European Stop Tyrosine Kinase Inhibitor Study

NCT01596114 | Completed Phase 3 DMC

• 2 other identifiers: ELN-0012011-000440-22
• Study Type: interventional
• Target: 868
• Locations: 10 countries
• Sites: 50

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

Conditions

Chronic Myeloid Leukemia

Keywords

TKI; CML; Stopping; chronic phase; in remission

Outcome Measures

Primary Outcomes (1)

• molecular relapse-free survival

  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))

  3 years

Secondary Outcomes (4)

• Overall and progression-free survival

  3 years

• Treatment costs

  3 years

• QoL

  3 years

• Time to recovery

  3 years

Study Arms (1)

Stop treatment

EXPERIMENTAL

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

Other: Stopping treatment with TKI

Interventions

Stopping treatment with TKI OTHER

stopping until loss of MMR

Stop treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Baseline data and documentation on treatment before study entry available
• Both sexes but fertile women only if using effective contraceptive
• Health insurance coverage
• years or older

You may not qualify if:

• 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

Sponsors & Collaborators

• European LeukemiaNet: lead

Study Sites (50)

Fakultní nemocnice

Brno, 625 00, Czechia

Location

Fakultní nemocnice Hradec Králové

Hradec Králové, 50005, Czechia

Location

University Hospital Olomouc

Olomouc, 775 20, Czechia

Location

University Hospital Plzen

Pilsen, 30460, Czechia

Location

Fakultni nemocnice Kralovske Vinohrady

Prague, 100 34, Czechia

Location

Ústav hematologie a krevní transfuze

Prague, 12820, Czechia

Location

Odense University Hospital

Odense, 5000, Denmark

Location

Helsinki University Central Hospital

Helsinki, 00029 HUCH, Finland

Location

CHU d'Angers

Angers, 49933, France

Location

Institut Bergonié

Bordeaux, 33000, France

Location

Université Victor Segalen

Bordeaux, 33076, France

Location

Hôpital André Mignot

Chesnay, 78157, France

Location

Chu Estaing

Clermont-Ferrand, 63003, France

Location

Hôpital Claude Huriez

Lille, 59037, France

Location

Hôpital Édouard Herriot

Lyon, 69437, France

Location

Institut Paoli-Calmettes (IPC)

Marseille, 13273, France

Location

Centre Hospitalier Universitaire (CHU) de Nantes

Nantes, 44093, France

Location

Hôpital de l'Archet

Nice, 06200, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

Hôpital Necker-Enfants Malades

Paris, 75743, France

Location

Hopital de la Milétrie, Centre Hospitalier Universitaire (CHU) de Poitiers

Poitiers, 86021, France

Location

Hôpital Pontchaillou

Rennes, 35033, France

Location

Hôpital Purpan

Toulouse, 31059, France

Location

CHU de Tours

Tours, 37044, France

Location

Hôpital de Brabois

Vandœuvre-lès-Nancy, 54511, France

Location

Uniklinik RWTH

Aachen, 52074, Germany

Location

Universitätsklinikum

Bonn, 53105, Germany

Location

Klinikum

Chemnitz, 09113, Germany

Location

Universitätsklinikum

Jena, 07747, Germany

Location

Klinikum Kempten-Oberallgäu

Kempten, 87439, Germany

Location

Universitätsmedizin Mannheim, Universität Heidelberg

Mannheim, 68163, Germany

Location

Universitätsklinikum Giessen und Marburg GmbH

Marburg, 35033, Germany

Location

MVZ Klinikum Straubing GmbH

Straubing, 94315, Germany

Location

University of Athens, Society of Hematology

Athens, 11526, Greece

Location

VU Academic Medical Center

Amsterdam, 1007 MB, Netherlands

Location

Albert Schweitzer Hospital

Dordrecht, 3300, Netherlands

Location

Oslo universitetssykehus HF Rikshospitalet

Oslo, 0372, Norway

Location

Stavanger University Hospital

Stavanger, 4068, Norway

Location

University Hospital of Northern Norway

Tromsø, 9038, Norway

Location

Norwegian University of Science and Technology

Trondheim, 7489, Norway

Location

Instituto Português de Oncologia Francisco Gentil

Lisbon, 1099-023, Portugal

Location

Karoliniska Univ hospital Huddinge

Huddinge, 141 86, Sweden

Location

Univ hospital Linköping

Linköping, 581 85, Sweden

Location

Sunderby hospital

Luleå, 971 80, Sweden

Location

Lunds Universitet

Lund, 221 85, Sweden

Location

Univ hospital Örebro

Örebro, 701 85, Sweden

Location

Karoliniska Univ sjh Solna

Stockholm, 171 76, Sweden

Location

Länssj Sundsvall

Sundsvall, 851 86, Sweden

Location

Norrlands Univ hospital

Umeå, 901 85, Sweden

Location

Uppsala University hospital

Uppsala, 751 85, Sweden

Location

Related Publications (7)

• 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.

  PMID: 33589755 BACKGROUND

• 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.

  PMID: 32058176 BACKGROUND

• 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.

  PMID: 29980572 BACKGROUND

• 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.

  PMID: 28074067 BACKGROUND

• 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.

  PMID: 29735299 RESULT

• 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.

  PMID: 27890936 RESULT

• 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.

  PMID: 29510895 RESULT

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

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

Study Officials

• Susanne Saussele, Prof. Dr.

  Universitätsmedizin Mannheim, Universität Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2012
• First Posted: May 10, 2012
• Study Start: May 30, 2012
• Primary Completion: December 3, 2014
• Study Completion: December 31, 2019
• Last Updated: November 5, 2021

Record last verified: 2021-10

Locations

DK (1); SE (9); NO (4); NL (2); GR (1); PT (1); DE (8); FR (17); CZ (6); FI (1)