Assessment of duration of MMR or better 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 and maintained stable MR4 for at least one year…
ID
Source
Brief title
Condition
- Leukaemias
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is molecular relapse-free survival, measured at 12 months
and 36 months after 2nd stop or 3rd stop.
Secondary outcome
- number of patients who re-achieved stable MR4.5, and were proposed a 2nd stop
or 3rd stop
- number of patients who accepted/refused 2nd stop or 3rd stop 2 and 3 years
after study entry; whereas stable MR4.5 is defined as two PCRs during 6 months
before stopping demonstrating MR4.5
- safety profile, tolerability and AEs under nilotinib treatment
- QoL profiles under nilotinib treatment and comparison with previous TKI
therapy before switch and after stopping
- 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
- incidence of any AEs (e.g. from musculoskeletal system) that arise after
stopping TKI treatment a second time
Background summary
Results of the STIM studies showed that stopping of the TKI intake did not
endanger patients; most patients who experienced molecular relapse did so
within 6 months of imatinib cessation and remained responsive to re-treatment
with imatinib as observed in the pilot study.
In the EURO-SKI study, a majority of the patients have undergone treatment with
imatinib first-line with more than 90% of patients in the interim analysis.
Actually, among the first 200 eligible patients with at least 6 months of
follow-up, 123 patients remained without molecular relapse defined as loss of
MMR at one time point.
So far, only limited experience is available with second generation TKIs and
for patients who stopped a second time or third time after molecular relapse in
a first or second treatment-free phase.
The first-line studies of nilotinib (ENESTnd) in newly diagnosed patients
indicated that nilotinib induces faster and deeper molecular responses than
imatinib. Although, up to now, this has not translated into a survival
advantage, it is possible, but not yet shown, that this might result in higher
rates of successful discontinuation.
Study objective
Assessment of duration of MMR or better 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 and maintained stable MR4 for at
least one year and MR4.5 for at least 6 months before stopping in patients -
- who failed a first stop in the EURO-SKI study (standardized criteria)
-- who failed a first stop or second stop outside the EURO-SKI study but would
have had fulfilled same eligible criteria and were stopped according to
EURO-SKI criteria
-- who failed a first stop or second stop outside the EURO-SKI study without
fulfilling EURO-SKI criteria
Study design
Study is an open label, prospective, uncontrolled multicenter trial.
Intervention
- a Nilotinb treatment phase for 24 months
- Treatment -Free Remission (TFR) phase, if patient has re-achieved a MR4 for
at least 1 year and MR4.5 for at least 0.5 year.
Study burden and risks
As no treatment is given, it is possible to expect some quality of life
benefit, especially in patients that have suffered side effects on TKI
treatment. At least in part of patients the benefit will be to be off therapy
for a longer period than 6 months.
Risks for nilotinib treatment phase:
Nilotinib is approved for first-line therapy in CML and the toxicity profile is
well known as the drug is in clinical use since 2006.
No additional risk is predictable; to manage potential toxicity 3-monthly
visits are indicated within the study.
Risks for the treatment free remission phase:
In EURO-SKI, trial 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. 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.
Burden in the treatment free remission phase is once a month hospital visit and
blood collection for close monitoring of residual disease by qRT-PCR after
stopping TKI, the first 6 months after stopping, followed by 6 weeks visits in
the next 6 months.
Seminarstraat 2
Heidelberg 69115
DE
Seminarstraat 2
Heidelberg 69115
DE
Listed location countries
Age
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 prior attempt(s) to stop imatinib or other TKIs
therapy either within EURO-SKI or not
· Pretreatment at least one year with any TKI after 1st or 2nd stop
· Written informed consent
Exclusion criteria
· Previous hematological relapse after first or second 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.
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 | EUCTR2015-004998-33-NL |
| ClinicalTrials.gov | NCT02917720 |
| CCMO | NL59532.029.16 |