Phase I and pharmacologic study of sequential @entity1945 , @entity3003 , and XXXX .

@entity1 @entity137 @entity5 @entity3003 @entity1149 @entity2879 @entity1398 @entity74 @entity151 @entity1945
Inhibition of topoisomerase I by @entity1945 results in a compensatory increase in topoisomerase II levels associated with increased in vitro sensitivity of @entity5 to @entity2879 . Maximum synergy has been observed for the sequence of @entity1945 followed by @entity2879 . This is the pharmacologic rationale for the sequence of @entity1945 0.4 mg/m(2) per day for 7 days continuous i.v. infusion, @entity3003 i.v. on day 8, and @entity2879 50 mg per day p.o. days 9 through 20. The @entity3003 dosage was escalated from an AUC of 4 to 5 to 6 (Calvert formula). Up to six treatment cycles were administered at 28-day intervals. Eligible @entity1 had metastatic @entity1149 ( @entity1149 ) or extensive @entity151 ( @entity151 ), no prior chemotherapy, performance status 0-2, and adequate organ function. Follow-up was twice weekly in the first cycle for CBC and for @entity1945 and @entity2879 concentrations. Follow-up, thereafter, was weekly. @entity5 response was assessed after two and six cycles and then as clinically indicated. At @entity3003 AUCs of 4 and 5, no NCI grade 4 @entity137 was observed in cycle 1 in cohorts of three @entity1 each. At the AUC of 5, two @entity1 experienced dose-limiting events after cycle 3, one grade 4 @entity1398 lasting >3 days (no fever) and one failure to recover an absolute neutrophil count >1500/microl by day 35. This was, therefore, deemed the maximal tolerable dose. Number of treatment cycles per @entity1 ranged between 1 and 6, and three @entity1 completed six cycles. All @entity1 were male, age 47-71, with @entity1149 in one and @entity151 in six. The @entity1 with @entity1149 had @entity74 after one cycle. One complete and three partial responses were observed in five @entity1 with @entity151 . Mean steady-state plasma concentrations during @entity1945 infusion ranged from 0.73 to 1.69 ng/ml, and mean @entity2879 concentrations ranged from 60 to 230 ng/ml. This sequence of @entity1945 , @entity3003 , and @entity2879 appeared tolerable and active. @entity1398 was the dose-limiting @entity137 .
