Document Detail


Phase II study of SU5416--a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor--in patients with refractory myeloproliferative diseases.
MedLine Citation:
PMID:  12673719     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with myeloproliferative disorders (MPD), including agnogenic myeloid metaplasia (AMM), chronic myeloid leukemia in blastic phase (CML-BP), and chronic myelomonocytic leukemia (CMML). VEGF is a soluble, circulating, angiogenic molecule that acts through receptor tyrosine kinases (RTK), including VEGF receptor 2 (VEGFR-2). SU5416 is a small-molecule RTK inhibitor (RTKI) that targets VEGFR-2, c-kit, and fms-related tyrosine kinase Flk2. METHODS: Adult patients with advanced CMML, AMM, CML-BP, or other BCR-ABL negative MPD were entered on a multicenter, Phase II study. RESULTS: Thirty-two patients (19 patients with BCR-ABL negative MPD, 6 patients with CMML, 4 patients with CML-BP, and 3 patients with AMM) with a median age of 66 years (range, 29-85 years) received SU5416 145 mg/m(2) twice weekly intravenously for a median of three 4-week cycles (maximum, 12 cycles). Drug-related Grade 3-4 toxicities included acute abdominal pain (13%), bone pain (9%), infusion-related dyspnea (9%) or headache (6%), fatigue (6%), diarrhea (3%), and catheter site reactions (3%). Eleven patients (34%) did not receive a second cycle of therapy (6 patients had progressive disease, 3 because of adverse events; 2 patients withdrew due to lack of response). One patient with AMM achieved a partial response. Eight patients received more than 6 months of therapy. CONCLUSIONS: SU5416 had minimal clinical activity in patients with MPD. Long-term administration of a twice-weekly, hyperosmolar, intravenous solution containing polyoxyl 35 castor oil was difficult. More tolerable RTKI may be worthy of further investigation in patients with MPD.
Authors:
Francis J Giles; Maureen A Cooper; Lewis Silverman; Judith E Karp; Jeffrey E Lancet; Maurizio Zangari; Paul J Shami; Khuda D Khan; Alison L Hannah; Julie M Cherrington; Deborah A Thomas; Guillermo Garcia-Manero; Maher Albitar; Hagop M Kantarjian; Alison T Stopeck
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Publication Detail:
Type:  Clinical Trial; Clinical Trial, Phase II; Journal Article; Multicenter Study    
Journal Detail:
Title:  Cancer     Volume:  97     ISSN:  0008-543X     ISO Abbreviation:  Cancer     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-04-03     Completed Date:  2003-05-07     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0374236     Medline TA:  Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1920-8     Citation Subset:  AIM; IM    
Copyright Information:
Copyright 2003 American Cancer Society.
Affiliation:
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. frankgiles@aol.com
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Bone Marrow / pathology
Endothelial Growth Factors / metabolism
Female
Fusion Proteins, bcr-abl / metabolism
Humans
Indoles / adverse effects,  therapeutic use*
Intercellular Signaling Peptides and Proteins / metabolism
Lymphokines / metabolism
Male
Middle Aged
Myeloproliferative Disorders / drug therapy*,  metabolism,  pathology
Protein-Tyrosine Kinases / antagonists & inhibitors
Pyrroles / adverse effects,  therapeutic use*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factors
Chemical
Reg. No./Substance:
0/Endothelial Growth Factors; 0/Fusion Proteins, bcr-abl; 0/Indoles; 0/Intercellular Signaling Peptides and Proteins; 0/Lymphokines; 0/Pyrroles; 0/SU 5416; 0/Vascular Endothelial Growth Factor A; 0/Vascular Endothelial Growth Factors; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2

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