Updated results (n ¼ 45) will be provided. Methods: ACCURACY is an open-label, multicenter study of AL101 (4 and 6 mg IV QW) in R/M ACC subjects (bone-only disease allowed) with 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 PS of <2.Primary endpoint: ORR by RECIST v1.1 (or modified MD Anderson bone criteria), by investigator. Secondary endpoints: ORR by central review, duration of response and safety. The study was amended, based on the safety and activity in the 4 mg cohort, to add a cohort of 42 subjects at 6mg. The study will provide at least 80% power to detect an increase of the response rate from 8% to 25% using a type I error of 5%. Results: 45 subjects were enrolled at 4 mg QW; 39 are evaluable for efficacy. The most common ( 15%) treatment-related AEs (all Grades) included diarrhea (51%), nausea (49%), fatigue (47%), and vomiting (24%) with 24% Grade 3/4. Grade 3 events included diarrhea (4%), nausea (2%), fatigue (2%), and hypophosphatemia (9%). There were no Grade 4 or treatment-related deaths. In the 4mg group there were 6 partial responses and 21 stable disease out of 39 evaluable subjects. Most PRs were achieved by week 16, 13/39 of subjects were on study for at least 24 weeks or are still on drug not having reached 24 weeks. Conclusions: Investigational AL101 has clinical activity in R/M Notch mutant ACC and appears to be well tolerated. The trial was amended to enroll additional subjects at 6 mg QW. Clinical
    • 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

      Ho, A. L.; Bowles, D. W.; Even, C.; Hao, D.; Kang, H.; Metcalf, Robert; Muzaffar, J.; Oliva, M.; Perez, C. A.; Popovtzer, A.; et al. (2021)
      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.