Pharmacogenomics Validation for Imatinib in Chronic Myeloid Leukemia

Leukemia, Myelogenous, Chronic, BCR-ABL Positive Clinical Trial

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Official title:

Retrospective Study to Validate Pharmacogenetics Model for Imatinib Metabolism in Patients With Chronic Myeloid Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01437202
• Other study ID #: AMC-H-64
• Status: Completed
• Phase: N/A
• First received: September 19, 2011
• Last updated: July 8, 2014
• Start date: September 2011
• Est. completion date: October 2012

Study information

• Verified date: July 2014
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Institutional Review Board
• Study type: Observational

Clinical 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.

Description:

1. 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.

2. 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).

3. 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.

4. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: October 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• Treated with imatinib mesylate less than 3 months

• Not agree with the intention of this study

Study Design

Observational Model: Cohort, Time Perspective: Retrospective

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital, University of Toronto	Toronto
Korea, Republic of	Asan Medical Center, University of Ulsan College of Medicine	Seoul
Korea, Republic of	Samsung Medical Center, Sungkyunkwan University School of Medicine	Seoul

Sponsors (1)

Lead Sponsor	Collaborator
Asan Medical Center

Countries where clinical trial is conducted

Canada,  Korea, Republic of, 

References & Publications (7)

Awidi 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. — View Citation

Gardner 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. — View Citation

Gorre 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. Epub 2001 Jun 21. — View Citation

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. Epub 2004 Jun 15. — View Citation

Kantarjian 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. Review. — View Citation

Kim 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 — View Citation

Mahon 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Median time to CCyR (complete cytogenetic response)	Difference of median time to CCyR between cohorts according to the risk stratification by gene analysis		No
Secondary	Variance of Genotypes from CML patients with Korean ethnicity			No
Secondary	Median time to MCyR (Major cytogenetic responses)	Difference of median time to MCyR between cohorts according to the risk stratification by gene analysis		No