Abstract OT-29-01: Tenacity: A phase 2, multicenter, open-label, single-arm study of AL101 monotherapy in patients with notch-activated triple negative breast cancer
Authors: Traina Tiffany A , Cobain Erin F , Evron Ella , Duksin Chen , Gordon Gary 
Published: February 2021

Abstract
Background: There is an urgent need to identify new therapeutic strategies for triple-negative breast cancer (TNBC), a sub-type associated with poor prognosis. The Notch pathway is activated during mammary gland development and has been implicated as a key driver in breast cancer (Collu, 2007). The frequency of Notch mutations or gene rearrangements was reported at 5 to 16% in TNBC tumors and over-expression of Notch was associated with worse overall survival (Robinson, 2011; Stoeck, 2014; Wang, 2015). AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling. In preclinical models, AL101 exerts its antitumor activity through direct inhibition of cell proliferation and indirectly via inhibition of tumor angiogenesis. In TNBC patient-derived xenograft (PDX) tumor models, the presence of activating Notch mutations/fusions correlated with robust response to AL101 monotherapy (ASCO 2019, Abstr 1064). AL101 has been studied in three Phase 1 studies in more than 200 subjects with various cancers (ASCO 2018, Abstr 2515) and is currently being studied in a Phase 2 study for patients with Adenoid Cystic Carcinoma with Notch activating mutations (ACCURACY- NCT03691207). Preliminary data reported from this trial showed clear signs of clinical activity along with a favorable safety profile (ESMO 2019, Abstr 3568). Trial design: The TENACITY study is an open-label, international, multicenter, single arm Phase 2, Simon two-stage optimal design for targeted therapy study of AL101 monotherapy in subjects with Notch-activated recurrent or metastatic TNBC who have received ≤ 3 lines of prior therapy. Patients with stable, asymptomatic CNS metastases are eligible. Notch activation will be determined by Next Generation Sequencing (NGS) of tumor DNA/RNA to detect somatic mutations and gene rearrangements. Target enrollment is 67 subjects. The design will include a lead-in cohort of 6 subjects to ascertain safety of AL101, 6 mg weekly (QW). After the 6th subject completes 4 weeks of therapy, safety will be assessed and subsequent dosage of AL101 will be determined (continue at 6 mg QW versus reduction to 4 mg QW). The primary endpoint is overall response rate (ORR), based on RECIST v1.1 as assessed by the treating investigator. The study design has 80% power with type I error level of 5% to detect an ORR of 23%. Key Secondary endpoints include progression free survival, clinical benefit rate, duration of response, overall survival and quality of life. Study will open to enrollment in July 2020. For further information on this trial, email chen.d@ayalapharma.com or visit clinicaltrials.gov (NCT04461600).
Citation Format: Tiffany A Traina, Erin F Cobain, Ella Evron, Chen Duksin, Gary Gordon. Tenacity: A phase 2, multicenter, open-label, single-arm study of AL101 monotherapy in patients with notch-activated triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-29-01.