To determine the relation between tumor tissue phosphoproteomic profiles and progression-free survival (PFS) in patients with advanced RCC
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pretreatment tumor tissue phosphoproteomic profile, radiological response to
standard treatment, PFS.
Phosphoproteomic profiles will be determined from the tumor biopsy and
correlated to radiological response and PFS. Phosphotyrosine signaling pathways
aberrantly activated in individual subgroups, identified by unsupervised
hierarchical clustering, will be examined in relation to the clinical effect of
the different kinase inhibitors. The classifier will be based on activity of
one or multiple signaling pathways and protein networks and will be subjected
to an internal validation such as the ten-fold cross validation technique to
estimate its generalization performance.
Primary endpoint: Prediction accuracy of the phosphoproteomic classifier
Secondary outcome
-To determine the relation between pre-treatment PamChip kinase activity
profiling and PFS
-To determine whether genome-wide mutational profiles by Massively Parallel
Sequencing (MPS) can be related to PFS
-To determine whether both pre- and on-treatment serum proteomic profiles are
related to PFS
-To determine the value of the frequency and phenotype of immunoregulatory
cells in blood and tumor tissue for treatment response prediction.
-To determine the relation between genetic polymorphisms and pharmacokinetic
parameters (systemic and intratumoral drug concentrations) and PFS.
-To determine the value of tumor exosomes from urine and serum as potential
source of biomarkers.
Background summary
The rapid development of agents blocking kinases has established the use of
molecularly targeted therapy as the preferred treatment approach for patients
with metastatic renal cell cancer (RCC). Five kinase inhibitors (sunitinib,
everolimus, temsirolimus, sorafenib and pazopanib) are now approved for
clinical use. Response rates differ among these agents, importantly depending
on line of treatment. In first-line treatment sunitinib results in 47%
objective response rates, where in second-line after cytokines 34% responds.
Thus far, it is unclear which patient with advanced renal cell cancer will
respond to targeted therapy. In order to select patients for targeted
therapies, several profiling approaches have been explored but to date no
adequate and reliable test is available. It is assumed that responses to
targeted agents depend on specific receptor and protein signalling activities
in tumor tissues. Therefore, we propose that protein phosphorylation profiling
with phosphoproteomics may be a potential clinical diagnostic tool to predict
for tumor response to targeted therapy. This approach is expected to increase
efficacy, reduce costs and prevent toxicities from (ineffective) targeted
agents.
Study objective
To determine the relation between tumor tissue phosphoproteomic profiles and
progression-free survival (PFS) in patients with advanced RCC
Study design
Multicentered, observational study with non-therapeutic intervention prior to
standard treatment. The study consists of a training-phase and independent
validation-phase. This protocol only covers the training phase, where a
predictive classifier will be build. A feasibility analysis will be performed
when 20 patients are included.
Study burden and risks
In this study, a fresh tumor biopsy from a metastasis or a primary tumor will
be taken. In all subjects subsequent standard treatment will be initiated
according to current clinical guidelines. In addition to this biopsy,
collection of urine and blood is performed upon inclusion and the same
procedure is optional on 2 other time points during treatment.
The tumor biopsy may cause physical discomfort and adverse events. Follow-up
may include additional blood drawings before and during treatment which will be
combined with laboratory analysis needed for routine outpatient clinic visits.
Results of this study will be used for personalized treatment selection
strategies that may increase response rates to standard therapy and prevent
toxicity of ineffective therapy in renal cell carcinoma patients.
De Boelelaan 1117
1081 HV Amsterdam
NL
De Boelelaan 1117
1081 HV Amsterdam
NL
Listed location countries
Age
Inclusion criteria
• Patients with advanced (unresectable and/or metastatic) renal cell cancer;
• Patients who will start treatment with sunitinib, pazopanib, sorafenib, axitinib or everolimus;
• At least one tumor lesion should be accessible for biopsy. Bone metastases are excluded as possible biopsy site;
• Age >- 18 years;
• Patients must have at least one measurable lesion. Lesions must be evaluated by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST);
• WHO performance status 0 - 2;
• Able to provide written informed consent;
Exclusion criteria
• Clinical findings associated with an unacceptably high tumor biopsy risk, according to the judgement of the investigator;
• Radiotherapy on target lesions during study or within 4 weeks of the start of study drug;
• Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-006009-85-NL |
| CCMO | NL39036.029.12 |