<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03262974</url>
  </required_header>
  <id_info>
    <org_study_id>Imatinib Pharmacogenetics</org_study_id>
    <nct_id>NCT03262974</nct_id>
  </id_info>
  <brief_title>Effect of Pharmacogenetics on Imatinib Plasma Level and Response</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Imatinib, the tyrosine kinase inhibitor, is used for treatment of Philadelphia positive&#xD;
      chronic myeloid leukemia. Despite its efficacy and favorable pharmacokinetic profile, there&#xD;
      is a large inter-individual variability in imatinib plasma concentrations, which may lead to&#xD;
      treatment failure and disease progression. Polymorphisms in genes related to absorption,&#xD;
      distribution, metabolism and excretion of imatinib may affect the bioavailability and&#xD;
      consequently the response to the drug.&#xD;
&#xD;
      The study aims to investigate the possible effect of genetic polymorphisms in certain&#xD;
      metabolizing enzymes [CYP3A5*3 (rs776746), CYP2C8*3 (rs11572080 and rs10509681)] and membrane&#xD;
      transporters [ABCB1 2677G&gt;T/A (rs2032582) and SLC22A1 1222A &gt; G (rs628031)] by PCR on the&#xD;
      plasma level (by HPLC-UV) and molecular response (MMR) of imatinib in patients with CML.&#xD;
&#xD;
      The study also aims to provide CML patients with a personalized treatment option, thereby&#xD;
      probably improving the response and reducing the side effects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction:&#xD;
&#xD;
      Chronic myeloid leukaemia (CML) is a myeloproliferative disease with an incidence of one to&#xD;
      two cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of&#xD;
      leukemia in adults.&#xD;
&#xD;
      The introduction of imatinib, the tyrosine kinase inhibitor (TKI), in the early 21st century&#xD;
      is considered a breakthrough in the treatment of CML. In the vast majority of patients,&#xD;
      treatment with imatinib induces cytogenetic and even molecular responses with very low or&#xD;
      undetectable BCR-ABL1 transcript levels. These patients remain free from progression to blast&#xD;
      crisis. However, imatinib does not cure the disease because it is unable to eradicate the&#xD;
      leukaemic stem cells, which therefore provides a potential reservoir for relapse.&#xD;
&#xD;
      Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual&#xD;
      variability in imatinib plasma concentrations, which may lead to treatment failure and&#xD;
      disease progression.&#xD;
&#xD;
      Polymorphisms in genes related to absorption, distribution, metabolism and excretion of&#xD;
      imatinib may affect the bioavailability and consequently the response to the drug.&#xD;
&#xD;
      Aim of the study:&#xD;
&#xD;
      The study aims to investigate the possible effect of genetic polymorphisms in certain&#xD;
      metabolizing enzymes [CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681)] and&#xD;
      membrane transporters [ABCB1 2677 G&gt;T/A (rs 2032582) and SLC22A1 1222 A &gt; G (rs 628031)] on&#xD;
      the plasma level and molecular response (MMR) of imatinib in patients with CML.&#xD;
&#xD;
      These polymorphisms were selected based on their relevance to the pharmacokinetics of&#xD;
      imatinib and on their frequency in Caucasians.&#xD;
&#xD;
      The study also aims to provide CML patients with a personalized treatment option, thereby&#xD;
      probably improving the response and reducing the side effects.&#xD;
&#xD;
      Patients and methods:&#xD;
&#xD;
      Patients:&#xD;
&#xD;
      The study will include patients with documented hematological, cytogenetic and molecular&#xD;
      diagnosis of chronic phase CML, who are on continuous treatment with 400 mg oral dose of&#xD;
      imatinib per day for at least 12 month at Medical Oncology Department, South Egypt Cancer&#xD;
      Institute (SECI), Assiut. Egypt.&#xD;
&#xD;
      Exclusion criteria are: duration of imatinib therapy less than 12 months, poor compliance to&#xD;
      treatment and identification of gene mutation(s) in the kinase domain of BCR- ABL1.&#xD;
&#xD;
      The patients will be divided into 2 groups according to their molecular response to imatinib&#xD;
      as follow:&#xD;
&#xD;
      Group I: CML patients with MMR Group II: CML patients without MMR Patients in both groups&#xD;
      will be compared as regard the plasma level of imatinib and the selected genetic&#xD;
      polymorphisms.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Blood sampling:&#xD;
&#xD;
      Three blood samples (3 ml for each) will be collected into EDTA-containing tubes by&#xD;
      venipuncture for measurement of imatinib plasma level, measurement of BCR- ABL1 transcription&#xD;
      level and for genotyping.&#xD;
&#xD;
      Measurement of Imatinib trough level:&#xD;
&#xD;
      Blood samples will be collected after 24 hours from the previous dose (trough) and after at&#xD;
      least 5 days of regular use of the drug to ensure that the steady state is reached. Within 1&#xD;
      hour of collection, the blood samples will be centrifuged at 3,000 rpm for 10 minutes at room&#xD;
      temperature and will be stored at -20°C until analysis.&#xD;
&#xD;
      Plasma level of imatinib will be measured by high-performance liquid chromatography with&#xD;
      ultraviolet detection (HPLC-UV) according to the method described by Barratt et al.&#xD;
&#xD;
      Measurement of BCR- ABL1 transcription level:&#xD;
&#xD;
      Total RNA will be extracted from peripheral blood leucocytes by the available RNA extraction&#xD;
      kits. The BCR- ABL1 transcription level will be quantified by using real-time polymerase&#xD;
      chain reaction (PCR) analysis to assess the molecular response to imatinib after 12 months of&#xD;
      treatment with imatinib.&#xD;
&#xD;
      Genotyping:&#xD;
&#xD;
      The DNA will be extracted from leukocytes by the available DNA extraction kits and will be&#xD;
      stored at -80°C until genotyping.&#xD;
&#xD;
      Genotyping will be performed for CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs&#xD;
      10509681), ABCB1 2677 G&gt;T/A (rs 2032582) and SLC22A1 1222 A &gt; G (rs 628031) by the PCR&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 29, 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">November 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Major molecular response to imatinib</measure>
    <time_frame>12 months from starting the drug</time_frame>
    <description>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,</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">60</enrollment>
  <condition>Chronic Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>CML patients with MMR</arm_group_label>
    <description>CYP3A5*3 , CYP2C8*3 , ABCB1 2677G&gt;T/A and SLC22A1 1222A &gt; G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CML patients without MMR</arm_group_label>
    <description>CYP3A5*3 , CYP2C8*3 , ABCB1 2677G&gt;T/A and SLC22A1 1222A &gt; G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>PCR</intervention_name>
    <description>PCR</description>
    <arm_group_label>CML patients with MMR</arm_group_label>
    <arm_group_label>CML patients without MMR</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>HPLC-UV</intervention_name>
    <description>HPLC-UV</description>
    <arm_group_label>CML patients with MMR</arm_group_label>
    <arm_group_label>CML patients without MMR</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      DNA will be extracted from blood samples and frozen at -80 for further analysis&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        CML patients treated at Medical Oncology Department, South Egypt Cancer Institute (SECI),&#xD;
        Assiut. Egypt.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Documented hematological, cytogenetic and molecular diagnosis of Philadelphia positive&#xD;
             CML&#xD;
&#xD;
          -  Imatinib treatment for at least 12 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Poor compliance to treatment&#xD;
&#xD;
          -  identification of gene mutation(s) in the kinase domain of BCR- ABL1.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Safwat Mangoura</last_name>
    <role>Study Chair</role>
    <affiliation>Pharmacology department, Faculty of Medicine, Assiut University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>South Egypt Cancer Institute</name>
      <address>
        <city>Assiut</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 24, 2017</study_first_submitted>
  <study_first_submitted_qc>August 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 28, 2017</study_first_posted>
  <last_update_submitted>July 18, 2023</last_update_submitted>
  <last_update_submitted_qc>July 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 19, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Mohammed Sayed Molla</investigator_full_name>
    <investigator_title>Assistant lecturer</investigator_title>
  </responsible_party>
  <keyword>Imatinib</keyword>
  <keyword>Pharmacogenetics</keyword>
  <keyword>CML</keyword>
  <keyword>Plasma level</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Results of genotyping</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03262974
org study id: Imatinib Pharmacogenetics
nct id: NCT03262974
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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
observational model: Other
time perspective: Retrospective
measure: Major molecular response to imatinib
time frame: 12 months from starting the drug
description: 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,
arm group label: CML patients with MMR
description: CYP3A5*3 , CYP2C8*3 , ABCB1 2677G>T/A and SLC22A1 1222A > G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR
arm group label: CML patients without MMR
description: CYP3A5*3 , CYP2C8*3 , ABCB1 2677G>T/A and SLC22A1 1222A > G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR
intervention type: Diagnostic Test
intervention name: PCR
description: PCR
arm group label: CML patients with MMR
arm group label: CML patients without MMR
intervention type: Diagnostic Test
intervention name: HPLC-UV
description: HPLC-UV
arm group label: CML patients with MMR
arm group label: CML patients without MMR
DNA will be extracted from blood samples and frozen at -80 for further analysis
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Safwat Mangoura
role: Study Chair
affiliation: Pharmacology department, Faculty of Medicine, Assiut University
facility: 
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Mohammed Sayed Molla
investigator title: Assistant lecturer
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
sharing ipd: Undecided
ipd description: Results of genotyping