search
Back to results

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

Primary Purpose

Chronic Myeloid Leukemia

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
TKI discontinuation
nilotinib
Sponsored by
European LeukemiaNet
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Myeloid Leukemia focused on measuring TKI discontinuation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Universitätsklinikum Freiburg
  • Universitätsmedizin Mannheim
  • Klinikum rechts der Isar
  • Medizinische Hochschule Hannover
  • Universitätsklinikum der RWTH
  • Klinikum Bayreuth
  • Klinikum Chemnitz
  • Onkologische Schwerpunktpraxis
  • Universitätsklinikum Halle (Saale)
  • Schwerpunktpraxis Onkologie
  • Klinikum der Philipps-Universität
  • Kliniken Ostalb, Stauferklinikum Schwäbisch Gmünd
  • Universitätsklinikum Rostock
  • Schwarzwald-Baar Klinikum
  • Amsterdam UMC, locatie VUmc

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TKI-stop, pre-treatment with nilotinib

Arm Description

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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)
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;
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.
Time to re-achievement of MR4.5 after restart of therapy
Assessment of molecular response after 3 years
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
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
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
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
Identification of clinical and biological factors correlating with the persistence of MMR or better after 6 months
Proportion of female patients without molecular relapse

Full Information

First Posted
March 2, 2016
Last Updated
November 4, 2021
Sponsor
European LeukemiaNet
Collaborators
Heidelberg University, Ludwig-Maximilians - University of Munich
search

1. Study Identification

Unique Protocol Identification Number
NCT02917720
Brief Title
2nd or 3rd TKI-stop After 2 Years Nilotinib Pre-treatment in CML-patients
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 2016 (Actual)
Primary Completion Date
September 2026 (Anticipated)
Study Completion Date
September 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
European LeukemiaNet
Collaborators
Heidelberg University, Ludwig-Maximilians - University of Munich

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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%.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Myeloid Leukemia
Keywords
TKI discontinuation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
75 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TKI-stop, pre-treatment with nilotinib
Arm Type
Experimental
Arm Description
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
Intervention Type
Other
Intervention Name(s)
TKI discontinuation
Intervention Description
2nd or 3rd TKI stop after pre-treatment with nilotinib.
Intervention Type
Drug
Intervention Name(s)
nilotinib
Intervention Description
Pre-treatment with nilotinib 300 mg/bid for 2 years
Primary Outcome Measure Information:
Title
Assessment of duration of MMR or better at 12 months after stopping TKI therapy a second or third time
Description
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
Time Frame
12 months after stopping
Secondary Outcome Measure Information:
Title
Assessment of quality of life (QoL) profiles under nilotinib treatment and comparison with previous TKI therapy before switch and after stopping
Description
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)
Time Frame
5 years
Title
Identification of clinical and biological factors correlating with the persistence of MMR or better after stopping TKI
Description
Proportion of high risk patients according to the risk score at 6 months after stopping TKI;
Time Frame
6 months after stopping
Title
Estimation of overall survival
Description
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.
Time Frame
3 years
Title
Time to re-achievement of MR4.5 after restart of therapy
Description
Assessment of molecular response after 3 years
Time Frame
3 years
Title
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
Description
Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second time
Time Frame
3 years
Title
Assessment of duration of MMR or better
Description
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
Time Frame
36 months after stopping
Title
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
Description
Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second time
Time Frame
2 years treatment with nilotinib 300 mg/bid
Title
Estimation of progression-free survival
Description
Progression-free survival is defined as overall survival plus the additional events progression to accelerated phase or blast crisis that also terminate PFS
Time Frame
3 years
Title
Identification of clinical and biological factors correlating with the persistence of MMR or better after 6 months
Description
Proportion of female patients without molecular relapse
Time Frame
6 months after stopping

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susanne Geiselhart
Organizational Affiliation
Heidelberg University
Official's Role
Study Chair
Facility Information:
Facility Name
Universitätsklinikum Freiburg
City
Freiburg
State/Province
Baden-Württemberg
ZIP/Postal Code
79108
Country
Germany
Facility Name
Universitätsmedizin Mannheim
City
Mannheim
State/Province
Baden-Württemberg
ZIP/Postal Code
68167
Country
Germany
Facility Name
Klinikum rechts der Isar
City
München
State/Province
Bayern
ZIP/Postal Code
81675
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
State/Province
NRW
ZIP/Postal Code
30625
Country
Germany
Facility Name
Universitätsklinikum der RWTH
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Klinikum Bayreuth
City
Bayreuth
ZIP/Postal Code
95445
Country
Germany
Facility Name
Klinikum Chemnitz
City
Chemnitz
ZIP/Postal Code
09113
Country
Germany
Facility Name
Onkologische Schwerpunktpraxis
City
Esslingen
ZIP/Postal Code
73728
Country
Germany
Facility Name
Universitätsklinikum Halle (Saale)
City
Halle (Saale)
Country
Germany
Facility Name
Schwerpunktpraxis Onkologie
City
Heilbronn
ZIP/Postal Code
74072
Country
Germany
Facility Name
Klinikum der Philipps-Universität
City
Marburg
ZIP/Postal Code
35033
Country
Germany
Facility Name
Kliniken Ostalb, Stauferklinikum Schwäbisch Gmünd
City
Mutlangen
ZIP/Postal Code
73557
Country
Germany
Facility Name
Universitätsklinikum Rostock
City
Rostock
ZIP/Postal Code
18057
Country
Germany
Facility Name
Schwarzwald-Baar Klinikum
City
Villingen-Schwenningen
ZIP/Postal Code
78052
Country
Germany
Facility Name
Amsterdam UMC, locatie VUmc
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs