E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nilotinib will be evaluated in patients having showed a suboptimal cytogenetic response to imatinib |
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MedDRA Classification |
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 complete cytogenetic response (CCyR ) rate at 12 months of nilotinib compared to imatinib in adult patients with Ph+ CML in CP who have a suboptimal cytogenetic response to imatinib. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the rate of major molecular response (MMR) of nilotinib compared to imatinib in adult patients with Ph+ CML in CP at 12 months.
To evaluate the rate of complete molecular response (CMR) of nilotinib compared to imatinib in adult patients with Ph+ CML in CP at 12 months.
To evaluate the time to and duration of CCyR of nilotinib compared to imatinib in adult patients with Ph+ CML in CP.
To evaluate the time to and duration of MMR of nilotinib compared to imatinib in adult patients with Ph+ CML in CP.
To evaluate the time to and duration of CMR of nilotinib compared to imatinib in adult patients with Ph+ CML in CP.
To describe overall survival and progression-free survival up to 5 years in adult patients with Ph+ CML in CP.
To evaluate the safety profile of nilotinib compared to imatinib in adult patients with Ph+ CML in CP.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male and female patients ≥ 18 years of age. ECOG performance status of 0,1, or 2. Diagnosis of Ph+ CML-CP defined as: <15% blasts in peripheral blood and bone marrow, < 30% blasts plus promyelocytes in peripheral blood and bone marrow < 20% basophils in the peripheral blood ≥100 x 109 /L (>/ 100,000 /mm3) platelets No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly Patients with suboptimal cytogenetic response to a dose of at least 400 mg imatinib defined as ≥ 6 to < 12 months of treatment and have 36 - 95% Ph+ metaphases, or ≥ 12 to < 18 months of treatment and have 1 - 35% Ph+ metaphases. Total bilirubin <1.5XULN; SGOT and SGPT <2.5XULN; creatinine < 1.5XULN, potassium and magnesium ≥ LLN or correctable with supplements. Serum amylase and lipase ≤ 1.5xULN, alkaline phosphatase ≤ 2.5XULN unless considered tumor related.
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E.4 | Principal exclusion criteria |
Prior accelerated phase or blast phase CML. Previously documented T315I mutation. Achieved prior PCyR or CCyR and lost that response prior to entering the study. Presence of chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+. Patients who have received more than 18 months of imatinib therapy. Intolerance to imatinib 400 mg/day defined as the inability to maintain dosing of at least 400 mg daily for the previous 3 months. Previous treatment with any other tyrosine kinase inhibitor except imatinib. Impaired cardiac function including any of the following: LVEF by echocardiography < 45% or below the institutional lower range (whichever is greater); complete left bundle branch block; ST depression > 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads; congenital long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant resting brachycardia (< 50 bpm); QTcF > 450 msec at baseline; right bundle branch block plus left anterior hemiblock, bifascicular block; myocardial infarction ≤ 3 months; uncontrolled angina; other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with antihypertensives). Treatment with strong inhibitors of CYP3A4 or medications that have been well documented to prolong the QT interval is contraindicated (see Concomitant Therapy section in protocol).
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy Complete cytogenetic Response (CCyR) rate at 12 months (CCyR is defined as 0% Ph+ metaphases)
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | 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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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 | 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 | 64 |
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 |
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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
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Therapy with nilotinib or imatinib will be continued for up to 5 years while on study, until progression or the development of intolerance of treatment, whichever occurs first. Patients will receive nilotinib as long as they have not discontinued from this study up to the 5 year study duration. Patients will receive imatinib as long as they have not discontinued from this study (or crossed over to nilotinib) for up to the 5 year study duration. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |