Erlichman C, Moore M, Kerr I G, Wong B, Eisenhauer E, Zee B, Whitfield L R
Department of Medicine, Princess Margaret Hospital, University of Toronto, Ontario, Canada.
Cancer Res. 1991 Dec 1;51(23 Pt 1):6317-22.
We performed a phase I trial of CI-937 (DUP937), an anthrapyrazole, with the following objectives: (a) to determine the maximally tolerated dose in humans; (b) to define the toxicity spectrum of this agent; (c) to describe the pharmacokinetics of the drug; (d) to test a pharmacokinetics based hypothesis of dose escalation; and (e) to relate drug pharmacokinetics to pharmacodynamics. CI-937 was administered as a single bolus injection every 3-4 weeks at doses ranging from 3.6 to 25.2 mg/m2. Thirty-two patients and 57 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 30 patients on the first course using a sensitive and selective radioimmunoassay. The maximally tolerated dose in patients with no prior therapy was 25.2 mg/m2 and dose-limiting toxicity was neutropenia. Thrombocytopenia, nausea, vomiting, stomatitis, and alopecia were mild. A partial response was recorded in a patient with mesothelioma. The area under the curve increased linearly with dose, and total body clearance of CI-937 was independent of dose. The mean total body clearance was 107 +/- 55.8 ml/min/m2, mean steady state volume of distribution was 492 +/- 469 liters/m2, and terminal half-life was 3.78 +/- 2.86 days. The extended factors of 2 methods of pharmacologically guided dose escalation were intended for use but ultimately were equivalent to that of the modified Fibonacci dose escalation method. Dose and the area under the curve were significant predictors of a percentage change in WBC and neutrophil count in a univariate analysis. Only dose and baseline neutrophil count predicted a percentage change in WBCs in a multifactor analysis. Dose and prior chemotherapy predicted percentage change in neutrophil count in a multifactor analysis. We conclude that the dose-limiting toxicity of CI-937 is neutropenia and that the recommended phase II starting dose is 22 mg/m2.
我们开展了一项关于蒽吡唑类药物CI-937（DUP937）的I期试验，目标如下：（a）确定人体最大耐受剂量；（b）明确该药物的毒性谱；（c）描述药物的药代动力学；（d）检验基于药代动力学的剂量递增假说；（e）将药物药代动力学与药效动力学相关联。CI-937每3 - 4周静脉推注一次，剂量范围为3.6至25.2 mg/m²。32例患者共接受了57个疗程的治疗，可进行毒性评估。在首个疗程中，对30例患者使用灵敏且具选择性的放射免疫分析法进行药代动力学分析。未接受过前期治疗的患者最大耐受剂量为25.2 mg/m²，剂量限制性毒性为中性粒细胞减少。血小板减少、恶心、呕吐、口腔炎和脱发症状较轻。一名间皮瘤患者出现部分缓解。曲线下面积随剂量呈线性增加，CI-937的全身清除率与剂量无关。平均全身清除率为107±55.8 ml/min/m²，平均稳态分布容积为492±469升/m²，终末半衰期为3.78±2.86天。原本打算使用两种药理指导剂量递增方法的扩展系数，但最终与改良斐波那契剂量递增方法等效。在单因素分析中，剂量和曲线下面积是白细胞和中性粒细胞计数百分比变化的显著预测指标。在多因素分析中，只有剂量和基线中性粒细胞计数可预测白细胞的百分比变化。在多因素分析中，剂量和既往化疗可预测中性粒细胞计数的百分比变化。我们得出结论，CI-937的剂量限制性毒性为中性粒细胞减少，推荐的II期起始剂量为22 mg/m²。
