Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia.
Selinexor 联合柔红霉素和阿糖胞苷治疗先前未治疗的低危急性髓系白血病的 I 期临床试验。

摘要

PURPOSE:Induction chemotherapy results in complete remission (CR) rates of 20% to 50% among patients with poor-risk AML. Selinexor is an oral selective inhibitor of nuclear export with promising single-agent activity. By inhibiting the primary export protein, XPO1, selinexor localizes and activates tumor suppressor proteins in the nucleus and inhibits DNA damage repair, rationalizing combination with DNA-damaging agents.
PATIENTS AND METHODS:This was a single-arm phase I clinical trial of selinexor combined with cytarabine and daunorubicin (7+3). Dose escalation was selinexor alone (3+3) with an expansion at the MTD. Cohorts 1 and 2 received 60 and 80 mg orally, respectively, twice weekly during induction. Consolidation cycles (≤ 2) with selinexor at induction dose plus 5+2 were allowed for patients who achieved CR. MTD and recommended phase II dose of selinexor were the primary endpoints.
RESULTS:Twenty-one patients with poor-risk AML were enrolled. All 21 patients were included in the safety evaluations and survival analyses (4 in each of 2 cohorts; 13 in the expansion); 8 (53%) of the 19 patients evaluable for response achieved CR/CRi. MTD was not reached. Selinexor 80 mg (orally, twice weekly) was used in the expansion phase. The most common grade 3/4 nonhematologic treatment-emergent adverse events were febrile neutropenia (67%), diarrhea (29%), hyponatremia (29%), and sepsis (14%). At median follow-up (28.9 months), 38% of patients were alive. Median overall survival was 10.3 months.
CONCLUSIONS:Selinexor plus 7+3 is a safe regimen for patients with newly diagnosed poor-risk AML and warrants further investigation in a larger clinical trial.

译文

目的: 诱导化疗导致低风险 AML 患者的完全缓解率为 20% 至 50%。Selinexor 是一种口服选择性核出口抑制剂,具有良好的单药活性。通过抑制初级输出蛋白 XPO1,selinexor 定位并激活细胞核中的肿瘤抑制蛋白,抑制 DNA 损伤修复,使与 DNA 损伤剂的结合合理化。
患者和方法: 这是一项 selinexor 联合阿糖胞苷和柔红霉素的单臂 I 期临床试验 (7 3)。剂量增加是单独的 selinexor (3 3),在 MTD 有扩张。队列 1 和 2 分别口服 60 和 80 mg,诱导期间每周两次。对于达到 CR 的患者,允许在诱导剂量加 5 2 时使用 selinexor 的巩固周期 (≤ 2)。MTD 和推荐的 selinexor II 期剂量是主要终点。
结果: 21 例低危 AML 患者被纳入。所有 21 名患者都包括在安全性评估和生存分析中 (2 个队列各 4 名; 扩张 13 名); 8 名 (53%) 在 19 例可评估反应的患者中,达到了 CR/CRi。未达到 MTD。在扩张阶段使用 Selinexor 80 mg (口服,每周两次)。最常见的 3/4 级非血液学治疗出现的不良事件是发热性中性粒细胞减少症 (67%) 、腹泻 (29%) 、低钠血症 (29%) 和败血症 (14%)。在中位随访 (28.9 个月) 时,38% 的患者存活。中位总生存期为 10.3 个月。
结论: 对于新诊断的风险低的 AML 患者,Selinexor plus 7 3 是一种安全的方案,值得在更大的临床试验中进一步研究。

Cytarabine

神经 化学疗法药物 治疗药物
概述  :  

阿糖胞苷是一种化学疗法药物。主要用于急性粒细胞白血病,为首选药;也用于急性淋巴细胞白血病及非淋巴细胞白血病的诱导缓解期及维持巩固期,慢性粒细胞白血病的急变期;对消化道肿瘤及恶性淋巴瘤等也有一定疗效。 结构 作用机理 阿糖胞苷能够干扰DNA的合成,同时也是一种抗代谢物。它能够在人体内被迅速转化为阿糖胞嘧啶三磷酸,其会在细胞周期S期中,抑制DNA多聚酶及少量掺入DNA,而阻止DNA的合成。所

cytarabine   [sai'tærə,bi:n]

释义    n. 阿糖孢苷

例句     Drugs such as methotrexate, cytarabine and hydrocortisone are injected into the spinal fluid to prevent CNS leukemia.甲氨蝶呤、阿糖胞苷和皮质醇等药物被注射到患者的脊髓液中,以预防中枢神经系统白血病的发生。

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