BIOREN (Predictive BIOmarkers in Metastatic RENal Cancer)

Study Overview
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Brief Summary
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The BIOREN project aims are to characterize the genetic background of renal cell carcinomas and their immune environment, to try and identify biomarkers of response and to better understand the mechanisms of resistance to nivolumab in renal cancer.

Detailed Description
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Around 338,000 new cases of renal cell carcinoma (RCC) are diagnosed worldwide per year (1). RCC is one of the most immune responsive human cancers. For a long time the only available treatment were high-dose IL-2 and IFN-α with only a few patients achieving durable responses. Clinical trials conducted in the past 15 years have led to the approval of several anti-angiogenic treatments, mainly vascular endothelial growth factor receptor (VEGFR) inhibitors and mTOR inhibitors. Currently most patients receive first line anti-VEGF therapy. Recently a better understanding of the mechanisms by which tumours evade the immune system has led to the development of checkpoint inhibitors, such as anti CTLA-4, anti-PD-1 and anti-PD-L1 antibodies that have been tested in various tumour types. Recently, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved the human IgG4 anti-PD1 monoclonal antibody, nivolumab, for advanced/metastatic clear cell RCC (ccRCC) patients who have received prior antiangiogenic therapy. PD-1 is a key immune-checkpoint receptor (ICR) expressed by activated T cells, which mediates immunosuppression primarily in peripheral tissues, where T cells may encounter the immunosuppressive PD-1 ligands, PD-L1 (B7-H1) and PD-L2(B7-DC) on tumour cells, stromal cells or both. Despite encouraging results, the clinical response to anti-PD1 is not as wide as expected and there are not any biomarkers 1) that are able to predict which patients will respond and 2) that predict response to nivolumab in patients with ccRCC. BIOREN is a translational, prospective, observational 3-cohort study. The aims of BIOREN are to characterize the genetic background of the tumours and also their immune environment, to try and identify biomarkers of response and to better understand the mechanisms of resistance to nivolumab in renal cancer. We will focus on: Tregs function and modulation of function, NK cells known to be regulated by nivolumab, The biological rationale for coupling CXCR4 antagonist with anti PD-1 therapy, analysed with mice models, To try to identify biomarkers of response by further characterization of the tumours and evaluating the immune status. The project will enrol patients receiving in 2nd or 3rd line treatment for metastatic ccRCC: Nivolumab but also, as control cohorts, either everolimus or axitinib (approved treatments in this setting), as well as cabozantinib in France (recently approved in 2nd or 3rd line). French blood samples and archival FFPE (formalin-fixed paraffin embedded) specimens will be analysed in in France, and also sent to the partners of the Transcan project Consortium (Israel, Italy and Spain).

Official Title
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BIOREN (Predictive BIOmarkers in Metastatic RENal Cancer) - A Translational Study on Immunotherapy for Metastatic Renal Cancer

Conditions
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Renal Cancer Metastatic

Intervention / Treatment
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* Biological: Immunological and tumour characterization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years-old. Histology proven locally advanced (unresectable) or metastatic clear cell renal cell carcinoma (mccRCC). Starting 2nd or 3rd line of treatment with nivolumab, everolimus, axitinib or cabozantinib as per summaries of product characteristics (SmPC) or 1st line treatment with sunitinib or pazopanib or receiving 2nd or 3rd line of treatment with nivolumab Signed informed consent. Exclusion Criteria: Psychological, familial, sociological, geographical conditions that would limit compliance with study protocol requirements. Pregnant or breastfeeding woman

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: Immunological and tumour characterization|FFPE, blood samples (liquid biopsy, heparin and EDTA blood) performed in patients presenting a renal metastatic cancer receiving treatment as standard practice according to physician's choice (2nd or 3rd line of treatment with nivolumab, everolimus, axitinib or cabozantinib [in France only], as per product SmPC or 1st line treatment with sunitinib or pazopanib or receiving 2nd or 3rd line of treatment with nivolumab)|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Tregs function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment | Ex vivo effect of CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/ US2013/0079292A1) and other Tregs targets antagonists (ICOS, CD39/CD73) or agonists (TLR7L) as putative anti-PD1 resistance mechanisms | Evolution of percentage of CD4+CD25+ CD127low FOXP3+ cells between inclusion and up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of NK function/cytotoxicity on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment | NK cytotoxicity will be evaluated through NK cell degranulation (CD107a assay), intracellular staining of the lytic proteins, Grz A and GrzB and intracellular cytokines, GM-CSF, IFNγ, IL-10, TNF. NK cell will be characterized for CXCR4; maturation markers: CD16, CD56, CD57, CD62L, NKG2A; activating receptors markers: CD25, CD69, NKp44, NKp30, NKp46, NKG2D. Ex vivo effect of CXCR4 antagonists on NK cytotoxicity. | Evolution between inclusion and up to 24 months | 
| Exploration of the biological rationale for coupling CXCR4 antagonist with anti-PD-1 in in vivo models of renal cancer (mice models). | immunocompetent model (RENCA), human xenograft model (786 cell) and humanized model | Up to 24 months | 
| Identification of response biomarkers | Characterization of the tumours using different techniques (RNASeq whole genome, NGS analysis, IHC, HTG focus RNAseq) | Up to 24 months | 
| Identification of biomarkers of response | Immune status (Multi-IF analysis, TCR sequencing and clonality analysis, Anti-HERV T cell and humoral response) | Evolution between inclusion and up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal cancer metastatic, Immunotherapy, Predictive biomarkers, Translational study