Immune Modulation Study in Patients With Metastatic Melanoma Treated With Anti-PD1 Monoclonal Antibodies

Study Overview
=================
Brief Summary
-----------------
This is an open mono-centric prospective non-randomized study in patients with metastatic melanoma treated with Anti-PD1 monoclonal antibodies (Nivolumab). The aim of the study is to identify the immune cells modulations differences between patients who present a complete, partial or stable response and patients who have non-response to the therapy in order to establish an improving response rate strategy.

Official Title
-----------------
Immune Modulation Study in Patients With Metastatic Melanoma Treated With Anti-PD1 Monoclonal Antibodies

Conditions
-----------------
Metastatic Melanoma

Intervention / Treatment
-----------------
* Biological: blood sampling
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women aged ≥ 18 years Patient with metastatic or unresectable melanoma Anti-PD1 monoclonal antibodies treatment indication Patient affiliated to a social security regime Signed Written Informed Consent. agree with the storage of his biological samples Women of childbearing potential must as mentioned in the summary of product characteristics (SPC) using two effective methods of contraception during treatment, and men whose partner is of childbearing potential must use effective contraception during treatment. For all patients treated men and women, contraception should be continued during the four months following the discontinuation of nivolumab. Exclusion Criteria: development of haematological tumor during treatment Patients requiring concomitant chronic treatment with systemic corticosteroids or other immunosuppressive agents Patients with autoimmune disease. Patient with Occular melanoma

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab, patients with BRAF mutation<br>Nivolumab (dose equal to 3mg/kg), 10 mg/ml solution for infusion. injection of Nivolumab every two weeks from day 0 and until relapse, toxicity motivating withdrawal or temporary suspension of treatment or up to 54 weeks. Blood sampling at different time | Biological: blood sampling<br>* Blood samples (44mL) will be taken before starting treatment with Nivolumab and at week 2, week 12, week 54 or at relapse (before week 54)<br>Drug: Nivolumab<br>* injection of Nivolumab every two weeks from day 0 and until relapse, toxicity motivating withdrawal or temporary suspension of treatment or up to 54 weeks.<br>|
| Experimental: Nivolumab, patients with BRAF wild type<br>Nivolumab (dose equal to 3mg/kg), 10 mg/ml solution for infusion. injection of Nivolumab every two weeks from day 0 and until relapse, toxicity motivating withdrawal or temporary suspension of treatment or up to 54 weeks. Blood sampling at different time | Biological: blood sampling<br>* Blood samples (44mL) will be taken before starting treatment with Nivolumab and at week 2, week 12, week 54 or at relapse (before week 54)<br>Drug: Nivolumab<br>* injection of Nivolumab every two weeks from day 0 and until relapse, toxicity motivating withdrawal or temporary suspension of treatment or up to 54 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change the absolute number of dendritic cells before treatment and on treatment | absolute number / mm 3 of dendritic cells | before treatment (week 0), at week 2, at week 12, at week 54 or at relapse (before 54 weeks) | 
| change the percentage of cells producing cytokines in dendritic cells before treatment and on treatment | % of cells producing cytokines in dendritic cells | before treatment (week 0), at week 2, at week 12, at week 54 or at relapse (before 54 weeks) | 
| change the absolute number of subpopulations of T lymphocytes before treatment and on treatment | absolute number / mm 3 of different subpopulations of T lymphocyte | before treatment (week 0), at week 2, at week 12, at week 54 or at relapse (before 54 weeks) | 
| change the absolute number of monocytes before treatment and on treatment | absolute number / mm 3 of monocytes | before treatment (week 0), at week 2, at week 12, at week 54 or at relapse (before 54 weeks) | 
| change the percentage of cells producing cytokines in subpopulations of T lymphocytes before treatment and on treatment | % of cells producing cytokines in subpopulations of T lymphocytes | before treatment (week 0), at week 2, at week 12, at week 54 or at relapse (before 54 weeks) | 
| change the percentage of cells producing cytokines in monocytes before treatment and on treatment | % of cells producing cytokines in monocytes | before treatment (week 0), at week 2, at week 12, at week 54 or at relapse (before 54 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| correlation between biological parameters and progression-free survival | absolute number / mm 3 of different population of cells and % of cells producing cytokines in the different population of cells will be correlated with the progression free survival | progression between the date of first injection of immunotherapy and week 54 based on RECIST and ir-RECIST criterion | 
| correlation between biological parameters on overall survival | absolute number / mm 3 of different population of cells and % of cells producing cytokines in the different population of cells will be correlated with the overall survival | death between the date of first injection of immunotherapy and week 54 | 
| Identify predictive factors of overall response rate at week 12 based on RECIST and ir-RECIST criteria | predictive factors like histological and cytological initial tumor type, initial immunological status will be evaluated at inclusion and correlated with the response | response evaluation at week 12 | 
| impact of treatments received prior to inclusion in the study on the biological parameters before and on treatment | absolute number / mm 3 of different population of cells and % of cells producing cytokines in the different population of cells will be correlated with treatments received prior to inclusion | antitumor treatment received from diagnosis of melanoma to inclusion | 
| correlation between the occurrence of autoimmune side effects and the biological parameters before and on treatment | absolute number / mm 3 of different population of cells and % of cells producing cytokines in the different population of cells will be correlated with autoimmune side effects, based on CTCAE classification | occurence of autoimmune side effects from day 0 to week 54 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Melanoma, Anti-PD1 monoclonal antibodies, Immune modulation, BRAF