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The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+, BCR-, ABL+ Chronic Myeloid Leukemia (CML) in Early Chronic Phase: a Phase IIIb, Multicenter Study to Assess the Complete Molecular Response

Phase 3
18 Years
Open (Enrolling)
Chronic Myeloid Leukemia

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Trial Information

The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+, BCR-, ABL+ Chronic Myeloid Leukemia (CML) in Early Chronic Phase: a Phase IIIb, Multicenter Study to Assess the Complete Molecular Response

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administred 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 choise 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

- 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:

- Concomitant medications known to interact with CYP450 isoenzymes (CYP3A4,
CYP2C9,andCYP2C8:link for complete list:

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete molecular response

Outcome Description:

To assess the complete molecular response (CMR4) rate at 24 months of treatment. For the purpose of this protocol, CMR is defined as a negative results of quantitative RT-PCR for BCR-ABL transcripts in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000, that corresponds to at least a 4-log reduction (hence, CMR4)

Outcome Time Frame:

At 24 months of treatment

Safety Issue:



Italy: Ethics Committee

Study ID:




Start Date:

January 2012

Completion Date:

November 2017

Related Keywords:

  • Chronic Myeloid Leukemia
  • Chronic Myeloid Leukemia,
  • Nilotinib,
  • Philadelphia positive,
  • BCR-ABL+
  • Early chronic phase
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive