Neoplasms

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Colorectal Neoplasms

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Gastrointestinal Neoplasms

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Gastrointestinal Diseases

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Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Durvalumab

Tremelimumab

Antineoplastic Agents, Immunological

* Durvalumab for 12 months
* Tremelimumab for up to 4 doses/cycles
* FOLFOX

Study will be performed in 2 step:

STEP 1 (phase Ib) will assess the safety of the combination of Durvalumab 750mg q2w + tremelimumab 75mg q4w + FOLFOX during the 2 first cycles of treatment (1 month)

STEP 2 (phase II) will assess the efficacy of the combination of Durvalumab 750mg q2w + tremelimumab 75mg q4w + FOLFOX

Durvalumab, Tremelimumab and ,FOLFOX

Colo-rectal cancer is still one of the leading causes of cancer death worldwide. In France, approximately 40 500 new cases are diagnosed each year. With more than 17 500 deaths in France in 2011, colo-rectal cancer is responsible for more than 12% of all cancer deaths, the overwhelming of deaths occurring in patients with metastatic disease.

Many studies highlight the fact that colo-rectal cancer has immunogenic properties and that host immune responses can influence survival. Recent data have provided a clearer understanding of the factors limiting the antitumor immune response in colo-rectal cancer. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) and PD ligand 1 (PD-L1) pathway.

PD-1 is expressed on activated immune cells and can link to PD-L1 express on Antigen-Presenting-Cell. Usually, this pathway is involved in promoting T-cells tolerance and preventing tissue damage in settings of chronic inflammation. In pathological context, the PD-1/PD-L1 pathway contributes to immune suppression and evasion. Many human solid tumors including colo-rectal cancer express PD-L1, and this expression is associated with a worse prognosis. The interaction of PD-1 with the ligand PD-L1 inhibits T-cell proliferation, survival, and effectors functions; induces apoptosis of tumor-specific T cells; promotes the differentiation of CD4+ T cells into immunosuppressive regulatory T cells; and increases the resistance of tumor cells to cytotoxic T lymphocytes attack. Thus, the blockage of the PD-1/PD-L1 interactions represents a logical target for cancer immunotherapy and in particular colo rectal cancer immunotherapy strategy.

Preclinical studies have shown that PD-L1 blockade improves the immune response by restoring T-cell effectors functions. Recent work in two in vivo tumor models shows a strong interest in using an anti-PD-L1 in combination with standard treatment of colo-rectal cancer (FOLFOX). In these models, the survival of mice that are treated with the combination therapy reached 40% when no mice were alive with FOLFOX treatment alone. This result may be explained, in one hand by cytotoxicity of 5FU and in the other hand by the restoration of anti-tumor immune activity of anti-PD-L1. These results suggest that the combination of chemotherapy with immunotherapy would act synergistically in patients with colo-rectal cancer.

Research Hypothesis: Combination of chemotherapy (FOLFOX) with immunotherapy association (anti-PD-L1 + anti-CTLA-4) would act synergistically in patients with colo-rectal cancer.

Phase Ib primary objective (STEP 1): To determine the safety of the combination of Durvalumab (Anti-PD-L1) + Tremelimumab (Anti-CTLA-4) + FOLFOX

Phase II primary objective (STEP 2): To determine the efficacy of the combination of Durvalumab (Anti-PD-L1) + Tremelimumab (Anti-CTLA-4) + FOLFOX in terms of progression free survival (PFS).

Phase II secondary Objective: To determine efficacy of the combination of Durvalumab (Anti-PD-L1) + Tremelimumab (Anti-CTLA-4) + FOLFOX in terms of response to treatment and overall survival.

Step 1: Phase Ib with the aim to confirmed the safety of the association of Durvalumab (q2w 750mg) + Tremelimumab (q4w 75mg) + FOLFOX

Step 2: Phase II with the aim to assess efficacy of the association of Durvalumab (q2w 750mg) + Tremelimumab (q4w 75mg) + FOLFOX

Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC

Phase Ib/II Trial Evaluating the Safety, Tolerability and Immunological Activity of Durvalumab (MEDI4736) (Anti-PD-L1) Plus Tremelimumab (Anti-CTLA-4) Combined With FOLFOX in Patients With Metastatic Colorectal Cancer

AstraZeneca

Centre Georges Francois Leclerc

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC	NCT03202758	Colorectal Canc...	Durvalumab, Tre...	18 Years -	Centre Georges Francois Leclerc
Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC	NCT03202758	Colorectal Canc...	Durvalumab, Tre...	18 Years -	Centre Georges Francois Leclerc

Spots Global Cancer Trial Database for durvalumab, tremelimumab and ,folfox