Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas
Condition: Sarcoma; Soft Tissue Sarcoma; Locally Advanced Sarcoma; Unresectable Sarcoma; Metastatic Sarcoma
MeSH terms: Sarcoma
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to test the combination of the chemotherapy drugs Gemcitabine,
      bevacizumab, and docetaxel with valproic acid to treat patients with metastatic sarcoma.
      Valproic acid is used by people who have seizures to prevent seizures from happening;
      however, its use in cancer is investigational. This study will help define the proper dosing
      of this valproic acid. We will assess the safety of valproic acid with the combination of the
      above chemotherapy drugs and check for possible side effects. Valproic acid may improve the
      function of the chemotherapy drugs against the cancer.
    

Detailed description: 
      Soft tissue sarcomas (STS) are a heterogeneous group of benign and malignant tumors of
      various supportive tissues arising from the mesoderm. There are 56 known subtypes classified
      by the tissue of origin. Soft tissue sarcomas account for 1% of all human malignancies. These
      tumors share a common mesenchymal origin with the vasculature. Many of the signaling pathways
      involved in angiogenesis also drive sarcoma tumor cell growth. Autocrine and paracrine
      vascular endothelial growth factor (VEGF) - and platelet-derived growth factor
      (PDGF)-mediated growth plays a role in the pathogenesis of several sarcoma subtypes1. Despite
      promising preclinical data supporting a role for angiogenesis inhibition in sarcoma,
      relatively few clinical trials have evaluated antiangiogenic therapy in sarcoma.

      Most of the studies for the use of anti-angiogenic drugs have been taken from phase I trials
      of refractory solid tumors showing a lack of response in sarcomas. This may be due to an
      inadequate dose, wrong sequence of the treatment or lack of studies with combination
      treatments. Given the heterogeneity of sarcomas there may be a benefit in certain subgroups
      that can easily be missed. A recent clinical trial has shown improved cytotoxic cell kill and
      response rates by epigenetically modifying the tumor environment prior to chemotherapy. It is
      believed that the efficacy of angiogenesis inhibitors has been shown to be greatly improved
      when they are combined with other anticancer drugs.

      Tumor metastasis is highly dependent on angiogenesis progressing through a metastatic cascade
      that includes primary tumor growth, modification of tumor cell growth and behavior and
      formation of new blood vessels. This angiogenic switch is believed to be the result of
      changes in the balance of angiogenesis stimulators, inhibitors and modulators present at the
      site of the tumor growth. These changes are due to both genetic alterations involving RAS,
      RAF, MYC, SRC, EGFR and HER-2 and tumor suppressor genes and epigenetic circumstances such as
      hypoxia, inflammation or hormonal stimulation. It is clear that vascular endothelial growth
      factor (VEGF) has emerged as the key stimulatory molecule for promoting angiogenesis in a
      variety of human malignancies. Other pro-angiogenic factors can be induced or amplified in
      the presence of hypoxia hypoglycemia, inflammatory cytokines and altered cell-cell contact.
      Thus it would be of interest to combine epigenetic modifiers like Valproic acid, a histone
      deacetylase inhibitor, with Bevacizumab, an anti-angiogenic agent against VEGF and standard
      chemotherapy (Gemcitabine /docetaxel) to better modulate the cytotoxic effects against
      sarcomas.
    

Intervention name(s): Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid
Intervention type(s): Drug
Other intervention name(s): Avastin; Gemzar; Taxotere; Depakene; Stavzor
Intervention MeSH terms: Bevacizumab; Gemcitabine; Docetaxel; Valproic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sarcoma; Soft Tissue Sarcoma; Locally Advanced Sarcoma; Unresectable Sarcoma; Metastatic Sarcoma; Valproic Acid; Bevacizumab; Histone Deacetylase Inhibitor