Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study

Bradley J. Monk, Michael W. Sill, Joan L. Walker, Christopher J. Darus, Gregory Sutton, Krishnansu S. Tewari, Lainie P. Martin, Jeanne Schilder, Robert L. Coleman, Jai Balkissoon, Carol Aghajanian

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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/m2) 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.

Original languageEnglish (US)
Pages (from-to)2279-2286
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number19
DOIs
StatePublished - Jul 1 2016

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Carcinoma
Disease-Free Survival
Blood Vessels
Endothelial Growth Factors
Bevacizumab
fosbretabulin
Hypertension
Intestinal Fistula
Tromethamine
Random Allocation
Platinum
Disease Progression
Neoplasms
Cell Death
Necrosis
Monoclonal Antibodies
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma : An NRG oncology/gynecologic oncology group study. / Monk, Bradley J.; Sill, Michael W.; Walker, Joan L.; Darus, Christopher J.; Sutton, Gregory; Tewari, Krishnansu S.; Martin, Lainie P.; Schilder, Jeanne; Coleman, Robert L.; Balkissoon, Jai; Aghajanian, Carol.

In: Journal of Clinical Oncology, Vol. 34, No. 19, 01.07.2016, p. 2279-2286.

Research output: Contribution to journalArticle

Monk, Bradley J. ; Sill, Michael W. ; Walker, Joan L. ; Darus, Christopher J. ; Sutton, Gregory ; Tewari, Krishnansu S. ; Martin, Lainie P. ; Schilder, Jeanne ; Coleman, Robert L. ; Balkissoon, Jai ; Aghajanian, Carol. / Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma : An NRG oncology/gynecologic oncology group study. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 19. pp. 2279-2286.
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title = "Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study",
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/m2) 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.",
author = "Monk, {Bradley J.} and Sill, {Michael W.} and Walker, {Joan L.} and Darus, {Christopher J.} and Gregory Sutton and Tewari, {Krishnansu S.} and Martin, {Lainie P.} and Jeanne Schilder and Coleman, {Robert L.} and Jai Balkissoon and Carol Aghajanian",
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T1 - Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma

T2 - An NRG oncology/gynecologic oncology group study

AU - Monk, Bradley J.

AU - Sill, Michael W.

AU - Walker, Joan L.

AU - Darus, Christopher J.

AU - Sutton, Gregory

AU - Tewari, Krishnansu S.

AU - Martin, Lainie P.

AU - Schilder, Jeanne

AU - Coleman, Robert L.

AU - Balkissoon, Jai

AU - Aghajanian, Carol

PY - 2016/7/1

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N2 - 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/m2) 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.

AB - 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/m2) 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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