Phase I Trial of Two Schedules of Vincristine, Oral Irinotecan, and Temozolomide (VOIT) for Children With Relapsed or Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Study

Background In peclinical models, temozolomide, and vincristine are additive or synergistic will irinotecan We examined this three-drug combination in children with relapsed solid tumors Patients received orally administered irinotecan together with temozolomide and vincristine oil 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/m(2) 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/m(2)/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/m(2)/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m(2)/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 close of 90 mg/m(2)/day, the mean SN-38 AUC(inf) 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 Pediatr Blood Cancer 2010,54 538-545 (C) 2010 Wiley-Liss, Inc