Phase I clinical trial of weekly combined topotecan and irinotecan
Phase I clinical trial of weekly combined topotecan and irinotecan
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DOI：
10.1097/00000421-200108000-00003
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发表时间：
2001-08-01
影响因子：
2.6
通讯作者：
Lokich, J
中科院分区：
文献类型：
--
作者：
Lokich, J
联合使用CYP 1A 1类似物可以通过增加类似物共有的细胞毒性部分的血清和细胞内浓度来增加功效。拓扑替康和伊立替康是两种喜树碱类似物，在不同的人类肿瘤（卵巢中的拓扑替康;结肠中的伊立替康）和不同的实验肿瘤系统中具有活性。这些数据表明，不同的耐药机制可能是有效的两种药物，如果不完全的交叉耐药性之间存在类似物，伴随给药可能是有利的。该I期研究的目的是1）在一项阶段试验设计中确定拓扑替康和伊立替康每周一次联合给药是否可以以与拓扑替康或伊立替康单药给药相同的剂量强度给药;以及2）确定血液学和/或血液学检查是否或非血液学毒性增加，拓扑替康和伊立替康一起给药，作为可能的II期试验的前奏，在反应性肿瘤类别。伊立替康每周给药30 - 45分钟，共4次，剂量水平为50、75、100和125 mg/m2/wk。拓扑替康给药30分钟（伊立替康给药后），每个伊立替康剂量水平（1.0和1.5 mg/m2）内有两个剂量水平。伴随使用单剂量粒细胞-巨噬细胞集落刺激因子（G-CSF），白细胞计数在1，000个细胞/mm（3）和3，500个细胞/ mm（3）之间，以维持方案。拓扑替康和伊立替康联合给药的最大耐受剂量（MTD）定义为允许拓扑替康和伊立替康与G-CSF以或接近每种单药报告的剂量强度给药4周的剂量。21例患者接受了32个4周周期。剂量限制性毒性为血液学毒性，所有剂量水平均发生IV级白细胞减少症和中性粒细胞减少症。与伊立替康相关的腹泻综合征没有明显增加。伊立替康的MTD（125 mg/m2/wk）与伊立替康单药的MTD相同。伴随使用拓扑替康（0.5 mg/m2/wk）的MTD为5天拓扑替康方案中拓扑替康单药剂量（2.5 mg/m2/wk）的60%，但仅为每周方案中拓扑替康单药剂量（5 mg/m2/wk）的30%。拓扑异构酶I抑制剂的剂量增加最低限度时，类似物伴随每周一次的时间表。有必要进行拓扑替康和伊立替康单药与拓扑替康和伊立替康联合给药的比较试验，以提供类似物联合给药可提高疗效的原理证明。
Combining antineoplastic analogues may increase efficacy by increasing the serum and intracellular concentration of the cytotoxic moiety shared by the analogues. Topotecan and irinotecan are two camptothecan analogues that are active in different human tumors (topotecan in ovary; irinotecan in colon) and in different experimental tumor systems. These data suggest that different mechanisms of drug resistance may be operative for the two agents, and if incomplete cross-resistance exists between analogues, concomitant administration may be advantageous. The objectives of this phase I study were 1) to determine in a phase trial design whether topotecan and irinotecan administered concomitantly on a weekly schedule can be delivered at the same dose intensity as that of single-agent topotecan or irinotecan delivery; and 2) to determine whether hematologic and/or nonhematologic toxicity is increased with topotecan and irinotecan administered together as a prelude to a possible phase II trial in responsive tumor categories. Irinotecan was administered for 30 to 45 minutes weekly X 4 at four dose levels: 50, 75, 100, and 125 mg/m(2)/wk. Topotecan was administered for 30 minutes (after irinotecan administration) at two dose levels within each of the irinotecan dose levels (1.0 and 1.5 mg/m(2)). Concomitant single-dose granulocyte-macrophage colony-stimulating factor (G-CSF) was used for leukocyte counts between 1,000 cells/mm(3) and 3,500 cells/ mm(3) to maintain schedule. Maximum tolerated dosage (MTD) for the topotecan and irinotecan combination was defined as that which permitted 4 weeks of topotecan and irinotecan administration with G-CSF at or near the dose intensity reported for each single agent. Twenty-one patients received 32 4-week cycles. Dose-limiting toxicity was hematologic with grade IV leukopenia and neutropenia occurring at all dose levels. There was no apparent increase in the diarrhea syndrome associated with irinotecan. The MTD for irinotecan (at 125 mg/m(2)/wk) is the same MTD as with single-agent irinotecan use. The MTD for concomitant topotecan 0.5 mg/m(2)/wk) is 60% of the single-agent topotecan dose for the 5-day topotecan schedule (at 2.5 mg/m(2)/wk) but only 30% of the single-agent topotecan dose for the weekly schedule (5 mg/m(2)/wk). The topoisomerase I inhibitor dose is increased minimally when the analogues are administered concomitantly on a weekly schedule. Comparative trials of single-agent topotecan and irinotecan versus the combination of topotecan and irinotecan would be necessary to provide the proof of principle that combining analogues can increase therapeutic effectiveness.