Novel Combination May Extend Survival in Ovarian Cancer

Two agents with contrasting mechanisms of actions exert synergistic effects while limiting tumor blood supply in ovarian cancer. Patient enrollment began this month (October 2014) for a new phase 1b/2 clinical study1 to evaluate this novel combination with the VDA fosbretabulin plus pazopanib.

Two agents with contrasting mechanisms of actions exert synergistic effects while limiting tumor blood supply in ovarian cancer. Patient enrollment began this month (October 2014) for a new phase Ib/II clinical study1to evaluate this novel combination with the vascular disrupting agent (VDA) fosbretabulin plus the oral antiangiogenic tyrosine kinase inhibitor, pazopanib (Votrient).

Depriving tumor cells of blood flow has proven useful in many cancer therapies. Fosbretabulin represents a new approach to this strategy by disrupting existing tumor vasculature, thereby blocking nutrients and oxygen from the tumor. The agent binds tubulin in the endothelial cells that line the highly permeable tumor vessels, obstructing blood flow to the solid mass.

Preclinical studies indicate that cells at the tumor rim may survive and revascularize after VDA treatment, possibly due to activation of circulating endothelial progenitor cells. Antiangiogenic treatment may disrupt this process and enhance the effects of the VDA.2

Pazopanib, one of several anticancer agents that have been developed to prevent new blood vessel formation, targets multiple angiogenic pathways by inhibiting several protein kinase receptors, including the receptors for VEGF, PDGF, and FGF, among others.

To test fosbretabulin and pazopanib in combination, the randomized controlled trial is estimated to enroll 128 patients with relapsed ovarian cancer in the United Kingdom, and will include a dose-escalation portion and a phase II portion that compares pazopanib with the combination of pazopanib and fosbretabulin.

“This study is an important first step to evaluate the potential combination of a vascular disrupting agent with an oral antiangiogenic agent,” said professor Gordon Rustin, director of Medical Oncology, Mount Vernon Cancer Centre and a chief investigator for the study.

“Recent clinical data suggest that combining fosbretabulin with the antiangiogenic agent bevacizumab (Avastin) may provide a complementary effect in ovarian cancer patients, and we are hopeful to see a positive result in this new study that would further advance nonchemotherapeutic treatment approaches for patients with relapsed ovarian cancer,” Rustin said.

Conducted by the Gynecologic Oncology Group (GOG) and sponsored by the National Cancer Institute, the ongoing trial evaluating fosbretabulin in combination with bevacizumab (Avastin) has shown promising results.3The intravenously delivered antiangiogenic agent bevacizumab is a recombinant humanized monoclonal antibody against VEGF, a key mediator of tumor growth. The phase II study randomized 107 patients with <3 prior regimens to receive fosbretabulin and bevacizumab or bevacizumab alone. The median progression-free survival for bevacizumab compared with bevacizumab + fosbretabulin was 4.8 and 7.3 months, respectively (hazard ratio = 0.685,P< .05). Patients who received the combination therapy had more adverse events, particularly hypertension (35% vs 15%), compared with those taking the single agent.4

"These findings validate both the novel approach and the complementary mechanisms of combining the vascular disrupting agent fosbretabulin and an antiangiogenic agent like bevacizumab (Avastin) in patients with ovarian cancer," said Bradley J. Monk, MD, FACS, FACOG, principal investigator for the trial, and professor and director, division of Gynecologic Oncology and department of Obstetrics and Gynecology at the University of Arizona Cancer Center.

"This promising combination warrants further evaluation particularly given the significant need for new treatment options in relapsed ovarian cancer."

References

  1. Oxigene. Oxigene Announces First Patient Enrolled in Phase 1b/2 Study of Fosbretabulin Combined With Pazopanib in Patients With Advanced Recurrent Ovarian Cancer. http://investor.oxigene.com/releasedetail.cfm?ReleaseID=875031. Accessed August 17, 2014.
  2. Nathan P, Zweifel M, Padhani AR, et al. Phase I trial of combretastatin A4 phosphate(CA4P) in combination with bevacizumab in patients with advanced cancer.Clin Cancer Res. 2012;18(12):3428-39.
  3. Oxigene. UPDATE -- Oxigene Announces Positive Topline Results From Randomized Phase 2 Study GOG186I of ZYBRESTAT(R) in Combination With Avastin(R) for Recurrent Ovarian Cancer. http://investor.oxigene.com/releasedetail.cfm?ReleaseID=832026. Accessed August 17, 2014.
  4. Monk B, Sill M, Walker P, et al. Randomized Phase 2 Evaluation of Bevacizumab Versus Bevacizumab/Fosbretabulin in Recurrent Ovarian, Tubal or Peritonieal Carcinoma: A Gynecologic Oncology Group Study. Oral Session to be presented at: 15th Biennial Meeting of the International Gynecologic Cancer Society, 2014 Nov 8-11; Melbourne, Australia