A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.
A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.
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DOI：
10.1158/1078-0432.ccr-11-2703
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发表时间：
2012-06-15
期刊：
影响因子：
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通讯作者：
Dezube BJ
中科院分区：
文献类型：
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作者：
Hong DS;Kurzrock R;Supko JG;He X;Naing A;Wheler J;Lawrence D;Eder JP;Meyer CJ;Ferguson DA;Mier J;Konopleva M;Konoplev S;Andreeff M;Kufe D;Lazarus H;Shapiro GI;Dezube BJ
Bardoxolone methyl是一种新型的合成三萜类化合物和抗氧化炎症调节剂，可有效诱导Nrf 2并抑制NF-κB和Janus激活的激酶/STAT信号传导。这项首次人体I期临床试验旨在确定剂量限制性毒性（DLT）、最大耐受剂量（MTD）和II期研究的适当剂量;表征药代动力学和药效学参数;并评估抗肿瘤活性。甲基巴多索龙每天口服给药一次，持续28天周期的21天。采用加速滴定设计，直至发生2级相关不良事件。然后采用标准的3 + 3剂量递增，直至达到MTD。单剂量和稳态血浆药物动力学的药物进行了表征。通过测量NAD（P）H：醌氧化还原酶（NQO 1）mRNA水平，在外周血单核细胞（PBMC）中检查Nrf 2活化的评估。对肿瘤活检组织进行炎症、细胞周期和凋亡标记物的免疫组织化学评估。DLT为3级可逆性肝转氨酶升高。MTD确定为900 mg/d。1例套细胞淋巴瘤患者出现完全肿瘤缓解，1例间变性甲状腺癌患者出现部分缓解。PBMCs中NQO 1 mRNA水平升高，肿瘤活检组织中NF-κB和细胞周期蛋白D1水平降低。估计的肾小球滤过率（eGFR）也增加。甲基巴多索龙耐受性良好，MTD为900 mg/d。eGFR的增加表明甲基bardoxolone可能对慢性肾脏疾病有益。观察到了客观的肿瘤反应和药效学作用，支持了其他合成三萜类化合物在癌症中的持续开发。
Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer.