TY - JOUR
T1 - Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas
AU - Heymach, John V.
AU - Desai, Jayesh
AU - Manola, Judith
AU - Davis, Darren W.
AU - McConkey, David J.
AU - Harmon, David
AU - Ryan, David P.
AU - Goss, Geraldine
AU - Quigley, Travis
AU - Van Den Abbeele, Annick D.
AU - Silverman, Stuart G.
AU - Connors, Susan
AU - Folkman, Judah
AU - Fletcher, Christopher D.M.
AU - Demetri, George D.
PY - 2004/9/1
Y1 - 2004/9/1
N2 - Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas. Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m2 twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment. Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after I month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months. Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor of KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.
AB - Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas. Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m2 twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment. Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after I month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months. Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor of KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.
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U2 - 10.1158/1078-0432.CCR-04-0157
DO - 10.1158/1078-0432.CCR-04-0157
M3 - Article
C2 - 15355900
AN - SCOPUS:4444250452
VL - 10
SP - 5732
EP - 5740
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 17
ER -