Bradley J Monk1, Michael W Sill2, Joan L Walker2, Christopher J Darus2, Gregory Sutton2, Krishnansu S Tewari2, Lainie P Martin2, Jeanne M Schilder2, Robert L Coleman2, Jai Balkissoon2, Carol Aghajanian2. 1. Bradley J. Monk, University of Arizona Cancer Center at Dignity Health St Joseph's Hospital and Medical Center, Phoenix, AZ; Michael W. Sill, Roswell Park Cancer Institute, Buffalo; Carol Aghajanian, Memorial Sloan Kettering Cancer Center, New York, NY; Joan L. Walker, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Christopher J. Darus, Maine Medical Center, Portland, ME; Gregory Sutton, Washington University School of Medicine, St. Louis, MO; Krishnansu S. Tewari, University of California Irvine Medical Center, Orange; Jai Balkissoon, Pharmaceutical Product Development International, South San Francisco, CA; Lainie P. Martin, Fox Chase Cancer Center, Philadelphia, PA; Jeanne M. Schilder, Indiana University Medical Center, Indianapolis, IN; and Robert L. Coleman, The University of Texas MD Anderson Cancer Center, Houston, TX. bradley.monk@chw.edu. 2. Bradley J. Monk, University of Arizona Cancer Center at Dignity Health St Joseph's Hospital and Medical Center, Phoenix, AZ; Michael W. Sill, Roswell Park Cancer Institute, Buffalo; Carol Aghajanian, Memorial Sloan Kettering Cancer Center, New York, NY; Joan L. Walker, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Christopher J. Darus, Maine Medical Center, Portland, ME; Gregory Sutton, Washington University School of Medicine, St. Louis, MO; Krishnansu S. Tewari, University of California Irvine Medical Center, Orange; Jai Balkissoon, Pharmaceutical Product Development International, South San Francisco, CA; Lainie P. Martin, Fox Chase Cancer Center, Philadelphia, PA; Jeanne M. Schilder, Indiana University Medical Center, Indianapolis, IN; and Robert L. Coleman, The University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract
PURPOSE: The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. PATIENTS AND METHODS: Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS: The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. CONCLUSION: On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.
RCT Entities:
PURPOSE: The vascular disrupting agent fosbretabulintromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. PATIENTS AND METHODS: Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS: The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. CONCLUSION: On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.
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