Background. In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Methods. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. Results. On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m 2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m 2/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received ≥6 courses. Conclusions. The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.
- Oral irinotecan
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health