semaxinib and Kidney-Neoplasms

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

Vascular endothelial growth factor (VEGF) is expressed in up to 70% of renal cell carcinomas (RCCs) and is a rational therapeutic target. SU5416 is a small molecule inhibitor of VEGF-mediated signaling through Flk-1, a transmembrane tyrosine kinase. IFN-alpha also possesses dose- and schedule-dependent antiangiogenic effects at doses lower than those used for RCC therapy. We hypothesized that SU5416 plus low dose IFN-alpha 2B (Intron-A) would result in a 1-year event-free survival (EFS), exceeding 20% in patients with metastatic RCC using the results of a randomized immunotherapy trial as historical control. Efficacy was correlated with serial plasma VEGF and plasminogen activator inhibitor-1 levels and with positron emission tomography scans.. Thirty patients were treated with SU5416 145 mg/m(2) i.v. twice weekly plus Intron-A 1 million units s.c. twice daily, cycled every 6 weeks.. Fifteen patients (50%) had stable disease (SD) at 12 weeks, including 1 minor response and 8 with progressive disease (27%). Median survival time was 10 months, and 1-year EFS was 6% (95% confidence interval, 1-35). The most common grade 3 or 4 toxicities included fatigue and lymphopenia, among others. There were 3 on-study deaths, 2 of which were infection-related. Significant declines in median plasma levels of VEGF pre- and posttherapy were observed. In 5 patients with paired FDG and O-15 positron emission tomography scans, tumor metabolism and perfusion were unchanged in 3 patients with SD, increased in 1 patient with progression, and decreased in 1 patient with SD.. Although SU5146 plus low-dose IFN exhibits biological activity in RCC as evidenced by significant declines in serial VEGF and plasminogen activator inhibitor-1 plasma levels, the 1-year EFS of 6% and adverse toxicity profile diminishes enthusiasm for additional studies with this combination in advanced RCC.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; California; Carcinoma, Renal Cell; Cell Line, Tumor; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Immunotherapy; Indoles; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Pyrroles; Recombinant Proteins; Time Factors; Tomography, Emission-Computed; Treatment Outcome; Vascular Endothelial Growth Factor A

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