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Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy (REVOLUTION)

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ClinicalTrials.gov Identifier: NCT03891485
Recruitment Status : Recruiting
First Posted : March 27, 2019
Last Update Posted : September 11, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute, Naples

Brief Summary:
The project aims to identify Nivolumab predictive biomarkers in metastatic renal cancer patients through functional evaluation of peripheral Tregs and NKs. Moreover the efficacy of new CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/ US2013/0079292A1) will be ex vivo evaluated in modulating Tregs and NKs function

Condition or disease Intervention/treatment
RCC Metastatic Renal Cell Carcinoma Biological: Immunological and tumour characterization

Detailed Description:

Renal cell carcinomas (RCCs) is a disease with an estimated 338,000 new cases diagnosed worldwide. Approximately 30% of patients present with metastatic disease. Since November 2015 the human IgG4 anti-PD-1 monoclonal antibody, Nivolumab, was approved to treat advanced (metastatic) clear cell renal cell carcinoma (ccRCC) patients who have received a prior anti-angiogenic therapy. PD-1 (also know as CD279), is an immune checkpoint receptor (ICR) expressed on the surface of T cells. The binding with its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) expressed on tumour cells, stromal cells or both suppress effector T cells activation and inflammatory activity promoting self-tolerance and allowing cancer cells to evade immune system. Despite encouraging results in multiple solid tumors the clinical anti-PD1 response is not as wide as expected due to multiple immuno-escape mechanisms; moreover there aren't biomarkers to predict or follow RCC patient's response to Nivolumab.

Immune evasion comprise the recruitment of immunosuppressive cells and reduced access of T-effector cells to tumor microenvironment. T-regulatory cells (Tregs) suppress a whole range of immune cells and ICRs regulate generation and/or suppression of their function. Immune cell access to tumor is controlled by the chemokine CXCL12, CXCR4 ligand. CXCL12 repels tumor-specific effector T cells and recruits suppressive cell populations at tumor sites. von Hippel-Lindau (VHL) gene mutations, detectable in 70% of RCC patients, regulate immune response inducing PD-L1 expression and promoting Natural Killer (NK) cells function. Thus NK function is a crucial element in nivolumab sensitivity.

The project will enroll patients receiving Nivolumab in 2nd or 3rd line treatment for metastatic ccRCC and, as control cohorts, either everolimus or axitinib.

Aims of the project are:

  • To evaluate 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
  • To evaluate NK function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment. Ex vivo effect of CXCR4 antagonists

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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy
Actual Study Start Date : December 2016
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021



Intervention Details:
  • 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, or other second line according to physician's choice)


Primary Outcome Measures :
  1. Tregs function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment. [ Time Frame: Evolution between inclusion up to 24 months ]
    Treg function will be mesured as % inhibition of T-effector proliferation (Tregs/T-effector 1:1 ratio). %T-effector proliferation in the presence of patients derived Tregs (Tregs/T-effector 1:1). Ex vivo effect of CXCR4 antagonists ( PCT/IB2011/000120; EP 2 528 936 B1/US2013/0079292A1) and other Tregs targets antagonists (ICOS, CD39/CD73) or agonists (TLR7L) will be assessed to identify novel anti-PD1 resistance mechanisms.

  2. NK function/cytotoxicity on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment [ Time Frame: Evolution between inclusion and up to 24 months ]
    NK cytotoxicity will be measured as % NK cell degranulation (CD107a assay), intracellular staining Grz A and GrzB and intracellular cytokines, GM-CSF, IFNγ, IL-10, TNF. Ex vivo effect of CXCR4 antagonists will be evaluated on NK cytotoxicity.


Secondary Outcome Measures :
  1. Exploration of the biological rationale for coupling CXCR4 antagonist with anti-PD-1 in in vivo models of RCC (mice models) [ Time Frame: 36 months ]

    The effect of anti-PD1 and CXCR4 antagonists on tumor and tumor microenvironment cells will be evaluated in:

    • Immunocompetent model (RENCA): % tumor growth; % positive cells Granzyme/ Foxp3
    • Human xenograft model (786 cell): % tumor growth


Biospecimen Retention:   Samples Without DNA

Archival FFPE specimen.

Blood samples performed during standard visits and not requiring additional blood tests:

  • Heparin blood
  • EDTA blood


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Men and women with histological confirmation of advanced/metastatic RCC
Criteria

Men and women with histological confirmation of advanced/metastatic RCC with not more than 2 previous therapy lines

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 or axitinib
  • Signed informed consent.

Exclusion Criteria:

  • Psychological, familial, sociological, geographical conditions that would limit compliance with study protocol requirements.
  • Pregnant or breastfeeding woman

Information from the National Library of Medicine

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): NCT03891485


Contacts
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Contact: Stefania Scala, MD, PhD 0815903820 s.scala@istitutotumori.na.it

Locations
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Italy
IRCCS Istituto Nazionale Tumori di Napoli Recruiting
Naples, Italy, 80131
Contact: Stefania Scala, MD, PhD    0815903820    s.scala@istitutotumori.na.it   
Principal Investigator: Stefania Scala, MD, PhD         
Principal Investigator: Sandro Pignata, MD, PhD         
Sponsors and Collaborators
National Cancer Institute, Naples
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Responsible Party: National Cancer Institute, Naples
ClinicalTrials.gov Identifier: NCT03891485    
Other Study ID Numbers: 21/16 oss
First Posted: March 27, 2019    Key Record Dates
Last Update Posted: September 11, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Cancer Institute, Naples:
Nivolumab
CXCR4 antagonist
mRCC
Tregs-NKs
Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases