A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia.
Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.
Fiedler
Walter
W
Department of Oncology/Hematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. fiedler@uke.uni-hamburg.de
Mesters
Rolf
R
Tinnefeld
Heike
H
Loges
Sonja
S
Staib
Peter
P
Duhrsen
Ulrich
U
Flasshove
Michael
M
Ottmann
Oliver G
OG
Jung
Wolfram
W
Cavalli
Franco
F
Kuse
Rolf
R
Thomalla
Joerg
J
Serve
Hubert
H
O'Farrell
Anne M
AM
Jacobs
Mark
M
Brega
Nicoletta M
NM
Scigalla
Paul
P
Hossfeld
Dieter K
DK
Berdel
Wolfgang E
WE
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001853:Bone Marrow / Q000378:metabolism; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008833:Microcirculation; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011758:Pyrroles / Q000627:therapeutic use*; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C084881:flt3 ligand protein; C116890:Semaxinib