Phase I clinical and pharmacokinetic study of Kahalalide F in patients with advanced androgen refractory prostate cancer
Phase I clinical and pharmacokinetic study of Kahalalide F in patients with advanced androgen refractory prostate cancer
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DOI：
10.1158/1078-0432.ccr-04-1534
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发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Schellens, JHM
中科院分区：
文献类型：
--
作者：
Rademaker-Lakhai, JM;Horenblas, S;Schellens, JHM
目的：目的是确定卡哈拉利特F（KF）在雄激素难治性前列腺癌患者中的最大耐受剂量、不良事件特征和剂量限制性毒性。此外，评价了KIT给药后的药代动力学和初步抗肿瘤活性。KF是从海洋食草性软体动物Elysia rufescens.Experimental Design中分离的含脱氢氨基丁酸的肽，患有晚期或转移性雄激素难治性前列腺癌的成人患者接受KIT作为静脉输注超过1小时，每3周连续5天。起始剂量为20 μ g/m2/天。采用非房室模型对所有患者进行临床药代动力学研究。前列腺特异性抗原水平被评估为抗前列腺癌活性的替代标志物。结果：32名患者接受了9个剂量水平（每天20-930微克/平方米）的治疗。最大耐受剂量为930 μ g/m2/天。剂量限制性毒性是可逆的，无症状的通用毒性标准3级和4级转氨酶升高。11期研究的推荐剂量为每天560 μ g/m2。药代动力学分析显示，在推荐剂量范围内呈剂量线性。此后，观察到了超过比例的增加。消除迅速，平均（SD）终末半衰期（t（1/2））为0.47小时（0.11小时）。1例患者在80 μ g/m2/天剂量水平下出现部分应答，前列腺特异性抗原下降至少50%，持续时间大于或等于4周。5名患者病情稳定。结论：KF可以安全地连续5天静脉输注1小时，剂量为每天560 μ g/m（2），每3周1次。
Purpose: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KIT administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid-containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens.Experimental Design: Adult patients with advanced or metastatic androgen refractory prostate cancer received KIT as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 mug per m(2) per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer.Results: Thirty-two patients were treated at nine dose levels (20-930 mug per m(2) per day). The maximum tolerated dose on this schedule was 930 mug per m(2) per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase 11 studies is 560 mug per m 2 per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t(1/2)) of 0.47 hour (0.11 hour). One patient at dose level 80 mug per m(2) per day had a partial response with a prostate-specific antigen decline by at least 50% for greater than or equal to4 weeks. Five patients showed stable disease.Conclusions: KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 mug per m(2) per day once every 3 weeks.