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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

Phase 4
18 Years
Open (Enrolling)
Metastatic Renal Cell Carcinoma

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Trial Information

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

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

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

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.

Inclusion Criteria

Inclusion criteria :

- Patients with renal tumor in place, resectable, with at least one measurable
metastasis 1.5 cm and indication of antiangiogenic therapy

- Histopathologically confirmed clear cell renal cell carcinoma (biopsy) and
possibility of adequate tumor sampling prior to treatment

- No prior systemic treatment for RCC

- Male or female, 18 years

- Performance status ECOG 0-1

- Life expectancy 3 months

- Adequate organ function as defined by the following criteria:

- Total serum bilirubin 2 x ULN (Gilbert's disease exempt)

- Serum transaminases and alcalines phosphatases 2.5 x ULN, or in case of liver or bone
metastasis 5x ULN

- Serum creatinine 2 x ULN, creatinine clearance 80 ml/mn

- Absolute neutrophil count (ANC) 1500/mm3

- Platelets 100,000/mm3

- Hemoglobin 10.0 g/dL

- INR 1.7 or prothrobin time (PT) 6sec over

- Negative pregnancy test within 7 days prior to registration

- Signed and dated IRB/ICE-approved informed consent.

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other study procedures.

- Patient covered by the national health system

Exclusion criteria :

- Previous nephrectomy

- Renal sarcoma, papillary tumors or collecting duct carcinoma

- Treatment in a clinical trial in the last 30 days

- Previous treatment with Sunitinib or other antiangiogenics

- Any of the following within 12 months prior to treatment initiation: severe/unstable
angina, myocardial infarction, coronary artery bypass graft, symptomatic congestive
heart failure, thrombo-embolic accident or cerebrovascular accident including
transient ischemic attack.

- Uncontrolled hypertension defined as systolic blood pressure >150mmHg or diastolic
pressure >90mmHg, despite optimal medical treatment

- Ongoing cardiac dysrhythmia of grade 2, atrial fibrillation of any grade, QTc
interval >0.50

- Treatment with anticoagulant agents and treatment with therapeutic doses of warfarin
within 2 weeks prior to first day of Sunitinib. Low dose warfarin for deep vein
thrombosis prophylaxis is permitted up to 2mg/day. Low molecular weight heparin or
aspirin are allowed

- Any medical condition that might interfere with oral medication absorption

- Brain metastasis. Note: Brain scan or MRI is mandatory

- LVEF value < 50%

- Prior radiation therapy.

- Pregnancy or breastfeeding. Women and men must agree to use effective contraception
during the study period. Acceptable contraception includes implants, oral
contraceptives, intrauterine devices, surgical sterilization.

- Any acute or chronic medical or psychiatric condition or laboratory abnormality that
would make the patient inappropriate with this study.

- Any second malignancy within the last 5 years with the exception of basal cell
carcinoma, cervical cancer in situ and pT1/a bladder cancer with no evidence of
recurrent disease for 12 months.

- Hypersensitivity to the Sunitinib malate or any excipient of Sutent

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the prognostic value of several factors (biomarkers and imaging) to identify responders

Outcome Time Frame:

36 weeks

Safety Issue:


Principal Investigator

Stephane OUDARD, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Ministry of Health

Study ID:




Start Date:

December 2008

Completion Date:

December 2011

Related Keywords:

  • Metastatic Renal Cell Carcinoma
  • Renal cell carcinoma
  • Antiangiogenics
  • Biomarkers
  • Imagery
  • Carcinoma
  • Carcinoma, Renal Cell