Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma

• DOI: 10.1007/s10637-019-00739-x
• Publication Date: 2019-04-07T00:47:43Z
• Authors: C. Even; U. Lassen; J. Merchan; C. Le Tourneau; J-C Soria; C. Ferte; F. Ricci; J. T. Diener; E. Yuen; C. Smith; G. J. Oakley; K. A. Benhadji; Christophe Massard
• Keywords: Discontinuation; Adenoid Cystic Carcinoma

Summary Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral inhibitor, an expansion cohort patients with adenoid cystic carcinoma (ACC) who received dose-escalation-recommended 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, baseline tumor tissue were enrolled. Primary objectives to identify safe RP2D, confirm this cohorts, document activity. Secondary included progression-free survival (PFS). ACC RP2D regimen 50 mg thrice per week 28-day cycle until disease progression other discontinuation criteria met. Results Twenty-two enrolled (median age 60 years). Median treatment duration was 3 cycles 6 remaining on treatment. There no objective responses; 1 (5%) patient had unconfirmed partial response. Disease control rate 73% 4 stable ≥6 months. PFS 5.3 months (95%CI: 2.4-NE)) for 22 patients; 7.7 4.0-NR) 2.4 1.1-NE) subgroup second-line ( n = 7) ≥ third-line 9), respectively. Frequent treatment-related-adverse events (all grades) diarrhea, fatigue, vomiting, decreased appetite, dry mouth, skin. new signals. Conclusion induced manageable toxicity limited clinical activity, without confirmed responses, heavily pretreated ACC.