Dees E C, Whitfield L R, Grove W R, Rummel S, Grochow L B, Donehower R C
Johns Hopkins Oncology Center, Baltimore Maryland 21287, USA.
Clin Cancer Res. 2000 Oct;6(10):3885-94.
5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyra no[4,3,2-cd]-indazol-8-ol trihydrochloride (CI-958) is the most active member of a new class of DNA intercalating compounds, the benzothiopyranoindazoles. Because of its broad spectrum and high degree of activity as well as a favorable toxicity profile in preclinical models, CI-958 was chosen for further development. The Phase I study described here was undertaken to determine the toxicity profile, maximum tolerated dose, and pharmacokinetics of CI-958 given as an i.v. infusion every 21 days. Adult patients with advanced refractory solid tumors who had adequate renal, hepatic, and hematological function, life expectancy, and performance status were eligible for this study. Written informed consent was obtained from all patients. Patients received a 1- or 2-h infusion of CI-958 at 21-day intervals. The starting dose was 5.2 mg/m2, and at least three patients were evaluated at each dose level before proceeding to a new dose level. A pharmacokinetically guided dose escalation design was used until reaching a predetermined target area under the plasma concentration versus time curve (AUC), after which a modified Fibonacci scheme was used. Forty-four patients (21 men and 23 women; median age, 59 years) received 162 courses of CI-958. Neutropenia and hepatorenal toxicity were the dose-limiting toxicities, which defined the maximum tolerated dose of CI-958 to be 875 mg/m2 when given as a 2-h infusion every 21 days. There were no tumor responses. Two patients had stable disease for >250 days. The recommended Phase II dose is 560 mg/m2 for patients with significant prior chemotherapy and 700 mg/m2 for patients with minimal prior chemotherapy. Pharmacokinetic analysis of plasma and urine concentration-time data from each patient was performed. At the recommended Phase II dose of 700 mg/m2, mean CI-958 clearance was 370 ml/min/m2, mean AUC was 33800 ng-h/ml, and mean terminal half-life (t1/2) was 15.5 days. The clearance was similar at all doses, and plasma CI-958 AUC increased proportionally with dose, consistent with linear pharmacokinetics. The percentage reduction in absolute neutrophil count from baseline was well predicted by AUC using a simple Emax model. The pharmacokinetically guided dose escalation saved five to six dose levels in reaching the maximum tolerated dose compared with a standard dose escalation scheme. This may represent the most successful application to date of this dose escalation technique.
5-[(2-氨基乙基)氨基]-2-[2-(二乙氨基)乙基]-2H-[1]苯并硫代吡喃并[4,3,2-cd]吲唑-8-醇三盐酸盐（CI-958）是一类新型DNA嵌入化合物——苯并硫代吡喃并吲唑中活性最强的成员。由于其具有广谱、高活性以及在临床前模型中良好的毒性特征，CI-958被选中进行进一步研发。此处描述的I期研究旨在确定每21天静脉输注一次CI-958的毒性特征、最大耐受剂量和药代动力学。有足够的肾、肝和血液学功能、预期寿命以及体能状态的晚期难治性实体瘤成年患者符合本研究条件。所有患者均获得了书面知情同意。患者每21天接受1或2小时的CI-958输注。起始剂量为5.2mg/m²，在进入新的剂量水平之前，每个剂量水平至少评估3名患者。采用药代动力学指导的剂量递增设计，直至达到血浆浓度-时间曲线下面积（AUC）的预定目标，之后采用改良的斐波那契方案。44例患者（21例男性和23例女性；中位年龄59岁）接受了162个疗程的CI-958治疗。中性粒细胞减少和肝肾毒性是剂量限制性毒性，这确定了每21天进行2小时输注时CI-958的最大耐受剂量为875mg/m²。没有肿瘤反应。2例患者疾病稳定超过250天。对于既往有显著化疗史的患者，推荐的II期剂量为560mg/m²，对于既往化疗最少的患者为700mg/m²。对每位患者的血浆和尿液浓度-时间数据进行了药代动力学分析。在推荐的II期剂量700mg/m²时，CI-958的平均清除率为370ml/min/m²，平均AUC为33800ng·h/ml，平均终末半衰期（t1/2）为15.5天。所有剂量下清除率相似，血浆CI-958 AUC与剂量成比例增加，符合线性药代动力学。使用简单的Emax模型，AUC能很好地预测绝对中性粒细胞计数相对于基线的降低百分比。与标准剂量递增方案相比，药代动力学指导的剂量递增在达到最大耐受剂量时节省了五到六个剂量水平。这可能代表了该剂量递增技术迄今为止最成功的应用。
