|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not and are pretreated at least one year with any TKI after 1st stop
|Medical condition in easily understood language
|CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy and are pretreated at least one year with any TKI after the last stop
|Diseases [C] - Blood and lymphatic diseases [C15]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|Assessment of duration of MMR or better at 12 and 36 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 objectives of the trial
|• Assessment of patients who re-achieved stable MR4.5, and were proposed a 2nd stop
• Assessment of safety profile, tolerability and AEs under nilotinib (NIL) treatment
• Assessment of QoL profiles under NIL treatment and comparison with previous TKI therapy before switch and after stopping
• Identification of clinical and biological factors correlating with the persistence of MMR or better after stopping TKI , gender, duration of TKI treatment, immunological status; stop according to EUROSKI criteria y/n, molecular level at first stop
• Treatment outcome in correlation with predefined biomarkers (pDC: CD86, PD-1L, PD1 expression, genetic expression profile)
• Estimation of overall and progression-free survival, and probabilities of a restart of TKI treatment without prior molecular relapse
• Time to re-achievement of MR4.5 after restart of therapy
• Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second time
|Trial contains a sub-study
|Full title, date and version of each sub-study and their related objectives
|Substudy 1: Cellular immune marker
To determine the individual response of each patient to IFN stimulation in vitro, cytokine and chemokine production of PBMC may be analyzed.
Moreover, serum will be analyzed to evaluate cytokine/chemokine profiles associated with response.
Substudy 2: Telomere length analysis
The aim of the study is to investigate the prognostic role of telomere shortening in patients with CML and molecular response to TKI treatment for disease recurrence upon cessation of TKI treatment. In addition, we will compare telomere length in (predominantly) normal blood cells at treatment discontinuation (BCR-ABL/ABL ratio < 0.001) to normal cells (in case of persisting remission) vs. leukemic cells in case of disease recurrence.
Substudy 3: Investigating the TKI withdrawal syndrome
In EURO-SKI, in the Nordic countries a withdrawal syndrome was described in about 15-20% of patients after stopping imatinib. As has been seen after stopping for the first time, myalgia and arthralgia, especially in the upper arms and shoulders may also be expected to occur at a second stop trial.
To further investigate the syndrome we here purpose to investigate the following parameters and correlate these with the clinical outcome:
• crosslinked N-Telopeptide, type I collagen (NTx) (ELISA)
• PTH and/or Calcitonin (at local laboratory)
Substudy 4: Immunological Status 2
Currently, only few predictive factors for successful stopping are known, for example the depth of response and the duration of imatinib treatment before stop. If there is a role of B-cell mediated humoral immunity in sustaining molecular remissions in patients who stop TKI treatment is unknown.
There is a need for tools that may help selecting patients who have optimal chance of successful discontinuation, while preventing patients who have very few chance of success from stopping. In addition, we need to gain knowledge on the mechanism of sustained remission. To meet these goals, we will perform immunological research on participants of the NAUT study.
We expect that these immunological side-studies will, first, enable us to identify biomarkers for successful second discontinuation and, second, to find ways to modulate the immune system in order to improve the success of treatment discontinuation.
Substudy 5: Biomarkers predicting relapse
There is still no data about the predictive role of molecular markers at the time point of TKI discontinuation. One goal of this substudy is to analyze expression signatures of white blood cells from peripheral blood and bone marrow of CML patients at time of stopping, especially immune signatures, in order of better understanding the suppression of minimal disease.
Substudy 6: Soluble CD62L and TACE activity
Immunological surveillance of MRD in CML may be of particular relevance for long-term control or even cure of the disease. Vice versa, insufficient immunological MRD control may be associated with disease recurrence upon discontinuation of TKI in patients with deep molecular response. We recently demonstrated that increased shedding of CD62L from the membrane of immune cells due to increased TACE (tumor necrosis factor-alpha converting enzyme) activity and the subsequent increase of soluble CD62L (sCD62L) are closely associated to disease burden and later molecular response in CP-CML treated up-front with the 2nd generation TKI nilotinib. Whether either sCD62 or TACE activity may serve as relapse-sensing tools upon TKI discontinuation remains elusive.
Aims: Prospective evaluation of sCD62L and TACE activity as relapse sensing tools for later molecular relapse upon discontinuation of 2nd generation TKI in CML.
|Principal inclusion criteria
|• Age ≥ 18 years
• Patients with Ph -chromosome and/or the BCR-ABL fusion gene (either b3a2 and/or b2a2) 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 fter 1st stop or 2nd stop, respectively
• Written informed consent
|Principal exclusion criteria
|• Previous hematological relapse after first stop of TKI.
• Failure to any TKI at any time during CML treatment TKI according to actual 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
• Contraindication against nilotinib (see following)
• Impaired cardiac function including any of the following:
o 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.
|E.5 End points
|Primary end point(s)
|The primary endpoint is molecular relapse-free survival, measured at 12 months and 36 months after 2nd or 3rd stop.
|Timepoint(s) of evaluation of this end point
|The final analysis will be performed after all enrolled patients have an at least three-year follow-up after 1 Month after discontinuation (Visit S1). With regard to hypothesis testing, the probability of molecular relapsefree survival in patients without a premature restart of TKI will be estimated and the number of patients with a premature restart will not
be part of the denominator for the hypothesis testing. However, the probability of molecular relapse-free survival based on a denominator including all recruited patients will be provided, too.
|Secondary end point(s)
|With a maximum observation time of five years (two years nilotinib treatment and three-year follow-up after 2nd or 3rd stop), overall survival and progression-free survival probabilities are expected to be relatively high (>90% for overall survival). Thus, regression modelling will not be possible for these variables. In any case, results will be described by the Kaplan-Meier method. The probabilities of a restart of TKI treatment without prior molecular relapse will be calculated by the CIF.
Estimation of the number of patients in MR4.5 who would be eligible for stopping TKI therapy will be based on the information gained by regression modelling.
The number of patients who regain MR4 and MR4.5 and the time to MR4 recovery will be analysed.
The times 12 and 36 months were chosen to be in primary focus. However, other times might prove to be particularly important, e.g. 18 or 24 months after TKI discontinuation. Depending on the outcome of molecular relapse-free survival over time, an additional logistic regression analysis will be performed at a further time emerging to be of specific interest.
|Timepoint(s) of evaluation of this end point
|The times 12 and 36 months were chosen to be in primary focus. However, other times might prove to be particularly important, e.g. 18 or 24 months after TKI discontinuation. Depending on the outcome of molecular relapse-free survival over time, an additional logistic regression analysis will be performed at a further time emerging to be of specific interest.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The final analysis will be performed after all enrolled patients have an at least three-year follow-up after stopping TKI
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days