Prediction of Response to Kinase Inhibitors Based on Protein Phosphorylation Profiles in Tumor Tissue From Advanced Renal Cell Cancer Patients

Study Overview
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Brief Summary
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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.

Official Title
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Prediction of Response to Kinase Inhibitors Based on Protein Phosphorylation Profiles in Tumor Tissue From Advanced Renal Cell Cancer Patients

Conditions
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Renal Cell Cancer

Participation Criteria
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Eligibility Criteria
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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 drug. Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sunitinib<br> | |
| Sorafenib<br> | |
| Everolimus<br> | |
| Pazopanib<br> | |
| Axitinib<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to treatment |  | Follow up once every 4 months until disease progression or death of the patient | 
| Progression Free Survival | To determine the relation between tumor tissue phosphoproteomic profiles and progression-free survival (PFS) in patients with advanced RCC | once every 4 months until disease progression or death of the patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PamChip kinase activity profiling and PFS |  | Sample collection at inclusion is mandatory (1). Collection after 2-4 weeks of treatment (2) and upon progression (3) are optional | 
| genome-wide mutational profiles by Massively Parallel Sequencing (MPS) |  | Sample collection at inclusion is mandatory (1). Collection after 2-4 weeks of treatment (2) and upon progression (3) are optional | 
| serum proteomic profiles |  | Sample collection at inclusion is mandatory (1). Collection after 2-4 weeks of treatment (2) and upon progression (3) are optional | 
| the value of the frequency and phenotype of immunoregulatory cells in blood and tumor tissue |  | Sample collection at inclusion is mandatory (1). Collection after 2-4 weeks of treatment (2) and upon progression (3) are optional | 
| genetic polymorphisms and pharmacokinetic parameters |  | Sample collection at inclusion is mandatory (1). Collection after 2-4 weeks of treatment (2) and upon progression (3) are optional | 
| tumor exosomes from urine and serum |  | Sample collection at inclusion is mandatory (1). Collection after 2-4 weeks of treatment (2) and upon progression (3) are optional |