Chronic Myeloid LeukemiaNCT03262974
Effect of Pharmacogenetics on Imatinib Plasma Level and Response
An observational study of Chronic Myeloid Leukemia, run by Assiut University at 1 site in Egypt.
Trial summary
Imatinib, the tyrosine kinase inhibitor, is used for treatment of Philadelphia positive chronic myeloid leukemia. Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Myeloid Leukemia
- What is being tested?
- PCR and HPLC-UV
- How many people
- 60 participants
- Where
- 1 siteEgypt
- Study dates
- 29 Oct 2017to 1 Oct 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: CML patients treated at Medical Oncology Department, South Egypt Cancer Institute (SECI), Assiut. Egypt.
Who may be able to join
- Documented hematological, cytogenetic and molecular diagnosis of Philadelphia positive CML
- Imatinib treatment for at least 12 months
Who cannot join
- Poor compliance to treatment
- identification of gene mutation(s) in the kinase domain of BCR- ABL1.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Investigation of the Possible Role of Genetic Polymorphism in Certain Metabolizing Enzymes and Membrane Transporters on Both Plasma Level and Molecular Response of Imatinib in Patients With Chronic Myeloid Leukemia
Imatinib, the tyrosine kinase inhibitor, is used for treatment of Philadelphia positive chronic myeloid leukemia. Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression. Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug.
The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5*3 (rs776746), CYP2C8*3 (rs11572080 and rs10509681)] and membrane transporters [ABCB1 2677G>T/A (rs2032582) and SLC22A1 1222A > G (rs628031)] by PCR on the plasma level (by HPLC-UV) and molecular response (MMR) of imatinib in patients with CML.
The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.
Read the detailed description
Introduction:
Chronic myeloid leukaemia (CML) is a myeloproliferative disease with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.
The introduction of imatinib, the tyrosine kinase inhibitor (TKI), in the early 21st century is considered a breakthrough in the treatment of CML. In the vast majority of patients, treatment with imatinib induces cytogenetic and even molecular responses with very low or undetectable BCR-ABL1 transcript levels. These patients remain free from progression to blast crisis. However, imatinib does not cure the disease because it is unable to eradicate the leukaemic stem cells, which therefore provides a potential reservoir for relapse.
Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression.
Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug.
Aim of the study:
The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681)] and membrane transporters [ABCB1 2677 G>T/A (rs 2032582) and SLC22A1 1222 A > G (rs 628031)] on the plasma level and molecular response (MMR) of imatinib in patients with CML.
These polymorphisms were selected based on their relevance to the pharmacokinetics of imatinib and on their frequency in Caucasians.
The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.
Patients and methods:
Patients:
The study will include patients with documented hematological, cytogenetic and molecular diagnosis of chronic phase CML, who are on continuous treatment with 400 mg oral dose of imatinib per day for at least 12 month at Medical Oncology Department, South Egypt Cancer Institute (SECI), Assiut. Egypt.
Exclusion criteria are: duration of imatinib therapy less than 12 months, poor compliance to treatment and identification of gene mutation(s) in the kinase domain of BCR- ABL1.
The patients will be divided into 2 groups according to their molecular response to imatinib as follow:
Group I: CML patients with MMR Group II: CML patients without MMR Patients in both groups will be compared as regard the plasma level of imatinib and the selected genetic polymorphisms.
Methods:
Blood sampling:
Three blood samples (3 ml for each) will be collected into EDTA-containing tubes by venipuncture for measurement of imatinib plasma level, measurement of BCR- ABL1 transcription level and for genotyping.
Measurement of Imatinib trough level:
Blood samples will be collected after 24 hours from the previous dose (trough) and after at least 5 days of regular use of the drug to ensure that the steady state is reached. Within 1 hour of collection, the blood samples will be centrifuged at 3,000 rpm for 10 minutes at room temperature and will be stored at -20°C until analysis.
Plasma level of imatinib will be measured by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) according to the method described by Barratt et al.
Measurement of BCR- ABL1 transcription level:
Total RNA will be extracted from peripheral blood leucocytes by the available RNA extraction kits. The BCR- ABL1 transcription level will be quantified by using real-time polymerase chain reaction (PCR) analysis to assess the molecular response to imatinib after 12 months of treatment with imatinib.
Genotyping:
The DNA will be extracted from leukocytes by the available DNA extraction kits and will be stored at -80°C until genotyping.
Genotyping will be performed for CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681), ABCB1 2677 G>T/A (rs 2032582) and SLC22A1 1222 A > G (rs 628031) by the PCR
- Conditions
- Chronic Myeloid Leukemia
- Being tested
- PCR, HPLC-UV
- Keywords
- Imatinib, Pharmacogenetics, CML, Plasma level
- Medical subject headings
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PCRDiagnostic test
PCR
HPLC-UVDiagnostic test
HPLC-UV
| Study group | Role | What they receive |
|---|---|---|
| CML patients with MMR | CYP3A5*3 , CYP2C8*3 , ABCG2 421 C>A and SLC22A1 1222A > G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR Receives: Diagnostic Test: PCR; Diagnostic Test: HPLC-UV | |
| CML patients without MMR | CYP3A5*3 , CYP2C8*3 , ABCG2 421 C>A and SLC22A1 1222A > G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR Receives: Diagnostic Test: PCR; Diagnostic Test: HPLC-UV |
What is being measured
The primary outcome is the main question the study is designed to answer.
Major molecular response to imatinib
A major molecular response (MMR) to imatinib therapy is defined as a BCR-ABL1 RNA level ≤ 0.1% on the International Scale (a consensus standardized measurement scale intended to allow direct comparison of BCR-ABL1 RNA levels in any laboratory adopting its use). The International Scale was specifically designed so that, by definition, 100% is the median pretreatment baseline level of BCR-ABL1 RNA in early chronic phase CML and a 1,000-fold reduction from baseline is defined as 0.1% (MMR) (Press,
Measured: 12 months from starting the drug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2017
- Study start29 Oct 2017
- Primary completion1 Oct 2023
- Study completion1 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by Assiut UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Retrospective
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assiut University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mohammed Sayed Molla, Assiut University
- Investigators
- Safwat Mangoura, Study chair, Pharmacology department, Faculty of Medicine, Assiut University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03262974
- Sponsor's protocol ID
- Imatinib Pharmacogenetics
- Status last verified
- Oct 2023
- First submitted
- 24 Aug 2017
- Last updated
- 27 Oct 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Results of genotyping
Publications
Mangoura SA, Abdel-Raheem MH, Eltyb HA, Molla MS, Hussein AMR. Influence of CYP2C8*3 and ABCG2 C421A genetic polymorphisms on trough concentration and molecular response of imatinib in Egyptian patients with chronic myeloid leukemia. Cancer Chemother Pharmacol. 2024 Dec 23;95(1):12. doi: 10.1007/s00280-024-04723-y.
PubMed 39714624
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of the Possible Role of Genetic Polymorphism in Certain Metabolizing Enzymes and Membrane Transporters on Both Plasma Level and Molecular Response of Imatinib in Patients With Chronic Myeloid Leukemia
- ClinicalTrials.gov ID
- NCT03262974
- Acronym / sponsor ID
- Imatinib Pharmacogenetics
- Conditions
- Chronic Myeloid Leukemia
- Keywords
- Imatinib, Pharmacogenetics, CML, Plasma level
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Assiut UniversityUniversity, hospital or other
- Study start
- 29 Oct 2017 (actual)
- Primary completion
- 1 Oct 2023 (actual)
- Study completion
- 1 Oct 2023 (actual)
- First posted
- 28 Aug 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Imatinib, the tyrosine kinase inhibitor, is used for treatment of Philadelphia positive chronic myeloid leukemia. Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression. Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug.
The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5*3 (rs776746), CYP2C8*3 (rs11572080 and rs10509681)] and membrane transporters [ABCB1 2677G>T/A (rs2032582) and SLC22A1 1222A > G (rs628031)] by PCR on the plasma level (by HPLC-UV) and molecular response (MMR) of imatinib in patients with CML.
The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.
Detailed description
Introduction:
Chronic myeloid leukaemia (CML) is a myeloproliferative disease with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.
The introduction of imatinib, the tyrosine kinase inhibitor (TKI), in the early 21st century is considered a breakthrough in the treatment of CML. In the vast majority of patients, treatment with imatinib induces cytogenetic and even molecular responses with very low or undetectable BCR-ABL1 transcript levels. These patients remain free from progression to blast crisis. However, imatinib does not cure the disease because it is unable to eradicate the leukaemic stem cells, which therefore provides a potential reservoir for relapse.
Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression.
Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug.
Aim of the study:
The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681)] and membrane transporters [ABCB1 2677 G>T/A (rs 2032582) and SLC22A1 1222 A > G (rs 628031)] on the plasma level and molecular response (MMR) of imatinib in patients with CML.
These polymorphisms were selected based on their relevance to the pharmacokinetics of imatinib and on their frequency in Caucasians.
The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.
Patients and methods:
Patients:
The study will include patients with documented hematological, cytogenetic and molecular diagnosis of chronic phase CML, who are on continuous treatment with 400 mg oral dose of imatinib per day for at least 12 month at Medical Oncology Department, South Egypt Cancer Institute (SECI), Assiut. Egypt.
Exclusion criteria are: duration of imatinib therapy less than 12 months, poor compliance to treatment and identification of gene mutation(s) in the kinase domain of BCR- ABL1.
The patients will be divided into 2 groups according to their molecular response to imatinib as follow:
Group I: CML patients with MMR Group II: CML patients without MMR Patients in both groups will be compared as regard the plasma level of imatinib and the selected genetic polymorphisms.
Methods:
Blood sampling:
Three blood samples (3 ml for each) will be collected into EDTA-containing tubes by venipuncture for measurement of imatinib plasma level, measurement of BCR- ABL1 transcription level and for genotyping.
Measurement of Imatinib trough level:
Blood samples will be collected after 24 hours from the previous dose (trough) and after at least 5 days of regular use of the drug to ensure that the steady state is reached. Within 1 hour of collection, the blood samples will be centrifuged at 3,000 rpm for 10 minutes at room temperature and will be stored at -20°C until analysis.
Plasma level of imatinib will be measured by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) according to the method described by Barratt et al.
Measurement of BCR- ABL1 transcription level:
Total RNA will be extracted from peripheral blood leucocytes by the available RNA extraction kits. The BCR- ABL1 transcription level will be quantified by using real-time polymerase chain reaction (PCR) analysis to assess the molecular response to imatinib after 12 months of treatment with imatinib.
Genotyping:
The DNA will be extracted from leukocytes by the available DNA extraction kits and will be stored at -80°C until genotyping.
Genotyping will be performed for CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681), ABCB1 2677 G>T/A (rs 2032582) and SLC22A1 1222 A > G (rs 628031) by the PCR
Study design
- Observational model
- Other
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| CML patients with MMR | – | Diagnostic Test: PCR, Diagnostic Test: HPLC-UVCYP3A5*3 , CYP2C8*3 , ABCG2 421 C>A and SLC22A1 1222A > G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR |
| CML patients without MMR | – | Diagnostic Test: PCR, Diagnostic Test: HPLC-UVCYP3A5*3 , CYP2C8*3 , ABCG2 421 C>A and SLC22A1 1222A > G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- CML patients treated at Medical Oncology Department, South Egypt Cancer Institute (SECI), Assiut. Egypt.
Key inclusion criteria (2 listed)
- Documented hematological, cytogenetic and molecular diagnosis of Philadelphia positive CML
- Imatinib treatment for at least 12 months
Key exclusion criteria (2 listed)
- Poor compliance to treatment
- identification of gene mutation(s) in the kinase domain of BCR- ABL1.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PCRPCR | Diagnostic test | CML patients with MMR, CML patients without MMR |
| HPLC-UVHPLC-UV | Diagnostic test | CML patients with MMR, CML patients without MMR |
Primary outcome
Major molecular response to imatinib
Time frame: 12 months from starting the drug
A major molecular response (MMR) to imatinib therapy is defined as a BCR-ABL1 RNA level ≤ 0.1% on the International Scale (a consensus standardized measurement scale intended to allow direct comparison of BCR-ABL1 RNA levels in any laboratory adopting its use). The International Scale was specifically designed so that, by definition, 100% is the median pretreatment baseline level of BCR-ABL1 RNA in early chronic phase CML and a 1,000-fold reduction from baseline is defined as 0.1% (MMR) (Press,
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2023.
- Derived from this study: PubMed 39714624Mangoura SA, Abdel-Raheem MH, Eltyb HA, Molla MS, Hussein AMR. Influence of CYP2C8*3 and ABCG2 C421A genetic polymorphisms on trough concentration and molecular response of imatinib in Egyptian patients with chronic myeloid leukemia. Cancer Chemother Pharmacol. 2024 Dec 23;95(1):12. doi: 10.1007/s00280-024-04723-y.
- Individual participant dataSharing planned: Undecided. Results of genotyping
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Safwat Mangoura study chair
Pharmacology department, Faculty of Medicine, Assiut University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Chronic Myeloid Leukemia, run by Assiut University at 1 site in Egypt.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Egypt. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Major molecular response to imatinib (time frame: 12 months from starting the drug). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03262974, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2023.