Phase I study of sorafenib in patients with refractory or relapsed acute leukemias

Abstract

Background Sorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias.

Design and methods: Fifty patients received one of two different schedules; Schedule "A": once or twice daily, five days per week, every week for a 21 day cycle, and Schedule "B": once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules.

Results: Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation. Conclusions Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenib-based combinations. (ClinicalTrials.gov Identifier: NCT00217646).

Figures

Figure 1.

Percentage changes in bone marrow blasts from baseline according to FLT3 mutation status. Patients with both internal tandem duplication (ITD) and D835 mutation are counted as ITD mutation. Only information from patients with at least one follow-up bone marrow examination in addition to the baseline is included. *= no follow-up marrow done due to disease progression (ITD=4, WT=3, D835=3). 0=no change in marrow blast percentage.

Figure 2.

Changes in median number of peripheral blood absolute blast count (total white blood cell count X % blasts) with time according to FLT3 mutation status. Patients with both internal tandem duplication (ITD) and D835 mutation are counted as ITD mutation. (N, ITD=34, Wild-type/D835=16) in a compassionate use

Figure 3.

Apoptosis and changes in mitochondrial membrane potential in peripheral blood mononuclear cells (PBMC). Apoptosis induction in PBMCs (collected prior to sorafenib and on days 1 and 4) was measured by annexin V binding and percentage of cells with changes in mitochondrial membrane potential was measured by staining with chloromethyl-X-rosamine (CMXRos, Invitrogen Co) using flow cytometry.