E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Myelogenous Leukemia (CML) Ph+ chronic phase |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 6.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009013 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the 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 after 12 months. To evaluate the rate of complete molecular response (CMR) of nilotinib compared to imatinib in adult patients with Ph+ CML in CP after 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 | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Male or female patients >= 18 years of age. ECOG performance status of 0, 1, or 2. Diagnosis of Ph+ CML in 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 >=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. Bone marrow karyotyping is required. FISH analysis is not allowed. 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. Ability to provide written informed consent prior to any study related screening procedures being performed. |
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E.4 | Principal exclusion criteria |
Prior accelerated phase or blast phase CML. Previously documented T315I mutations. 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 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 one of the following: LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) by echocardiography Complete left bundle branch block ST depression of >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 long QT syndrome History of or presence of significant ventricular or atrial tachyarrhythmias Clinically significant resting brachycardia (<50 bpm) QTcF > 450 msec on baseline ECG Right bundle branch block plus left anterior hemiblock, bifascicular block Myocardial infarction within one year of baseline visit Unstable angina diagnosed or treated within the past 12 months 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 (please see Section 6.6.4 for further guidance). Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery). History of acute pancreatitis within one year of study entry or medical history of chronic pancreaitis. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required). Any other malignancy that is clinically significant or requires active intervention. Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection). History of significant congenital or acquired bleeding disorder unrelated to cancer. Previous radiotherapy to >= 25% of the bone marrow. Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery. Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon). Treatment with other investigational agents within 30 days of Day 1 (first dose of study drug). History of non-compliance to medical regimens or inability to grant consent. Women who are pregnant, breast feeding, or of childbearing potential without a negative serum pregnancy test at baseline. Male or female patients of childbearing potential unwilling to use effective barrier contraceptives throughout the trial and for 3 months following discontinuation of study drug. Post-menopausal women must be ammenorrheic for at least 12 months to be considered of non-childbearing potential. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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 | 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 | No |
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 | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
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 |