Clinical trial NCT01596114: European Stop Tyrosine Kinase Inhibitor Study
Official title: Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukemia After Stopping TKI
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia
Keywords: TKI
CML
Stopping
chronic phase
in remission
Lead sponsor: European LeukemiaNet
Sponsor class: NETWORK
First posted: 2012-05-10
Enrollment: 868
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


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

Primary outcomes:
measure: molecular relapse-free survival
timeFrame: 3 years
Secondary outcomes:
measure: Overall and progression-free survival
timeFrame: 3 years
measure: Treatment costs
timeFrame: 3 years
measure: QoL
timeFrame: 3 years
measure: Time to recovery
timeFrame: 3 years
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: Fakultní nemocnice
city: Hradec Kralove
country: Czechia
facility: Fakultní nemocnice Hradec Králové
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
city: Plzen
country: Czechia
facility: University Hospital Plzen
city: Prague
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady
city: Prague
country: Czechia
facility: Ústav hematologie a krevní transfuze
city: Odense
country: Denmark
facility: Odense University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Angers
country: France
facility: CHU d'Angers
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bordeaux
country: France
facility: Université Victor Segalen
city: Chesnay cedex
country: France
facility: Hôpital André Mignot
city: Clermont Ferrand
country: France
facility: Chu Estaing
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Lyon
country: France
facility: Hôpital Édouard Herriot
city: Marseille
country: France
facility: Institut Paoli-Calmettes (IPC)
city: Nantes
country: France
facility: Centre Hospitalier Universitaire (CHU) de Nantes
city: Nice
country: France
facility: Hôpital de l'Archet
city: Paris cedex 10
country: France
facility: Hôpital Saint-Louis
city: Paris Cedex 15
country: France
facility: Hôpital Necker-Enfants Malades
city: Poitiers
country: France
facility: Hopital de la Milétrie, Centre Hospitalier Universitaire (CHU) de Poitiers
city: Rennes
country: France
facility: Hôpital Pontchaillou
city: Toulouse
country: France
facility: Hôpital Purpan
city: Tours
country: France
facility: CHU de Tours
city: Vandoeuvre-lès-Nancy
country: France
facility: Hôpital de Brabois
city: Aachen
country: Germany
facility: Uniklinik RWTH
city: Bonn
country: Germany
facility: Universitätsklinikum
city: Chemnitz
country: Germany
facility: Klinikum
city: Jena
country: Germany
facility: Universitätsklinikum
city: Kempten
country: Germany
facility: Klinikum Kempten-Oberallgäu
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim, Universität Heidelberg
city: Marburg
country: Germany
facility: Universitätsklinikum Giessen und Marburg GmbH
city: Straubing
country: Germany
facility: MVZ Klinikum Straubing GmbH
city: Athens
country: Greece
facility: University of Athens, Society of Hematology
city: Amsterdam
country: Netherlands
facility: VU Academic Medical Center
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Hospital
city: Oslo
country: Norway
facility: Oslo universitetssykehus HF Rikshospitalet
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tromsø
country: Norway
facility: University Hospital of Northern Norway
city: Trondheim
country: Norway
facility: Norwegian University of Science and Technology
city: Lisboa
country: Portugal
facility: Instituto Português de Oncologia Francisco Gentil
city: Huddinge
country: Sweden
facility: Karoliniska Univ hospital Huddinge
city: Linköping
country: Sweden
facility: Univ hospital Linköping
city: Luleå
country: Sweden
facility: Sunderby hospital
city: Lund
country: Sweden
facility: Lunds Universitet
city: Stockholm
country: Sweden
facility: Karoliniska Univ sjh Solna
city: Sundsvall
country: Sweden
facility: Länssj Sundsvall
city: Umeå
country: Sweden
facility: Norrlands Univ hospital
city: Uppsala
country: Sweden
facility: Uppsala University hospital
city: Örebro
country: Sweden
facility: Univ hospital Örebro
Study officials:
affiliation: Universitätsmedizin Mannheim, Universität Heidelberg
name: Susanne Saussele, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.