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Mini Oral - Head & neck cancer

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)

Date

18 Sep 2020

Session

Mini Oral - Head & neck cancer

Presenters

Renata Ferrarotto

Citation

Annals of Oncology (2020) 31 (suppl_4): S599-S628. 10.1016/annonc/annonc277

Authors

R. Ferrarotto1, L.J. Wirth2, J. Muzaffar3, C.P. Rodriguez4, B. Xia5, C.A. Perez6, D.W. Bowles7, E. Winquist8, S.J. Hotte9, R. Metcalf10, C. Even11, G.B. Gordon12, G. Gordon12, A. Ho13

Author affiliations

  • 1 Thoracic Head And Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 77030 - Houston/US
  • 2 Hematology/oncology, Massachusetts General Hospital, Harvard Medical School, 2114 - Boston/US
  • 3 Department Of Head And Neck-endocrine Oncology, Moffitt Cancer Center, 33612 - Tampa/US
  • 4 Seattle Cancer Care Alliance, Clinical Research Division, University of Washington/Fred Hutchinson Cancer Center, 98109 - Seattle/US
  • 5 Norris Cancer Center, University of Southern California, 90033 - Los Angeles/US
  • 6 Head And Neck Group, Medical Oncology And Hematology, Sylvester Comprehensive Cancer Center, 33136 - Miami/US
  • 7 Division Of Medical Oncology, University of Colorado Cancer Center, 80045 - Aurora/US
  • 8 Department Of Oncology, London Cancer Center, N6A 5W9 - London/CA
  • 9 Oncology, Juravinski Cancer Centre, L8V 5C2 - Hamilton/CA
  • 10 Department Of Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 11 Department De Cancerolgie Cervico-faciale Et Orl, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 12 Clinical, Ayala Pharmaceuticals, 19810 - Wilmington/US
  • 13 Solid Tumor Oncology Division, Head And Neck Service, Memorial Sloan Kettering Cancer Center, 11017 - New York/US
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Resources

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Abstract 919MO

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 Notchmut (AACR ‘19, Abstr 4885). Notchmut 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 Notch1-4mut (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. 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.

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