Pitot H C, McElroy E A, Reid J M, Windebank A J, Sloan J A, Erlichman C, Bagniewski P G, Walker D L, Rubin J, Goldberg R M, Adjei A A, Ames M M
Division of Medical Oncology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Clin Cancer Res. 1999 Mar;5(3):525-31.
Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens).
多拉司他汀 -10（dola -10）是一种强效抗有丝分裂肽，从海洋软体动物耳状芋螺中分离得到，可抑制微管蛋白聚合。dola -10的临床前研究已证明其在细胞培养和小鼠模型中对多种小鼠和人类肿瘤具有活性。这项I期临床试验的目的是确定dola -10在晚期实体瘤患者中的最大耐受剂量、药代动力学和生物学效应。采用改良的斐波那契剂量递增方案，每21天静脉推注递增剂量的dola -10。在第一个治疗周期进行药代动力学研究。在使用dola -10治疗前、6周时以及研究结束时对每位患者进行神经学检测。30名符合条件的患者共接受了94个周期（中位数为2个周期；最多为14个周期）的dola -10治疗，剂量范围为65至455微克/平方米。对于预处理较少的患者（先前化疗方案为两个或更少），在剂量为455微克/平方米时出现了粒细胞减少的剂量限制性毒性；对于预处理严重的患者（先前化疗方案超过两个），在剂量为325微克/平方米时出现了该毒性。非血液学毒性一般较轻。药物注射部位的局部刺激较轻，且与剂量无关。9名患者出现了新的或加重的轻度周围感觉神经病变症状，但这并非剂量限制性毒性。这种毒性在已有周围神经病变的患者中更常见。药代动力学研究表明药物分布迅速，血浆消除期延长（t 1/2z = 320分钟）。浓度 - 时间曲线下面积与给药剂量成比例增加，而在所研究的剂量范围内清除率保持恒定。相关性分析表明dola -10浓度 - 时间曲线下面积值与白细胞计数相对于基线的下降之间存在密切关系。总之，每3周静脉推注dola -10耐受性良好，粒细胞减少为剂量限制性毒性。对于先前治疗较少的患者（先前化疗方案为两个或更少），最大耐受剂量（以及推荐的II期起始剂量）为400微克/平方米；对于预处理严重的患者（先前化疗方案超过两个），最大耐受剂量为325微克/平方米。
