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Association Between Side Effects Occurrence and Concentrations of Ibrutinib and Idelalisib (PK-E3I)

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ClinicalTrials.gov Identifier: NCT02824159
Recruitment Status : Recruiting
First Posted : July 6, 2016
Last Update Posted : September 21, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital, Toulouse

Brief Summary:

Recently, European Medicines Agency approved ibrutinib and idelalisib to treat Chronic Lymphocytic Leukemia (CLL) and two lymphomas: Follicular Lymphoma (FL) for ibrutinib and Mantle cell lymphoma (MCL) for idelalisib.

Clinical trials for ibrutinib and idelalisib were performed with a small number of patients (300-350) and showed several side effects profiles. Since, pharmacokinetic properties of these 2 drugs highlight a interindividual variability of pharmacokinetic. The aim of this study is to determine the association between clinically significant side effects occurrence during the first year of treatment and plasma mean concentration of the steady state of ibrutinib or idelalisib at 1 month.


Condition or disease Intervention/treatment
Hematological Malignancies Other: Blood samples for pharmacokinetics exploration Other: Imagery Other: Quality of life scale Other: Detection of adverse events Genetic: Saliva samples Genetic: Blood sample Other: Biological statement Other: Clinical examination

Detailed Description:

Recently, European medicines agency approved ibrutinib and idelalisib in the treatment of Chronic Lymphocytic Leukemia (CLL) and two lymphomas: Follicular Lymphoma (FL) for ibrutinib and Mantle cell lymphoma (MCL) for idelalisib. Nevertheless, clinical trials for these two drugs were performed for only 300-350 patients and showed several side effects profiles, the most frequent were diarrhea, infection, cutaneous rash… For some patients, treatment had to be reduced or stopped temporary or definitely.

Pharmacokinetic properties of these two drugs highlight an interindividual pharmacokinetic considerable variability. The aim of this clinical research study is to determine the association between clinically significant side effects occurrence during the first year of treatment (serious adverse reaction and/or grade CTCAE ≥ 3 and/or leading a dosage concession) and plasma mean concentration of the steady state of ibrutinib or idelalisib performed at 1 month.

To determine plasma mean concentration of the steady state of ibrutinib or idelalisib, blood tests will be performed every scheduled monitoring at visit 1 month during a pharmacokinetic exploration and during scheduled medical consultation (2, 3, 6 and 12 months) and every unscheduled visit in case of side effect occurrence.

Every scheduled monitoring visit, blood tests will be performed to determine plasma concentration in drug. Complementary blood or salivary samples will be collected before the treatment, 24 months later and in case of relapse to determine genetic characteristics. In parallel, a logbook will be completed by the patient to collect side effects. Finally, an oncology certified nurse call patients every 2 weeks. In case of side effect occurrence a visit will be organized in the next 3 days and a blood test will be performed.


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Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Real Life Assessment of the Association and Its Determinants Between Side Effects and Plasmatic Concentrations of Two Protein Kinase Inhibitors: Ibrutinib (IMBRUVICA®) and Idelalisib (ZYDELIG®) in Hematological Malignancies Treatment.
Study Start Date : April 2016
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Patient with haematologic malignancies

Interventions to be administrated are :

  • Clinical examinations
  • Biological statement
  • Blood samples for pharmacokinetics exploration
  • Imagery with positron emission tomography scan or resonance magnetic imagery
  • Saliva samples for genetics analyses
  • Blood samples for treatment mutation resistance search
  • Quality of life scale questionary
  • Detection of adverse events
Other: Blood samples for pharmacokinetics exploration
6 blood sample at regular intervals

Other: Imagery
Efficacity will be assessed with 3 sessions of resonance magnetic imaging or positron emission tomography scan

Other: Quality of life scale
Quality of life will be evaluated with questionaries 5 times during the study

Other: Detection of adverse events
The detection will be assessed using the AMA (assistance des malades ambulatoires) system

Genetic: Saliva samples
Saliva samples will be collected to explore genetic characteristics of germinal DNA (genes involved in drug pharmacokinetic)

Genetic: Blood sample
A unique blood sample will be performed in order to determine characteristics of tumoral DNA (resistance to treatment mutation)

Other: Biological statement

The following parameters will be assessed :

  • Complete blood count
  • Hemoglobin
  • Hepatic enzymes
  • Creatinine clearance
  • Lactate dehydrogenase rate
  • Total bilirubin rate
  • Cluster of differentiation 4 T lymphocytes rate
  • Total gamma-globulins rate

Other: Clinical examination

The clinical examination are composed by :

  • Weigh, Height and body mass index measurement
  • Clinical state of patient during examination
  • Stage of the disease (OMS grade, binet classification, Ahn Arbor classification)
  • Presence of B symptomatology
  • Prognostic factors (Genetic, Mantle Cell Lymphoma International Prognostic Index, Follicular Lymphoma International Prognostic Index, presence of lymph nodes, other target organs ...)




Primary Outcome Measures :
  1. Evaluation of clinically significant side effect occurence with plasma balance mean concentration in ibrutinib [ Time Frame: 1 months after treatment initiation ]
    Plasma balance mean will be calculated with 6 blood samples collected at regular intervals during the visit

  2. Evaluation of clinically significant side effect occurence with plasma balance mean concentration in idelalisib [ Time Frame: 1 months after treatment initiation ]
    Plasma balance mean will be calculated with 6 blood samples collected at regular intervals during the visit


Secondary Outcome Measures :
  1. Clinically significant side effect occurrence (Serious adverse reaction and/or grade CTCAE ≥ 3 and/or leading a dosage concession) as assessed by AMA (Assistance des Malades Ambulatoires) system [ Time Frame: through the end of study (24 months) ]
  2. Plasma balance mean concentration in ibrutinib with collection of blood samples [ Time Frame: 1 month after inclusion ]
    Plasma balance mean will be calculated with 6 blood samples collected at regular intervals during the visit

  3. Plasma balance mean concentration in idelalisib with collection of blood samples [ Time Frame: 1 month after inclusion ]
    Plasma balance mean will be calculated with 6 blood samples collected at regular intervals during the visit

  4. The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey [ Time Frame: Day 1 ]
  5. The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey [ Time Frame: 3 months after inclusion ]
  6. The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey [ Time Frame: 6 months after inclusion ]
  7. The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey [ Time Frame: 12 months after inclusion ]
  8. The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey [ Time Frame: 18 months after inclusion ]
  9. The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey [ Time Frame: 24 months after inclusion ]
  10. Response to treatment assessed by positron emission tomography-Scan [ Time Frame: Day 0 ]
    complete response, partial, stable disease, disease progression

  11. Response to treatment assessed by positron emission tomography-Scan [ Time Frame: 6 months after inclusion ]
    complete response, partial, stable disease, disease progression

  12. Response to treatment assessed by positron emission tomography-Scan [ Time Frame: 12 months after inclusion ]
    complete response, partial, stable disease, disease progression

  13. Response to treatment assessed by positron emission tomography-Scan [ Time Frame: 24 months after inclusion ]
    complete response, partial, stable disease, disease progression

  14. Forgetting to take medication reported by the patient as recorded in a logbook given to the patient [ Time Frame: 3 months after inclusion ]
  15. Forgetting to take medication reported by the patient as recorded in a logbook given to the patient [ Time Frame: 6 months after inclusion ]
  16. Perception of side effect reported by patient as noted in a logbook by the patient [ Time Frame: 3 months after inclusion ]
  17. Perception of side effect reported by patient as noted in a logbook by the patient [ Time Frame: 6 months after inclusion ]
  18. Effect of patients characteristics on plasma balance mean concentration in ibrutinib [ Time Frame: 1 months after inclusion ]
  19. Effect of patients characteristics on plasma balance mean concentration in idelalisib [ Time Frame: 1 months after inclusion ]
  20. Effect of patients genetic polymorphism on plasma balance mean concentration in idelalisib [ Time Frame: 1 months after inclusion ]
  21. Effect of patients therapeutic target DNA polymorphism on treatment response to ibrutinib [ Time Frame: Through the completion of study (24 months) ]
  22. Effect of patients therapeutic target DNA polymorphism on treatment response to idelalisib [ Time Frame: Through the completion of study (24 months) ]
  23. Treatment failure rate in relation with mean concentration of ibrutinib [ Time Frame: 1 month after inclusion ]
  24. Treatment failure rate in relation with mean concentration of idelalisib [ Time Frame: 1 month after inclusion ]
  25. Evaluation of total exposition to ibrutinib (AUCt,ss) with residual concentration at steady state [ Time Frame: Through the completion of study (24 months) ]
  26. Evaluation of total exposition to idelalisib (AUCt,ss) with residual concentration at steady state [ Time Frame: Through the completion of study (24 months) ]
  27. Association of adverse event and quality of life with Short Form (36) Health Survey [ Time Frame: Through the completion of study (24 months) ]
  28. Association of prognostic factors at inclusion and plasma balance mean concentration in ibrutinib [ Time Frame: 1 month after inclusion ]
  29. Association of prognostic factors at inclusion and plasma balance mean concentration in idelalisib [ Time Frame: 1 month after inclusion ]

Biospecimen Retention:   Samples With DNA

Samples to be collected are :

  • Blood samples for dosage of drug in plasma (No DNA)
  • Blood samples (genetic profile of drug elimination and presence of treatment resistance mutation) and saliva samples (genetic profile drug elimination )


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with haematologic malignancies
Criteria

Inclusion Criteria:

  • Evidence of Chronic Lymphocytic Leukaemia (CLL), or Follicular Lymphoma (FL) or Mantle cell lymphoma (MCL) and a first prescription of idelalisib or ibrutinib
  • Patients must give written informed consent
  • Patients with Health Insurance System

Exclusion Criteria:

  • Patient who several blood tests can't be performed (poor venous access)
  • Patients under legal guardian
  • Pregnant or breastfeeding women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02824159


Contacts
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Contact: Loïc Ysebaert, MD Ysebaert.Loic@iuct-oncopole.fr
Contact: Fabien Despas, PHD fabien.despas@univ-tlse3.fr

Locations
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France
Cancer University Institute of Toulouse Oncopole Recruiting
Toulouse, France, 31059
Contact: Guy Laurent, MD    5 31 15 62 09 ext +33    Laurent.guy@iuct-oncopole.fr   
Contact: Sandra Debaros    5.61.14.59.89 ext +33    debarros.s@chu-toulouse.fr   
Sponsors and Collaborators
University Hospital, Toulouse
Investigators
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Principal Investigator: Loïc Ysebaert, MD Cancer University Institute of Toulouse Oncopole

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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT02824159     History of Changes
Other Study ID Numbers: 15 7754 07
2015-005572-17 ( EudraCT Number )
First Posted: July 6, 2016    Key Record Dates
Last Update Posted: September 21, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by University Hospital, Toulouse:
ibrutinib
idelalisib
side effect
pharmacokinetic
plasma balance mean concentration

Additional relevant MeSH terms:
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Neoplasms
Idelalisib
Protein Kinase Inhibitors
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action