Study Evaluating the Influence of LV5FU2 Bevacizumab Plus Anakinra Association on Metastatic Colorectal Cancer
Status:
Completed
Trial end date:
2017-05-15
Target enrollment:
Participant gender:
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.
Phase:
Phase 2
Details
Lead Sponsor:
Centre Georges Francois Leclerc
Treatments:
Bevacizumab Interleukin 1 Receptor Antagonist Protein