Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.
Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.
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DOI：
10.2147/ott.s136992
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发表时间：
2017
影响因子：
4
通讯作者：
Antonia SJ
中科院分区：
文献类型：
--
作者：
Creelan BC;Gabrilovich DI;Gray JE;Williams CC;Tanvetyanon T;Haura EB;Weber JS;Gibney GT;Markowitz J;Proksch JW;Reisman SA;McKee MD;Chin MP;Meyer CJ;Antonia SJ
Omaveloxolone 是一种半合成齐墩果烷三萜类化合物，可有效激活 Nrf2 并随后发挥抗氧化功能。我们进行了首次人体 I 期临床试验 (NCT02029729)，主要目标是确定 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。对于患有 4 期复发/难治性黑色素瘤或非小细胞肺癌的患者，在 28 天的周期中每天连续口服一次 Omaveloxolone。采用加速滴定设计直至发生 2 级相关不良事件 (AE)。采用标准的3+3剂量递增。对该药物的单剂量和稳态血浆药代动力学进行了表征。通过量化靶基因 mRNA 表达来评估外周血单核细胞中下游 Nrf2 的激活。奥马维洛酮以四种剂量水平进行了测试，最高为 15 毫克，每天口服一次。未检测到剂量限制性毒性，且未确定最大耐受剂量。所有与药物相关的 AE 的严重程度均为 1 级或 2 级，且无需采取临床行动。最常见的药物相关不良事件是碱性磷酸酶升高（18%）和贫血（18%）。不需要中断或减少药物。奥马维洛酮被迅速吸收，并且在不同剂量水平下暴露量呈比例增加。除了一些例外，观察到 Nrf2 抗氧化基因的激活呈时间依赖性和剂量依赖性的总体趋势。尽管一名肺癌受试者的病情稳定超过一年，但未观察到确诊的放射学反应。奥马维洛酮在生物活性剂量下具有良好的耐受性，尽管该试验的样本量较小，限制了明确的结论。这些发现支持进一步研究 omaveloxolone 在癌症中的作用。
Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.