PHASE I & II
TRIALS OF IRINOTECAN IN CHILDREN WITH NEUROBLASTOMA
Tsuchida Y1, Kaneko M2
1Gunma Children’s
Medical Center, Gunma, Japan
2University of
Tsukuba, Tsukuba, Japan
Objectives: Camptothecin was
first isolated from the Chinese tree Camptotheca acuminata. A
water-soluble derivative of camptothecin, irinotecan, was subsequently
synthesized, and it was shown by our in vivo experiments and by that
of others that irinotecan is an active agent against neuroblastoma. No
other newly developed agents showed efficacy as strong as irinotecan.
Therefore, Phase I and II trials of irinotecan were performed on Japanese
children as a first step for its clinical application.
Methods: In the Phase I
study, 28 patients with refractory diseases from 8 hospitals received
irinotecan 50-200 mg/m2/day by i.v. 2-hr infusion over 3 days,
repeated once after an interval of 25 days. Diagnoses were neuro- blastoma
in 26 and other solid tumors in 2. The doses were escalated in increments
of 10 to 20 mg/m2/day. After determination of the maximum
tolerated dose of irinotecan in children, a Phase II trial was begun to
determine the efficacy of irinotecan against neuroblastoma.
Results: Dose limiting
toxicities were observed at the dose of 200 mg/m2/day for 3
days. Diarrhea and hematopoietic toxicities were the dose-limiting factors,
and the former required support with intravenous fluid administration.
Partial response (PR) was attained in 4 of 11 patients who received
irinotecan two cycles of 140 mg/m2/day to 200 mg/m2/day.
The maximum tolerated dose was determined to be a dose of irinotecan 180
mg/m2/day administered for 3 consecutive days. The Phase II
trial at this dose level is now ongoing, and already showed that irinotecan
was strongly effective against neuroblastoma in some of the patients.
Conclusion: Our studies would
conclude that irinotecan is a promising new drug in the treatment of
advanced neuroblastoma.