Nilotinib ± Peg-IFN for First Line Chronic Phase CML Patients

Study Overview
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Brief Summary
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This is a phase III trial comparing, for newly diagnosed chronic phase CML patients, nilotinib 600 mg BID as a standard arm and nilotinib 600 mg BID combined to interferon alfa 2 a (pegylated form improving tolerance and maybe enhancing is efficacy) at increased doses for a total of 24 months of combination, in a 1:1 randomized manner. The assessment for the primary efficacy endpoint will be performed at 12 months (since nilotinib initiation) and is the rate patients obtaining MR4.5 will be measured at this time point.

Official Title
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Randomized Multicenter Phase III Study Comparing the Rate of Molecular Response 4.5 at 12 Months in Newly Diagnosed Philadelphia Positive Chronic Phase Chronic Myelogenous Leukemia Patients Receiving Either Frontline Nilotinib 600 mg Daily or Nilotinib 600 mg Daily Combined to Pegylated Interferon-alfa 2a (Peg-IFN)

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Nilotinib (Tasigna ®), capsules of 150 mg
* Drug: Nilotinib (Tasigna ®) and Pegylated interferon alfa 2a (Pegasys®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients CP-CML, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript), diagnosed less than 3 months prior to study entry Age of at least 18 years-old and less than 65 years Patient for whom treatment with Nilotinib is expected No other CML treatment except for hydroxyurea and/or anagrelide No previous TKI treatment. No previous treatment with IFN even for other purposes. SGOT and SGPT < 2.5 UNL Serum creatinine < 2 UNL No planned allogeneic stem cell transplantation Signed informed consent ECOG score 0 to 2 Exclusion Criteria: Contra-indication to IFN Transcripts other than M-Bcr Pregnancy, lactation HIV positivity, chronic hepatitis B or C. Prior or concurrent malignancy other than CML (exceptions to be mentioned) History of arterial occlusive disease or (peripheral, carotids or severe coronary heart disease). Permanent elevation of total cholesterol and triglycerides despite treatment Severe psychiatric/neurological disease (previous or ongoing) Concomitant auto-immune disease Other investigational product ongoing Ongoing immunosuppressive treatment Ongoing treatment at risk for inducing torsades de pointes QTcF > 450ms despite correction of predisposing factors (i.e electrolytes…) Congenital long QTcF Unstabilised thyroid disorder No health insurance coverage

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nilotinib<br>Control arm, this compound been licensed in this indication. | Drug: Nilotinib (Tasigna ®), capsules of 150 mg<br>* Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months<br>|
| Experimental: Peg-IFN alfa 2a (Pegasys®) and Nilotinib<br>Arm testing the efficacy of a combination of nilotinib and Peg-IFN alfa 2a as frontline therapy for first line chronic phase CML patients. | Drug: Nilotinib (Tasigna ®), capsules of 150 mg<br>* Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months<br>Drug: Nilotinib (Tasigna ®) and Pegylated interferon alfa 2a (Pegasys®)<br>* Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months and Pegylated interferon alfa 2a subcutaneously once a week (auto-injection syringes of 135 and 90 micrograms) at 30 micrograms/week the first month alone (= priming procedure), then at 30 micrograms/2weeks the first month of combination to nilotinib and then at 45 micrograms/week thereafter until month 24 after nilotinib initiation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular response (MR) 4.5 at 12 months of nilotinib 300 mg twice a day versus a combination of low-dose Peg-Interferon (Peg-IFN) to nilotinib 300 mg twice a day in newly diagnosed CP-CML Chronic Phase Chronic Myelogenous Leukemia patients. | Centralised assessment of the BCR-ABL transcripts at 12 months since nilotinib initiation | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular Response 4.5 at 1, 2, 3, 6, 9, 12 months of nilotinib, and duration of MR4.5 during the second year of treatment (18, 24 and 36 months). | Centralised assessment of the BCR-ABL transcripts every month for 3 months and every three months until 12 months and thereafter every 6 months until 36 months assessment. | 36 months | 
| Major Molecular Response at 1, 2, 3, 6, 9, 12 months of nilotinib, and duration of MMR during the second year of treatment (18, 24 and 36 months). | Centralised assessment of the BCR-ABL transcripts every month for 3 months and every three months until 12 months and thereafter every 6 months until 36 months assessment. | 36 months | 
| Rate of patients with BCR-ABL/ABL (IS) ≥10% at 3 months. | Centralised assessment of the BCR-ABL transcripts at 3 months. | 3 months after nilotinib initiation | 
| Rate of CCyR (complete cytogenetic responses: bone marrow Philadelphie positive at 0 % on at least 20 metaphases) at 3, 6, 12 months of nilotinib. | Local bone marrow cytogenetic assessment (on 20 metaphases) | Assessment at 3, 6 and 12 months | 
| Safety of the nilotinib combined to Peg-IFN or not (hematological and non-hematological adverse events (AE) graded according to the NCI CTC AE v3). | Continuous evaluation of the AEs and SAEs reported during 36 months | 36 months | 
| Quality of life of patients treated in both arms | EORTC-QLQ C30 and C24 questionnaire at months -1 (Arm B), month 0, 1, 6, 12, 24, 36. | 36 months | 
| Doses-reductions/interruptions of drugs in both arms. Mean daily doses of nilotinib and Peg-IFN administered. | Continuous recording of dose intensity along the study for 24-36 months. | 24 months for Peg-IFN, and 36 months for both drugs | 
| Compliance to drugs in each arms | Morisky questionnaire to be fulfilled at 1, 6, 12, 24 and 36 months after nilotinib initiation. | 36 months | 
| Molecular relapse rate at 6 and 12 months after nilotinib withdrawal in patients obtaining 2-year stable MR4.5. | Local (but standardized) assessment of the BCR-ABL transcripts every months for 3 months. | 36 months | 
| Event-free survival. | Survival since randomization without any event defined as loss of CHR, loss of PCyR or CCyR, death from any cause, progression towards accelerated phase or blast crisis. | 36 months | 
| Progression-free survival | Survival without progression towards accelerated of blast phase, death. | 36 months | 
| Overall survival. | Survival without death from any cause | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peg-IFN, nilotinib, MR4.5, CML, chronic phase, first-line