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
2115 - Preclinical in vivo screening to predict responder patients depend on EGFR status
Presenter: Yejin Kim
Session: Poster Display session 3
Resources:
Abstract
3349 - Interplay between miR-17-5p and MALAT-1 Shapes The Cytokine Storm in Triple Negative Breast Cancer (TNBC) Tumor Microenvironment
Presenter: Raghda Soliman
Session: Poster Display session 3
Resources:
Abstract
4014 - Clinical verification on the relationship between lipid metabolism and the immune microenvironment of breast cancer
Presenter: Wataru Goto
Session: Poster Display session 3
Resources:
Abstract
4158 - The clinical and transcriptional signatures of human CD204 reveal an applicable marker for tumor associated macrophage in breast cancer
Presenter: Yunjie He
Session: Poster Display session 3
Resources:
Abstract
5392 - Activated effector T cells co-expressing multiple inhibitory receptors (IRs) are enriched in the tumor immune microenvironment in high grade serous ovarian cancer (HGSOC)
Presenter: Alice Bergamini
Session: Poster Display session 3
Resources:
Abstract
2617 - Oncolytic reovirus as a new anti-tumor strategy in castration resistant prostate cancer
Presenter: Yunlim Kim
Session: Poster Display session 3
Resources:
Abstract
2995 - Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21
Presenter: Ali Memarian
Session: Poster Display session 3
Resources:
Abstract
3597 - Myeloid derived suppressor cells but not regulatory T cells are associated with adaptive immunity and clinical outcomes in anal squamous cell carcinoma
Presenter: Christophe Borg
Session: Poster Display session 3
Resources:
Abstract
3430 - Evaluation of immune responses among responders (R) and non-responders (non-R) in a humanized mouse model with colorectal cancer (CRC) xenografts treated with combination immunotherapy
Presenter: Juan Marín Jiménez
Session: Poster Display session 3
Resources:
Abstract
1995 - ¬¬Advanced melanoma patients with high CD16+ macrophages have better response and survival to anti-PD-1 based immunotherapy
Presenter: Hansol Lee
Session: Poster Display session 3
Resources:
Abstract