title: 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.
abstract: 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/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 dose 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 >or=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.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. lars.wagner@cchmc.org
authors.forename: Lars M
authors.initials: LM
authors.lastname: Wagner
authors.forename: John P
authors.initials: JP
authors.lastname: Perentesis
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Marvin D
authors.initials: MD
authors.lastname: Nelson
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D014750:Vincristine; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide