Oral Debio 1143 (AT406), an Antagonist of Inhibitor of Apoptosis Proteins, Combined With Daunorubicin and Cytarabine in Patients With Poor-Risk Acute Myeloid Leukemia-Results of a Phase I Dose-Escalation Study
Oral Debio 1143 (AT406), an Antagonist of Inhibitor of Apoptosis Proteins, Combined With Daunorubicin and Cytarabine in Patients With Poor-Risk Acute Myeloid Leukemia-Results of a Phase I Dose-Escalation Study
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DOI：
10.1016/j.clml.2015.02.020
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发表时间：
2015-07-01
影响因子：
2.7
通讯作者：
Zanna, Claudio
中科院分区：
文献类型：
--
作者：
DiPersio, John F.;Erba, Harry P.;Zanna, Claudio
低风险急性髓性白血病（AML）患者接受Debio 1143治疗，口服剂量为5 400 mg，每5周1次，沿着柔红霉素和阿糖胞苷。耐受性是可接受的，并且通过细胞凋亡抑制蛋白1抑制和细胞因子的血浆增加证明了靶向活性。与100毫克的剂量，肿瘤反应略大于“7加3”组合的患者更有利的cytogeneticfactor.Background：治疗急性髓细胞白血病（AML）仍然是困难的，由于治疗耐药性的发展，这可能是克服通过拮抗剂的抑制剂凋亡蛋白（IAP）。患者和方法：目前的多中心、开放标签、剂量递增研究旨在评估Debio 1143（以前称为AT-406）（一种新型IAP拮抗剂）在诱导周期内与柔红霉素和阿糖胞苷的标准“7 + 3方案”沿着给予低风险AML患者时的耐受性、药代动力学（PK）、药效学（PD）和疗效。连续性患者队列在治疗第1 - 5天接受每日一次100、200、300或400 mg口服Debio 1143。定期采集血样，直至记录血液学恢复或缓解。在第0、14和29天采集骨髓样本，分别在第1、3、5、8和10天以及第1、2和8天采集PK和PD样本。结果：在29例入组患者中，23例完成了研究。认为与治疗相关的任何级别的最常见不良事件是恶心（31%的患者）、腹泻（14%）和发热性中性粒细胞减少症（14%）。暴露量超过剂量比例，5天内无蓄积。在CD 34/CD 117（+）细胞和母细胞中可检测到细胞IAP 1的抑制。共有11例患者（38%）达到完全缓解，大多数在100 mg剂量队列中。其中，6例（56%）在研究期间复发。在Debio 1143首次给药后，有反应的患者更频繁地显示出肿瘤坏死因子-a和白细胞介素-8的血浆升高。结论：Debio 1143
Poor-risk patients with acute myeloid leukemia (AML) were treated with Debio1143 at an oral dose of 5 400 mg every 5 weeks, along with daunorubicin and cytarabine. The tolerability was acceptable, and on-target activity was demonstrated by cellular inhibitor of apoptosis protein 1 suppression and plasma increases in cytokines. With the 100-mg dose, the tumor response was slightly greater than for the "7 plus 3" combinations in patients with more favorable cytogenetic factors.Background: Treatment of acute myeloid leukemia (AML) remains difficult owing to the development of treatment resistance, which might be overcome through antagonists of inhibitors of apoptosis proteins (IAPs). Patients and Methods: The present multicenter, open-label, dose-escalation study aimed to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Debio1143 (formerly AT-406), a new IAP antagonist, when given along with a standard "7 plus 3 regimen" of daunorubicin and cytarabine to poor-risk patients with AML during the induction cycle. Consecutive patient cohorts received once-daily 100, 200, 300, or 400 mg of oral Debio1143 on treatment days 1 to 5. Blood samples were collected regularly until hematologic recovery or response was documented. Bone marrow samples were collected on days 0, 14, and 29 and PK and PD samples on days 1, 3, 5, 8, and 10 and 1, 2, and 8, respectively. Results: Of the 29 enrolled patients, 23 completed the study. The most common adverse events of any grade deemed related to treatment were nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). Exposure exceeded dose proportionality, without accumulation over 5 days. Inhibition of cellular IAP1 was detectable in the CD34/CD117(+) cells and blasts. A total of 11 patients (38%) achieved complete remission, most in the 100-mg dose cohort. Of these, 6 (56%) developed a relapse within the study period. The patients with a response more frequently showed plasma increases of tumor necrosis factor-a and interleukin-8 after the first dose of Debio1143. Conclusion: Debio1143