European Stop Tyrosine Kinase Inhibitor Study (EURO-SKI)

• ClinicalTrials.gov Identifier: NCT01596114
• Recruitment Status: Completed
• First Posted: May 10, 2012
• Last Update Posted: November 5, 2021
• Sponsor: European LeukemiaNet
• Information provided by (Responsible Party): European LeukemiaNet

Tracking Information

• First Submitted Date: May 8, 2012
• First Posted Date: May 10, 2012
• Last Update Posted Date: November 5, 2021
• Actual Study Start Date: May 30, 2012
• Actual Primary Completion Date: December 3, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2012)

molecular relapse-free survival [ Time Frame: 3 years ]

Evaluation of molecular relapse-free survival after stopping TKI (survival without molecular relapse defined by BCR-ABL1 > 0.1% on the IS at one time point (loss of major molecular response, MMR))

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 9, 2012)

• Overall and progression-free survival [ Time Frame: 3 years ]
  Overall and progression-free survival and the probabilities of a restart of TKI without prior molecular relapse
• Treatment costs [ Time Frame: 3 years ]
  Saved treatment costs / country from the time off TKI therapy considering also the more frequent PCR monitoring
• QoL [ Time Frame: 3 years ]
  Patient reported QoL and symptom burden over time
• Time to recovery [ Time Frame: 3 years ]
  Analysing the time to recovery of CMR4 after loss of MMR

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: European Stop Tyrosine Kinase Inhibitor Study
• Official Title: Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukemia After Stopping TKI

Brief Summary

The EURO-SKI is a multicenter open label, uncontrolled trial estimating the persistence of molecular remission in Chronic Myeloid Leukemia (CML) patients after stopping Tyrosine Kinase Inhibitor (TKI). Main goal is the assessment of the duration of major molecular response (MMR) or better after stopping TKI therapy.

Secondary goals include:

• Identification of clinical and biological factors affecting the persistence of complete molecular remission after stopping TKI (e.g. level of Complete molecular remission (CMR), risk score, duration of TKI treatment, type of TKI pretreatment)
• Evaluation of quality of life (QoL) in patients stopping TKI
• Evaluation of medico-economic impact of stopping TKI
• Estimating the number of patients in CMR who are eligible for stopping TKI therapy by setting up a screening log
• Time to recovery of CMR There will be no randomised comparison. Based on the experience of the STIM trial (Mahon et al., Lancet Onc 2010) we expect an overall six-month molecular-relapse-free survival probability of at least 40%. An interim analysis will be performed after a pilot phase where 200 patients have been observed for at least six months. Formally, it is planned to test the null hypothesis H0: Six-month molecular relapse-free survival probability P ≤ 40% against the alternative hypothesis H1: Six-month molecular-relapse-free survival probability P > 40%. Eligible are adult CML patients in chronic phase on TKI treatment in CMR for at least one year (> 4 log reduction of BCR-ABL transcripts on IS, TKI treatment for at least 3 years, confirmed by a PCR within a standardized CMR laboratory). Clinical and biological monitoring will be performed during 3 years: Associated scientific projects are performed. Recruitment period: 2 years; follow up: 3 years. Planned patient recruitment in main phase: n=500

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Myeloid Leukemia

Intervention

Other: Stopping treatment with TKI

stopping until loss of MMR

Study Arms

Experimental: Stop treatment

TKI treatment will be stopped in CML patients with very deep molecular responses for at least one year and at least 3 years TKI treatment

Intervention: Other: Stopping treatment with TKI

Publications *

• Richter J, Lubking A, Soderlund S, Lotfi K, Markevarn B, Sjalander A, Stenke L, Deneberg S, Ahlstrand E, Myhr-Eriksson K, Panayiotidis P, Gedde-Dahl T, Zackova D, Mayer J, Olsson-Stromberg U, Mahon FX, Saussele S, Hjorth-Hansen H, Koskenvesa P. Molecular status 36 months after TKI discontinuation in CML is highly predictive for subsequent loss of MMR-final report from AFTER-SKI. Leukemia. 2021 Aug;35(8):2416-2418. doi: 10.1038/s41375-021-01173-w. Epub 2021 Feb 15. No abstract available.
• Soderlund S, Persson I, Ilander M, Guilhot J, Hjorth-Hansen H, Koskenvesa P, Richter J, Saussele S, Mustjoki S, Olsson-Stromberg U. Plasma proteomics of biomarkers for inflammation or cancer cannot predict relapse in chronic myeloid leukaemia patients stopping tyrosine kinase inhibitor therapy. Leuk Res. 2020 Mar;90:106310. doi: 10.1016/j.leukres.2020.106310. Epub 2020 Jan 23.
• Bouillon AS, Ventura Ferreira MS, Awad SA, Richter J, Hochhaus A, Kunzmann V, Dengler J, Janssen J, Ossenkoppele G, Westerweel PE, Te Boekhorst PAW, Mahon FX, Hjorth-Hansen H, Isfort S, Fioretos T, Hummel S, Schemionek M, Wilop S, Koschmieder S, Saussele S, Mustjoki S, Beier F, Brummendorf TH. Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia. Blood Adv. 2018 Jul 10;2(13):1572-1579. doi: 10.1182/bloodadvances.2018017772.
• Schutz C, Inselmann S, Saussele S, Dietz CT, Mu Ller MC, Eigendorff E, Brendel CA, Metzelder SK, Bru Mmendorf TH, Waller C, Dengler J, Goebeler ME, Herbst R, Freunek G, Hanzel S, Illmer T, Wang Y, Lange T, Finkernagel F, Hehlmann R, Huber M, Neubauer A, Hochhaus A, Guilhot J, Xavier Mahon F, Pfirrmann M, Burchert A. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017 Apr;31(4):829-836. doi: 10.1038/leu.2017.9. Epub 2017 Jan 11. Erratum In: Leukemia. 2018 Jan 30;:
• Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, Janssen JJWM, Mayer J, Koskenvesa P, Panayiotidis P, Olsson-Stromberg U, Martinez-Lopez J, Rousselot P, Vestergaard H, Ehrencrona H, Kairisto V, Machova Polakova K, Muller MC, Mustjoki S, Berger MG, Fabarius A, Hofmann WK, Hochhaus A, Pfirrmann M, Mahon FX; EURO-SKI investigators. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018 Jun;19(6):747-757. doi: 10.1016/S1470-2045(18)30192-X. Epub 2018 May 4.
• Ilander M, Olsson-Stromberg U, Schlums H, Guilhot J, Bruck O, Lahteenmaki H, Kasanen T, Koskenvesa P, Soderlund S, Hoglund M, Markevarn B, Sjalander A, Lotfi K, Dreimane A, Lubking A, Holm E, Bjoreman M, Lehmann S, Stenke L, Ohm L, Gedde-Dahl T, Majeed W, Ehrencrona H, Koskela S, Saussele S, Mahon FX, Porkka K, Hjorth-Hansen H, Bryceson YT, Richter J, Mustjoki S. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017 May;31(5):1108-1116. doi: 10.1038/leu.2016.360. Epub 2016 Nov 28.
• Rinaldetti S, Pfirrmann M, Manz K, Guilhot J, Dietz C, Panagiotidis P, Spiess B, Seifarth W, Fabarius A, Muller M, Pagoni M, Dimou M, Dengler J, Waller CF, Brummendorf TH, Herbst R, Burchert A, Janbetaen C, Goebeler ME, Jost PJ, Hanzel S, Schafhausen P, Prange-Krex G, Illmer T, Janzen V, Klausmann M, Eckert R, Buschel G, Kiani A, Hofmann WK, Mahon FX, Saussele S. Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial. Clin Lymphoma Myeloma Leuk. 2018 Apr;18(4):266-271. doi: 10.1016/j.clml.2018.02.004. Epub 2018 Feb 8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 14, 2020): 868
• Original Estimated Enrollment (submitted: May 9, 2012): 500
• Actual Study Completion Date: December 31, 2019
• Actual Primary Completion Date: December 3, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• CML in CP under treatment with TKI in first line or in second line because of toxicity to first line TKI or with TKI in combination
• Duration of TKI treatment before enrolment at least 3 years
• At least complete molecular remission MR4
• Before inclusion confirmation of CMR4 through a EUTOS-CMR laboratory
• Baseline data and documentation on treatment before study entry available
• Both sexes but fertile women only if using effective contraceptive
• Health insurance coverage
• 18 years or older

Exclusion Criteria:

• Under 18 years old
• Hospitalized patients without ability to give informed consent
• Adults under law protection or without ability to consent
• Previous or planned allogeneic stem cell transplantation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Denmark, Finland, France, Germany, Greece, Netherlands, Norway, Portugal, Sweden
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01596114
• Other Study ID Numbers: ELN-001; 2011-000440-22 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: European LeukemiaNet
• Original Responsible Party: Same as current
• Current Study Sponsor: European LeukemiaNet
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Susanne Saussele, Prof. Dr.; Universitätsmedizin Mannheim, Universität Heidelberg

• PRS Account: European LeukemiaNet
• Verification Date: October 2021