E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CHRONIC MYELOGENOUS LEUKEMIA CML-CP |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009013 |
E.1.2 | Term | Chronic myeloid leukaemia |
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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 |
1. Primary objectives To compare the efficacy MMR rate at 12 months of nilotinib at 400mg BID with that of Gleevec/Glivec 400 mg QD in newly diagnosed, previously untreated Philadelphia chromosomepositive CML-CP patients. To compare the efficacy MMR rate at 12 months of nilotinib at 600 mg QD with that of Gleevec/Glivec 400 mg QD in newly diagnosed, previously untreated Philadelphia chromosomepositive CML-CP patients. The primary efficacy endpoint is the rate of major molecular response MMR at 12 months after the start of first study medication as measured by 8805; 3 log reduction of BCR-ABL transcript from standardized baseline or 8804; 0.1 BCR-ABL/control gene by international scale, measured by RQ-PCR. |
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E.2.2 | Secondary objectives of the trial |
2. Key secondary objectives To compare the rate of 8805; 4 log reduction in BCR-ABL transcript levels from the standardized baseline established in the IRIS study or 8804; 0.01 BCR-ABL/control gene by international scale in nilotinib treatment arms to Gleevec/Glivec in adult patients with Ph CML in CP at 12 months. To compare the rate of complete cytogenetic response CCyR in nilotinib treatment arms to Gleevec/Glivec in adult patients with Ph CML in CP at 12 months. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Inclusion criteria Male or female patients 8805; 18 years of age ECOG 0, 1, or 2. Patients with CML-CP within 6 months of diagnosis date of initial diagnosis is the date of first cytogenetic analysis . Standard conventional cytogenetic analysis must be done on bone marrow. FISH cannot be used Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation of Philadelphia chromosome of 9;22 translocations presence of BCR-ABL a review of a minimum 20 metaphases is required Documented chronic phase CML will meet all the criteria defined by 15 blasts in peripheral blood and bone marrow 30 blasts plus promyelocytes in peripheral blood and bone marrow 20 basophils in the peripheral blood 8805; 100 x 109/L 8805; 100,000/mm3 platelets No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly Adequate end organ function as defined by total bilirubin 1.5 x ULN SGOT and SGPT 2.5 x ULN creatinine 1.5 x ULN Serum amylase and lipase 8804; 1.5 x ULN Alkaline phosphatase 8804; 2.5 x ULN unless considered tumor related. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug. Patients must have the following laboratory values 8805; LLN lower limit of normal or corrected to within normal limits with supplements prior to the first dose of study medication. Potassium 8805; LLN Magnesium 8805; LLN Phosphorus 8805; LLN Ability to provide written informed consent prior to any study related screening procedures being performed. |
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E.4 | Principal exclusion criteria |
Exclusion criteria Previously documented T315I mutations. Treatment with tyrosine kinase inhibitor s prior to study entry is not allowed, except in the following situation in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of Gleevec/Glivec at any dose may be prescribed to the patient but for no longer than 2 weeks in duration. Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide Impaired cardiac function including any one of the following LVEF 45 or below the institutional lower limit of the normal range whichever is higher as determined by echocardiogram Inability to determine the QT interval on ECG Complete left bundle branch block Use of a ventricular-paced pacemaker Congenital long QT syndrome or a known family history of long QT syndrome. History of or presence of clinically significant ventricular or atrial tachyarrhythmias Clinically significant resting brachycardia 50 beats per minute 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 Myocardial infarction within 12 months prior to starting study Other clinically significant heart disease e.g. unstable angina, congestive heart failure or uncontrolled hypertension . Known cytopathologically confirmed CNS infiltration in absence of suspicion of CNS involvement, lumbar puncture not required . 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 8805; 25 of the bone marrow. Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery. Treatment with other investigational agents within 30 days of Day 1. History of non-compliance to medical regimens or inability to grant consent. Use of therapeutic coumarin derivatives i.e., warfarin, acenocoumarol, phenprocoumon Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention Patients actively receiving therapy with strong CYP3A4 inhibitors e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications http //medicine.iupui.edu/flockhart/table.htm. Novartis must be contacted if a patient needs to be started on any of these drugs during study treatment. Impairment of gastrointestinal GI function or GI disease that may significantly alter the absorption of study drug e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis. Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease. 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 Please see http //www.torsades.org/medical-pros/drug-lists/printable-drug list.cfm for a comprehensive list of agents that prolong the QT interval Patients who are a pregnant, b breast feeding, c of childbearing potential without a negative pregnancy test pls see protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint The primary efficacy endpoint is the rate of major molecular response MMR at 12 months after the start of first study medication as measured by 8805; 3 log reduction of BCR-ABL transcript from standardized baseline or 8804; 0.1 BCR-ABL/control gene by international scale, measured by RQ-PCR. |
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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 | No |
E.6.7 | Pharmacodynamic | Yes |
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 | 0 |
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 | 0 |