Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Kidney Diseases

Adenocarcinoma

Carcinoma, Renal Cell

Urologic Neoplasms

Urologic Diseases

Urogenital Neoplasms

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Coagulants

Angiogenesis Inhibitors

Adjuvants, Immunologic

Platelet Factor 4

Patients having a radical or partial nephrectomy.

Patients treated by RCC-directed targeted therapy

2 blood samples of 10mL + one urine sample

* on pre-operative d-1/d, post-operative d1 and d5(+/-2),
* one month post-operative,
* at the end of the study in the absence of disease progression or at the date of recurrence or progression if the case arises.

Biological sample

2 blood samples of 10mL + one urine sample

* before starting the therapy
* at first therapeutic evaluation (2 or 3 months depending on the treatment chosen)
* at the end of the study or at the date of disease progression.

Jean-Christophe BERNHARD, Dr

Despite novel treatment options, Renal Cell Carcinoma (RCC) has been characterized by a constant increase in its mortality and consequently requires an important involvement in translational research.

The aim of this study is to evaluate the interest of CXCL4, CXCL4L1 and CXCR3 as biomarkers in localized, locally advanced or metastatic RCC. Indeed these chemokines have shown anti-angiogenic and anti-tumor properties in experimental models and may be particularly interesting for prognostic and predictive purposes.

Based on a physiopathological rationale, the use of RCC-directed antiangiogenic therapies into clinical practice leads to conclusive results and makes RCC a particularly well-suited tumor type to study factors involved in the angiogenic process. Furthermore the intensive use of targeted therapies in clinical practice raised new questions about their management.

Therefore the identification of new molecular biomarkers is important:

* to improve the precision of prognostic models currently based on clinical, biological or histopathological variables
* to identify high risk patients that could benefit from an adjuvant treatment or a closer postoperative follow-up
* to predict the response to antiangiogenic therapies and therefore identify the drug which is likely to be the most effective within an ever increasing pharmacopeia
* to follow the therapy as precisely as possible, predict or attest the disease progression justifying a therapeutic modification

Low CXCL4, CXCL4L1 and CXCR3 tumor expression levels are associated with bad prognosis factors in RCC. Consequently their interest in RCC is worth being evaluated, in two subgroups : Localized / locally advanced renal cell carcinoma and Metastatic renal cell carcinoma.

Level of Expression and Prognostic Value of CXCL4, CXCL4L1 and CXCR3 in Renal Cell Carcinoma

Prognostic value of the markers of interest (CXCL4, CXCL4L1 et CXCR3) will be evaluated by the association of these markers with time to event occurrence.

Localized or locally advanced renal cell carcinoma group:

* local recurrence
* contralateral recurrence
* extra-renal distant recurrence (metastatic progression)
* specific cancer death
* nonspecific cancer death

Metastatic renal cell carcinoma group :

* local recurrence for patients who underwent a nephrectomy
* contralateral reccurence
* metastatic progression
* specific cancer death
* nonspecific cancer death

Predictive value of therapeutic response will be assessed for patients receiving systemic therapy. It will be evaluated by the association of markers of interest with the therapeutic response.

* RECIST criteria: patients showing a complete response or a partial response, will be considered as "responders"
* The progression of the longest diameter of tumor, the proportion of intra-tumor necrosis (Choi criteria) and +/- the perfusion characteristics of tumor if primitive tumor

University Hospital, Bordeaux

Sunitinib

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Sunitinib, SUTENT, 50 mg daily p.o., on schedule 4/2, for 2 cycles. Two weeks of rest prior to surgery (week 11 and 12).

Radical nephrectomy at the end of week 12. Sunitinib 50 mg/d, schedule 4/2, reintroduced 2 weeks after surgery (week 14, may be postponed by one or two weeks if wound healing delay or surgical complications). Treatment until disease progression, unacceptable toxicity or consent withdrawal. Dose reduction depending on the type and severity of toxicity.

At the end of the treatment period patients will be treated at the discretion of the Investigator.

Sunitinib (SUTENT)

Stephane OUDARD, MD

The aim of this study is to identify and/or validate biomarkers and imaging markers to predict and monitor the activity of a new class of therapeutic agents called antiangiogenics for the treatment of metastatic renal cell carcinoma (mRCC). Suntinib, approved for this indication, will be administred before and after nephrectomy and biomarkers sampling and imaging will be operated to monitor the activity and identify prognostic factors in mRCC.

BACKGROUND Sunitinib, SUTENT, is a promising multi-target TKI in the treatment of metastatic renal cell carcinoma after cytokine failure. In previous phase II studies, ORR is 40% and TTP = 8,7 months. A phase III randomized trial of Sunitinib versus interferon alpha as first-line therapy for patients with mRCC showed a significantly longer PFS in the Sunitinib group (11 months) than in the interferon group (5 months), hazard ratio of 0.42 (95% CI, 0.32 to 0.54, p \< 0.001). Initial approval in second line treatment of mRCC was extended to first line therapy on 11-01-2007.

Mechanisms of action involved in the therapeutic effects of antiangiogenic compounds are not fully elucidated. As of today, there are no validated biomarkers or imaging markers to predict and monitor the activity of this type of compound.

Recent findings in the field of cancer biology, tumor angiogenesis, immunology and imaging provide several biomarker candidates that can be assessed in metastatic renal cell carcinoma.

BASIC RESEARCH Biomarkers It seems interesting to measure the different biological markers that could be modulated by this antiangiogenic therapeutic. Some of them are known as prognostic factors in the metastatic renal carcinoma, others are directly linked to the mechanism of action of Sunitinib. Due to the biopsy prior to treatment initiation and nephrectomy after treatment initiation, it will be possible to evaluate biomarkers modification and to assess the potential link with the tumour response.

VHL gene alterations (mutations, deletions, and hypermethylations) are observed at high frequencies of up to 80% in cases of clear-cell renal cell carcinoma. The molecular mechanisms involved in angiogenesis in the presence of such genetic alterations are not yet well known. The functions of the pVHL/aHIF/VEGF/angiogenesis pathway will be investigated in all the renal cell carcinoma obtained from the biopsy and nephrectomy. Molecular markers defined by VHL status, expression and proteomic profiling may be helpful in predicting the responders.

Sunitinib is a potent inhibitor of the tyrosine kinase activity of several receptors: VEGFR-2, the main receptor responsible for mediating the proangiogenic effects of vascular endothelial growth factor (VEGF), expressed by vascular endothelial cells; PDGFR, the receptor for the platelet-derived growth factor (PDGF), expressed in pericytes which serve as structural supporting cells for endothelial cells. Consistent with its biochemical activity, Sunitinib inhibits the in vitro mitogenic response of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF or bFGF (basic fibrosblast growth factor), another proangiogenic factor.

VEGF gene polymorphisms In physiologic and pathologic conditions, important variations in VEGF blood levels have been reported to correlate with constitutional VEGF-A gene polymorphisms located in intronic regions. Moreover, VEGF-A polymorphisms have been described as predisposition and prognostic factors in several human malignancies such as bladder, breast, melanoma, prostate and head and neck carcinomas. Hence, it is interesting to see whether these polymorphisms could affect tumor and clinical presentation and correlate with VEGF-levels and response to antiangiogenic treatment with sunitinib.

Immunology Tumor angiogenesis can impact immune response in renal cell carcinoma patients. A naturally occurring CD4+ T cell subset, regulatory CD4+CD25+ T cells, has emerged as the dominant T cell population governing peripheral self- tolerance by inhibiting effector T cell. The ability of anti-angiogenic therapy to block VEGF may allow better maturation of dendritic cells and a reduction of the number of regulatory CD4+CD25+T cells.

The aim of this project will be to test whether the administration of Sunitinib modulates the concentrations of regulatory CD4+CD25+T cells, and if a correlation between the immunology parameters and the response can be observed.

Imaging Radiological evaluation of tumor response is also challenging with anti-angiogenic drugs. Criteria based solely on size may be inadequate for evaluation of anti-angiogenic therapy efficacy. The unbridled expansion of tumor vessels leads to development of abnormal vessels, with distinct microvascular characteristics: high perfusion (blood flow), and porous walls leaking molecules into the interstitium (permeability).

New imaging techniques as dynamic contrast-enhanced CT are being developed to quantify and characterize these unique properties, and may be used as markers of response to angiogenesis inhibitors. Imaging assays of angiogenic status therefore offer the potential to clinically measure anti angiogenic effects of drugs on the tumor vessels themselves, effects that may not be reflected in changing tumor dimensions. These effects may be detectable hours or days from time of treatment initiation, rather than in weeks or months needed typically to detect a change in tumor size. Exploration of local tumor vascular architecture can help to understand mechanism of action of Sunitinib. This vasculature seems to be of poor functionality and tumor vascularization cannot be adequately assessed only by global index such as global tumor blood flow. In addition, exploration of renal tumor vascularization with contrast-enhanced US will be performed to compare blood flow determined by CT and US.

Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma

A Study of Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma With Sunitinib BEFORE and AFTER Nephrectomy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Level of Expression and Prognostic Value of CXCL4, CXCL4L1 and CXCR3 in Renal Cell Carcinoma	NCT01339975	Carcinoma Carcinoma Renal... Kidney Neoplasm... Kidney Diseases Chemokines	Biological samp... Biological samp...	18 Years -	University Hospital, Bordeaux
Level of Expression and Prognostic Value of CXCL4, CXCL4L1 and CXCR3 in Renal Cell Carcinoma	NCT01339975	Carcinoma Carcinoma Renal... Kidney Neoplasm... Kidney Diseases Chemokines	Biological samp... Biological samp...	18 Years -	University Hospital, Bordeaux
Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma	NCT00930345	Metastatic Rena...	Sunitinib (SUTE...	18 Years -	Assistance Publique - Hôpitaux de Paris
Level of Expression and Prognostic Value of CXCL4, CXCL4L1 and CXCR3 in Renal Cell Carcinoma	NCT01339975	Carcinoma Carcinoma Renal... Kidney Neoplasm... Kidney Diseases Chemokines	Biological samp... Biological samp...	18 Years -	University Hospital, Bordeaux

Spots Global Cancer Trial Database for antiangiogenics