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Poster Display session 3

3568 - ACCURACY a phase (P) 2 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.

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Tumour Site

Head and Neck Cancers

Presenters

Renata Ferrarotto

Citation

Annals of Oncology (2019) 30 (suppl_5): v449-v474. 10.1093/annonc/mdz252

Authors

R. Ferrarotto1, A. Ho2, L.J. Wirth3, J. Muzaffar4, C. Rodriguez5, E. Dekel6, R.M. Walker7, C. Nadri-Shay8, A. Vergara-Silva9

Author affiliations

  • 1 Thoracic Head And Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 2 Solid Tumor Oncology Division, Head And Neck Service, Memorial Sloan Kettering Cancer Center, New York/US
  • 3 Hematology/oncology, Massachusetts General Hospital Cancer Center, Harvard University, Boston/US
  • 4 Head And Neck And Endocrine Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa/US
  • 5 Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle/US
  • 6 Clinical Operations, Ayala Pharmaceuticals, Inc., Wilmington/US
  • 7 Biomarkers And Companion Diagnostics, Ayala Pharmaceuticals, Inc., Wilmington/US
  • 8 Regulatory Affairs, Ayala Pharmaceuticals, Inc., Wilmington/US
  • 9 Medical Affairs, Ayala Pharmaceuticals, Inc., Wilmington/US

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Abstract 3568

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 mg 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 mg 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 ≥ 2 pts respond, 24 additional pts are enrolled in stage 2. If ≥ 6 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), n18
Screen failures, n6
Treated, n12
Median number of cycles, n1.5
Gender, n
Male Female8 4
Median age, years56.5
Race, n
White Black Asian Other Not Reported N/A6 1 0 1 2 2
ECOG performance status, n
0 1 N/A6 4 2
Disease status, n
With nodal or visceral metastases With bone-exclusive metastases10 2
Type of mutations, n
In the NRR region In the PEST domain In the NRR and PEST regions3 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 ≥ 2 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.

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