title: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors.
abstract: BACKGROUND
  The combination of irinotecan, temozolomide, and vincristine is appealing because of potentially synergistic mechanisms of action and non-overlapping toxicities. This phase I study was designed to determine the toxicity and maximum tolerated dose (MTD) of escalating daily protracted doses of irinotecan given in this combination. With extended accrual, we more fully explored the toxicity of multiple courses at the MTD.
  
  
  METHODS
  Patients under 22 years with recurrent or refractory solid tumors were eligible. A course of chemotherapy was given every 28 days. Cefpodoxime was given for diarrhea prophylaxis. Vincristine (1.5 mg/m2, max 2 mg) was given intravenously (IV) on days 1 and 8. Temozolomide (100 mg/m2/day) was given orally on days 1-5. Irinotecan was given IV over 1 hr on days 1-5 and 8-12. Dose escalation was done in the standard 3 + 3 cohort design, starting at 15 mg/m2/day.
  
  
  RESULTS
  Twenty-five of 26 eligible patients were evaluable for toxicity and response. They received 111 courses (1-13, median 4). Dose limiting toxicity (DLT-pancreatitis, transaminitis) was seen in two of three patients at dose level 2 (20 mg/m2). No patients at level 1 had DLT during the first two cycles. Thus, the MTD of irinotecan in this combination is 15 mg/m2/day x 10 doses. Hematologic toxicity was mild and not prolonged. Grade 3 diarrhea was seen in five courses. Responses included two complete and two partial with 12 stable disease (SD) (median 6 months).
  
  
  CONCLUSIONS
  This combination is safe and shows activity in pediatric patients with recurrent malignancy.
authors.affiliation: Jimmy Everest Section of Pediatric Hematology/Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. rene-mcnall@ouhsc.edu
authors.forename: René Y
authors.initials: RY
authors.lastname: McNall-Knapp
authors.forename: Cydni N
authors.initials: CN
authors.lastname: Williams
authors.forename: Elaine N
authors.initials: EN
authors.lastname: Reeves
authors.forename: Richard L
authors.initials: RL
authors.lastname: Heideman
authors.forename: William H
authors.initials: WH
authors.lastname: Meyer
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D014750:Vincristine; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide