Nilotinib 300 mg BID in Newly Diagnosed CP-CML Patients to Verify Disappearance of CD34+/Lin-Ph+ Cells

Study Overview
=================
Brief Summary
-----------------
This is a multicentre, single-arm study of nilotinib 300 mg BID in newly diagnosed patients with CP-CML. This study is designed to establish the disappearance of Ph+ stem cells (CD34+/lin-) in BM during nilotinib treatment. In addition, in this study the investigators aim to perform Gene Expression Profiling (GEP) of CML enrolled patients using Affymetrix GeneChip Instruments and Software Systems, and Affymetrix GeneChip Human Genome U133 Plus 2.0 (whole human transcriptome analysis) at diagnosis and at 3 different time points during treatment with Nilotinib (after 3, 6, 12 months).

Detailed Description
-----------------
This study is designed to establish the disappearance of Ph+ stem cells (CD34+/lin-) in BM during nilotinib treatment. The primary efficacy endpoint is to measure the rate of CD34+/lin-Ph+ cells in the BM after 6 months of treatment. In order to obtain this result, BM blood of all enrolled patients will be stored after 6 months of treatment with nilotinib. The isolated CD34+/lin- cells will be employed for standard FISH analysis. These endpoints will be obtained at the central laboratory of Niguarda Ca' Granda Hospital, Milano, Italy. Secondary endpoints will be reached performing: the same analyzes on CD34+/lin- cells at diagnosis, at 3 and 12 months of treatment; cytogenetic analysis to estimate the rate of CCyR at 3, 6 and 12 months; this analysis will be performed at each local laboratory; molecular analysis to determinate the rate of MR (≤ 10%, ≤ 1%, MMR, MR4,5 IS) at 3, 6 and 12 months in the peripheral blood; the molecular analysis will be performed using the Labnet standardized laboratories in Lombardy.

Official Title
-----------------
An Open Label, Single Arm, Phase II Study of Nilotinib 300 mg BID in Newly Diagnosed CP-CML Patients, in Order to Verify Disappearance of CD34+/Lin-Ph+ Cells From Bone Marrow During Treatment

Conditions
-----------------
Leukemia, Myeloid, Chronic-Phase

Intervention / Treatment
-----------------
* Drug: Nilotinib 300mg BID


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph chromosome (9;22) translocation within 3 months of diagnosis Patients Ph negative or with variant translocations by standard cytogenetic analysis but Ph positive by FISH, are eligible as well Age ≥ 18 years old (no upper age limit given) WHO performance status ≤2 Normal serum levels ≥ LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin or phosphorus, or correctable to within normal limits with supplements, prior to the first dose of study medication 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 bilirubin ≤ 1.5 x ULN, except know Mb Gilbert Serum lipase and amylase ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN Written informed consent signed prior to any study procedures being performed Exclusion Criteria: Pre-treatment with HU for > 3 months and with imatinib is not permitted Prior accelerated phase including clonal evolution or blast crisis Contraindication to excipients in study medication 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 Clinically significant ventricular or atrial tachyarrhythmias Clinically significant resting bradycardia (<50 beats per minute) QTcF >450 msec on screening ECG.If QTcF >450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion Myocardial infarction within 12 months prior to starting nilotinib Other clinical significant heart disease (e.g. unstable angina,congestive heart failure,uncontrolled hypertension) Acute (i.e. within 1 year of starting study medication) or chronic pancreatitis 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 be strong inducers or inhibitors of the CYP450 Isoenzyme CYP3A4:see link for complete list (http://medicine.iupui.edu/flockhart/table.htm) 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 14 days prior to administration of nilotinib.Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential.Female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug Treatment with any haematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF) ≤1 week prior to starting study drug Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>study of nilotinib 300 mg BID | Drug: Nilotinib 300mg BID<br>* Nilotinib<br>* Other names: Nilotinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD34+/lin-Ph+ cells | To measure the rate of CD34+/lin-Ph+ cells in the BM after 6 months of treatment. In order to obtain this result, BM blood of all enrolled patients (see Appendix 1) will be stored after 6 months of treatment with nilotinib. The isolated CD34+/lin- cells will be employed for standard FISH analysis. | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD34+/lin- cells (composite measure) | Secondary endpoints will be reached performing: the same analyzes on CD34+/lin- cells at diagnosis, at 3 and 12 months of treatment; cytogenetic analysis to estimate the rate of CCyR at 3, 6 and 12 months; this analysis will be performed at each local laboratory; molecular analysis to determinate the rate of MR (≤ 10%, ≤ 1%, MMR, MR4,5 IS) at 3, 6 and 12 months in the peripheral blood; the molecular analysis will be performed using the Labnet standardized laboratories in Lombardy. The Outcome Measure indicates that the measure is a composite. | 12 month |