title: Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma.
abstract: Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n=13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n=2) or 0.2 mg/kg per day (n=4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non-dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 microM (0.11-0.37 microM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 microM; area under the concentration times time curve (AUC0-24) was 2.50 microM-hr (1.28-3.85 microM-hr) and 4.37 microM-hr and 4.69 microM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Bassem I
authors.initials: BI
authors.lastname: Razzouk
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Shaun
authors.initials: S
authors.lastname: Xiao
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Brien
authors.forename: Wendy
authors.initials: W
authors.lastname: Goodspeed
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced / Q000188:drug therapy; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy; D003872:Dermatitis / Q000188:drug therapy / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006261:Headache / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy; D007262:Infusions, Intravenous; D015473:Leukemia, Promyelocytic, Acute / Q000150:complications / Q000188:drug therapy*; D008223:Lymphoma / Q000150:complications / Q000188:drug therapy*; D008297:Male; D009325:Nausea / Q000139:chemically induced / Q000188:drug therapy; D010087:Oxides / Q000009:adverse effects / Q000493:pharmacokinetics*; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy; D012008:Recurrence; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy; D014882:Water-Electrolyte Balance / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide