Phase I pharmacokinetic (PK) & pharmacogenetic study of sequential infusional irinotecan (IR) and fluorouracil (FU)

Abstract

2075 Background: Preclinical studies show that initial exposure to IR prior to FU is superior to concurrent exposure or the reverse sequence. IR given over 24h may be better tolerated than 0.5–1.5h infusions. Methods: 32 patient (pts) with GI tract cancers participated. IR was initially given at 4 levels (70–140 mg/m2/24h ) followed by LV 500 mg/m2/0.5h & FU 2000 mg/m2/48h starting d 1 & 15 of a 4-wk cycle. FU was then increased in 3 cohorts up to 3900 mg/m2/48h. Dose adjustments (incr./decr.) were based on individual pts toxicity. Plasma levels (Cp) of IR & FU were measured by HPLC & fluorescence or UV detection. Promoter polymorphisms in UGT1A1 & thymidylate synthase (TS) were measured by PCR of genomic DNA & DNA sequencing or agarose gel electrophoresis. Results: 2 pts had dose-limiting toxicity (DLT) during the first complete cycle at 140/3900 of IR/FU (2wk delay for ANC recovery; gr 3 nausea despite antiemetics), while 1/6 pts at 140/3120 had DLT (gr 3 diarrhea, gr 4 ANC). For 60 cycles (9 pts) at 140/3120 IR/FU, the # cycles with DLTs included gr 4 ANC, 1; gr 3 diarrhea, 1; gr 3 fatigue, 1. Overall per pt toxicities included: gr 2/3 diarrhea, 4/4; gr 2/3 stomatitis, 3/0; gr 3/4 AGC, 8/4; no pt had acute cholinergic symptoms. 4/22 pts with colorectal cancer had confirmed partial responses (PR); 2 of these had prior bolus IR/FU. Cpss 5-FU averaged 3.2 (2000), 3.2 (2500), 4.4 (3120) & 5.1 μM (3900 mg/m2/48h). The mean Cp values for IR are shown below. The ratio of free to SN-38G was lower in 9 pts with a (TA)6/6 genotype than in 21 pts with ≥ 1 (TA)7 alleles (0.22 v. 0.35, p=0.037). The distribution of TS genotypes for the 28-base repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all 4 PR pts had the 2/3 genotype. Conclusions: Doses (mg/m2) of IR 140/24h, LV 500/0.5h & FU 3120/48hr starting days 1&15 every 4wks are well tolerated. Analyses of extended IR PK sampling & pharmacodynamic correlations are ongoing. No significant financial relationships to disclose.