Study Evaluating the Influence of LV5FU2 Bevacizumab Plus Anakinra Association on Metastatic Colorectal Cancer (IRAFU)
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|ClinicalTrials.gov Identifier: NCT02090101|
Recruitment Status : Completed
First Posted : March 18, 2014
Last Update Posted : August 9, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Colorectal Cancer||Drug: ANAKINRA||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||32 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study Evaluating the Influence of LV5FU2 Bevacizumab Plus Anakinra Association on Vascularization of Liver Metastases of Metastatic Colorectal Cancer: Proof of Concept Study|
|Actual Study Start Date :||October 10, 2014|
|Actual Primary Completion Date :||October 10, 2014|
|Actual Study Completion Date :||May 15, 2017|
LV5FU2 + bevacizumab + anakinra
- Response rate after 2 months in patients with colorectal cancer with liver metastases treated with anakinra and LV5FU2/bevacizumab [ Time Frame: after 2 months of treatment ]
- Response rate by echography [ Time Frame: 15 days after the beggining of treatment ]
- Tumor control rate [ Time Frame: At 2, 4, 6, 9 and 12 months after the beginning of treatment ]
- Overall survival [ Time Frame: At 2, 4, 6, 9 and 12 months after the beginning of treatment ]
- Rate and safety profile according to NCI-CTCAE v4 [ Time Frame: Every 15 days before each cycle of treatment ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02090101
|Centre Georges François Leclerc|
|Dijon, Burgundy, France, 21079|