Leukemia, Myelogenous, Chronic, BCR-ABL PositiveVATICNCT01437202
Pharmacogenomics Validation for Imatinib in Chronic Myeloid Leukemia
An observational study of Leukemia, Myelogenous, Chronic, BCR-ABL Positive, run by Asan Medical Center at 3 sites in 2 countries.
Trial summary
This is a multicenter, retrospective, observational study to validate a pharmacogenetics model for imatinib metabolism and resistance in patients with chronic myeloid leukemia among patients in different independent cohort. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- How many people
- 100 participants
- Where
- 3 sitesin 2 countries
- Study dates
- Sep 2011to Oct 2012
- 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: Patients who were diagnosed as chronic myeloid leukemia, treated with imatinib more than 3 months, at Asan Medical Center, Seoul, Korea.
Who may be able to join
- Chronic myeloid leukemia of any stage including chronic phase, accelerated or blastic phase.
- Age>18 years
- Complete set of clinical data available for review (demographic data, stage, treatment history, cytogenetic reports, and latest BCR/ABL RQ-PCR results)
- Treated with imatinib mesylate at least 3 months
Who cannot join
- Treated with imatinib mesylate less than 3 months
- Not agree with the intention of this study
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
South Korea2 sites
Asan Medical Center, University of Ulsan College of Medicine
Seoul
Samsung Medical Center, Sungkyunkwan University School of Medicine
Seoul
About this study
Official title: Retrospective Study to Validate Pharmacogenetics Model for Imatinib Metabolism in Patients With Chronic Myeloid Leukemia
This is a multicenter, retrospective, observational study to validate a pharmacogenetics model for imatinib metabolism and resistance in patients with chronic myeloid leukemia among patients in different independent cohort.
Read the detailed description
- The activity of Imatinib(IM) is mediated by blocking the activity of BCR/ABL tyrosine kinase in CML cells. However, some of the patients failed to achieve optimal response, and a substantial proportion of patients develop resistance to IM.
- IM is a substrate for the adenosine triphosphate binding cassette (ABC) transporters, ABCB1 and ABCG2, while the active uptake of IM into cells is mediated by the human organic cationic transporter-1 (hOCT1). Also, IM is metabolized through first pass drug metabolism by the cytochrome P450 - CYP3A4 and CYP3A5. In addition, it is delivered in a bound form with a plasma protein referred to α1-acid glycoprotein (AGP).
- Accordingly, the intracellular or systemic level of imatinib should be influenced by these factors such as ABCB1, ABCG2, hOCT1, CYP3A4, CYP3A5 or AGP genes. Inter-individual variability of 5 candidate genes associated with drug transport/metabolism (i.e. ABCB1, ABCG2, hOCT1, CYP3A4/3A5 and AGP) could affect the expression of corresponding proteins, thus influencing the treatment outcomes of imatinib therapy.
- In the investigators' previous study, the investigators reported the cumulative incidences of MCyR and CCyR was significantly affected by the predictive model using 2 genotypes and disease stage. These predictive models for CCyR/MMoR or LOR/treatment failure seemed to work well. However, external validation of these predictive models is warranted especially using ethnically different independent cohort.
- Keywords
- imatinib, drug resistance, pharmacogenetics
- 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.
| Study group | Role | What they receive |
|---|---|---|
| high risk group | Identified by the predictive model using 2 genotypes and disease stage | |
| intermediate risk group | Identified by the predictive model using 2 genotypes and disease stage | |
| Low risk group | Identified by the predictive model using 2 genotypes and disease stage |
What is being measured
The primary outcome is the main question the study is designed to answer.
Median time to CCyR (complete cytogenetic response)
Difference of median time to CCyR between cohorts according to the risk stratification by gene analysis
Secondary outcomes (2)
Variance of Genotypes from CML patients with Korean ethnicity
Median time to MCyR (Major cytogenetic responses)
Difference of median time to MCyR between cohorts according to the risk stratification by gene analysis
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2011 (estimated)
- Study startSep 2011
- Primary completionSep 2012
- Study completionOct 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Leukemia, Myelogenous, Chronic, BCR-ABL PositiveStudies of the same condition, open and under way.
- More trials run by Asan Medical CenterThe 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
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 100 participants (actual)
Sponsor and investigators
- Lead sponsor
- Asan Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dae-Young Kim, Asan Medical Center
- Investigators
- Jong Won Kim, MD, PhD, Study chair, Samsung Medical Center, Sungjyunkwan University School of Medicine, Seoul, KoreaDae-Young Kim, MD, Principal investigator, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01437202
- Sponsor's protocol ID
- AMC-H-64
- Acronym
- VATIC
- Status last verified
- Jul 2014
- First submitted
- 19 Sep 2011
- Last updated
- 9 Jul 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Kantarjian HM, Cortes JE, O'Brien S, Luthra R, Giles F, Verstovsek S, Faderl S, Thomas D, Garcia-Manero G, Rios MB, Shan J, Jones D, Talpaz M. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood. 2004 Oct 1;104(7):1979-88. doi: 10.1182/blood-2004-02-0711. Epub 2004 Jun 15.
PubMed 15198956Kantarjian HM, Talpaz M, Giles F, O'Brien S, Cortes J. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006 Dec 19;145(12):913-23. doi: 10.7326/0003-4819-145-12-200612190-00008.
PubMed 17179059Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001 Aug 3;293(5531):876-80. doi: 10.1126/science.1062538. Epub 2001 Jun 21.
PubMed 11423618Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003 Mar 15;101(6):2368-73. doi: 10.1182/blood.V101.6.2368.
PubMed 12609962Awidi A, Salem II, Najib N, Mefleh R, Tarawneh B. Determination of imatinib plasma levels in patients with chronic myeloid leukemia by high performance liquid chromatography-ultraviolet detection and liquid chromatography-tandem mass spectrometry: methods' comparison. Leuk Res. 2010 Jun;34(6):714-7. doi: 10.1016/j.leukres.2009.08.005. Epub 2009 Sep 9.
PubMed 19744707Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther. 2006 Aug;80(2):192-201. doi: 10.1016/j.clpt.2006.05.003.
PubMed 16890580Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009 Jul 15;15(14):4750-8. doi: 10.1158/1078-0432.CCR-09-0145. Epub 2009 Jul 7.
PubMed 19584153
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Retrospective Study to Validate Pharmacogenetics Model for Imatinib Metabolism in Patients With Chronic Myeloid Leukemia
- ClinicalTrials.gov ID
- NCT01437202
- Acronym / sponsor ID
- VATIC / AMC-H-64
- Keywords
- imatinib, drug resistance, pharmacogenetics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 100 participants (actual)
- Lead sponsor
- Asan Medical CenterUniversity, hospital or other
- Study start
- Sep 2011
- Primary completion
- Sep 2012 (actual)
- Study completion
- Oct 2012 (actual)
- First posted
- 20 Sep 2011 (estimated)
- 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.
This is a multicenter, retrospective, observational study to validate a pharmacogenetics model for imatinib metabolism and resistance in patients with chronic myeloid leukemia among patients in different independent cohort.
Detailed description
- The activity of Imatinib(IM) is mediated by blocking the activity of BCR/ABL tyrosine kinase in CML cells. However, some of the patients failed to achieve optimal response, and a substantial proportion of patients develop resistance to IM.
- IM is a substrate for the adenosine triphosphate binding cassette (ABC) transporters, ABCB1 and ABCG2, while the active uptake of IM into cells is mediated by the human organic cationic transporter-1 (hOCT1). Also, IM is metabolized through first pass drug metabolism by the cytochrome P450 - CYP3A4 and CYP3A5. In addition, it is delivered in a bound form with a plasma protein referred to α1-acid glycoprotein (AGP).
- Accordingly, the intracellular or systemic level of imatinib should be influenced by these factors such as ABCB1, ABCG2, hOCT1, CYP3A4, CYP3A5 or AGP genes. Inter-individual variability of 5 candidate genes associated with drug transport/metabolism (i.e. ABCB1, ABCG2, hOCT1, CYP3A4/3A5 and AGP) could affect the expression of corresponding proteins, thus influencing the treatment outcomes of imatinib therapy.
- In the investigators' previous study, the investigators reported the cumulative incidences of MCyR and CCyR was significantly affected by the predictive model using 2 genotypes and disease stage. These predictive models for CCyR/MMoR or LOR/treatment failure seemed to work well. However, external validation of these predictive models is warranted especially using ethnically different independent cohort.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| high risk group | – | –Identified by the predictive model using 2 genotypes and disease stage |
| intermediate risk group | – | –Identified by the predictive model using 2 genotypes and disease stage |
| Low risk group | – | –Identified by the predictive model using 2 genotypes and disease stage |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients who were diagnosed as chronic myeloid leukemia, treated with imatinib more than 3 months, at Asan Medical Center, Seoul, Korea.
Key inclusion criteria (4 listed)
- Chronic myeloid leukemia of any stage including chronic phase, accelerated or blastic phase.
- Age>18 years
- Complete set of clinical data available for review (demographic data, stage, treatment history, cytogenetic reports, and latest BCR/ABL RQ-PCR results)
- Treated with imatinib mesylate at least 3 months
Key exclusion criteria (2 listed)
- Treated with imatinib mesylate less than 3 months
- Not agree with the intention of this study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Median time to CCyR (complete cytogenetic response)
Difference of median time to CCyR between cohorts according to the risk stratification by gene analysis
2 secondary outcomes
Variance of Genotypes from CML patients with Korean ethnicity
Median time to MCyR (Major cytogenetic responses)
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 9 Jul 2014.
- Background: PubMed 15198956Kantarjian HM, Cortes JE, O'Brien S, Luthra R, Giles F, Verstovsek S, Faderl S, Thomas D, Garcia-Manero G, Rios MB, Shan J, Jones D, Talpaz M. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood. 2004 Oct 1;104(7):1979-88. doi: 10.1182/blood-2004-02-0711. Epub 2004 Jun 15.
- Background: PubMed 17179059Kantarjian HM, Talpaz M, Giles F, O'Brien S, Cortes J. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006 Dec 19;145(12):913-23. doi: 10.7326/0003-4819-145-12-200612190-00008.
- Background: PubMed 11423618Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001 Aug 3;293(5531):876-80. doi: 10.1126/science.1062538. Epub 2001 Jun 21.
- Background: PubMed 12609962Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003 Mar 15;101(6):2368-73. doi: 10.1182/blood.V101.6.2368.
- Background: PubMed 19744707Awidi A, Salem II, Najib N, Mefleh R, Tarawneh B. Determination of imatinib plasma levels in patients with chronic myeloid leukemia by high performance liquid chromatography-ultraviolet detection and liquid chromatography-tandem mass spectrometry: methods' comparison. Leuk Res. 2010 Jun;34(6):714-7. doi: 10.1016/j.leukres.2009.08.005. Epub 2009 Sep 9.
- Background: PubMed 16890580Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther. 2006 Aug;80(2):192-201. doi: 10.1016/j.clpt.2006.05.003.
- Results publication: PubMed 19584153Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009 Jul 15;15(14):4750-8. doi: 10.1158/1078-0432.CCR-09-0145. Epub 2009 Jul 7.
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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.
Jong Won Kim, MD, PhD study chair
Samsung Medical Center, Sungjyunkwan University School of Medicine, Seoul, Korea
Dae-Young Kim, MD principal investigator
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Leukemia, Myelogenous, Chronic, BCR-ABL Positive, run by Asan Medical Center at 3 sites in 2 countries.
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 4 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 9 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in South Korea, Canada. 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?
Median time to CCyR (complete cytogenetic response). 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 NCT01437202, which also lists 7 linked publications.
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 9 Jul 2014.