2nd or 3rd TKI-stop After 2 Years Nilotinib Pre-treatment in CML-patients

NCT ID: NCT02917720

Last Updated: 2025-09-22

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-30
• Study Completion Date: 2027-09-30

Brief Summary

The main goal of the study is the assessment of duration of major molecular response (MMR) or better at 12 and 36 months after stopping tyrosine kinase inhibitors (TKI) therapy a second or third time in patients with at least three years prior TKI treatment comprising at least two years of nilotinib treatment within this trial and maintained stable MR4 (BCR-ABL ratio <0,01% on international Scale (IS) for at least one year and MR4.5 (BCR-ABL ratio <0,0032% on IS) for at least 6 months:

• who failed a first stop in the EURO-SKI study (standardized criteria)
• who failed a first or second stop outside the EURO-SKI study but would have had fulfilled same eligible criteria and were stopped according to EURO-SKI rules
• who failed a first or second stop outside the EURO-SKI study without fulfilling EURO-SKI rules

Detailed Description

The proposal is to re-treat patients with a minimum of two years with nilotinib 2x300 mg/d resulting in total of at least three years TKI treatment who show recurrent disease after unsuccessful first or second stop after TKI treatment in or outside the EURO-SKI study.

If MR4 or better is re-achieved and maintained for at least one year and MR4.5 or better is re-achieved and maintained for at least 6 months, patients will be eligible for a second stop attempt within this study. For MR4, three consecutive PCRs with MR4 or deeper should be measured within one year and for MR4.5, two PCRs during 6 months should demonstrate a MR4.5.

Patients who exhibited hematological relapse after the first stop attempt will not be eligible for a second stop attempt within this study.

After inclusion, 3 monthly monitoring will be performed under nilotinib treatment within the trial. Patients fulfilling the criteria mentioned above will then enter the screening phase.

After verification of MR4.5, TKI treatment will be stopped and patients followed in the same manner as described in EURO-SKI (monthly PCRs for 6 months, 6-weekly PCRs 7-12 months after stopping, thereafter 3-monthly). If MMR is lost (BCR-ABL >0.1% (IS)), TKI treatment will once again be restarted; here the same TKI (nilotinib) is recommended.

It is assumed that after failure of first (or second) stop a switch to treatment with 2GTKI may increase the chance of stopping a second (or third) time [Legros et al. Blood 2012; Rea et al. Blood 2014] It is expected that the rate of a successful second (or third) stop at 12 and 36 months is more than 25%.

Conditions

Chronic Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

TKI-stop, pre-treatment with nilotinib

Treatment after unsuccessful 1st or 2nd discontinuation at least two year with nilotinib (300 mg/bid). In total, retreatment with TKI for at least 3 years before entering screening for stopping phase is warranted. Clinical monitoring every 3 months during this 2 years.

Patients who re-achieved and maintained MR4 for at least 12 months and MR4.5 for at least 6 months can enter screening phase for TFR .If MR4.5 is confirmed by an validated laboratory, patient may enter stopping phase of the study. Patient not fulfilling these criteria can be screened again every 3 months until month 48. After TKI-stop hematological monitoring and quantitative PCR of BCR/ABL1 (month 1-6 after stopping: monthly; month 7-12 after stopping: every 1.5 months, thereafter once every three months, for 3 years in total.

Relapse is defined as BCR-ABL1 > 0.1% on IS at a single time point (loss of MMR) In case of relapse restart of TKI. In general, the same TKI (nilotinib) as before second stop is recommended

Group Type: EXPERIMENTAL

TKI discontinuation

Intervention Type: OTHER

2nd or 3rd TKI stop after pre-treatment with nilotinib.

nilotinib

Intervention Type: DRUG

Pre-treatment with nilotinib 300 mg/bid for 2 years

Interventions

TKI discontinuation

2nd or 3rd TKI stop after pre-treatment with nilotinib.

Intervention Type: OTHER

nilotinib

Pre-treatment with nilotinib 300 mg/bid for 2 years

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 years
• Patients with Ph chromosome and/or the BCR-ABL (either b3a2 and /or b2a2) fusion gene positive CML
• CML in CP having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not
• Pretreatment at least one year with any TKI after 1st stop
• Written informed consent

Exclusion Criteria

• Previous hematological relapse after first stop of TKI.
• Failure to any TKI at any time during CML treatment according to current ELN criteria
• Previous planned or performed allo SCT
• Previous AP/BC at any time in the history of the disease
• High cardiac risk according to ESC score (≥ 10 Points)
• Impaired cardiac function including any of the following:
• Use of a ventricular paced pacemaker; congenital long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant resting bradycardia (<50 bpm); QTcF >450 msec at baseline, myocardial infarction before baseline; other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension).
• Treatment with inhibitors of CYP3A4 or medications that have been well documented to prolong the QT interval is contraindicated.
• History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis.
• Positive hepatitis B virus serology test or HBV infection
• Any other malignancy except if neither clinically significant nor requires active intervention.
• Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, acute or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).
• Women who are pregnant, breast feeding, or of childbearing potential without a negative serum pregnancy test at baseline. Male or female patients of childbearing potential unwilling to use an effective barrier contraceptive method

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Heidelberg University

OTHER

Sponsor Role: collaborator

Ludwig-Maximilians - University of Munich

OTHER

Sponsor Role: collaborator

European LeukemiaNet

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susanne Geiselhart

Role: STUDY_CHAIR

Heidelberg University

Locations

Universitätsklinikum Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Universitätsmedizin Mannheim

Mannheim, Baden-Wurttemberg, Germany

Klinikum rechts der Isar

München, Bavaria, Germany

Medizinische Hochschule Hannover

Hannover, North Rhine-Westphalia, Germany

Universitätsklinikum der RWTH

Aachen, , Germany

Klinikum Bayreuth

Bayreuth, , Germany

Klinikum Chemnitz

Chemnitz, , Germany

Onkologische Schwerpunktpraxis

Esslingen am Neckar, , Germany

Universitätsklinikum Halle (Saale)

Halle, , Germany

Schwerpunktpraxis Onkologie

Heilbronn, , Germany

Klinikum der Philipps-Universität

Marburg, , Germany

Kliniken Ostalb, Stauferklinikum Schwäbisch Gmünd

Mutlangen, , Germany

Universitätsklinikum Rostock

Rostock, , Germany

Schwarzwald-Baar Klinikum

Villingen-Schwenningen, , Germany

Amsterdam UMC, locatie VUmc

Amsterdam, , Netherlands

Countries

Germany; Netherlands

Other Identifiers

2015-004998-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ELN-002

Identifier Type: -

Identifier Source: org_study_id