Abstract 904P
Background
Notch signaling plays a key role in ACC tumorigenesis. Notchmut are found in ∼20% of ACC tumors, which are aggressive with a poor prognosis (Ferrarotto 2016, Ho 2019). No therapies are approved for R/M ACC. AL101, an investigational γ-secretase inhibitor, blocks Notch signaling and inhibits tumors in ACC patient-derived xenograft models with Notchmut (AACR ‘19, Abstr 4885). AL101 has clinical activity at 4 mg once weekly (QW) with a disease control rate of 68% (15% partial response) and appears to be well tolerated (Ferrarotto ESMO ‘20, #919MO). Based on the safety and activity in the 4-mg cohort, a cohort of 42 additional subjects was added to evaluate treatment with 6 mg QW.
Methods
ACCURACY is an open-label, multicenter phase II study of AL101 (4 and 6 mg intravenous QW) in subjects with R/M ACC and 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 performance status of 0-1. Primary end point was overall response rate (ORR) by RECIST v1.1 (or modified MD Anderson bone criteria), as assessed by investigators. Secondary end points were ORR by central review, duration of response, and safety. The study provides ≥80% power to detect an increase of the ORR from 8% to 25% using a type I error of 5%.
Results
A total of 37 subjects were enrolled in the 6-mg QW cohort. Table: 904P
Disposition and baseline characteristics of subjects treated with AL101a
| 4 mg QW | 6 mg QW | |
| Treated, n | 45 | 37 |
| Gender, n (%) Male Female | 20 (44) 25 (56) | 21 (57) 16 (43) |
| Median age, years | 50 | 59 |
| Race, n (%) White Black Asian Other/not reported | 31 (69) 4 (9) 2 (4) 8 (18) | 28 (76) 2 (5) 1 (3) 6 (16) |
| Prior systemic therapy, n (%) | 27 (60) | 19 (51) |
| Disease status at screening, n (%)b Metastatic Local recurrence Treatment naïve and metastatic | 42 (93) 15 (33) 4 (9) | 31 (84) 10 (27) 5 (14) |
| Most common sites of metastases, n (%)b Lung Bone Liver | 22 (49) 13 (29) 8 (18) | 20 (54) 12 (32) 11 (30) |
QW=once weekly. aData cutoff April 9, 2021. bSubjects may select more than 1 category.
Most common (≥20%) treatment-related adverse events of all grades in the 6-mg cohort were diarrhea (73%; grade 3 (gr3) 11%), fatigue (49%; gr3 5%), nausea (41%; gr3 3%), hypophosphatemia (27%; gr3 0%), vomiting (27%; gr3 0%), decreased appetite (22%; gr3 3%), and rash (22%; gr3 0%).
Conclusions
AL101 6 mg QW appears to be well tolerated in Notchmut R/M ACC. Efficacy and pharmacokinetic data will be presented. Accrual and follow-up to the 6-mg cohort is ongoing.
Clinical trial identification
NCT03691207; EudraCT 2019-000309-64.
Editorial acknowledgement
Editorial assistance was provided by Emily Cullinan, PhD, CMPP, and Francesca Balordi, PhD, of The Lockwood Group (Stamford, CT, USA), funded by Ayala Pharmaceuticals.
Legal entity responsible for the study
Ayala Pharmaceuticals, Inc.
Funding
Ayala Pharmaceuticals, Inc.
Disclosure
A.L. Ho: Financial Interests, Personal and Institutional, Funding, Clinical Trial: Ayala Pharmaceuticals; Financial Interests, Personal and Institutional, Advisory Board: Ayala Pharmaceuticals; Financial Interests, Personal and Institutional, Advisory Board: Rgenta Therapeutics; Financial Interests, Personal and Institutional, Stocks/Shares: Rgenta Therapeutics; Financial Interests, Personal and Institutional, Other, data safety monitor board : Affyimmune Therapeutics; Financial Interests, Personal and Institutional, Advisory Board: Exelixis; Financial Interests, Personal and Institutional, Advisory Board: Prelude Therapeutics; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Merck; Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Novartis; Financial Interests, Personal and Institutional, Advisory Board: Novartis; Financial Interests, Personal and Institutional, Speaker’s Bureau: Novartis; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Eisai; Financial Interests, Personal and Institutional, Advisory Board: Eisai; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Funding, Clinical Trial: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Genentech/Roche; Financial Interests, Personal and Institutional, Other, Consulting fees: Genentech/Roche; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Celldex Therapeutics; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Bayer; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Eli Lilly and Company; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Astellas Pharma; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Daiichi Sankyo; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Allos Therapeutics; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Pfizer; Financial Interests, Personal and Institutional, Advisory Board: Sanofi Genzyme; Financial Interests, Personal and Institutional, Advisory Board: Sun Pharma; Financial Interests, Personal and Institutional, Advisory Board: Regeneron; Financial Interests, Personal and Institutional, Advisory Board: TRM Oncology; Financial Interests, Personal and Institutional, Funding, Clinical Trial: Kura Oncology; Financial Interests, Personal and Institutional, Other, Travel/Congress Fees: Kura Oncology; Financial Interests, Personal and Institutional, Other, Travel/Congress Fees: Ignyta; Financial Interests, Personal and Institutional, Other, Travel/Accommodation support : Janssen; Financial Interests, Personal and Institutional, Other, Consulting fees: CureVac; Financial Interests, Personal and Institutional, Invited Speaker: Medscape. C. Even: Financial Interests, Personal and Institutional, Other, Advisor: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Other, Advisor: Merck Sharp & Dohme; Financial Interests, Personal and Institutional, Other, Advisor: Innate Pharma; Financial Interests, Personal and Institutional, Other, Advisor: Merck Serono. D. Hao: Financial Interests, Personal and Institutional, Other, Honoraria: Bayer; Financial Interests, Personal and Institutional, Other, Honoraria: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Other, Honoraria: LeoPharma; Financial Interests, Personal and Institutional, Other, Honoraria: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Purdue Pharma; Financial Interests, Institutional, Research Grant: Takeda. H. Kang: Financial Interests, Personal and Institutional, Advisory Board: Exelixis; Financial Interests, Personal and Institutional, Advisory Board: Achilles Therapeutics; Financial Interests, Personal and Institutional, Advisory Board: Bayer; Financial Interests, Personal and Institutional, Advisory Board: MitoImmune Therapeutics; Financial Interests, Personal and Institutional, Other, Consulting Fees: Pin Therapeutics. R. Metcalf: Financial Interests, Personal and Institutional, Other, Consultancy: AstraZeneca; Financial Interests, Personal and Institutional, Other, Travel Grant: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Other, Consultancy: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Other, Consultancy: Bayer; Financial Interests, Personal and Institutional, Other, Consultancy: Roche. M. Oliva: Financial Interests, Personal and Institutional, Invited Speaker: Merck; Financial Interests, Personal and Institutional, Other, Personal Fees: Merck; Financial Interests, Personal and Institutional, Invited Speaker: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Other, Personal Fees: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Personal and Institutional, Other, Personal Fees: MSD. C.A. Perez: Financial Interests, Personal and Institutional, Advisory Board: Regeneron Pharmaceuticals, In ; Financial Interests, Personal and Institutional, Advisory Board: Kimera Labs Inc. C.P. Rodriguez: Financial Interests, Personal and Institutional, Advisory Board: Cue Biopharma; Financial Interests, Personal and Institutional, Invited Speaker: Clinical Care Options Ltd. C.M. Van Herpen: Financial Interests, Personal and Institutional, Other, Consultancy: Bayer; Financial Interests, Personal and Institutional, Other, Consultancy: Bristol-Myers Squibb; Financial Interests, Personal and Institutional, Other, Consultancy: Ipsen Pharma; Financial Interests, Personal and Institutional, Other, Consultancy: MSD. E. Winquist: Financial Interests, Personal and Institutional, Advisory Board: Amgen; Financial Interests, Personal and Institutional, Advisory Board: Bayer; Financial Interests, Personal and Institutional, Advisory Board: Eisai; Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Advisory Board: Roche; Financial Interests, Personal and Institutional, Invited Speaker: Ayala; Financial Interests, Institutional, Funding, Clinical Trial: Canadian Cancer Trials Group; Financial Interests, Institutional, Funding, Clinical Trial: Eisai; Financial Interests, Institutional, Funding, Clinical Trial: GlaxoSmithKline; Financial Interests, Institutional, Funding, Clinical Trial: Merck; Financial Interests, Institutional, Funding, Clinical Trial: Roche; Financial Interests, Personal and Institutional, Research Grant: Eisai. L.J. Wirth: Financial Interests, Personal and Institutional, Advisory Board: Bayer; Financial Interests, Personal and Institutional, Advisory Board: Blueprint Medicines; Financial Interests, Personal and Institutional, Advisory Board: Cue Biopharma; Financial Interests, Personal and Institutional, Advisory Board: Exelixis; Financial Interests, Personal and Institutional, Advisory Board: Genentech; Financial Interests, Personal and Institutional, Advisory Board: Loxo Oncology; Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Advisory Board: Rakuten Medical; Financial Interests, Personal and Institutional, Advisory Board: Eisai; Financial Interests, Personal and Institutional, Other, Consultancy: Eisai; Financial Interests, Personal and Institutional, Advisory Board: Lilly; Financial Interests, Personal and Institutional, Other, Consultancy: Lilly. F.P. Worden: Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Advisory Board: Exelexis; Financial Interests, Personal and Institutional, Advisory Board: Eli Lilly; Financial Interests, Personal and Institutional, Advisory Board: CUE BioPharma; Financial Interests, Personal and Institutional, Advisory Board: Eisai. G. Gordon: Financial Interests, Personal and Institutional, Other, Consultant: Ayala Pharmaceuticals; Financial Interests, Personal and Institutional, Other, Consultant: Edgewise Therapeutics; Financial Interests, Personal and Institutional, Other, Consultant: Jounce Therapeutics; Financial Interests, Personal and Institutional, Other, Consultant: OnKure Therapeutics; Financial Interests, Personal and Institutional, Other, Consultant: Rubius Therapeutics; Financial Interests, Personal and Institutional, Other, Consultant: Zentalis Pharmaceuticals. G.B. Gordon: Financial Interests, Personal and Institutional, Full or part-time Employment: Ayala Pharmaceuticals; Financial Interests, Personal and Institutional, Stocks/Shares: Ayala Pharmaceuticals. R. Ferrarotto: Financial Interests, Personal and Institutional, Other, Personal Fees: Regeneron-Sanofi; Financial Interests, Personal and Institutional, Other, Personal Fees: Ayala Pharmaceuticals; Financial Interests, Personal and Institutional, Other, Personal Fees: KLUS Pharma; Financial Interests, Personal and Institutional, Other, Personal Fees: Medscape; Financial Interests, Personal and Institutional, Other, Personal Fees: Carevive Systems; Financial Interests, Personal and Institutional, Other, Personal Fees: Prelude Therapeutics; Financial Interests, Personal and Institutional, Other, Personal Fees: Bicara Therapeutics; Financial Interests, Personal and Institutional, Other, Personal Fees: Intellisphere; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Merck; Financial Interests, Personal and Institutional, Research Grant: Genentech; Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal and Institutional, Research Grant: Oropharynx Program Stiefel; Financial Interests, Personal and Institutional, Research Grant: ASCO Career Development Award; Financial Interests, Personal and Institutional, Research Grant: MD Anderson Khalifa Award. All other authors have declared no conflicts of interest.