Sorafenib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Leukemia

OBJECTIVES:

Primary

- Determine the maximum-tolerated dose (MTD) and recommended phase II dose of sorafenib
in pediatric patients with relapsed or refractory solid tumors.

- Determine whether pediatric patients with relapsed or refractory leukemia can tolerate
the MTD of sorafenib for solid tumors.

- Determine the tolerability, active N-oxide metabolite, pharmacodynamics, and activity
of sorafenib a the MTD in a subset of patients with acute myeloid leukemia (AML) and
FLT3-ITD mutation.

- Determine the toxicities of this drug in these patients.

- Determine the pharmacokinetics of this drug in these patients.

Secondary

- Determine, preliminarily, the antitumor activity of this drug within the confines of a
phase I trial.

- Assess the biologic effect of sorafenib on circulating endothelial cells (CEC),
circulating CEC precursors (CECP), VEGF, and VEGF-2 in peripheral blood.

- Assess the gene expression, proteomic profile, and ERK phosphorylation in blasts of
patients with refractory leukemia treated with this regimen.

- Assess the effect of sorafenib on solid tumor vascularity and tumor blood flow using
dynamic contrast-enhanced MRI (DEMRI) in patients with measurable soft tissue tumors.

- Analyze tumor samples and leukemic blasts for the presence of ras, raf, or FLT3
(leukemias) mutations.

- Analyze the plasma inhibitory activity for FLT3 phosphorylation in peripheral blood of
patients with AML and FLT3-ITD mutation.

- Determine the tolerability, pharmacokinetics of sorafenib and sorafenib's active
N-oxide metabolite, pharmacodynamics, and activity of sorafenib administered at the MTD
for refractory leukemias in a subset of patients with AML and FLT3-ITD mutation.

- Analyze the plasma inhibitory activity for FLT3 phosphorylation in peripheral blood
samples obtained at the time of PK studies in patients with FLT3-ITD mutation AML.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to
diagnosis (malignant solid tumor vs leukemia).

- Stratum 1 (refractory solid tumor patients): Patients receive oral sorafenib twice
daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence
of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of sorafenib until the maximum-tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity (DLT). Once the MTD is determined, up to 6
additional patients under 12 years of age may be treated at the MTD. The MTD dose level is
also expanded to enroll up to 6 patients with refractory leukemia.

- Stratum 2 (refractory leukemia patients): A cohort of 3-6 patients with leukemia
receives treatment as in stratum 1 at the MTD determined in stratum 1. If 2 of 3 or 2
of 6 patients experience a DLT at the solid tumor MTD, sorafenib is reduced by one dose
level. The leukemia MTD is defined as the dose at which < 1/3 of patients experience
DLT during course 1 of treatment.

- Stratum 3 (acute myeloid leukemia and FLT3-ITD mutation patients): Patients receive
sorafenib as in stratum 1 at the MTD determined in stratum 2.

Patients undergo blood sample collection for pharmacokinetics, pharmacodynamics (in leukemia
blasts only), circulating endothelial cells (CEC), circulating CEC precursors (CECP), VEGF
and VEGF-2 , gene expression, proteomic profile, ERK phosphorylation, and FLT3
phosphorylation activity. Tumor tissue samples may also be analyzed for the presence of ras,
raf, or FLT3.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 77 patients will be accrued for this study.