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

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/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/ dose for solid tumors and 150 mg/m2/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/m2/dose and 150 mg/m2/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.

The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

“…The mean C max observed in the NHP in this study was 5.8±2.1 μg/mL, while the day 1 C max in adult phase I studies of oral sorafenib for refractory solid tumors ranged from 2.3 to 3.0 μg/mL at the recommended dose of 400 mg twice daily [20]. At the MTD of 200 mg/m 2 /dose in a phase I trial of refractory solid tumors in children, the mean single day plasma AUC 0-24h was 28±17 μg•h/mL [21], which is similar to the mean plasma AUC 0-24h of 28±4.3 μg•h/mL in the NHP. Thus, the dose used in the NHP achieved sorafenib concentrations and exposure similar to those observed in both adults and children with refractory cancers at their respective recommended doses.…”

“…Plasma concentrations of sorafenib after oral administration in adult and pediatric phase I trials were highly variable across patients [21][22][23][24][25]. Some of the variability after oral dosing could be due to factors relating to absorption such as the potential slow dissolution of the tablets in the gastrointestinal tract [22].…”

Phase 2 trial of sorafenib in children and young adults with refractory solid tumors: A report from the Children's Oncology Group

“…A phase 1 study of sorafenib in children with refractory solid tumors and leukemia (ADVL0413) conducted by the Children’s Oncology Group (COG) Phase 1 and Pilot Consortium recommended a phase 2 dose of 200 mg/m 2 /dose every 12 hours continuously for children and adolescents with solid tumors and 150 mg/m 2 /dose for children with leukemia [4]. Similar to adults, common toxicities observed were rash, palmar-plantar erythrodysesthesia, hypertension, elevated serum transaminases, lipase elevation, diarrhea, and mild myelosuppression.…”

Sorafenib treatment in children with relapsed and refractory neuroblastoma: an experience of four cases

“…Studies have demonstrated that sorafenib inhibits growth of human neuroblastoma tumor xenografts in mice by targeting both neuroblastoma cells and tumor blood vessels 6, 7. Sorafenib has been evaluated in pediatric patients with solid tumors or leukemia in two phase I studies in combination with other agents 8, 9 and, thereafter, in a Children's Oncology Group phase I trial as single‐agent therapy 10. Hypertension, diarrhea, rash, fatigue, and increased serum levels of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) were the most common sorafenib‐related toxicities.…”