The efficacy of the
topoisomerase I inhibitor, 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11), administered by oral gavage has been examined against a panel of six independently derived
neuroblastoma xenografts.
Irinotecan was administered either daily for 5 days on 12 consecutive weeks ¿(d x 5)12¿ or for 5 days on two consecutive 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, resulting in the same total dose being administered (3 g/kg) over the period of treatment. At the MTD for the 12 consecutive week schedule there were two of 42 toxicity related deaths, whereas intermittent scheduling at the MTD resulted in none of 42 deaths. The intermittent schedule ¿[(d x 5)2]4¿ was less toxic than
therapy given (d x 5)12, as at the end of treatment mice weighed 92 +/- 4% (SD; n = 6 experiments) and 81 +/- 4% (SD; n = 6 experiments) 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 the orbital conjunctiva that developed late in the course of
therapy. Given (d x 5)12,
irinotecan caused complete regressions of all six
neuroblastoma 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 schedule of administration, reducing the dose/administration to determine the lowest dose levels that produced objective regressions of these
neuroblastoma xenografts and determined the daily systemic exposure associated with these dose levels. In four lines examined objective responses were obtained at dose levels of 12.5 or 6.25 mg/kg. The daily plasma AUC exposures associated with minimum dose achieving response in NB1691 (12.5 mg/kg), NB1643 (6.25 mg/kg) and NBEB (12.5 mg/kg) for
irinotecan lactone were 219, 152 and 653 ng-h/ml, respectively; and for
SN-38 lactone were 704, 418 and 987 ng-h/ml, respectively. These results indicate that childhood
neuroblastoma xenografts are highly sensitive to
irinotecan given by
oral administration and therapeutic activity is similar to i.v.
irinotecan administered on similar schedules.