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

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.

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.

Study Overview

• Status: Completed
• Conditions: Hematological Malignancies
• Intervention / Treatment: 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.

• Study Type: Observational
• Enrollment (Actual): 121

Contacts and Locations

Study Locations

• France
  • Toulouse, France, 31059
    • Cancer University Institute of Toulouse Oncopole

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with haematologic malignancies

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

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 ...)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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		through the end of study (24 months)
Plasma balance mean concentration in ibrutinib with collection of blood samples	Plasma balance mean will be calculated with 6 blood samples collected at regular intervals during the visit	1 month after inclusion
Plasma balance mean concentration in idelalisib with collection of blood samples	Plasma balance mean will be calculated with 6 blood samples collected at regular intervals during the visit	1 month after inclusion
The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey		Day 1
The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey		3 months after inclusion
The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey		6 months after inclusion
The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey		12 months after inclusion
The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey		18 months after inclusion
The health-related quality (HRQoL) by the self-reported French version of the Short Form (36) Health Survey		24 months after inclusion
Response to treatment assessed by positron emission tomography-Scan	complete response, partial, stable disease, disease progression	Day 0
Response to treatment assessed by positron emission tomography-Scan	complete response, partial, stable disease, disease progression	6 months after inclusion
Response to treatment assessed by positron emission tomography-Scan	complete response, partial, stable disease, disease progression	12 months after inclusion
Response to treatment assessed by positron emission tomography-Scan	complete response, partial, stable disease, disease progression	24 months after inclusion
Forgetting to take medication reported by the patient as recorded in a logbook given to the patient		3 months after inclusion
Forgetting to take medication reported by the patient as recorded in a logbook given to the patient		6 months after inclusion
Perception of side effect reported by patient as noted in a logbook by the patient		3 months after inclusion
Perception of side effect reported by patient as noted in a logbook by the patient		6 months after inclusion
Effect of patients characteristics on plasma balance mean concentration in ibrutinib		1 months after inclusion
Effect of patients characteristics on plasma balance mean concentration in idelalisib		1 months after inclusion
Effect of patients genetic polymorphism on plasma balance mean concentration in idelalisib		1 months after inclusion
Effect of patients therapeutic target DNA polymorphism on treatment response to ibrutinib		Through the completion of study (24 months)
Effect of patients therapeutic target DNA polymorphism on treatment response to idelalisib		Through the completion of study (24 months)
Treatment failure rate in relation with mean concentration of ibrutinib		1 month after inclusion
Treatment failure rate in relation with mean concentration of idelalisib		1 month after inclusion
Evaluation of total exposition to ibrutinib (AUCt,ss) with residual concentration at steady state		Through the completion of study (24 months)
Evaluation of total exposition to idelalisib (AUCt,ss) with residual concentration at steady state		Through the completion of study (24 months)
Association of adverse event and quality of life with Short Form (36) Health Survey		Through the completion of study (24 months)
Association of prognostic factors at inclusion and plasma balance mean concentration in ibrutinib		1 month after inclusion
Association of prognostic factors at inclusion and plasma balance mean concentration in idelalisib		1 month after inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Loïc Ysebaert, MD, Cancer University Institute of Toulouse Oncopole

Publications and helpful links

General Publications

• Gallais F, Ysebaert L, Despas F, De Barros S, Dupre L, Quillet-Mary A, Protin C, Thomas F, Oberic L, Allal B, Chatelut E, White-Koning M. Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies. Clin Pharmacokinet. 2020 Sep;59(9):1171-1183. doi: 10.1007/s40262-020-00884-0.

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): November 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: June 30, 2016
• First Submitted That Met QC Criteria: June 30, 2016
• First Posted (Estimate): July 6, 2016

Study Record Updates

• Last Update Posted (Actual): December 28, 2020
• Last Update Submitted That Met QC Criteria: December 24, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: pharmacokinetic; ibrutinib; idelalisib; side effect; plasma balance mean concentration
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: 15 7754 07; 2015-005572-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided