A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.
A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.
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EZN-3042 是一种新型生存素信使核糖核酸 (mRNA) 拮抗剂，与化疗联合治疗复发性急性淋巴细胞白血病 (ALL) 儿童的 I 期研究：儿童白血病和淋巴瘤 (TACL) 治疗进展报告财团。
DOI：
10.1097/mph.0b013e3182a8f58f
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Carroll WL
中科院分区：
文献类型：
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作者：
Raetz EA;Morrison D;Romanos-Sirakis E;Gaynon P;Sposto R;Bhojwani D;Bostrom BC;Brown P;Eckroth E;Cassar J;Malvar J;Buchbinder A;Carroll WL
为了应对儿童复发性ALL的治疗挑战，一项将Survivin mRNA拮抗剂EZN-3042与再次诱导化疗相结合的1期研究被开发用于B淋巴母细胞白血病骨髓复发或更多的儿童患者。EZN-3042在第-5天和第-2天作为单一药物给药，然后在第8、15、22和29天与4种药物再诱导平台联合使用。对EZN-3042的毒性和生物活性进行了评价。6名患者进入剂量水平1(EZN-3042 2.5 mg/kg/剂量)。观察到两种剂量限制毒性：一名患者出现3级GGT升高，另一名患者出现3级胃肠道出血。单药给药后，Survivin基因和蛋白表达下调，5例资料充足的患者中有2例表达下调。虽然观察到了一些生物活性，但EZN-3042与强化再诱导化疗的结合不能耐受导致Survivin表达持续下调的剂量。在该药物的进一步临床开发停止后，该试验在剂量水平1完成后终止。
To address therapeutic challenges in childhood relapsed ALL, a phase 1 study combining a survivin mRNA antagonist, EZN-3042, with re-induction chemotherapy was developed for pediatric patients with second or greater bone marrow relapses of B lymphoblastic leukemia. EZN-3042 was administered as a single agent on days -5 and -2 and then in combination with a 4-drug re-induction platform on days 8, 15, 22 and 29. Toxicity and the biological activity of EZN-3042 were assessed. Six patients enrolled at dose level 1 (EZN-3042 2.5 mg/kg/dose). Two dose limiting toxicities were observed: one patient developed a grade 3 GGT elevation and another patient developed grade 3 gastrointestinal bleeding. Downmodulation of survivin mRNA and protein was assessed after single agent dosing and decreased expression was observed in 2 of 5 patients with sufficient material for analysis. While some biological activity was observed, the combination of EZN-3042 with intensive re-induction chemotherapy was not tolerated at a dose that led to consistent downregulation of survivin expression. The trial was terminated following the completion of dose level 1, after further clinical development of this agent was halted.