评估 Crenigacestat（LY3039478）联合地塞米松治疗 T 细胞急性淋巴细胞白血病和淋巴瘤患者的 1 期研究。
Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T-cell acute lymphoblastic leukemia and lymphoma.
机构信息
The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy.
出版信息
Cancer. 2021 Feb 1;127(3):372-380. doi: 10.1002/cncr.33188. Epub 2020 Oct 27.
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.
背景
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。
方法
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）。
结果
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。
结论
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。
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