The aim of the current study is to confirm the CMR rates of nilotinib in newly diagnosed CML-CP patients in a pan-European population using the EUTOS (*European Treatment and Outcome Study for CML*) standardised molecular laboratories. Secondary…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the rate of CMR after 18 months of nilotinib treatment.
Secondary outcome
Secondary Objectives:
* To evaluate the rate of annual progression and annual events at 12 and 24
months of treatment
* To evaluate the rate of major molecular response at 12 and 24 months of
treatment
* To evaluate the rate of complete cytogenetic response at 12 and 24 months of
treatment
* To evaluate the rate of CMR at 12 and 24 months of treatment
* To evaluate the annual rate of events in patients achieving a CMR at 12
months of treatment
* To evaluate the Event-Free Survival (EFS) and Overall Survival (OS) at 12
months and at 24 months of treatment
* To evaluate the safety and tolerability profile of nilotinib
Exploratory objectives:
* To identify the dynamics of molecular response and potential patterns
* To evaluate the kinetics of MMR at 3, 6, 9, 12, 15, 18, 21 and 24 months of
treatment
Background summary
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of
transformed, primitive haematopoietic progenitor cells. The hallmark of CML is
the Philadelphia (Ph) chromosome found in up to 95% of patients. The resulting
fusion gene encodes for a constitutively activated BCR-ABL tyrosine kinase
(Faderl et al 1999) whose activity imparts growth advantage to leukaemic cells.
The objective of treatment of CML is the normalization of haematopoiesis
(complete haematologic response [CHR]) the elimination of the Ph+ cells from
the bone marrow (complete cytogenetic response [CCyR]) and the reduction of the
BCR-ABL-transcript-ratio from samples of peripheral or bone marrow blood by a
factor of three logs on the international scale (Major Molecular Response, MMR
IS * 0.1%).
Chronic myeloid leukaemia can be effectively treated with Glivec (Imatinib) but
not all patients achieve an *optimum response* (Baccarani et al 2009). In
addition, some patients lose a previously obtained response, particularly in
years 2 and 3 of the treatment, and may progress to the advanced phases of CML
(accelerated phase AP and blast crisis BC, Hochhaus et al 2009). Nilotinib
(Tasigna®, AMN107) is a rationally designed second generation tyrosine kinase
inhibitor with improved target specificity over imatinib. Its efficacy and
safety in the treatment of patients who are resistant to or intolerant to
Imatinib (Kantarjian et al 2006, Kantarjian et al 2007, le Coutre et al 2008)
led to the registration in second line treatment of CML-CP and AP and to the
further evaluation of its use in the treatment of newly diagnosed CML. A
registration study of nilotinib in this indication (CAMN107A2303) is underway.
First results from this study (Saglio et al 2009) demonstrate a superiority of
a treatment of Nilotinib 300 mg twice daily (BID) or 400 mg BID over Imatinib
400 mg once daily (QD) in newly diagnosed patients in complete cytogenetic
response at 12 months (CCyR = 80%, 78% and 65% respectively) and also in the
major molecular response rate (MMR = 44%, 43% and 22%). In particular the
estimated rate of progression to AP/BC was also significantly lower in the two
Nilotinib arms (< 1% for both dosages) than for the Imatinib-treated patients
(4%).
Study objective
The aim of the current study is to confirm the CMR rates of nilotinib in newly
diagnosed CML-CP patients in a pan-European population using the EUTOS
(*European Treatment and Outcome Study for CML*) standardised molecular
laboratories. Secondary objectives include the assessment of the progression to
AP/BC and events in a larger population, the analysis of the dynamics of
molecular response and the identification of potential response patterns that
will allow for a better risk assessment of individual patients. New treatments
for newly diagnosed CML-CP should aim to further improve outcomes by seeking to
induce deeper and faster reductions in disease burden, and so move towards CMR
as an optimal response, as one step closer to cure. Despite the proven
prognostic value of molecular monitoring, the reduction of BCR-ABL does not
follow a uniform manner. Patients may reach a major molecular response as early
as 3 months (Rosti et al 2009) or not at all. In addition, some patients may
experience a steep decline in BCR-ABL but then not reach PCR-negativity. The
exploratory aim of this study is therefore to identify potential patterns of
molecular response and identify their impact on a possible prognosis.
Study design
The study design is a multicentre, single-arm, study of nilotinib 300 mg twice
daily (BID) in newly diagnosed patients with CML-CP. Overall, 936 patients will
be enrolled to receive nilotinib 300 mg BID and will be treated for a study
duration of up to 24 months. The main data analysis time point will be the time
when all 936 patients have completed 18 months of treatment (or discontinued
earlier).
Intervention
nilotinib 300 mg twice daily (BID) in newly diagnosed patients with CML-CP
Study burden and risks
The research design resembles the standard treatment of CML. Both visit
schedule and blood draws/bone marrow assessments are comparable to the practise
in the clinic.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
* Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph chromosome [t(9;22) translocation] (if the bone marrow sample is taken within 8 weeks of study start but before the patient consents, the bone marrow should not be repeated after the patient formally consents to the study)
* Ph negative cases or patients with variant translocations who are BCR-ABL positive in multiplex PCR (Cross et al 1994) are eligible as well
* Age <=> 18 years old (no upper age limit)
* WHO performance status 0-2
* Normal serum levels <=> LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin or phosphorus, or correctable to within normal limits with supplements, prior to the first dose of study medication
* AST and ALT <<= 2.5 x ULN or <<= 5.0 x ULN if considered due to leukaemia
* Alkaline phosphatase <<= 2.5 x ULN unless considered due to leukaemia
* Total bilirubin <<= 1.5 x ULN, except know Mb. Gilbert
* Serum lipase and amylase <<= 1.5 x ULN
* Serum creatinine <<= 1.5 x ULN
* Written informed consent prior to any study procedures being performed
Exclusion criteria
* Pretreatment with Hydroxyurea for a duration of > 6 months or > 3 months with imatinib (the investigator should notify the DMC requesting review of any patient who has received prior imatinib treatment for 6 or more weeks to ensure that the patient is not failing on imatinib). [(France only) Treatment with tyrosine kinase inhibitor(s) prior to study entry is not permitted, except in emergent cases where the patient requires disease management while awaiting study start. In this situation commercial supplies of Glivec (imatinib) at any dose may be prescribed to the patient but for no longer than 2 weeks in duration.]
* Contraindication to excipients in study medication
* Known impaired cardiac function, including any of the following:
* LVEF < 45%
- Complete left bundle branch block
- Right bundle branch block plus left anterior hemiblock, bifascicular block
- Use of a ventricular-paced pacemaker
- Congenital long QT syndrome
- History of or presence of clinically significant ventricular or atrial tachyarrhythmias
- Clinically significant resting bradycardia (<50 beats per minute)
- QTcF>450 msec on screening ECG. If QTcF > 450 msec and electrolytes are not within normal ranges before Nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
- Myocardial infarction with 12 months prior to starting Nilotinib
- Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
* History of acute (i.e., within 1 year of starting study medication) or chronic pancreatitis
* Other concurrent uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
* Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
* Concomitant medications with potential QT prolongation (see link for complete list: http://www.torsades.org/medical-pros/druglists/printable-drug-list.cfm)
* Concomitant medications known to be strong inducers or inhibitors of CYP450 isoenzyme CYP3A4: see link for complete list (http://medicine.iupui.edu/flockhart/table.htm)
* Patients who have undergone major surgery <= 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
* Patients who are pregnant or breast feeding, or women of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months in order to be considered of
non-childbearing potential. Female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug
* Treatment with any haematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) <= 1 week prior to starting study drug
* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
* Patients unwilling or unable to comply with the protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-017775-19-NL |
| CCMO | NL31981.029.10 |