Nilotinib in PH+, BCR-, ABL+ CML Patients (CML0811)

• Toxicity [ Time Frame: At three years from study entry ]
  Number of toxic events
• Compliance [ Time Frame: At 3 years from study entry ]
  Number of fully compliant patients and number of patients who do not comply with treatment
• The complete cytogenetic response (CCgR) rate [ Time Frame: At 3, 6, 12, 18 and 24 months from study entry ]
• The rate and the degree of molecular response [ Time Frame: At 3, 6, 12, 18 and 24 months from study entry ]
• The time to CCgR, the time to MMR and the time to CMR [ Time Frame: baseline ]
• Overall Survival (OS) [ Time Frame: At three years from study entry ]
  From the date of the first nilotinib dose to death
• Progression Free Survival (PFS) [ Time Frame: At three years from study entry ]
  From the date of the first nilotinib dose to progression to AP or BP or death
• Failure Free Survival (FFS) [ Time Frame: At three years from study entry ]
  From the date of the first nilotinib dose to failure* or progression or death
• Event Free Survival (EFS) [ Time Frame: At three years from study entry ]
  From the date of the first nilotinib to any event. Including treatment discontinuation for adverse events, failure, progression to AP or BP, or death, whichever comes first.
• Patient-reported quality of life (QoL) [ Time Frame: At baseline and then at 3, 6, 12, 18 and 24 months ]

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally twice daily for 24 months and indefinitely if it is in the interest of the patient.

The primary objective of the trial is to evaluate the efficacy of nilotinib, 300 mg twice daily with dose increase to 400 mg twice daily in case of suboptimal response or failure (excluding patients who will fail for progression to ABP), in a population of patients with Ph-positive, BCR-ABL positive CML in early CP.

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally at the dose of 300 mg twice daily (total daily dose 600 mg daily) for 24 months (study core), and indefinitely if it is in the interest of the patient (the drug will be given free-of-charge after 24 months to all those patients achieving the CMR4 at 24 months and in absence of safety concerns). Nilotinib dose is increased to 400 mg BID in case of suboptimal response or failure (with the exception of patients who will fail for progression to ABP: in case of progression to ABP, the patient will not be treated with study drug and the choice of the treatment will be up to the physician).

Study duration is estimated in 6 years, 1 year of estimated enrollment, 2 years therapy duration. Thereafter, information on course and survival is due for other 3 years.

The main data analysis will be performed when all patients will complete 24 months of treatment (or discontinued earlier). Safety and tolerability profile will be assessed by collecting hematologic and non-hematologic adverse events, laboratory examinations and ECG data. The molecular response will be assessed using the GIMEMA standardized molecular laboratories (Labnet network).

Inclusion Criteria:

• Age ≥ 18
• Male or female patients with diagnosis of Ph+ and/or BCR-ABL+ CML
• Early chronic phase (within 6 months from diagnosis)
• Pretreatment with Hydroxyurea or Anagrelide for a duration of up to 3 months and/or pretreatment with Imatinib for up to 30 days are permitted
• Normal serum levels of potassium, magnesium, phosphorus, total calcium corrected for serum albumin or phosphorus, or correctable to within normal limits with supplements prior to the first dose of study medication
• Written informed consent prior to any study procedures being performed
• AST and ALT ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to leukaemia
• Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukaemia
• Total direct bilirubin ≤ 1.5 x ULN, except know Mb. Gilbert
• Serum creatinine ≤ 1.5 x ULN

Exclusion Criteria:

• Known impaired cardiac function, including any of the following:
• LVEF < 45%
• Complete left bundle branch block
• Right bundle branch block plus left anterior hemiblock, bifascicular block
• Use of a ventricular-paced pacemaker
• Congenital long QT syndrome
• History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Clinically significant resting bradycardia (<50 beats per minute)
• QTc>450 msec on screening ECG. If QTc > 450 msec and electrolytes are not within normal ranges before Nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTc criterion.
• Myocardial infarction within 12 months prior to starting study drugs
• Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
• Serum lipase and amylase > 1.5 x ULN (upper limit of normal) or history of acute (i.e., within 1 year of starting study medication) or chronic pancreatitis
• Other concurrent uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
• Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
• Concomitant medications with potential QT prolongation (see link for complete list: http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm)
• Concomitant medications known to interact with CYP450 isoenzymes (CYP3A4, CYP2C9,andCYP2C8:link for complete list: http://medicine.iupui.edu/flockhart/table.html..
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who are pregnant or breast feeding, or women of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to administration of nilotinib).
• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
• Patients unwilling or unable to comply with the protocol