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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)
Ferrarotto, R. Wirth, L. J. Muzaffar, J. Rodriguez, C. P. Xia, B. Perez, C. A. Bowles, D. W. Winquist, E. Hotte, S. J. Metcalf, Robert
Ferrarotto, R.
Wirth, L. J.
Muzaffar, J.
Rodriguez, C. P.
Xia, B.
Perez, C. A.
Bowles, D. W.
Winquist, E.
Hotte, S. J.
Metcalf, Robert
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Abstract
Background: Notch signaling plays a key role in ACC tumorigenesis. AL101, an
investigational g-secretase inhibitor, blocks Notch signaling and inhibits tumor in ACC
patient-derived xenograft models with Notchmut (AACR ‘19, Abstr 4885). Notchmut are
found in w20% 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 ¼ 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. 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
Description
Date
2020
Publisher
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Keywords
Type
Meetings and Proceedings
Citation
Ferrarotto R, Wirth LJ, Muzaffar J, Rodriguez CP, Xia B, Perez CA, et al. 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). Annals of Oncology. 2020;31:S663-S.