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

Autor: Lewis Silverman, Guillermo Garcia-Manero, Paul J. Shami, Judith E. Karp, Maurizio Zangari, Maher Albitar, Khuda D. Khan, Deborah A. Thomas, Hagop Kantarjian, Jeffrey E. Lancet, Alison T. Stopeck, Julie M. Cherrington, Maureen A. Cooper, Alison L. Hannah, Francis J. Giles
Rok vydání: 2003
Předmět:
Adult
Male
Vascular Endothelial Growth Factor A
Cancer Research
medicine.medical_specialty
Indoles
medicine.drug_class
medicine.medical_treatment
Fusion Proteins
bcr-abl
Chronic myelomonocytic leukemia
Endothelial Growth Factors
Gastroenterology
Tyrosine-kinase inhibitor
chemistry.chemical_compound
Bone Marrow
hemic and lymphatic diseases
Internal medicine
medicine
Humans
Pyrroles
Bone pain
Myelofibrosis
Aged
Aged
80 and over
Lymphokines
Chemotherapy
Myeloproliferative Disorders
Vascular Endothelial Growth Factors
business.industry
Myeloid leukemia
Middle Aged
Protein-Tyrosine Kinases
medicine.disease
Vascular Endothelial Growth Factor Receptor-2
Vascular endothelial growth factor
Endocrinology
Oncology
chemistry
Intercellular Signaling Peptides and Proteins
Female
medicine.symptom
business
Progressive disease
Zdroj: Cancer. 97:1920-1928
ISSN: 1097-0142
0008-543X
DOI: 10.1002/cncr.11315
Popis: 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. 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. Cancer 2003;97:1920–8. © 2003 American Cancer Society. DOI 10.1002/cncr.11315
Databáze: OpenAIRE
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