The Pharmacokinetic Variability of Sunitinib in Patients With Metastatic Renal Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to determine the percentage of patients with a plasma concentration of sunitinib remaining at equilibrium ([Suni]REq) greater than 100 ng / ml (effective concentration according to the current literature).

Detailed Description
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The secondary objectives of this study are: To describe the distribution of constitutional genetic determinants related to sunitinib pharmacokinetics, and to study their correlation with the [Suni]REq, the advent of toxicity, the tumor response. To describe the variation in the [Suni]REq and the plasma concentration of the active entity remaining at equilibrium ([ActEnt]REq) at: the interindividual level, overtime, between chemotherapy cycles. To describe the variation in the ratio of the plasma concentration of the metabolite remaining at equilibrium ([Metab]REq) to the [Suni]REq at: the interindividual level, overtime, between chemotherapy cycles. To explore potential correlations between the [Suni]REq and toxicity, tumor response. To explore potential correlations between the [ActEnt]REq and toxicity, tumor response. To explore potential correlations between the ratio [Metab]REq / [Suni]REq and toxicity, tumor response.

Official Title
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The Pharmacokinetic Variability of Sunitinib in Patients With Metastatic Renal Cancer: Searching for Pharmacogenetic Determinants

Conditions
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Kidney Neoplasms

Intervention / Treatment
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* Genetic: Blood drawn for genotyping
* Biological: Blood drawn for pharmacokinetic measures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient was correctly informed concerning the implementation of the study, its objectives, constraints and patient rights The patient must have given his/her informed and signed consent The patient must be insured or beneficiary of a health insurance plan The patient has kidney cancer and should begin treatment with sunitinib (Sutent) at the time of inclusion Exclusion Criteria: The patient started treatment with sunitinib (Sutent) before inclusion The patient is participating in another interventional study The patient has participated in another interventional study within the last month The patient is in an exclusion period determined by a previous study The patient is under judicial protection, under tutorship or curatorship The patient refuses to sign the consent It is impossible to correctly inform the patient The patient is pregnant, parturient, or breastfeeding The patient has a contraindication (or an incompatible drug combination) for a treatment used in this 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 |
| --- | --- |
| The study population<br>Patients with kidney cancer and will be starting treatment via sunitinib at the study start will be included. Intervention: Blood drawn for genotyping Intervention: Blood drawn for pharmacokinetic measures | Genetic: Blood drawn for genotyping<br>* Blood will be drawn for genotyping (predefined list of genes) just before the start of sunitinib (baseline).<br>Biological: Blood drawn for pharmacokinetic measures<br>* Blood will be drawn for pharmacokinetic measures between CmD15 and CmD28 of each sunitinib cycle.* *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients with a plasma concentration of sunitinib remaining at equilibrium ([Suni]REq) greater than 100 ng / ml | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between C1D15* and C1D28* | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genotype: genetic polymorphisms of enzymes of phase I, phase II (conjugation), carriers of Phases 0 and III, the nuclear receptors PXR and CAR, pharmacological targets of sunitinib (tyrosine kinase receptors). | Predefined list of genes: ABCB1 ABCC2 ABCG2 CYP1A1 CYP1A2 CYP2A6 CYP2B6 CYP2C19 CYP2C8 CYP2C9 CYP2D6 CYP2E1 CYP3A4 CYP3A5 NR1I2 NR1I3 SLC15A2 SLC22A1 SLC22A2 SLC22A6 SLCO1B1 SLCO1B3 SULT1A1 UGT1A1 UGT2B15 UGT2B17 UGT2B7 VEGFR1,2,3 PDGFR-α et β KIT | Baseline (day 0) | 
| [Suni]REq per cure | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between CmD15* and CmD28* for 18 months | 
| The presence/absence of grade I, II, III, IV, V (CTCAE version 4.0) toxicities per cure |  | 18 months | 
| Tumor response per cure |  | 18 months | 
| Toxicity (yes/no) for each type of toxic event per cure | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between CmD15* and CmD28* for 18 months | 
| [Suni]REq at the 1st cure, averaged per initial dosing (37.5mg, 50 mg, 75 mg, 100mg) | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between C1D15* and C1D28* | 
| the average [Suni]REq over all cures |  | 18 months | 
| For each cure, the average [Suni]REq for cure 1 to cure m |  | 18 months | 
| For each cure, the ratio of the plasma concentration of the metabolite remaining at equilibrium ([Metab]REq) / [Suni]REq | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between CmD15* and CmD28* for 18 months | 
| [Metab]REq / [Suni]REq | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between C1D15* and C1D28* | 
| [Metab]REq / [Suni]REq averaged per initial dosing | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between C1D15* and C1D28* | 
| Mean [Metab]REq / [Suni]REq for all cures |  | 18 months | 
| For each cure, the average [Metab]REq / [Suni]REq for cure 1 to cure m |  | 18 months | 
| For each cure, the plasma concentration of the active entity remaining at equilibrium ([ActEnt]REq) |  | 18 months | 
| [ActEnt]REq | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between C1D15* and C1D28* | 
| [ActEnt]REq averaged per initial dosing | *Each patient will undergo several cycles of treatment with sunitinib during the monitoring period as part of routine care (= 18 months; the number of cycles per patient can vary, which is normal). Each cycle and each day of the cycle will be annotated with the letters C and D, respectively, followed by a number in chronological order. Thus C1D1 refers to to the first day of the first cycle; CmDn will be the nth day of the mth cycle. | Between C1D15* and C1D28* | 
| Mean [ActEnt]REq for all cures |  | 18 months | 
| For each cure, the average [ActEnt]REq for cure 1 to cure m |  | 18 months | 
| For each cure, the % of patients whose dosings were modified since the beginning of the study |  | 18 months | 
| Presence/absence of side effects noted in the summary of product characteristics for sunitinib |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic kidney cancer