Nilotinib + Pegylated Interferon Alpha 2a for Untreated Chronic Phase Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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The aim of this study is to demonstrate the safety and the efficacy of a combination of 2 treatments shown to have some efficacy in Chronic Phase Chronic Myelogenous Leukemia (CP CML) separately, but that have never been combined to date, and this combination is expected to substantially increase the molecular response rates.

Official Title
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Phase II Multicenter Study Evaluating the Efficacy and the Safety of a Combination of Nilotinib Plus Pegylated Interferon Alpha 2a for de Novo Chronic Phase Chronic Myelogenous Leukemia Patients

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: Nilotinib,Novartis,300 mg twice a day +Pegylated interferon 2a,Roche, 45 microg weekly starting Month 2-Month 12 or beyond according to investigator choice.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Performans status 0-2 CP CML diagnosed since less than 3 months without previous Tyrosine Kinase Inhibitor (TKI) or interferon treatment Adequate organic functions: Total Bilirubin < 1.5xUpper Normal Range (UNR). Aspartate Amino Transferase (ASAT) and Alanine Amino Transferase (ALAT) < 2.5xUNR. Alkaline phosphatase ≤ 2.5xUNR Amylase and lipase ≤ 1.5xUNR. Creatininemia < 1.5xUNR. Biological blood standards : Potassium ≥ Lower Normal Range (LNR) Magnesium ≥ LNR. Phosphorus ≥ LNR Calcium ≥ LNR. Negative pregnancy test within the last 7 days for women with childbearing potential. Informed consent signed up Compliance to tretament ensured, Valid social insurance Exclusion Criteria: Prior TKI or interferon treatment for the CML Contra-indication to IFN Pregnancy, breast feeding Human Immunodeficiency Virus positive, chronic hepatitis B or C. Other BCR-ABL transcript than M-bcr Cardiopathy defined as: Left Ventricular Ejection Fraction (LVEF) < 45%. Left bundle branch block Ventricular pacemaker. Congenital prolonged QT Past ventricular or significant auricular tachyarrythmia Clinically significant bradycardia (<50 per minute). QTc (Fredericia) > 450 ms (average on 3 Elektrokardiogramm (EKG)). Myocardial infarction in the last 12 months. Unstable angina within the last 12 months. Other significant cardiac diseases. Other uncontrolled severe disease (such as diabetes melittus etc…) Other ongoing malignant disease. Past history of congenital or acquired clinically significant bleeding disorder. Previous radiotherapy ≥25% of bone marrow. Serious surgery within the past 4 weeks Investigational treatment within the last 30 days prior to day 1. History of non compliance. Cytochrome P450 3A4 (CYP3A4) inhibitors that could not be withdrawn or modified (such as erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil). Severe gastro-intestinal disorders (such as gastric ulcer, uncontrolled nausea, malabsorption syndrome, small intestine resection, gastric shunt). Hepatic, renal or pancreatic chronic disorder unrelated to CML Recent history of acute pancreatitis within a year or history of chronic pancreatic disease . Any concommittant treatment inducing QT prolongation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nilotinib + pegylated interferon alpha 2a (PEG-IFN).<br> | Drug: Nilotinib,Novartis,300 mg twice a day +Pegylated interferon 2a,Roche, 45 microg weekly starting Month 2-Month 12 or beyond according to investigator choice.<br>* Combination of both treatments active by different means on the leukemic cells, in order to enhance the response rates of CP CML patients since diagnosis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of complete molecular remissions after 12 months of treatment with nilotinib + Pegylated Interferon (PEG-IFN) | The trial opens for enrolment in 2011 March 7th for 18 months. Each patient will be followed for 24 months after entry. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of Complete Molecular Response (CMR) at 1, 2, 3, 6, 9, 12, 15, 18 and 24 months. | CMR corresponds to a level of BCR-ABL transcripts < 0.001 % (BCR-ABL/ABL ratio < 0.001%). The BCR-ABL/ABL ratio will be analysed by Reverse Transcription Polymerase Chain Reaction (RT-PCR) at 1, 2, 3, 6, 9, 12, 15, 18 and 24 months to study kinetics of CMR. | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Stability of CMR : Proportion of patients maintaining their CMR at 18 and 24 months |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Kinetics of Major Molecular Response (MMR) at 1, 2, 3, 6, 9, 12, 15, 18 and 24 months. | MMR corresponds to a level of BCR-ABL transcripts < 0.1 % (BCR-ABL/ABL ratio < 0.1%). The BCR-ABL/ABL ratio is analysed by RT-PCR at 1, 2, 3, 6, 9, 12, 15, 18 and 24 months to study kinetics of MMR. | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Stability of MMR : proportion of patients maintaining their MMR at 18 and 24 months |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Cumulative Complete Cytogenetic Remission (CCyR) rates at 3, 6 and 12 months. |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Safety (hematologic and non-hematologic) of the combination nilotinib + PEG-IFN |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Dose reductions or interruptions of each treatment studied |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Progression free survival. |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Overall survival. |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Quality of life on nilotinib + PEG-IFN |  | Patients will be enrolled for 18 months and will be followed for 24 months | 
| Event free survival. |  | Patients will be enrolled for 18 months and will be followed for 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Myelogenous Leukemia, nilotinib, pegylated interferon, BCR-ABL Philadelphia chromosome, Hematologic, cytogenetic and molecular response rates and kinetics will be studied in addition to the safety of the combination