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/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.

Trial registration: ClinicalTrials.gov NCT01305213.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

Fosbretabulin mechanism of action. CA4P, combretastatin A4 mono tris phosphate. Reprinted with permission.

Fig 2.

CONSORT diagram.

Fig 3.

(A) Progression-free survival (PFS) analysis by intention to treat. (B) Overall survival (OS) analysis by intention to treat.

Fig 4.

Progression-free survival for prespecified covariates. The upper bound has been truncated at a hazard ratio equal to 2.5. *The true upper bound for 66 to ≤72 is 2.69. †The true upper bound for Other types is 4.797 (with only 16 people in this group). PFI, platinum-free interval.

Fig A1.

Progression-free survival (PFS) among platinum-resistant patients by treatment. The hazard ratio was 0.57 (log-rank P = .01) for comparison of the experimental level to the reference level by treatment stratified by measurable disease status (yes/no) and prior bevacizumab use (yes/no), using a Cox proportional hazards model. The CI is questionable, which may be the result of the small number of patients within some strata and is therefore not available.

Fig A2.

Progression-free survival (PFS) among platinum-sensitive patients with a PFI of more than 6 months. The hazard ratio was 0.67 (90% CI, 0.43 to 1.03; log-rank P = .14) for comparison of the experimental level to the reference level by treatment stratified by measurable disease status (yes/no), prior bevacizumab use (yes/no), and platinum sensitivity (> 12 months/ ≤ 12 months) using a Cox proportional hazards model. PFI, platinum-free interval.