EFFICACY OF ORAL IRINOTECAN AGAINST NEUROBLASTOMA XENOGRAFTS

The efficacy of the topoisomerase I inhibitor, piperidino]-1-piperidin o)-carbonyloxy-camptothecin (irinotecan, CPT-11), administered by oral gavage has been examined against a panel of six independently derived neuroblastoma xenografts. Irinotecan was administered either daily fo r 5 days on 12 consecutive weeks {(d x 5)12} or for 5 days on two cons ecutive weeks repeated every 21 days for 4 cycles {[(d x 5)2]4}. Given on the (d x 5)12 schedule the maximum tolerated dose (MTD) was 50 mg/ kg. For intermittent scheduling {[(d x 5)2]4}, the MTD was 75 mg/kg, r esulting in the same total dose being administered (3 g/kg) over the p eriod of treatment. At the MTD for the 12 consecutive week schedule th ere were two of 42 toxicity related deaths, whereas intermittent sched uling at the MTD resulted in none of 42 intermittent schedule {[(d x 5 )2]4} was less therapy given (d x 5)12, as at the end of treatment mic e weighed 92 +/- 4% (SD; n = 6 experiments) and 81 +/- 4% (SD; n = 6 e xperiments) of their body weight at the start of therapy, respectively . The latter schedule was associated with loose feces starting around week 8 of therapy, broken teeth and a high incidence of swelling of th e orbital conjunctiva that developed late in the course of therapy. Gi ven (d x 5)12, irinotecan caused complete regressions of all six neuro blastoma xenograft lines, Because mice tolerate significantly greater systemic exposure to SN-38 lactone than do patients (as determined by plasma AUC at the respective MTD), we evaluated the intermittent sched ule of administration, reducing the dose/administration to determine t he lowest dose levels that produced objective regressions of these neu roblastoma xenografts and determined the daily systemic exposure assoc iated with these dose levels. In four lines examined objective respons es were obtained at dose levels of 12.5 or 6.25 mg/kg, The daily plasm a AUC exposures associated with minimum dose achieving response in NB1 691 (12.5 mg/kg), NB1643 (6.25 mg/kg) and NBEB (12.5 mg/kg) for irinot ecan lactone were 219, 152 and 653 ng-h/ml, respectively; and for SN-3 8 lactone were 704, 418 and 987 ng-h/ml, respectively. These results i ndicate that childhood neuroblastoma xenografts are highly sensitive t o irinotecan given by oral administration and therapeutic activity is similar to i.v. irinotecan administered on similar schedules.