New Vascular Disrupting Agent In Combination With Avastin Produces a 64% Disease Stabilization Rate in a Small Phase I Solid Tumor Clinical Trial

In solid tumors, [vascular disrupting agents] VDA’s, such as ZYBRESTAT™, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies (e.g., bevacizumab/Avastin™), which are designed to prevent new blood vessel formation. … Specifically, Zybrestat™ was tested on advanced solid malignancies in Phase I clinical trial involving 14 patients. … Nine of fourteen patients experienced disease stabilization for greater than 12 weeks. Three patients experienced disease stabilization for greater than 24 weeks, with two of these patients continuing with stable disease at 47 and 29 weeks, respectively.

Based upon an abstract presentation made at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting recently held in Chicago on May 30th through June 3rd, the new vascular disrupting agent (VDA) Zybrestat™ (fosbretabulin) produced an advanced solid tumor disease stabilization rate of 64 percent.

Vascular disruption represents a new approach to a validated therapeutic strategy: depriving tumors of blood supply. In solid tumors, VDA’s, such as ZYBRESTAT™, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies (e.g., bevacizumab/Avastin™), which are designed to prevent new blood vessel formation. OXiGENE Inc. (OXiGENE) believes its VDA product candidates may offer advantages over current anti-angiogenic drugs, including superior efficacy and reduced side-effects.

In addition, there is a strong scientific rationale for combining VDA and anti-angiogenesis therapies. OXiGENE and its scientific collaborators have published preclinical research results showing that the combination of OXiGENE VDAs and certain anti-angiogenic drugs (i.e., monoclonal antibodies targeting vascular endothelial growth factor, or VEGF) have synergistic anti-tumor effects. Building upon these results, OXiGENE has undertaken the first-ever human clinical trial of a VDA (ZYBRESTAT) in combination with an anti-angiogenic agent (bevacizumab / AVASTIN.) The additional benefits of vascular disrupting agents include:

  • This method of treatment is designed to target newly formed abnormal blood vessels, rather than the established blood vessels found in healthy tissue, resulting in fewer side effects in the oncology setting than conventional disease treatments such as radiation and chemotherapy. VDAs are designed to address the complete spectrum of solid tumors, whereas other approaches, which directly target tumor cells, require the development of different drugs for different types of solid tumors.
  • VDAs are designed to target endothelial cells associated with new blood vessel formation, so drug resistant mutations are unlikely to occur.
  • Damaging one or two blood vessels can cause thousands of tumor cells to die.
  • The ability of VDAs to selectively target newly formed or abnormal blood vessels makes them well-suited for certain ocular diseases, such as age-related macular degeneration, in which the formation of new, abnormal blood vessels in the eye plays a key role in disease.

Specifically, Zybrestat™ was tested on advanced solid malignancies in Phase I clinical trial involving 14 patients. The patients were divided into three separate dosage cohorts, representing 45mg/m2 (cohort 1), 54mg/m2 (cohort 2) or 63mg/m2 (cohort 3) of Zybrestat™ every 14 days followed by bevacizumab (Avastin™) at a dosage of 10mg/kg four hours later. The study results indicated two grade 3/4 drug dosage limiting toxicities. Nine of fourteen patients experienced disease stabilization for greater than 12 weeks. Three patients experienced disease stabilization for greater than 24 weeks, with two of these patients continuing with stable disease at 47 and 29 weeks, respectively. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed statistically significant reductions in tumor perfusion/vascular permeability which reversed when Zybrestat™ was used as a monotherapy, but were sustained following the use of bevacizumab (Avastin™). The clinical trial investigators concluded that Zybrestat™ was safe and tolerable at the three dosage levels used, and noted that Zybrestat™ induced profound vascular changes in the solid tumor which were maintained by the presence of bevacizumab (Avastin™).

Sources:

Comment: ZYBRESTAT™ has broad potential therapeutic utility across a wide range of different solid tumor types, and can potentially be combined with mainstay oncology treatment modalities: chemotherapy, radiation therapy and newer, “molecularly-targeted therapies,” such as tumor angiogenesis inhibitors. Preclinical studies have demonstrated that ZYBRESTAT™ has synergistic or additive effects when incorporated in various combination regimens with all of these treatment modalities. There is a strong scientific rationale for combining ZYBRESTAT™ and tumor angiogenesis inhibiting drugs, and ZYBRESTAT™ is the first VDA to be tested in humans in combination with a tumor-angiogenesis-inhibiting drug (bevacizumab / AVASTIN®).

2 thoughts on “New Vascular Disrupting Agent In Combination With Avastin Produces a 64% Disease Stabilization Rate in a Small Phase I Solid Tumor Clinical Trial

  1. Was 12 weeks a threshold for success with monotherapy? Did I read that Zybrestat was not effect as a monotherapy in this trial because the results were temporary? When can we expect more good news? My mother-in-law has macular degeneration and has eye injections. Good luck and thank you, I have invested my faith and money in Oxgn and would love to see cancer victums have some hope.

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    • Chris,

      Thank you for your comment. As you know, Zybrestat is a new vacular disrupting agent produced by OXiGene, Inc. Your comment relates to an older post dated June 15, 2008. The current information about the use of Zybrestat against ovarian cancer can be found by clicking here. The current information about the potential use of Zybrestat in ophthalmology can be found by clicking here.

      It is likely that Zybrestat will continue to be tested against ovarian cancer in combination with other therapies, because the current standard of care 1st line treatment for ovarian cancer is use of a platinum drug & a taxane drugs. Zybrestat is used in tandem with these drugs so as to maximize the attack against ovarian cancer cells (e.g., one drug stops cell growth, while another cuts of tumor blood supply). Zybrestat works by destroying the existing blood vessel network within a tumor, whereas typical antiangiogenesis drugs work by stopping the growth of new blood vessels to the tumor.

      I have not heard about OXiGENE’s specific plans for use of Zybrestat in ophthalmology, but the use of Zybrestat in eye drop form is clearly more patient friendly than injection of the drug into the eye.

      And, it is good that all ovarian cancer patients see hope not only in Zybrestat, but in all of the clinical development drugs listed at Libby’s H*O*P*E*.

      Best, Paul

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