To assess the effect of switching CML patients, who have been treated with imatinib *2 years and who have stable detectable molecular residual disease above 0.01% (IS), to the combination of Nilotinib and PegIFN, in terms of the proportion of…
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Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* The proportion of patients with confirmed MR4.0 IS at Month 12.
For the substudies:
The predictive value for response of
* relative and absolute numbers of CD4+ and CD8+ T cells, NK cells, NKT cells,
B cells and regulatory T cells (CD4+, CD25+,
FoxP3+), as measured by flow cytometry assay pre- and post-treatment.
* the presence and frequency of BCR-ABL-, WT1, Prame- or PR1-specific cytotoxic
T-cells as measured by flow cytometry using tetramer technique.
* the cytotoxic capacity of lymphocytes, as measured by killing activity of NK
cells, IFN * production by and granzyme B staining of T cells after
stimulation, all performed pre- and post treatment.
* plasma cytokine profiles, as measured by the Luminex multiplex array system
pre- and post-treatment.
* phosphoproteomic profiles pre- and post-treatment.
* the frequency of residual leukemic stem cells, as detected by flow cytometry
using phospho-CRKL activity as a read-out of BCR-ABL activity.
Secondary outcome
* Safety and tolerability, including frequency and type of AEs/serious AEs.
* The proportion of patients with MR4.0 and with MR4.5 IS at or by Month 3, 6,
12, 18 and 24.
* The proportion of patients who complete the planned 9 months of combination
therapy with PegIFN (i.e. to Month 12 assessment).
* The rate of loss of CCyR, MMR and MR4.0 at Month 12, 18.
* The proportion of patients progressing to advanced disease phase.
* Overall survival.
* Quality of Life as assessed by standard questionaires
* ECOG performance rating at baseline, month 3, 6, 12 and 18.
Background summary
The tyrosine kinase inhibitor (TKI) imatinib has dramatically improved the
outcome for patients with chronic myeloid leukemia (CML) in chronic phase (CP).
Continued treatment with imatinib can further reduce the leukemic clone, in
some patients down to levels undetectable by sensitive, quantitative PCR, so
called *complete molecular response* (CMR), corresponding to at least a 4 to 5
log10 reduction versus a standardized baseline derived from the initial IRIS
study.
According to current ELN guidelines, achieving a response less than CCyR at 18
months and beyond on primary imatinib treatment is considered as *failure*,
while less than MMR at the same time point is denoted *suboptimal
response* (Baccarani, et al 2009).
Recent data indicate that second generation TKIs (2TKI) nilotinib and dasatinib
are more effective than imatinib inducing MMR and CMR in newly diagnosed CML CP
patients (Saglio, et al 2010; Kantarjian, et al 2010).
This is a clinically relevant difference, as in another study, about 40% of
patients who stopped imatinib after having achieved a sustained CMR for 2 years
showed prolonged freedom from relapse (Mahon, et al 2010).
This bears promise that improved treatment responses may increase the fraction
of patients who can stop treatment, hopefully permanently, representing
operational cure at least in a part of patients.
Pegylated interferon * (PegIFN) has a prominent immunomodulatory mode of action
and combined with imatinib improves treatment results compared to imatinib
monotherapy (NordCML002, Simonsson, et al 2011a; French SPIRIT, Preudhomme, et
al 2010). This advantage translates into higher CMR rates, and thus to
potentially future *cure*. The improvement in treatment results of nilotinib on
one side and the combination of imatinib + PegIFN on the other appears to be
similar in magnitude compared to standard imatinib treatment. Combining a 2TKI
such as nilotinib with PegIFN is therefore logical.
Nilotinib has modest immunological effects, whereas PegIFN is a powerful
immunomodulator which is believed to be important for its anti CML effect. The
mechanisms of action of these compounds are clearly different, and hence offer
the potential for additive or synergistic effects. Although previously not
tested in combination, both drugs are approved and deserve further clinical
testing.
Preliminary results from an international trial (ENESTcmr trial) shows that a
switch to a second line TKI (i.c. nilotinib) can significantly improve the rate
of complete molecular responses (23% vs 11% for switch to nilotinib vs
continuation of imatinib, respectively) in patients who have already received
and responded to imatinib for longer periods of time, but who still have failed
to reach undetectable transcript levels (CMR).
This study will give more information of the effect of switching from imatinib
to nilotinib in patients with stably detectable molecular residual disease
(between 0.01% and 1.0% IS). Moreover, in view of the results with combining
PegIFN to imatinib, we expect that the addition of PegIFN to nilotinib will
significantly add to the improvement in complete molecular response rates that
may be achieved with switching to nilotinib alone. This is highly relevant as
better suppression of Ph-positive hematopoiesis is expected to enable succesful
discontinuation of treatment in more patients.
Study objective
To assess the effect of switching CML patients, who have been treated with
imatinib *2 years and who have stable detectable molecular residual disease
above 0.01% (IS), to the combination of Nilotinib and PegIFN, in terms of the
proportion of patients who achieve confirmed MR4.0.
And to assess:
* the safety and tolerability of nilotinib alone or in combination with PegIFN.
* the duration of response
* the percentage of patients who lose response after cessation of IFN between
Month 12 and 18
* the adherence to combination treatment
* disease progression
* overall survival
* quality of life.
To compare safety and efficacy data with those from nilotinib treated patients
in the ENESTcmr study.
To perform immunological and other laboratory studies to explain effects and
toxicity.
To identify biomarkers for response.
Study design
Single arm, open label, multicenter study to assess the efficacy, safety and
tolerability of nilotinib 300 mg BID, alone and in combination with PegIFN 25
40 *g/week in patients not in CMR. Patients will be treated with nilotinib 300
mg BID at the beginning of the study to establish the tolerability before
adding PegIFN. Combination treatment will be continued until Month 12, which is
followed by monotherapy phase of nilotinib 300 mg BID. Overall study duration
for the individual patient is 24 months.
Intervention
Patients will be treated with nilotinib 300 mg BID at the beginning of the
study to establish the tolerability before adding PegIFN. Combination treatment
will be continued until Month 12, which is followed by monotherapy phase of
nilotinib 300 mg BID.
Study burden and risks
While imatinib is taken once daily with or without food, nilotinib must be
taken BID, on an empty stomach. This may be perceived by patients as an
increased burden of disease. However, most patients tolerate nilotinib better
than imatinib.
After three months pegylated interferon alpha will be added, aiming at
continuation for nine months. This drug is injected subcutaneously on a weekly
basis and may have several adverse effects, like flu-like symptoms, fatigue,
myalgia and arthralgia. Severe adverse effects are very rarely seen and consist
mainly of depression and interstitial pneumonitis.
There will be only two extra study visit for participants, at 1 and 4 months
after start of the study for regular lab studies and ECG. At the start of the
study, a bone marrow aspirate will be performed in 10 patients for stem cell
studies. Yearly bone marrow studies for cytogenetics are considered regular
care for CML patients, but are frequently omitted by clinicians when a major
molecular response is attained. Patients in this study are asked to fill in
short QoL questionnaires 5 times over the study period.
The adverse effects and extra disease burden caused by the switching to
nilotinib and the addition of PegIntron must be considered in view of the
ultimate purpose of discontinuation of CML treatment in the longer term and
possibly cure. Treatment may be discontinued when long-lasting deep responses
are achieved. This is expected to occur at clearly higher rates after treatment
with nilotinib and pegylated interferon than after imatinib.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
1. Patients *18 years of age.
2. At diagnosis CML in chronic phase.
3. Persistent disease demonstrated by two PCR positive tests (i.e. BCR ABL level above 0.01% IS) which have been performed during the past 9 months and more than 10 weeks apart. One of these should be performed within 1 month of registration.
4. Treatment with imatinib * 600 mg for at least 2 years.The dose must have been stable in the previous 6 months and, before that, may not have exceeded 600 mg because of pre-existent hematologic, cytogenetic or molecular resistance .
5. No other current or planned anti leukemia therapies.
6.ECOG Performance status 0,1, or 2.
7. Adequate organ function as defined by:
a)Total bilirubin < 1.5 x ULN. Does not apply to patients with isolated hyperbilirubinemia (e.g. Gilbert*s disease) grade < 3.
b) ASAT and ALAT < 2.5 x ULN.
c) Serum amylase and lipase *1.5 x ULN.
d) Alkaline phosphatase *2.5 x ULN.
e) Creatinine clearance >30 ml/min.
f) Mg++, K+ *LLN.
8. Life expectancy of more than 12 months in the absence of any intervention
9. Patient has given written informed consent to participate in the study.
Exclusion criteria
1.Prior accelerated phase or blast crisis.
2.Patient has received another investigational agent within last 6 months.
3.Previous treatment with nilotinib or dasatinib.
4.Prior stem cell transplantation.
5.Impaired cardiac function including any one of the following:
a) Inability to monitor the QT/QTc interval on ECG.
b) Long QT syndrome or a known family history of long QT syndrome.
c) Clinically significant resting brachycardia (<50 beats per minute).
d) QTc >450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re screened for QTc.
e) Myocardial infarction within 12 months prior to starting study.
f) Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension).
g) History of or presence of clinically significant ventricular or atrial tachyarrhythmias.
6.Known atypical BCR ABL transcript not quantifiable by standard RQ PCR
7.Presence of uncontrolled cardiovascular risk factors: history of cardiovascular events, like
myocardial infarction, symptomaticvascular disease, stroke or transient ischemic attacks;
untreated hypertension; untreated hypercholesterolemia, smoking, when patient refuses to quit;
poorly controlled diabetes mellitus(i.e. HbA1c >9.0% (>75 mmol/mol)) or clinically relevant
diabetic complications such as neuropathy, retinopathy, nephropathy, coronary or peripheral
vascular disease.
8.History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or carcinoma in situ of cervix uteri or breast.
9.Acute liver disease or cirrhosis.
10. Previous or active acute or chronic pancreatic disease.
11.Another severe and/or life threatening medical disease.
12.History of significant congenital or acquired bleeding disorder unrelated to cancer.
13.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
14.Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
15.Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
16.Patients who are:
a)pregnant.
b)breast feeding.
c)of childbearing potential without a negative pregnancy test prior to baseline.
d)male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post menopausal women must be amenorrheic for at least 12 months to be considered of non childbearing potential).
17. Interruption of imatinib therapy for a cumulative period in excess of 21 days in the preceding 3 months.
18. Major toxicity on imatinib in past 3 months.
19. History of non compliance, or other inability to grant informed consent.
20. Past or present history of alcohol abuse, use of illicit drugs, or severe psychiatric disorders, including depression.
21. Known hypersensitivity to any interferon preparation
22. Autoimmune hepatitis or a history of autoimmune disease
23. Pre existing thyroid disease unless it can be controlled with conventional treatment
24. Epilepsy and/or compromised central nervous system (CNS) function.
25. HCV/HIV patients.
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 | EUCTR2012-004321-25-NL |
| CCMO | NL42813.029.12 |
| Other | NTR |