Hong D S, Henary H, Falchook G S, Naing A, Fu S, Moulder S, Wheler J J, Tsimberidou A, Durand J B, Khan R, Yang P, Johansen M, Newman R A, Kurzrock R
Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 455, Houston, TX, 77030, USA,
Invest New Drugs. 2014 Dec;32(6):1204-12. doi: 10.1007/s10637-014-0127-0. Epub 2014 Jun 13.
PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the α-3 subunit of Na-K ATPase, as well as FGF-2 export, Akt and p70S6K, hence attenuating mTOR activity. This first-in-human study determined the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in patients with advanced cancer. Methods Forty-six patients received PBI-05204 by mouth for 21 of 28 days (3 + 3 trial design). Dose was escalated 100% using an accelerated titration design until grade 2 toxicity was observed. Plasma PK and mTOR effector (p70S6K and pS6) protein expressions were evaluated. Results Dose-limiting toxicities (grade 3 proteinuria, fatigue) were observed at dose level 8 (0.3383 mg/kg/day). Common possible drug-related adverse were fatigue (26 patients, 56.5%), nausea (19 patients, 41.3%) and diarrhea (15 patients, 32.6 %). Electrocardiogram monitoring revealed grade 1 atrioventricular block (N = 10 patients) and grade 2 supraventricular tachycardia (N = 1). The MTD was DL7 (0.2255 mg/kg) where no toxicity of grade ≥ 3 was observed in seven patients treated. Seven patients (15%) had stable disease > 4 months. Mean peak oleandrin concentrations up to 2 ng/mL were achieved, with area under the curves 6.6 to 25.5 μg/L*hr and a half-life range of 5-13 h. There was an average 10% and 35% reduction in the phosphorylation of Akt and pS6 in PBMC samples in 36 and 32 patients, respectively, tested between predose and 21 days of treatment. Conclusions PBI-05204 was well tolerated in heavily pretreated patients with advanced solid tumors. The recommended Phase II dose is 0.2255 mg/kg/day.
PBI-05204是一种夹竹桃提取物（NOE），含有强心苷欧夹竹桃苷，可抑制钠钾ATP酶的α-3亚基以及成纤维细胞生长因子-2（FGF-2）的输出、Akt和p70S6K，从而减弱雷帕霉素靶蛋白（mTOR）的活性。这项首次人体研究确定了PBI-05204在晚期癌症患者中的安全性、药代动力学（PK）和药效学（PD）。方法46例患者口服PBI-05204，疗程28天中的21天（3+3试验设计）。采用加速滴定设计将剂量提高100%，直至观察到2级毒性。评估血浆PK和mTOR效应物（p70S6K和pS6）蛋白表达。结果在剂量水平8（0.3383mg/kg/天）观察到剂量限制性毒性（3级蛋白尿、疲劳）。常见的可能与药物相关的不良反应为疲劳（26例患者，56.5%）、恶心（19例患者，41.3%）和腹泻（15例患者，32.6%）。心电图监测显示1级房室传导阻滞（N=10例患者）和2级室上性心动过速（N=1例）。最大耐受剂量（MTD）为DL7（0.2255mg/kg），接受治疗的7例患者未观察到≥3级毒性。7例患者（15%）疾病稳定超过4个月。平均最高欧夹竹桃苷浓度达到2ng/mL，曲线下面积为6.6至25.5μg/L*小时，半衰期范围为5至13小时。在36例和32例患者中，分别在给药前和治疗21天时检测外周血单核细胞（PBMC）样本，Akt和pS6磷酸化水平平均分别降低了10%和35%。结论PBI-05204在经过大量预处理的晚期实体瘤患者中耐受性良好。推荐的II期剂量为0.2255mg/kg/天。
