The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy.
Cancer. 2021 Feb 1;127(3):372-380. doi: 10.1002/cncr.33188. Epub 2020 Oct 27.
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.
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.
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.
Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T-ALL/T-LBL.
Notch 信号通路失调与 T 细胞急性淋巴细胞白血病（T-ALL）/T 细胞淋巴母细胞淋巴瘤（T-LBL）有关。Crenigacestat（LY3039478）可阻止 Notch 蛋白的裂解，可能使复发/难治性 T-ALL/T-LBL 患者受益。
JJCB 是一项在成人复发/难治性 T-ALL/T-LBL 患者中开展的、多中心、非随机、开放标签、剂量递增、1 期研究。符合条件的患者接受 Crenigacestat 每周 3 次口服，每 28 天周期中在第 1 天至第 5 天每天 2 次给予 24 mg 地塞米松。Crenigacestat 的起始剂量为 50mg，并采用改良的 3+3 方案进行剂量递增，以评估推荐剂量水平下的剂量限制性毒性（DLT）。
共有 36 例 T-ALL（n=31 [86.1%]）或 T-LBL（n=5 [13.9%]）患者接受 Crenigacestat 和地塞米松治疗。6 例（16.7%）患者发生 DLT：12 例患者中的 2 例（16.7%）在 75mg 组（4 级胃肠道出血和 3 级恶心、呕吐和腹泻），15 例患者中的 1 例（6.7%）在 100mg 组（3 级腹泻），3 例患者中的 3 例（100%）在 125mg 组（3 级腹泻、恶心和呕吐）。最大耐受剂量为 75mg 联合每日 24mg 地塞米松（第 1 天至第 5 天）。28 例（77.8%）患者发生 1 次或多次与研究治疗相关的治疗中出现的不良事件。最佳总体缓解为确认缓解，其中 1 例患者（2.8%）缓解持续时间为 10.51 个月。6 例（16.7%）患者达到疾病稳定，12 例（33.3%）患者发生疾病进展。其余 17 例（47.2%）患者不可评估。所有患者的中位无进展生存期为 1.18 个月（95%置信区间，0.76-2.14 个月）。药效学分析显示，血浆淀粉样β水平降低。
在复发/难治性 T-ALL/T-LBL 成人患者中，Crenigacestat 在推荐剂量下显示出有限的临床活性。
