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Background: Deregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL. Methods: JJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level. Results: In total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels. Conclusions: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL. This report describes the clinical activity of a highly potent and selective Notch inhibitor, Crenigacestat, in combination with dexamethasone in adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (‐LBL). In this study, the recommended phase 2 dose of 75 mg of Crenigacestat 3 times per week is established for patients with T‐ALL/T‐LBL in combination with dexamethasone. [ABSTRACT FROM AUTHOR]