semaxinib and Sarcoma

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.. Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment.. 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 1 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.. SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

Topics: Adult; Aged; Angiogenesis Inhibitors; Disease-Free Survival; Female; Humans; Indoles; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Proto-Oncogene Proteins c-kit; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Safety; Sarcoma; Survival Rate; Vascular Endothelial Growth Factor A

Vascular endothelial growth factor (VEGF) is a key regulator in angiogenesis. Preclinical and clinical data support the role of VEGF and angiogenesis in renal cell carcinoma (RCC), melanoma (M), and soft tissue sarcoma (STS). The tyrosine kinase inhibitor SU5416 is a potent inhibitor of the VEGF receptors 1 and 2.. We investigated 145 mg/m(2) SU5416 twice weekly in patients with advanced or metastatic RCC, M, and STS. The primary objectives were efficacy and safety. Disease assessments were performed after 4 and 8 weeks of treatment and every 2 months thereafter. Documented stable disease (SD) lasting for > or =3 months was considered an antitumor response.. A group of 29 patients was entered in the RCC trial, 20 patients in the M trial, and 31 patients in the STS trial. Response was observed in 6 (1 minor response and 5 SDs) of 24 evaluable patients (25%) in the RCC group, 6 (1 minor response and 5 SDs) of 26 patients (23%) in the STS group, and none of the patients in the M group. Progression-free survival ranged from 7 to 252 days (median 59 days) in the RCC group, from 7 to 260 days (median 60 days) in the STS group, and from 14 to 139 days (median 41 days) in the M group. Toxicities observed were those reported previously for SU5416.. SU5416 single agent is well tolerated. The antitumor response was low in patients with RCC and STS, whereas no responses were seen in patients with M.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Enzyme Inhibitors; Female; Humans; Indoles; Kidney Neoplasms; Male; Melanoma; Middle Aged; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Pyrroles; Sarcoma; Skin Neoplasms; Treatment Outcome

The angiogenesis inhibitor SU5416 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor-1 and -2. VEGF may be involved in hemostasis by altering the hemostatic properties of endothelial cells. We analyzed the effects of SU5416 on the coagulation cascade and the vessel wall in patients with advanced cancer.. Markers for thrombin generation, activation of the protein C pathway, fibrinolysis, and endothelial cell activation were measured in patients with renal cell carcinoma, soft tissue sarcoma, or melanoma on days 0, 14, and 28 of treatment with SU5416. Three of 17 sampled patients developed a thromboembolic event in the fifth week of treatment. Markers for thrombin generation and fibrinolysis did not show significant changes. We observed a significant increase in endogenous thrombin potential and of parameters reflecting endothelial cell activation (von Willebrand antigen, soluble tissue factor, and soluble E-selectin) in all patients (P< or =0.001). In patients experiencing a thromboembolic event, endogenous thrombin potential, soluble tissue factor, and soluble E-selectin increased to a significantly greater extent (P=0.029, P=0.021, and P=0.007, respectively).. VEGF is not only a permeability, proliferation, and migration factor, but it is also a maintenance and protection factor for endothelial cells.

Topics: Angiogenesis Inhibitors; Blood Coagulation; Blood Platelets; Carcinoma, Renal Cell; Cell Division; Cell Membrane Permeability; Cell Movement; Drug Administration Schedule; Endothelium, Vascular; Fibrinolysis; Hemostasis; Humans; Indoles; Kidney Neoplasms; Melanoma; Neovascularization, Pathologic; Protein C; Proto-Oncogene Proteins; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Thrombin; Vascular Endothelial Growth Factor Receptor-1

Neurogenic sarcomas are incurable, common malignant human peripheral nerve tumors subject to local recurrence and systemic metastasis. In this study, the vascularity, vascular endothelial growth factor (VEGF) expression, and effects of inhibiting VEGF receptor on growth of neurogenic sarcomas were examined. Vascularization and VEGF expression were 6.4- and 15-fold higher in tumors than in normal nerves. The small molecule inhibitor (SU5416) of VEGF receptor 2 had no effect on neurogenic sarcoma cell lines in vitro, but the growth of a human tumor explant xenograft model was reduced by 54.8% compared to vehicle. Reduction in tumor growth was due to decreased tumor angiogenesis, leading to reduction of tumor cell proliferation and increased apoptosis. Inhibiting VEGF function may therefore be a useful adjuvant therapy for neurogenic sarcomas.

Topics: Angiogenesis Inhibitors; Animals; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Indoles; Lymphokines; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Neovascularization, Pathologic; Neurofibromatosis 1; Neurons; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Time Factors; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors