Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T‐cell acute lymphoblastic leukemia and lymphoma

Abstract

BackgroundDeregulated 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.MethodsJJCB 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.ResultsIn 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.ConclusionsCrenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL.

Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

“…Not only do glucocorticoids improve the side effect profile of GSIs, but also the two treatments work synergistically to induce apoptosis of T‐ALL cells, possibly due to increased expression of the glucocorticoid receptor NR3C1 in the presence of the combination 42 . However, a recently reported phase 1 trial using a novel inhibitor of the NOTCH ICD in combination with dexamethasone continued to show dose limiting GI toxicity and limited clinical efficacy 44 . A more recent approach targeting PSEN1 aims to reduce the systemic toxicity associated with GSIs 45 .…”

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

“…However, in a clinical setting, the GSI crenigacestat (LY3039478) plus dexamethasone demonstrated limited clinical activity (which included, however, 1 CR that lasted for 10.51 months) and tolerability in adult patients with relapsed/refractory T-ALL/T-cell lymphoblastic lymphoma, and dexamethasone did not revert completely severe gastrointestinal adverse events that were registered in 16.7% of co-treated patients. The efficacy of Notch1 cleavage reduction varied from 66% in the group receiving 50 mg of crenigacestat to 87% in the group of 100-125 mg, but higher doses did not correspond with a better clinical outcome; moreover, the frequency of Notch1 activating mutations in this study was quite low (NCT02518113) [396]. The results of one more completed phase 1 study evaluating the combination of another GSI BMS-906024 with dexamethasone in patients with T-ALL/T-cell lymphoblastic lymphoma (NCT01363817) are still to be published.…”

“…Indeed, in one study, prednisone co-administration effectively reduced the gastrointestinal toxicity of crenigacestat (LY3039478) in patients with advanced or metastatic cancer, which allowed disease stabilization to be reached in 54.5% and 64.7% of individuals receiving different GSI dose regiments (NCT01695005) [395]. Despite this optimistic evidence, the previously described trial showed that dexamethasone did not help to overcome crenigacestat-related gastrointestinal toxicity that had led to treatment interruption in some responding patients (NCT02518113) [396].…”

Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition

“…estimated completion date is first quarter of 2025. Crenigacestat (formerly LY3039478) is a potent, oral, small molecule GSI that has been shown to inhibit Notch signaling in cell lines representing several different solid tumors and leukemia 101,102 . In a phase 1, open-label dose-escalation study in 110 patients with advanced or metastatic cancer (NCT01695005 103 ), crenigacestat showed evidence of clinical activity in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma with gastrointestinal adverse events (diarrhea and nausea) most frequently reported 104 .…”