| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009015 |
| E.1.2 | Term | Chronic myeloid leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009013 |
| E.1.2 | Term | Chronic myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 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 chromosome-positive CML-CP patients.
• To compare the efficacy (MMR rate at 12 months) of nilotinib at 300 mg BID with that of Gleevec/Glivec 400 mg QD in newly diagnosed, previously untreated Philadelphia chromosome-positive CML-CP patients.
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| E.2.2 | Secondary objectives of the trial |
•To compare the rate of durable MMR at 24 months, which is defined as the proportion of patients who are in MMR at both 12 and 24 months and who have no confirmed loss of MMR in between those 2 time points, of nilotinib at 400 mg BID with that of Gleevec/Glivec 400 mg QD in newly diagnosed, previously untreated Philadelphia chromosome-positive CML-CP patients.
•To evaluate the rate of MMR at 12 months between two nilotinib arms.
•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 and beyond 12 months.
• To evaluate the rate of MMR at 6 months and beyond 12 months in
all three treatment arms.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female patients 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
• ≥ 100 x 109/L (≥ 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 ≤ 1.5 x ULN
• Alkaline phosphatase ≤ 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 (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.):
• Potassium ≥ LLN
• Magnesium ≥ LLN
• Phosphorus ≥ LLN
• Total calcium (corrected for serum albumin) ≥ 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 |
•Patients who are considered Ph negative because they do not have a confirmed cytogenetic diagnosis of Philadelphia chromosome of (9,22) translocation.
•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 locally read 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 the average of 3 serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
• History of clinically documented myocardial infarction
• History of unstable angina (during the last 122 months)
• Other clinically significant heart disease (e.g. 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 ≥ 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 inducers (e.g, dexamthasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John’s Wort) 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.
• 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 prior to baseline and (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)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the rate of major molecular response (MMR) at 12 months after the start of first study medication as defined by ≥ 3 log reduction of BCR-ABL transcript from standardized baseline or ≤ 0.1% BCR-ABL/ABL% 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 | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 125 |
| 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 | No |
| 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 |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Colombia |
| Czech Republic |
| Denmark |
| Egypt |
| Finland |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Venezuela, Bolivarian Republic of |
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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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| Patients may continue treatment on protocol until the end of the study, which has been extended to a total of 10 calendar years from October 15, 2008 (last patient first treatment) or until disease progression or until it is no longer in the best interest of the patient to continue on study treatment. |
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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 | 11 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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