TyrosIne Kinase Inhibitors in Chronic Myeloid Leukemia: Efficacy and Tolerability. The TIKlet Study

NCT01860456 | Completed DMC

• 1 other identifier: TIKlet-2012-M1.5
• Study Type: observational
• Target: 412
• Locations: 1 country
• Sites: 2

Brief Summary

Rationale The pharmacokinetics of imatinib and nilotinib, two BCR/Abl tyrosine-kinase inhibitors (TKI), is variable among patients suffering from chronic myeloid leukemia (CML). Transmembrane transporters may play a pivotal role in interindividual variability in TKI disposition. Furthermore, minimum plasma concentrations (Cmin) higher than 1 mg/L could be associated with a higher likelihood of molecular and cytogenetic responses. The TIKlet study is aimed at evaluating correlations among the pharmacogenetics, pharmacokinetics and treatment efficacy/tolerability of imatinib and nilotinib in CML patients. 1\. PATIENTS AND METHODS 1.1. Patients Patients affected by CML will be enrolled after the informed consent will be signed, according to the following inclusion criteria:

• patients of both sexes,
• age between 18 and 80 years,
• treated with imatinib or nilotinib,
• included in follow-up activities at the participating Hematology Divisions,
• able to give informed consent,
• with a proved compliance with the scheduled treatment. The administration of other drugs will be allowed, being known the dose and duration of treatment, as well as smoking and herbal products. Alterations in organ functions or physicochemical exams, body mass index \>28 do not represent exclusion criteria. 1.2. Enrollment and follow-up visits During enrollment visit:
• patients will be informed about the study, their signed informed consent form will be collected and an individual alphanumeric code will be assigned.
• Patients' data will be recorded within the individual case report form (CRF) and a blood sample will be obtained. At follow-up visits, a blood sample will be collected for therapeutic drug monitoring (TDM) and patients' CRF will be updated. 1.3. Blood samples After centrifugation, the resulting plasma will be collected for TDM. During the enrollment visit, an aliquot of whole blood will be collected for molecular analyses. 1.4 Laboratory analyses TDM will be performed by high-performance liquid chromatography systems, then results will be evaluated by a population pharmacokinetic analysis. Single nucleotide polymorphisms will be investigated in the following genes: ABCB1, ABCG2, hOCT1, OCTN1, OATP1A2. Finally, response to drugs, in terms of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), and tolerability will be evaluated. Any possible correlation among drug disposition, pharmacogenetics and treatment effects will be analyzed.

Conditions

Chronic Myeloid Leukemia

Keywords

Chronic myeloid leukemia; Imatinib; Nilotinib; Polymorphism, Single Nucleotide; Pharmacokinetics; ATP-Binding Cassette Transporters; SLC Transporters; Treatment outcome; Toxicity

Outcome Measures

Primary Outcomes (1)

• Percentage differences in Imatinib/Nilotinib pharmacokinetic parameters according to Solute Carrier (SLC) and ATB-Binding Cassette (ABC) transporters polymorphisms in chronic myeloid leukemia patients

  Percentage difference in drugs pharmacokinetic parameters (apparent clearance \[CL/F\], minimum plasma concentration at steady state \[Cmin,ss\], area under the time concentration curve \[AUC\], terminal elimination half-life \[t1/2\]) according to polymorphisms of SLC and ABC transporters (wild-type homozygous vs. heterozygous and polymorphic homozygous patients)

  2 years

Secondary Outcomes (4)

• Time to Complete Cytogenetic Response (Time-to-CCyR) and Major Molecular Response (Time-to-MMR)

  2 years

• Time-to-CCyR or Time-to-MMR and Cmin,ss values or SLC / ABC genotype

  2 years

• Percentage of patients who achieve MMR/CCyR and Cmin,ss values or SLC/ABC genotype

  2 years

• Number of patients with Adverse Drug Reactions and Cmin,ss values or SLC / ABC genotype

  2 years

Study Arms (1)

CML Imatinib/Nilotinib

Patients affected by chronic myeloid leukemia and treated with imatinib or nilotinib

Drug: Imatinib/Nilotinib

Interventions

Imatinib/Nilotinib DRUG

Imatinib: 400 mg/day oral - Nilotinib: 600-800 mg/day oral

Also known as: Gleevec, Tasigna

CML Imatinib/Nilotinib

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients affected by CML from Hematology Units

You may qualify if:

• Patients affected by chronic myeloid leukemia
• Age limits: 18-80 years
• Male and female patients
• Treatment with imatinib/nilotinib since at least 3 weeks
• Optimal adherence
• Signed informed consent

You may not qualify if:

• Age \<18 or \>80 years
• Poor adherence
• Inability to attend follow-up visits
• Lack of signed informed consent
• Concomitant administration of other drugs will be allowed, but active pharmacological agents, their dose and duration of treatment should be recorded.

Sponsors & Collaborators

• University of Pisa: lead

Study Sites (2)

Unit of Hematology, Azienda Ospedaliero Universitaria Pisana

Pisa, 56126, Italy

Location

Division of Hematology and Transplants, University of Siena

Siena, 53100, Italy

Location

Related Publications (7)

• Di Paolo A, Polillo M, Capecchi M, Cervetti G, Barate C, Angelini S, Guerrini F, Fontanelli G, Arici R, Ciabatti E, Grassi S, Bocci G, Hrelia P, Danesi R, Petrini M, Galimberti S. The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia. Pharmacogenomics J. 2014 Aug;14(4):328-35. doi: 10.1038/tpj.2014.7. Epub 2014 Mar 4.

  PMID: 24589908 RESULT

• Carulli G, Barate C, Marini A, Ottaviano V, Cervetti G, Fontanelli G, Guerrini F, Arici R, Guerri V, Di Paolo A, Polillo M, Ferreri MI, Galimberti S, Petrini M. Reduced circulating B-lymphocytes and altered B-cell compartments in patients suffering from chronic myeloid leukaemia undergoing therapy with Imatinib. Hematol Oncol. 2015 Dec;33(4):250-2. doi: 10.1002/hon.2156. Epub 2014 Sep 25. No abstract available.

  PMID: 25256816 RESULT

• Crea F, Di Paolo A, Liu HH, Polillo M, Clermont PL, Guerrini F, Ciabatti E, Ricci F, Barate C, Fontanelli G, Barsotti S, Morganti R, Danesi R, Wang Y, Petrini M, Galimberti S, Helgason CD. Polycomb genes are associated with response to imatinib in chronic myeloid leukemia. Epigenomics. 2015 Aug;7(5):757-65. doi: 10.2217/epi.15.35. Epub 2015 Sep 7.

  PMID: 26343356 RESULT

• Galeotti L, Ceccherini F, Domingo D, Laurino M, Polillo M, Di Paolo A, Barate C, Fava C, D'Avolio A, Cervetti G, Guerrini F, Fontanelli G, Ciabatti E, Grassi S, Arrigoni E, Danesi R, Petrini M, Cornolti F, Saglio G, Galimberti S. Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia. Cancer Chemother Pharmacol. 2017 Apr;79(4):767-773. doi: 10.1007/s00280-017-3271-3. Epub 2017 Mar 13.

  PMID: 28289867 RESULT

• Galimberti S, Bucelli C, Arrigoni E, Barate C, Grassi S, Ricci F, Guerrini F, Ciabatti E, Fava C, D'Avolio A, Fontanelli G, Cambrin GR, Isidori A, Loscocco F, Caocci G, Greco M, Bocchia M, Aprile L, Gozzini A, Scappini B, Cattaneo D, Scortechini AR, La Nasa G, Bosi A, Leoni P, Danesi R, Saglio G, Visani G, Cortelezzi A, Petrini M, Iurlo A, Di Paolo A. The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia. Oncotarget. 2017 Sep 30;8(50):88021-88033. doi: 10.18632/oncotarget.21406. eCollection 2017 Oct 20.

  PMID: 29152138 RESULT

• Galimberti S, Grassi S, Barate C, Guerrini F, Ciabatti E, Perutelli F, Ricci F, Del Genio G, Montali M, Barachini S, Giuliani C, Ferreri MI, Valetto A, Abruzzese E, Ippolito C, Iurlo A, Bocchia M, Sicuranza A, Martino B, Iovino L, Buda G, Salehzadeh S, Petrini M, Di Paolo A, Mattii L. The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia. Front Oncol. 2018 Dec 6;8:555. doi: 10.3389/fonc.2018.00555. eCollection 2018.

  PMID: 30574454 RESULT

• Abruzzese E, Aureli S, Bondanini F, Ciccarone M, Cortis E, Di Paolo A, Fabiani C, Galimberti S, Malagola M, Malato A, Martino B, Trawinska MM, Russo D, de Fabritiis P. Chronic Myeloid Leukemia and Pregnancy: When Dreams Meet Reality. State of the Art, Management and Outcome of 41 Cases, Nilotinib Placental Transfer. J Clin Med. 2022 Mar 24;11(7):1801. doi: 10.3390/jcm11071801.

  PMID: 35407407 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood, plasma, DNA

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

Imatinib Mesylate; nilotinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Sara Galimberti, MD, PhD

  Department of Clinical and Experimental Medicine, University of Pisa

  PRINCIPAL INVESTIGATOR

• Antonello Di Paolo, MD, PhD

  Department of Clinical and Experimental Medicine, University of Pisa

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pharmacology

Study Record Dates

• First Submitted: May 15, 2013
• First Posted: May 22, 2013
• Study Start: May 1, 2013
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: June 5, 2025

Record last verified: 2025-06

Locations

IT (2)