A phase III multi-center, open label, randomised study of optimised imatinib versus nilotinib in adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP)

* 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.

*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)
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 14 days after the final dose of nilotinib or imatinib. Patients using an oral hormonal contraception method should complete their monthly treatment course.
Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
- Combination of any two of the following (a+b or a+c, or b+c) listed below:
o a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
o b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
o c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.