NCT03202758: MEDITREME

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

Completed Phase 1, PHASE2 Last updated 10 February 2023

What this trial tests

Phase 1, PHASE2 trial testing Durvalumab, Tremelimumab and ,FOLFOX in Colorectal Cancer Metastatic in 57 participants. Completed in 9 January 2023.

Timeline

29 August 2017

Primary endpoint
9 January 2023

9 January 2023

Quick facts

Lead sponsor	Centre Georges Francois Leclerc
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	57
Start date	29 August 2017
Primary completion	9 January 2023
Estimated completion	9 January 2023
Sites	5 locations across France

Drugs / interventions tested

• Durvalumab, Tremelimumab and ,FOLFOX — full drug profile →

Conditions studied

• Colorectal Cancer Metastatic — all drugs for Colorectal Cancer Metastatic →

Sponsor

Centre Georges Francois Leclerc — full company profile →

Who can join

18 and older, any sex, with Colorectal Cancer Metastatic. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Comprehensive review of targeted therapy for colorectal cancer.
   Xie YH, Chen YX, Fang JY. · · 2020 · cited 1162× · PMID 32296018 · DOI 10.1038/s41392-020-0116-z
2. Exploring immunotherapy in colorectal cancer.
   Weng J, Li S, Zhu Z, Liu Q, et al · · 2022 · cited 250× · PMID 35842707 · DOI 10.1186/s13045-022-01294-4
3. Review of PD-1/PD-L1 Inhibitors in Metastatic dMMR/MSI-H Colorectal Cancer.
   Oliveira AF, Bretes L, Furtado I. · · 2019 · cited 152× · PMID 31139574 · DOI 10.3389/fonc.2019.00396
4. Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives.
   Shi X, Wang X, Yao W, Shi D, et al · · 2024 · cited 139× · PMID 39090094 · DOI 10.1038/s41392-024-01885-2
5. Targeting Myeloid-Derived Suppressor Cell, a Promising Strategy to Overcome Resistance to Immune Checkpoint Inhibitors.
   Hou A, Hou K, Huang Q, Lei Y, et al · · 2020 · cited 115× · PMID 32508809 · DOI 10.3389/fimmu.2020.00783
6. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial.
   Thibaudin M, Fumet JD, Chibaudel B, Bennouna J, et al · · 2023 · cited 80× · PMID 37563240 · DOI 10.1038/s41591-023-02497-z
7. Immunotherapy in Colorectal Cancer: Current and Future Strategies.
   Ooki A, Shinozaki E, Yamaguchi K. · · 2021 · cited 80× · PMID 33537496 · DOI 10.23922/jarc.2020-064
8. Immune checkpoint inhibitors: breakthroughs in cancer treatment.
   Kong X, Zhang J, Chen S, Wang X, et al · · 2024 · cited 71× · PMID 38801082 · DOI 10.20892/j.issn.2095-3941.2024.0055