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

Chronic Myeloid Leukemia Clinical Trial

— NAUT  

Official title:

Multicenter Prospective Trial After 1st or 2nd Unsuccessful Treatment Discontinuation in Chronic Myeloid Leukemia ( CML) Estimating the Efficacy of Nilotinib in Inducing the Persistence of Molecular Remission After Stopping TKI a 2nd or 3rd Time

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02917720
• Other study ID #: ELN-002
• Secondary ID: 2015-004998-33
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 2016
• Est. completion date: September 2027

Study information

• Verified date: December 2023
• Source: European LeukemiaNet
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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%.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 75
• Est. completion date: September 2027
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Other:
• TKI discontinuation
2nd or 3rd TKI stop after pre-treatment with nilotinib.

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

Locations

Country	Name	City	State
Germany	Universitätsklinikum der RWTH	Aachen
Germany	Klinikum Bayreuth	Bayreuth
Germany	Klinikum Chemnitz	Chemnitz
Germany	Onkologische Schwerpunktpraxis	Esslingen
Germany	Universitätsklinikum Freiburg	Freiburg	Baden-Württemberg
Germany	Universitätsklinikum Halle (Saale)	Halle (Saale)
Germany	Medizinische Hochschule Hannover	Hannover	NRW
Germany	Schwerpunktpraxis Onkologie	Heilbronn
Germany	Universitätsmedizin Mannheim	Mannheim	Baden-Württemberg
Germany	Klinikum der Philipps-Universität	Marburg
Germany	Klinikum rechts der Isar	München	Bayern
Germany	Kliniken Ostalb, Stauferklinikum Schwäbisch Gmünd	Mutlangen
Germany	Universitätsklinikum Rostock	Rostock
Germany	Schwarzwald-Baar Klinikum	Villingen-Schwenningen
Netherlands	Amsterdam UMC, locatie VUmc	Amsterdam

Sponsors (3)

Lead Sponsor	Collaborator
European LeukemiaNet	Heidelberg University, Ludwig-Maximilians - University of Munich

Countries where clinical trial is conducted

Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of duration of MMR or better at 12 months after stopping TKI therapy a second or third time	Assessment of duration of MMR or better at 12 months after stopping TKI therapy a second 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 for at least one year and MR4.5 for at least 6 months	12 months after stopping
Secondary	Assessment of quality of life (QoL) profiles under nilotinib treatment and comparison with previous TKI therapy before switch and after stopping	To investigate QoL changes over time in relapse-free patients without TKI re-start as measured by the EORTC QLQ-C30 and CML 24 (one combined questionnaire)	5 years
Secondary	Identification of clinical and biological factors correlating with the persistence of MMR or better after stopping TKI	Proportion of high risk patients according to the risk score at 6 months after stopping TKI;	6 months after stopping
Secondary	Estimation of overall survival	Overall survival is calculated from the date of 2nd stop of TKI treatment until the date of death irrespective of the cause of death. Patients still alive at the date of analysis will be censored at the date of last follow-up.	3 years
Secondary	Time to re-achievement of MR4.5 after restart of therapy	Assessment of molecular response after 3 years	3 years
Secondary	Number of patients with grade 1 through grade 5 adverse events (AEs) that are related to study drug, graded according to NCI CTCAE Version 3.0	Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second time	3 years
Secondary	Assessment of duration of MMR or better	Assessment of duration of MMR or better at 36 months after stopping 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	36 months after stopping
Secondary	Number of patients with grade 1 through grade 5 adverse events (AEs) that are related to study drug, graded according to NCI CTCAE Version 3.0	Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second time	2 years treatment with nilotinib 300 mg/bid
Secondary	Estimation of progression-free survival	Progression-free survival is defined as overall survival plus the additional events progression to accelerated phase or blast crisis that also terminate PFS	3 years
Secondary	Identification of clinical and biological factors correlating with the persistence of MMR or better after 6 months	Proportion of female patients without molecular relapse	6 months after stopping