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A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children's Oncology Group Phase I Consortium report. Clin Cancer Res 2012 Nov 01;18(21):6011-22

Date

09/11/2012

Pubmed ID

22962440

Pubmed Central ID

PMC4008314

DOI

10.1158/1078-0432.CCR-11-3284

Scopus ID

2-s2.0-84868543745   81 Citations

Abstract

PURPOSE: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias.

EXPERIMENTAL DESIGN: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1.

RESULTS: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m(2)/dose) which resulted in de-escalation to 105 mg/m(2)/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m(2)/dose for solid tumors and 150 mg/m(2)/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%.

CONCLUSIONS: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m(2)/dose and 150 mg/m(2)/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing.

Author List

Widemann BC, Kim A, Fox E, Baruchel S, Adamson PC, Ingle AM, Glade Bender J, Burke M, Weigel B, Stempak D, Balis FM, Blaney SM

Author

Michael James Burke MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Antineoplastic Agents
Child
Child, Preschool
Female
Humans
Leukemia
Male
Neoplasms
Niacinamide
Phenylurea Compounds
Protein Kinase Inhibitors
Treatment Outcome
Young Adult
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a