919MO - 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)

Background

Notch signaling plays a key role in ACC tumorigenesis. AL101, an investigational γ-secretase inhibitor, blocks Notch signaling and inhibits tumor in ACC patient-derived xenograft models with Notch^mut (AACR ‘19, Abstr 4885). Notch^mut are found in ∼20% 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 = 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 Notch1-4^mut (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. Table: 919MO

Disposition and baseline characteristics of subjects treated with the investigational new drug AL101-4 mg

Treated, n Evaluable, n Median number of cycles, n	45 39 5
Gender, n, (%) Male Female	20 (44%) 25 (56%)
Median age, years	50 (range)
Race, n, (%) White Black Asian Other Not Reported	30 (68%) 4 (9%) 2 (4%) 2 (4%) 7 (16%)
ECOG performance status, n, (%) 0 1	21 (47%) 24 (53%)
Prior Systemic Therapy, n, (%)	45 (71%)
Disease status, n, (%) With nodal or visceral metastases With bone-exclusive metastases	42 (93%) 3 (7%)

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 trial identification

NCT03691207; EudraCT 2019-000309-64.

Editorial acknowledgement

Legal entity responsible for the study

Ayala Pharmaceuticals.

Funding

Ayala Pharmaceuticals.

Disclosure

R. Ferrarotto: Advisory/Consultancy: Regeneron-Sanofi; Advisory/Consultancy: Ayala Pharmaceuticals; Advisory/Consultancy: Klus Pharmaceuticals; Advisory/Consultancy: Medscape; Advisory/Consultancy: Carevive; Advisory/Consultancy: Prelude; Advisory/Consultancy: Carevive; Honoraria (institution), Clinical Trials: Merck; Honoraria (institution), Clinical Trials: Genentech; Honoraria (institution), Clinical Trials: Pfizer; Honoraria (institution), Clinical Trials: Oropharynx Program Stiefel; Honoraria (self): ASCO Career Development; Honoraria (self): MD Anderson Khalifa Award. L.J. Wirth: Advisory/Consultancy: Bayer; Advisory/Consultancy: Blueprint; Advisory/Consultancy: Cue Biopharma; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Merck; Advisory/Consultancy: Rakuten; Advisory/Consultancy: Eisai; Advisory/Consultancy: Lilly. C.P. Rodriguez: Advisory/Consultancy: Cue Biopharma; Speaker Bureau/Expert testimony: Clinical Care Options. B. Xia: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Genentech. C.A. Perez: Advisory/Consultancy: Regeneron; Advisory/Consultancy: Kimera Labs. E. Winquist: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck; Honoraria (self): Roche. S.J. Hotte: Research grant/Funding (institution): Ayala Pharmaceuticals. R. Metcalf: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy: Roche. C. Even: Advisory/Consultancy: Bristol-Myer Squibb; Advisory/Consultancy: Merck Sharpe and Dohme; Advisory/Consultancy: Innate; Advisory/Consultancy: Merck Serono. G.B. Gordon: Shareholder/Stockholder/Stock options, Full/Part-time employment: Ayala Pharmaceuticals; Advisory/Consultancy: Molecular Templates; Advisory/Consultancy: Intellia. G. Gordon: Advisory/Consultancy, Full/Part-time employment: Ayala Pharmaceuticals; Advisory/Consultancy: Agios; Advisory/Consultancy: Heron; Advisory/Consultancy: Jounce; Advisory/Consultancy: Brickell; Advisory/Consultancy: Onkure; Advisory/Consultancy: Aethlon; Advisory/Consultancy: Zenatlis; Advisory/Consultancy: Prevacept. A. Ho: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Ayala Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Bristol Meyer Squibb; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Celldex; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Daichi; Research grant/Funding (institution): Allos; Research grant/Funding (institution): Pfizer; Honoraria (self): Sanofi Genzyme; Honoraria (self): Sun Pharma; Honoraria (self): Regeneron; Research grant/Funding (institution), Travel/Accommodation/Expenses: TRM; Research grant/Funding (institution), Travel/Accommodation/Expenses: Kura; Travel/Accommodation/Expenses: Ignyta; Travel/Accommodation/Expenses: Jansen; Advisory/Consultancy: Curevac; Speaker Bureau/Expert testimony: Medscape. All other authors have declared no conflicts of interest.