The prognosis of patients with relapsed AML harboring Fms-like tyrosine kinase 3 gene (FLT3) mutations is extremely poor. Studies have demonstrated that microenvironment/leukemia interactions play a major role in the chemoresistance of leukemic stem cells residing in bone marrow niches and that the SDF-1a/CXCR4 axis is a key regulator of this interaction. The applicant states they have recently discovered that Sorafenib, an agent approved by the FDA for the treatment of renal cell and hepatocellular carcinoma, is a superb inhibitor of FLT3-ITD (internal tandem duplication) signaling in AML (IC502nM) with high clinical activity in Phase 1 studies as a single agent, and in combination with Idarubicin and Ara-C3. Sorafenib has shown greater clinical activity in early studies than PKC-412 or CEP-701, probably because of lower protein binding. A study by Dr. Small from Johns Hopkins has shown complete inhibition of FLT3-ITD phosphorylation by serum from patients treated with Sorafenib at MD Anderson Cancer Center. This effect was not consistent with other inhibitors. In the applicant's Phase 1 study, Sorafenib alone eradicated leukemic cells from circulation and showed a 55% reduction of bone marrow blasts. High CXCR4 levels have been associated with poor prognosis, and FLT3 mutations have been reported to highly upregulate CXCR4, thus anchoring leukemic cells/stem cells firmly in the bone marrow microenvironment. These findings provide the rationale for the currently proposed studies. The applicant has recently reported that in preclinical leukemia studies, inhibition of CXCR4 with an analogue of the first clinically available and recently FDA approved CXCR4 inhibitor (AMD3100, Plerixafar) resulted in mobilization of leukemic cells into the circulation and sensitization to the pro-apoptotic effects of the FLT3 inhibitor Sorafenib. G-CSF is now known to cleave SDF-1 and has been shown to enhance the effect of CXCR4 blockade. The applicant and others have used G-CSF for "priming" AML to chemotherapy, and it has been widely used for the treatment of relapsed AML in the FLAG protocol. In recent studies of stem cell mobilization, G-CSF was found to greatly enhance the ability of CXCR4 inhibitor AMD3100 to mobilize hematopoietic stem cells. AMD3100 has been extensively used, in combination with G-CSF, for the mobilization of normal hematopoietic stem cells into the circulation and was recently approved by the FDA for this indication. AML patients in remission who were treated with AMD3100/G-CSF had massive egress of AML cells into the circulation, providing first proof of principle in leukemia patients. In addition, preferential mobilization of AML over normal cells has been found, further supporting the clinical development of this therapeutic concept. Of note, Sorafenib is not toxic to normal hematopoietic cells. Based on these findings, the investigator proposes to test the hypothesis that mobilization of leukemic stem cells by disrupting the SDF-1a/CXCR4 axis by AMD3100/G-CSF will result in improved anti-leukemia activity of Sorafenib in AML patients with mutated FLT3. CXCR4 inhibitor AMD3100, G-CSF and Sorafenib will be administered sequentially to patients with advanced myeloid leukemia.

Public Health Relevance

(RELEVANCE): Acute myelogenous leukemia is a mostly fatal disease, in particular in patients whose leukemia cells are characterized by a mutation in the FLT3 gene. We have recently found, that the drug Sorafenib, which is FDA approved for certain other cancers, is a superb inhibitor of cells carrying this mutation, resulting in complete clearance of leukemia cells from the blood and a 55 percent reduction in bone marrow leukemia cells. We have further demonstrated, that these cells are protected in the bone marrow niches by a receptor termed CXCR4, and that blockade of this receptor by the drug Plerixafor approved for normal stem cell mobilization results in much improved elimination of leukemia cells after treatment with Sorafenib. Therefore, we are proposing to combine these 2 FDA approved drugs in a combination phase I trial with the immediate aim of determining the safety of this approach, and the ultimate goal to show that the combination is superior to Sorafenib alone.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
5R01FD003733-03
Application #
8324135
Study Section
Special Emphasis Panel (ZFD1-OPD-N (01))
Project Start
2009-09-21
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2012
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030