Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer
Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer
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DOI：
10.1093/annonc/mdl010
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发表时间：
2006-05-01
影响因子：
50.5
通讯作者：
Bukowski, RM
中科院分区：
文献类型：
--
作者：
Choueiri, TK;Mekhail, T;Bukowski, RM
背景：苯氧二醇是一种多途径凋亡引发剂，具有广泛的抗肿瘤活性和对肿瘤细胞的高度特异性。其生化作用特别适合逆转化疗耐药性，该药物正在被开发为实体癌标准化疗药物的化疗增敏剂。这项 I 期单中心试验旨在测试晚期实体瘤患者的连续静脉给药方案，以确定毒性、药代动力学和初步疗效。方法：以 14 天为一个周期，连续静脉输注 7 天，按患者间剂量递增，剂量为 0.65、1.3、3.3、20.0 和 27.0毫克/公斤/天（每层三至四名患者）。治疗周期持续直至疾病进展。毒性基于标准标准；疗效基于肿瘤负荷的变化（WHO）；在治疗周期的特定时间点对血浆样本进行药代动力学分析。结果：19 名接受过深度治疗的实体瘤患者平均接受了 3 个周期的治疗（范围 1-13）；两名患者接受了 >= 12 个周期。没有遇到剂量限制性毒性，呕吐和疲劳（一名患者）和皮疹（一名患者）是唯一显着的毒性。疾病稳定是最好的疗效结果，一名患者在 24 周时表现出疾病稳定。药代动力学表明，苯氧二醇的剂量和平均稳态血浆浓度之间存在线性关系。 结论：每 2 周连续输注 7 天的苯氧二醇，最高剂量为 27.0 mg/kg/天，耐受性良好。
Background: Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy.Methods: Phenoxodiol given by intravenous infusion continuously for 7 days on 14-day cycles was dose-escalated on an inter-patient basis at dosages of 0.65,1.3, 3.3, 20.0, and 27.0 mg/kg/day (three to four patients per stratum). Treatment cycles continued until disease progression. Toxicity was based on standard criteria; efficacy was based on changes in tumor burden (WHO); pharmacokinetic analysis was conducted on plasma samples at specified time points during treatment cycles.Results: Nineteen heavily-pre-treated patients with solid tumors received a median of three cycles of treatment (range 1-13); two patients received >= 12 cycles. No dose-limiting toxicities were encountered, with emesis and fatigue (one patient) and rash (one patient) the only significant toxicities. Stabilized disease was the best efficacy outcome, with one patient showing stable disease at 24 weeks. Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol.Conclusion: A 7-day continuous infusion of phenoxodiol given every 2 weeks is well tolerated up to a dose of 27.0 mg/kg/day.