title: Phase II study of SU5416--a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor--in patients with refractory myeloproliferative diseases.
abstract: 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.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. frankgiles@aol.com
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Cooper
authors.forename: Lewis
authors.initials: L
authors.lastname: Silverman
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zangari
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
authors.forename: Khuda D
authors.initials: KD
authors.lastname: Khan
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cherrington
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000473:pathology; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D016044:Fusion Proteins, bcr-abl