Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma.
OBJECTIVE
Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with multiple myeloma (MM). VEGF, a soluble circulating angiogenic molecule, acts via receptor tyrosine kinases, including VEGF receptor 2. SU5416 is a small molecule VEGF receptor 2 inhibitor.


METHODS
Adult patients with advanced MM were entered on a multicenter phase II study.


RESULTS
Twenty-seven patients (median age 69, range 39-79), median 4 (0-10) lines of prior therapy, 14 with prior thalidomide therapy, received SU5416 at 145 mg/m(2) twice weekly i.v. for a median of two 4-week cycles (range 0.2-9). Grade 3/4 toxicities were rarely observed; the most frequent was thrombocytopenia (12%). Mild-to-moderate toxicities included nausea (63%), headache (56%), diarrhea, vomiting (both 37%), and fatigue (33%). There were three thromboembolic episodes and five cases of new onset hypertension. Two (7%) patients did not complete the first 4-week cycle of therapy because of adverse events (pneumonia and headache). There were no objective responses. Four patients had disease stabilization for >/==" BORDER="0">4 months. A decrease in median VEGF plasma levels was observed in patients with stable disease (n = 7) compared with patients with progressive disease (n = 5). Overall median survival was 42 weeks (range 3-92+).


CONCLUSIONS
Although SU5416 had minimal clinical activity, signs of biological activity (decrease in plasma VEGF levels) suggest that angiogenic modulation may be of value in patients with MM.
Zangari
Maurizio
M
University of Arkansas for Medical Sciences, The Multiple Myeloma Institute for Research and Therapy, Little Rock, Arkansas, USA.
Anaissie
Elias
E
Stopeck
Alison
A
Morimoto
Alyssa
A
Tan
Nguyen
N
Lancet
Jeffrey
J
Cooper
Maureen
M
Hannah
Alison
A
Garcia-Manero
Guillermo
G
Faderl
Stephan
S
Kantarjian
Hagop
H
Cherrington
Julie
J
Albitar
Maher
M
Giles
Francis J
FJ
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use*; D012074:Remission Induction; D016879:Salvage Therapy; D015996:Survival Rate; D013792:Thalidomide / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2