Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors.
Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors.
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DOI：
10.1007/s10637-013-0047-4
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发表时间：
2014-06
影响因子：
3.4
通讯作者：
Stacpoole, P. W.
中科院分区：
文献类型：
--
作者：
Dunbar, E. M.;Coats, B. S.;Shroads, A. L.;Langaee, T.;Lew, A.;Forder, J. R.;Shuster, J. J.;Wagner, D. A.;Stacpoole, P. W.
关键词：
复发性恶性脑肿瘤（RMBTs）预后不良。二氯乙酸（DCA）激活线粒体氧化代谢，并已显示出对几种人类癌症的活性。我们在15名患有复发性WHO III - IV级胶质瘤或中枢神经系统外原发性癌症转移的成人中进行了一项口服DCA的开放标签研究。主要目的是检测治疗4周时RMBT的剂量限制性毒性，定义为任何4级或5级毒性，或直接归因于DCA的3级毒性，基于美国国家癌症研究所的不良事件通用毒性标准，版本4.0。次要目的涉及安全性、耐受性和关于疾病状态的假设生成数据。给药基于谷胱甘肽转移酶zeta 1/马来酰乙酰乙酸异构酶（GSTZ 1/MAAI）的单倍型变异，该酶参与DCA和酪氨酸催化剂。8例患者完成了至少1个4周周期。在此期间，未发生剂量限制性毒性。无患者因对DCA缺乏耐受性而退出，但2例受试者发生0-1级远端感觉异常，导致选择性退出和/或剂量调整。完成至少1个4周周期的所有受试者在此期间保持临床稳定，并保持DCA平均75.5天（范围26-312）。在复发性恶性胶质瘤和其他脑转移性肿瘤患者中，使用针对代谢性疾病确定的剂量范围长期口服DCA是可行的，且耐受性良好。基于遗传的给药的重要性得到证实，并应纳入未来的长期DCA给药试验。
Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.
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影响因子：
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