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首页> 外文期刊>Neuro-Oncology >A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study
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A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study

机译：enzastaurin在小儿难治性原发性中枢神经系统肿瘤患者中的第1期和药代动力学研究：小儿脑肿瘤联合体研究

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摘要

Background. We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies. Methods. Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m~2) and twice daily at 440 mg/m~2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. Results. Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m~2 given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transam-inase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m~2 dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease ＞3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. Conclusion. Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m~2/day administered once daily.
机译：背景。我们试图估计最大耐受或推荐的2期剂量，并描述enzastaurin（一种蛋白激酶Cβ的口服抑制剂）在患有中枢神经系统恶性肿瘤的儿童中的药代动力学和毒性。方法。 Enzastaurin每天以3种剂量水平（260、340和440 mg / m〜2）连续给药一次，每天两次以440 mg / m〜2 / day连续给药。在单剂量和稳定状态下评估血浆药代动力学。评价了外周血单个核细胞中蛋白激酶C和Akt细胞信号转导的抑制作用。在预处理的肿瘤样品中测量Akt途径活性。结果。入组患者33例； 1例不合格，3例早期进展性疾病继发性无价值。在剂量确定阶段没有剂量限制性毒性。每天两次接受440 mg / m〜2的两名参与者经历了3级血小板减少症的剂量限制性毒性，导致疗程2的开始延迟和3级丙氨酸转氨酶升高，在5天内没有恢复。治疗期间没有4级毒性。 enzastaurin的浓度随剂量增加和连续给药而增加；然而，每天一次与每天两次相比，恩扎他汀的440 mg / m〜2剂量水平没有显着差异。没有客观的回应；然而，有11名参与者的疾病稳定时间＞ 3个周期，其中7例患有神经胶质瘤，2例患有室间隔膜瘤，2例患有脑干神经胶质瘤。结论。 Enzastaurin对复发性中枢神经系统恶性肿瘤的儿童具有良好的耐受性，其中最常见的毒性是血尿，疲劳，贫血，血小板减少和恶心。推荐的第2阶段剂量为440 mg / m〜2 /天，每天一次。

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  • 来源
    《Neuro-Oncology》 |2015年第2期|303-311|共9页
  • 作者

    Lindsay B. Kilburn; Mehmet Kocak; Rodney L. Decker; Cynthia Wetmore; Murali Chintagumpala; Jack Su; Stewart Goldman; Anuradha Banerjee; Richard Gilbertson; Maryam Fouladi; Larry Kun; James M. Boyett; Susan M. Blaney;

  • 作者单位

    Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas,Center for Cancer and Blood Disorders, Children's National Medical Center, 111 Michigan Avenue NW, WA, DC 20010;

    Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee,Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee;

    Eli Lilly and Company, Indianapolis, Indiana;

    Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee;

    Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas;

    Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas;

    Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois;

    Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California;

    Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee;

    Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;

    Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee;

    Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee;

    Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas;

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  • 正文语种 eng
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  • 关键词

    brain tumor; enzastaurin; pediatric; pharmacokinetic; phase 1;

    机译：脑肿瘤;enzastaurin;儿科药代动力学阶段1;

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