A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.
A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.
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DOI：
10.1158/1078-0432.ccr-09-2429
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Leggas M
中科院分区：
文献类型：
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作者：
Arnold SM;Rinehart JJ;Tsakalozou E;Eckardt JR;Fields SZ;Shelton BJ;DeSimone PA;Kee BK;Moscow JA;Leggas M
AR-67是一种新型的第三代喜树碱，基于其活性内酯形式的血液稳定性和在临床前模型中的高效力而被选择用于开发。在这里，我们报告了静脉注射AR-67治疗难治性实体瘤成人的初步I期经验。采用加速滴定试验设计，每天输注AR-67超过1小时，每21天输注5次。在第1周期的第1天和第4天采集血浆以测定药代动力学参数。26例患者接受了9个剂量水平（1.2-12.4mg/m2/d）的治疗。在5例患者中观察到剂量限制性毒性（DLT），包括4级发热性中性粒细胞减少、3级疲乏和4级血小板减少。常见毒性包括：白细胞减少（23%）、血小板减少（15.4%）、疲乏（15.4%）、中性粒细胞减少（11.5%）和贫血（11.5%）。未观察到腹泻。最大耐受剂量（MTD）为7.5 mg/m2/天。在所有剂量下，内酯形式是血浆中的主要物质（> AUC的87%）。第4天未观察到药物蓄积。清除率随剂量增加而恒定，血液学毒性与暴露相关（p<0.001）。在1例非小细胞肺癌（NSCLC）受试者中观察到延长的部分缓解。在小细胞肺癌（SCLC）、NSCLC和十二指肠癌患者中观察到病情稳定。AR-67是一种新型的血液稳定的喜树碱，具有可预测的毒性特征和线性药代动力学。II期推荐剂量为7.5mg/m2/d ×5 q21 d。
AR-67 is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and high potency in preclinical models. Here we report the initial phase I experience with intravenous AR-67 in adults with refractory solid tumors. AR-67 was infused over 1 hour daily × 5, every 21-days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters. Twenty six patients were treated at 9 dosage levels (1.2–12.4mg/m2/day). Dose limiting toxicities (DLTs) were observed in 5 patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included: leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage (MTD) was 7.5 mg/m2/day. The lactone form was the predominant species in plasma (>87% of AUC) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (p<0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer (NSCLC). Stable disease was noted in patients with small cell lung cancer (SCLC), NSCLC, and duodenal cancer. AR-67 is a novel, blood stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5mg/m2/day ×5 q 21 days.