E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly diagnosed Philadelphia chromosome and/or BCR-ABL positive CML in chronic phase in adult patients |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052065 |
E.1.2 | Term | Chronic phase chronic myeloid leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the rate of MR4.0 at 18 months of nilotinib treatment |
|
E.2.2 | Secondary objectives of the trial |
• 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, as well as by, 12 and 24 months of treatment
• To evaluate the rate of complete and major cytogenetic response at, as well as by, 12 and 24 months of treatment
• To evaluate the rate of MR4.0 and MR4.5 at, as well as by, 12 and 24 months of treatment
•To evaluate the rate of CHR at, as well as by, 12 and 24 months of treatment
•To evaluate the annual rate of progressions and annual rate of events in patients achieving a MR4.0 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 rate of MR4.0 by 18 months of treatment
• To evaluate the safety and tolerability profile of nilotinib |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Sub-study: Biomarkers analysis as potential predictors of complete molecular response to nilotinib (CMR)
2. Multi-national sub-study: Stem cell identification and quantification in predicting response to first line
nilotinib treatment in patients with newly-diagnosed chronic myeloid leukemia
3. Multi-national sub-study: Immunological monitoring during first line treatment with nilotinib in early chronic
phase CML
4. Multi-national sub-study: Determination of plasma nilotinib levels (pharmacokinetics) and single cell
quantification of phosphoprotein response (pharmacodynamics) during nilotinib treatment in early chronic
phase CML
5. Sub-study: Evaluation of nilotinib plasma trough-levels and correlation with clinical response
6. Multi-national sub-study: Correlation of Genome wide DNA methylation profiling and Sokal risk and
response to treatment
7. Multi-national sub-study: Genetic and transcriptional prognostic and predictive markers in CML
8. Sub-study: Adherence to treatment and quality of life of patients receiving nilotinib as first-line therapy for
CML
9. Multi-national sub-study: Adherence to nilotinib first line treatment
10. Sub-study: Interaction of Ph+ stem cell to bone marrow microenvironment and pre-treatment ABL mutation
as biological determinants of response in CML patients treated frontline with nilotinib
11. Sub-study: Analysis of potential biomarkers in leukemic stem cells for predicting response to nilotinib treatment |
|
E.3 | Principal inclusion criteria |
Patients must meet all inclusion criteria and none of the exclusion criteria to enter the study. Patients must meet all inclusion criteria within 2 weeks of the start of study treatment (bone marrow examinations may be within 8 weeks) to enter the study.
• 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
• Pretreatment with Hydroxyurea for a duration of up to 6 months is
permitted as is treatment with Imatinib for up to 3 months 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.
• 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 |
|
E.4 | Principal 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).
• 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 within 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 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is to evaluate the rate of MR at month 18 after the start of study medication. In this protocol a MR4.0 is defined as either (i) detectable disease ≤0.01% BCR-ABLIS or (ii) undetectable disease in cDNA with ≥10,000 ABL transcripts. MR4.5 is defined as either (i) detectable disease ≤0.0032% BCR-ABLIS or (ii) undetectable disease with in cDNA with ≥32,000 ABL transcripts. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 331 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |