The Pharmacokinetic Variability of Sunitinib in Patients With Metastatic Renal Cancer

Overview

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).

Full Title of Study: “The Pharmacokinetic Variability of Sunitinib in Patients With Metastatic Renal Cancer: Searching for Pharmacogenetic Determinants”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: February 2018

Detailed Description

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.

Interventions

  • Genetic: Blood drawn for genotyping
    • Blood will be drawn for genotyping (predefined list of genes) just before the start of sunitinib (baseline).
  • Biological: Blood drawn for pharmacokinetic measures
    • 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.

Arms, Groups and Cohorts

  • The study population
    • 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

Clinical Trial Outcome Measures

Primary Measures

  • The percentage of patients with a plasma concentration of sunitinib remaining at equilibrium ([Suni]REq) greater than 100 ng / ml
    • Time Frame: Between C1D15* and C1D28*
    • *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.

Secondary Measures

  • 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).
    • Time Frame: Baseline (day 0)
    • 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
  • [Suni]REq per cure
    • Time Frame: Between CmD15* and CmD28* for 18 months
    • *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.
  • The presence/absence of grade I, II, III, IV, V (CTCAE version 4.0) toxicities per cure
    • Time Frame: 18 months
  • Tumor response per cure
    • Time Frame: 18 months
  • Toxicity (yes/no) for each type of toxic event per cure
    • Time Frame: Between CmD15* and CmD28* for 18 months
    • *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.
  • [Suni]REq at the 1st cure, averaged per initial dosing (37.5mg, 50 mg, 75 mg, 100mg)
    • Time Frame: Between C1D15* and C1D28*
    • *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.
  • the average [Suni]REq over all cures
    • Time Frame: 18 months
  • For each cure, the average [Suni]REq for cure 1 to cure m
    • Time Frame: 18 months
  • For each cure, the ratio of the plasma concentration of the metabolite remaining at equilibrium ([Metab]REq) / [Suni]REq
    • Time Frame: Between CmD15* and CmD28* for 18 months
    • *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.
  • [Metab]REq / [Suni]REq
    • Time Frame: Between C1D15* and C1D28*
    • *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.
  • [Metab]REq / [Suni]REq averaged per initial dosing
    • Time Frame: Between C1D15* and C1D28*
    • *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.
  • Mean [Metab]REq / [Suni]REq for all cures
    • Time Frame: 18 months
  • For each cure, the average [Metab]REq / [Suni]REq for cure 1 to cure m
    • Time Frame: 18 months
  • For each cure, the plasma concentration of the active entity remaining at equilibrium ([ActEnt]REq)
    • Time Frame: 18 months
  • [ActEnt]REq
    • Time Frame: Between C1D15* and C1D28*
    • *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.
  • [ActEnt]REq averaged per initial dosing
    • Time Frame: Between C1D15* and C1D28*
    • *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.
  • Mean [ActEnt]REq for all cures
    • Time Frame: 18 months
  • For each cure, the average [ActEnt]REq for cure 1 to cure m
    • Time Frame: 18 months
  • For each cure, the % of patients whose dosings were modified since the beginning of the study
    • Time Frame: 18 months
  • Presence/absence of side effects noted in the summary of product characteristics for sunitinib
    • Time Frame: 18 months

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Centre Hospitalier Universitaire de Nīmes
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Litaty Mbatchi, PharmD, Study Director, Centre Hospitalier Universitaire de Nîmes
  • Overall Contact(s)
    • Litaty Mbatchi, PharmD, +33.(0)4.66.68.32.07, litaty.mbatchi@chu-nimes.fr

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