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), n | 18 |
Screen failures, n | 6 |
Treated, n | 12 |
Median number of cycles, n | 1.5 |
Gender, n | |
Male Female | 8 4 |
Median age, years | 56.5 |
Race, n | |
White Black Asian Other Not Reported N/A | 6 1 0 1 2 2 |
ECOG performance status, n | |
0 1 N/A | 6 4 2 |
Disease status, n | |
With nodal or visceral metastases With bone-exclusive metastases | 10 2 |
Type of mutations, n | |
In the NRR region In the PEST domain In the NRR and PEST regions | 3 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.
Resources from the same session
1291 - PD-L1 expression in uncommon EGFR-mutant non-small cell lung cancer and its response to immunotherapy
Presenter: Yun Fan
Session: Poster Display session 3
Resources:
Abstract
2171 - CCND1 Amplification Contributes to Immunosuppression in Head and Neck Squamous Cell Carcinoma and the Association with a Poor Response to Immune Checkpoint Inhibitors
Presenter: Chloe Huang
Session: Poster Display session 3
Resources:
Abstract
2624 - Efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer patients with sensitive genes mutation
Presenter: Hui-Juan Cui
Session: Poster Display session 3
Resources:
Abstract
3494 - Neutrophil to Lymphocyte Ratio (NLR) kinetics as predictors of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (NSCLC) patients treated with nivolumab (N).
Presenter: Audrey Simonaggio
Session: Poster Display session 3
Resources:
Abstract
3964 - Predictive markers of checkpoint inhibitor activity in adult metastatic solid tumours
Presenter: Alexandra Pender
Session: Poster Display session 3
Resources:
Abstract
3041 - Blood-based TMB (bTMB) correlates with tissue-based TMB (tTMB) in a multi-cancer Phase I IO Cohort
Presenter: Daniel Araujo
Session: Poster Display session 3
Resources:
Abstract
3910 - Analysis of Molecular Profile Complexities for Immunotherapy Decision Support
Presenter: Robert Dóczi
Session: Poster Display session 3
Resources:
Abstract
4836 - The Role of Tumor Neoantigens in the Differential Response to Immunotherapy (IO) in EGFR and BRAF Mutated Lung Cancers - Quantity or Quality?
Presenter: Katrina Case
Session: Poster Display session 3
Resources:
Abstract
1929 - Impact of previous corticosteroid (CS) exposure on efficacy of Programmed Cell Death-(Ligand) 1 blockade in patients with advanced Non-Small-Cell Lung Cancer (NSCLC): a single Center retrospective analysis
Presenter: Fabrizio Nelli
Session: Poster Display session 3
Resources:
Abstract
2601 - Comparison 18F-FDG-PET/CT criteria for prediction of therapy response and clinical outcome in patients with metastatic melanoma treated with Ipilimumab and PD-1 inhibitors
Presenter: Sabrina Vari
Session: Poster Display session 3
Resources:
Abstract