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

Abstract

UNLABELLED:

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).

• Authors: Gautam Borthakur, Hagop Kantarjian, Farhad Ravandi, Weiguo Zhang, Marina Konopleva, John J Wright, Stefan Faderl, Srdan Verstovsek, Sheela Mathews, Michael Andreeff, Jorge E Cortes
• Journal: Haematologica (Haematologica) Vol. 96 Issue 1 Pg. 62-8 (Jan 2011) ISSN: 1592-8721 [Electronic] Italy
• PMID: 20952518 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzenesulfonates
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• Niacinamide
• Sorafenib

Topics

• Adult
• Aged
• Aged, 80 and over
• Benzenesulfonates (therapeutic use)
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, pathology)
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, pathology)
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, pathology)
• Prognosis
• Protein Kinase Inhibitors (therapeutic use)
• Pyridines (therapeutic use)
• Remission Induction
• Salvage Therapy
• Sorafenib
• Survival Rate
• Young Adult