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ELR+CXCL Cytokines in Metastatic Kidney Cancers: Predictive Markers of Resistance to Sunitinib (SUNITRES)

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ClinicalTrials.gov Identifier: NCT03097601
Recruitment Status : Active, not recruiting
First Posted : March 31, 2017
Last Update Posted : October 8, 2019
Sponsor:
Collaborator:
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Centre Antoine Lacassagne

Brief Summary:
Metastatic renal cell carcinomas (mRCC) are highly angiogenic tumors because of mutation of the pVHL gene leading to over-expression of VEGF. Therefore, mRCC represent a paradigm for the use of anti-angiogenic treatments targeting the VEGF/VEGFR pathway. Despite an increase of the time to progression these treatments, taken alone, are not curative with ineluctable progression especially for the reference treatment sunitinib a multi kinase inhibitors of VEGF, PDGF, CSF1 receptors and c-kit, FLT3 and RET. At progression on sunitinib, patients received mTOR inhibitors which is responsible, at least, of HIF1A mRNA translation, then on a third line sorafenib that inhibits VEGFR2, 3 PDGFR, c-KIT and B-RAF. The access to these different lines of treatment has finally prolonged survival but this situation is not satisfactory. Unexpected aspect associated with the use of anti-angiogenesis treatments was the diversity of the patients' response. Some patients are right away refractory and die rapidly, but the majority of patient has a transient response then progress and a few percentages of them are responder for a very long period of time. By only targeting normal endothelial cells and tumor neo-vascularization, the response should have been more homogenous, thus highlighting that the treatment induced a "Darwinian" adaptation of tumor cells and cells of the microenvironment. Two conclusions follow from these observations: 1- The need to identify predictive markers of efficacy; 2-The identification of druggable targets participating in progression on anti-angiogenic treatments. Our results have highlighted the ELR+CXCL cytokines, pro-inflammatory and pro-angiogenic cytokines as prognosis markers of survival of mRCC patients and relevant therapeutic targets on experimental tumors in mice. As VEGF/VEGFR, these cytokines are produced by tumor, endothelial and inflammatory cells. Their receptors (CXCR1, 2) are expressed physiologically by immune and endothelial cells and aberrantly by tumor cells generating at the same time autocrine proliferation loops, chronic angiogenesis and inflammation. Therefore, the CXCL/CXCR1,2 axis constitutes an independent axis of cancer development and propagation. However, the current standard of care is to administer anti-angiogenic therapies as the first line treatment. The objective of this project is linked to the identification of potent predictive markers of efficacy, easily measured in plasma samples. Deciphering the molecular mechanisms associated with the production of such cytokines by tumor cells and by cells of the microenvironment represents an interesting intellectual challenge and a relevant way to improve the current treatments by targeting, at progression on the current standard of care, other pathways than the VEGF/VEGFR axis.

Condition or disease Intervention/treatment
Metastatic Kidney Cancers Diagnostic Test: ELR+CXCL cytokines levels are of sunitinib response

  Show Detailed Description

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Study Type : Observational
Actual Enrollment : 60 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: ELR+CXCL Cytokines in Metastatic Kidney Cancers: Predictive Markers of Resistance to Sunitinib and New Relevant Therapeutic Targets in Refractory Patients
Actual Study Start Date : June 2, 2016
Estimated Primary Completion Date : December 30, 2019
Estimated Study Completion Date : December 30, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Cancer

Group/Cohort Intervention/treatment
sunitinib cohort
independent cohorts of patients who received sunitinib for metastic kidney cancer, on who we intend to demonstrate that ELR+CXCL cytokines levels are of sunitinib response
Diagnostic Test: ELR+CXCL cytokines levels are of sunitinib response
Demonstrate on independent cohorts of patients that ELR+CXCL cytokines levels are of sunitinib response




Primary Outcome Measures :
  1. ELR+CXCL cytokines [ Time Frame: December 2018 ]
    To determine of a threshold level of one or multiple ELR+CXCL cytokines indicative of progression for routine clinical practises


Secondary Outcome Measures :
  1. molecular mechanisms [ Time Frame: December 2020 ]
    To decipher the molecular mechanisms implicated in ELR+CXCL cytokines expression at the basal level and at progression on sunitinib. Expression of these cytokines by tumor cells and cells from the microenvironment (especially the Macrophages M1/Macrophages M2 ratio).


Biospecimen Retention:   Samples With DNA
Experiment on cell lines, on human samples and animal models. CXCL cytokines as predictive markers of sunitinib efficacy in order to demonstrate the mechanisms linked to the production of CXCL cytokines by mRCC or in response to treatments


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
patients with mRCC and treated by sunitinib after radical nephrectomy
Criteria

Inclusion Criteria:

  • patients with mRCC and treated by sunitinib after radical nephrectomy included in SUVEGIL 8 Clinical Trial (Sponsor : Centre Antoine Lacassagne)

Exclusion Criteria:

  • Non applicable

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): NCT03097601


Locations
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France
Centre Antoine LACASSAGNE
Nice, France, 06189
Sponsors and Collaborators
Centre Antoine Lacassagne
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Study Director: Christine LOVERA Centre Antoine Lacassagne

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Responsible Party: Centre Antoine Lacassagne
ClinicalTrials.gov Identifier: NCT03097601     History of Changes
Other Study ID Numbers: 2016/09
First Posted: March 31, 2017    Key Record Dates
Last Update Posted: October 8, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Neoplasms
Carcinoma, Renal Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Kidney Diseases
Urologic Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Sunitinib
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action