TDM for Optimized Outcome in Patients With mRCC.

Study Overview
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Brief Summary
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The purpose of this observational study is to assess the role of plasma concentration monitoring of treatment drugs for patients with metastatic renal cell carcinoma (mRCC) in terms of efficacy and side effects. Furthermore, the investigators intend to evaluate the role of anti-drug antibodies, amount of bound drug to T lymphocytes and receptor polymorphisms in CTLA-4 and PD-1 receptors in treatment failure among patients with mRCC treated with check point immunotherapy. Moreover, polymorphisms in the UGT1A1 gene will be correlated with the pazopanib treatment dose.

Detailed Description
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BACKGROUND: Treatment of metastatic renal cell carcinoma (mRCC) is ineffective among 25 % of patients. However, treatment still reduces patients' quality of life. From clinical experience, interindividual dose requirements vary greatly among patients with mRCC treated with tyrosine kinase inhibitors. The investigators expect this to partly be explained by great variation in the plasma concentration of treatment drugs. Furthermore, treatment failure among patients with mRCC treated with check point immunotherapy has not been fully investigated. RATIONALE: The few studies concerning plasma concentration measurement of tyrosine kinase inhibitors in patients with mRCC have found that a certain level of drug concentration is necessary for treatment efficacy. The role of plasma concentration in side effects is yet unknown. Anti drug antibodies against the check point inhibitor ipilimumab has been shown to reduce efficacy and lead to treatment failure among patients with malignant melanoma. The role of check point inhibitor binding to T lymphocytes and receptor polymorphism in CTLA-4 and PD-1 receptors in terms of efficacy have not yet been studied. A therapeutic drug interval will allow for quicker and more precise dosing, and early signs of treatment failure of checkpoint immunotherapy will allow for quicker change of therapy. HYPOTHESIS: Patients treated with TKIs and CPI for more than 6 months have an optimal plasma trough concentration. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicity in these patients are favorable compared with pivotal phase III study results. Patients treated with CPI obtaining response have a higher plasma trough concentration value of ipilimumab and nivolumab than patients with progressive disease (PD). Patients treated with CPI who develop PD have a higher amount of ADA than patients with response to treatment. The greater the amount of bound CPI to T lymphocytes the better the efficacy of CPI on clinical outcomes. Certain polymorphisms in CTLA-4 and PD-1 are associated with poor outcome. UGT1A1 polymorphism is associated with improved survival despite dose reductions in patients treated with pazopanib. MATERIALS AND METHODS: All eligible patients will have blood samples drawn at each clinical visit during a 6-months period. The plasma concentration of TKIs will be measured with liquid chromatography-mass spectrometry at the Department of Clinical Biochemistry at Aarhus University Hospital. Analysis of checkpoint immunotherapy will be be done using in-house bead-based assays, anti-human IgG detection antibody and in-house developed flow cytometry-based assay at the Institute for Inflammation Research at Rigshospitalet. Overall survival, progression free survival and quality of life using FKSI-19 questionnaire will be recorded for each patient. This is an observational study among all Danish patients treated for mRCC over a two year period.

Official Title
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Therapeutic Drug Monitoring for Optimized Outcome in Patients With Metastatic Renal Cell Carcinoma

Conditions
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Kidney Cancer, Renal Cell Carcinoma Metastatic, Drug Toxicity, Drug Side Effect, Drug Mechanism

Intervention / Treatment
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* Drug: Medical treatment for metastatic renal cell carcinoma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients in Denmark with medically treated metastatic renal cell carcinoma. Exclusion Criteria: No written informed consent.

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 |
| --- | --- |
| Cohort 1<br>Patients treated for metastatic renal cell carcinoma in Denmark over a 2-year period. | Drug: Medical treatment for metastatic renal cell carcinoma<br>* Medical treatment for metastatic renal cell carcinoma with axitinib, cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, ipilimumab and nivolumab.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Calculated from the date of inclusion, to the date of death of any cause or censored at the date at last follow-up. | 6 months follow-up for each patient. | 
| Progression free survival (PFS) | According to the RECIST v1.1 | 6 months follow-up for each patient. | 
| Quality of life according to NCCN-FACT FKSI-19. | National Comprehensive Cancer Network/ Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (NCCN-FACT FKSI-19). 19 items, each item scored on a 5 point Likert-scale, covering cancer quality of life. | 6 months follow-up for each patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In pts treated with ipilimumab/nivolumab: amount of antidrug antibodies (ADAs) developed. |  | 6 months follow-up for each patient. | 
| In pts treated with ipilimumab/nivolumab: amount of bound drug to PD-1 and CTLA-4 on T-lymphocytes using flow cytometry. |  | 6 months follow-up for each patient. | 
| In pts treated with ipilimumab/nivolumab: SNP-genotype of PD-1 and CTLA-4 receptors reported as proportion of patients with pp-, pq- and qq-genotype respectively. |  | 6 months follow-up for each patient. | 
| In pts treated with pazopanib: UGT1A1 genetic polymorphism | TA6/TA6, TA6/TA7 or TA7/TA7 | At baseline |