Phase II study of SU5416 - A small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor - In patients with refractory myeloproliferative diseases

Francis J. Giles, Maureen A. Cooper, Lewis Silverman, Judith 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

Research output: Contribution to journalArticle

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/m2 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. Longterm 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.

Original languageEnglish (US)
Pages (from-to)1920-1928
Number of pages9
JournalCancer
Volume97
Issue number8
DOIs
Publication statusPublished - Apr 15 2003
Externally publishedYes

    Fingerprint

Keywords

  • Agnogenic myeloid metaplasia
  • Angiogenesis
  • Chronic myeloid leukemia in blast phase
  • Myelofibrosis
  • SU5416
  • Tyrosine kinase inhibitor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this