Assessment of treatment-free remission (persistence of MMR) after second attempt of TKI discontinuation in patients who failed a relapsed in the EURO-SKI study or under EURO-SKI like conditions. Patients must have received at least three years of…
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Brief title
Condition
- Leukaemias
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients maintaining MMR at 6 and 12 months after
discontinuing TKI a second time (survival without loss of major molecular
response, MMR, defined as BCR-ABL1 > 0.1% on IS at one time point).
Secondary outcome
Assessment of:
1. Clinical and biological factors correlating with persistence of MMR or
better after second TKI stop (BCR-ABL level before 2nd stop, Sokal score,
gender, duration and type of TKI-treatment, duration of first TKI-stop,
immunological biomarkers)
2. Number of patients who re-achieved stable MR4, and were offered study
participation;.and Overall and progression-free survival and the occurrence of
a restart of TKI without prior molecular relapse.
3. Time to reachievement of MR4 after second loss of MMR.
4. Adverse events related to second TKI stop, clinical and biological factors
correlated to development of these AEs.
Background summary
In the EURO-SKI study, more than 800 patients with undetectable or low level
disease defined by MR4 or better, were included and stopped their treatment. At
EHA 2016, an analysis of 750 patients was presented. More than 55% of patients
remained in treatment free remission after 12 months, with loss of MMR defined
as trigger for re-treatment. In this study, almost all patients had used
imatinib before stopping. Second generation TKIs induce faster and deeper
molecular remissions, which may result in higher rates of successful
discontinuation.
Previously, a small study where patients failing a first stop in the STIM-study
were retreated with imatinib and then subjected to a second stop attempt after
having been in CMR at least 1 year has been reported. In this study 4 out of 16
patients (25%) remained in MMR with a median follow-up of 32 months (15-53
months), and no hematological relapses or progressions to AP/BC were observed.
The induction of faster and deeper responses by 2nd gen TKIs makes it tempting
to use these drugs in patients who relapsed after a discontinuation attempt by
imatinib. The first-line studies of nilotinib (ENESTnd) and dasatinib
(DASISION), comparing these drugs with imatinib in newly diagnosed patients,
clearly showed that 2GTKIs induce faster and deeper molecular responses than
imatinib.
Study objective
Assessment of treatment-free remission (persistence of MMR) after second
attempt of TKI discontinuation in patients who failed a relapsed in the
EURO-SKI study or under EURO-SKI like conditions. Patients must have received
at least three years of further TKI treatment of which the two last years
should be dasatinib. The patients must have been in MR4 for at least one year.
Study design
Multicenter phase 2 study, prospective, open label, uncontrolled.
Intervention
- Dasatinib treatment phase for 24 months.
- Treatment- Free Remission (TFR) phase, if patient had re-achieved a MR4 for
at least 1 year.
- Follow up for 3 years.
Study burden and risks
As no treatment is given after the discontinuation, it is possible to expect
some quality of life benefit, especially in patients that have suffered side
effects on TKI treatment.
As explained in this study stopping TKI in patients in CMR induces a risk of
molecular relaps of CML. Data from the EURO-SKI study show that in case of
relapse, resuming TKI allows controlling the disease again. Data from the
EURO-SKI study shows that it is safe and no patients progressed to AP/BC.
In this study, close monitoring of residual disease by RT-PCR after stopping
TKI will allow early detection of possible molecular relapse.
As has been seen after stopping imatinib for the first time, myalgia and
arthralgia, may also be expected to occur at a second stop trial.
In general, this is a benign phenomenon, not requiring therapy. However, in a
few cases, it has been necessary to treat this pain syndrome with
corticosteroids. These may also have adverse effects, like mood disorders,
induction of diabetes mellitus, osteoporosis and immune suppression.
Dag Hammarskölds väg 20
Uppsala 75185
SE
Dag Hammarskölds väg 20
Uppsala 75185
SE
Listed location countries
Age
Inclusion criteria
1. CML in chronical phase (CP) under TKI treatment after failing a prior attempt to stop treatment within EURO-SKI or outside the study but according to EURO-SKI trial procedures. For the latter group this requires at least 3 years of TKI treatment (first line or second line due to intolerance to first line) before first stop, and MR4 for at least one year before stopping.
2. Treated with TKI for at least one year after having failed a prior attempt to stop TKI. Previous TKI can be any.
3. Typical BCR/ABL1 transcript (b3a2 and/or b2a2) must have been confirmed at diagnosis or later during the disease course.
4. 18 years or older
Exclusion criteria
1. Previous hematological relapse after first stop of TKI.
2. Previous AP/BC at any time in the history of the disease.
3. Restart of TKI without loss of MMR after first stop
4. Current participation in another clinical study.
5. Previous or planned allogeneic stem cell transplantation.
6. Patients with contra-indications to dasatinib therapy due to comorbidities.
7. Subjects with acute hepatitis B virus (HBV) infections.
8. Uncontrolled or significant cardiovascular disease.
9. Pulmonary arterial hypertension.
10. Pleural or pericardial effusions of any grade at study entry are excluded
11. History of significant bleeding disorder unrelated to CML
12. Hypersensitivity to dasatinib and excipients of dasatinib tablets.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004106-34-NL |
| CCMO | NL62339.029.17 |