Study Evaluating the Influence of LV5FU2 Bevacizumab Plus Anakinra Association on Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      The metastatic colon cancer is a major public health problem despite advances in
      chemotherapy; few new drugs are in development for the treatment of this pathology.

      Many studies have shown that human colon cancer is a tumor that is recognized by the immune
      system and the presence of lymphocytic infiltrates in the tumor bed is associated with a
      better prognosis. Conversely, the effect of chemotherapy on the immune response is little
      studied.

      Recently the importance of myeloid suppressor cells (MDSC) in the development of colon cancer
      and the effect of 5- fluorouracil on this cell population has been highlighted. An
      accumulation of these cells in the blood and lymphoid organs during tumor progression is
      observed. Moreover, it has been established that the death of MDSC induced by 5-fluorouracil
      induces activation of caspase -1 and IL-1beta by these MDSC.

      These events promote the polarization of CD4 T cells in intratumoral Th17 lymphocytes. The
      IL- 17 produced by these cells exerts a pro-angiogenic effect in inducing proliferation of
      endothelial cells expressing and thus limits the effect of 5- fluorouracil endoglin.

      In humans, it has also been observed that chemotherapy using 5- fluorouracil and in
      particular LV5FU2 association +/- bevacizumab induces rapid death of blood MDSC as well as
      activation of caspase 1 in these cells. Thus, production of IL - 1 is detected in the serum
      of patients after 24 hours of the administration of 5-fluorouracil.

      Chronic inflammation and the production of interleukin- 1 can alter the effectiveness of anti
      -tumor immune responses and facilitate angiogenesis. Many preclinical data suggest a role of
      anti -tumor inhibition of IL- 1beta, but the effect of a combination of chemotherapy and an
      inhibitor of IL - 1beta has not yet been tested in human.

      Anakinra is a drug used in humans for many years to treat signs and symptoms of rheumatoid
      arthritis. In combination with methotrexate, in patients whose response to methotrexate alone
      is not satisfactory it had shown interesting results. The dose used clinically is 100 mg per
      day which is the dose that is proposed to be tested in this study.

      In this context it should be remembered that methotrexate is a chemotherapeutic agent from
      the class of antimetabolites such as 5- fluorouracil.

      RCP of this drug indicate that in studies originator toxicity was similar between the control
      arm and anakinra arm with an increase in serious infections (1.8 % vs 0.7 %) and an increased
      incidence of neutropenia (2.5 % neutropenia > grade = 1). The main toxicity observed is a
      painful inflammatory reaction at the injection site in 70 % of patients The investigators
      believe that this project could permit to validate in man preclinical observations showing an
      anti-tumor potential for combination anakinra and 5 fluorouracil.
    


Intervention name(s): ANAKINRA
Intervention type(s): Drug
Intervention MeSH terms: Interleukin 1 Receptor Antagonist Protein
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment