| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic myeloid leukemia in chronic phase and ≥ 2 years on Imatinib treatment with suboptimal molecular response (BCR-ABL level above 0.01% IS). |
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| E.1.1.1 | Medical condition in easily understood language |
| CML in chronic phase and ≥ 2 years on Imatinib treatment with a suboptimal molecular response. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009700 |
| E.1.2 | Term | CML |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 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. |
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| E.2.2 | Secondary objectives of the trial |
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.
|
|
| 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 |
Version 12 and versiondate 22-10-2014 for the following substudies:
- Immunophenotyping of lymphocyte subsets
- Assessment of antileukemic cytotoxic T-cell responses
- Plasma cytokine profiling
- Functional assessments from a subset of patients
- TKI pharmacodynamics analysis
- Exploratory study: CML stem cell detection by flowcytometry in CML patients with molecular responses.
Primary endpoints:
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 γ 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.
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|
| E.3 | Principal inclusion criteria |
1.Patients ≥18 years of age.
2.At diagnosis chronic myeloid leukemia 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:
8. Total bilirubin <1.5 x ULN (ULN = local lab upper limit of normal). Does not apply to patients with isolated hyperbilirubinemia (e.g. Gilbert’s disease) grade <3.
9. ASAT and ALAT <2.5 x ULN.
10. Serum amylase and lipase ≤1.5 x ULN.
11. Alkaline phosphatase ≤2.5 x ULN.
12. Creatinine clearance >30 ml/min.
13. Mg++, K+ ≥LLN.
14. Life expectancy of more than 12 months in the absence of any intervention
15. Patient has given written informed consent to participate in the study.
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|
| E.4 | Principal 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, symptomatic peripheral vascular 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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients with confirmed MR4.0 IS at Month 12 . |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A safety interim analysis by a Safety Monitoring Committee (SMC) is planned after 15 patients have completed the Month 6 study assessment, i.e. after 3 months of the combination therapy. The SMC will consist of three experienced hematologists. They will make a recommendation as to whether the study should continue, stop or be modified based on its findings. The SMC recommendation will be notified to the principal investigator verbally and in written form as soon as possible after the meeting. |
|
| E.5.2 | Secondary end point(s) |
• 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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
A safety interim analysis by a Safety Monitoring Committee (SMC) is planned after 15 patients have completed the Month 6 study assessment, i.e. after 3 months of the combination therapy.
The study should be stopped if 4 out of 5, 6 out of 10 or 8 out of 15 patients experience grade 4 hematological toxicity, or grade 3 non hematological toxicity after 3 months of PegIFN treatment.
An evaluation of the dose increase from 25 to 40 μg/week will be performed when 15 patients have passed the 9 month time point (i.e 3 months on 40 μg/week).
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| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 5 |
| 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 | 5 |
| 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 |
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