Efficacy and Safety of Nilotinib in CML-CP

Study Overview
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Brief Summary
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ENESTKorea is a phase 4, multi-institutional, single-arm, open-label study investigating the efficacy and safety of nilotinib at the currently approved dose (300 mg twice daily) and its exposure-outcome relationship, in adult patients diagnosed as Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

Detailed Description
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Nilotinib is a second-generation tyrosine kinase inhibitor with improved efficacy compared to imatinib. However, there are still many patients for whom the therapeutic response is inadequate, or toxicity is limiting the treatment. Serum concentration of nilotinib was shown to affect time to response and progression in previous studies. Therefore, the investigators hypothesized that the optimal plasma level of nilotinib that is sufficient to achieve adequate clinical response while not generating major adverse events could be elucidated by the analysis of combined clinical and pharmacokinetic data. ENESTKorea is a phase 4, multi-institutional, single-arm, open-label study investigating the efficacy and safety of nilotinib at the currently approved dose (300 mg twice daily), in adult patients diagnosed as Philadelphia chromosome (Ph)-positive chronic myeloid leukemia in chronic phase (CML-CP). Plasma samples are collected every three months, for up to 12 months, to determine plasma nilotinib concentrations (PNCs). The primary endpoint is the cumulative rate of molecular response 4.5 (MR4.5; BCR-ABL1IS ≤ 0.0032%) by 24 months. Secondary endpoints include the cumulative rates of MR3 (BCR-ABLIS ≤ 0.1%) and MR4 (BCR-ABLIS ≤ 0.01%) by 12 and 24 months; time to MR3, MR4, and MR4.5; progression-free survival (PFS); overall survival (OS). Correlations between PNCs and clinical outcomes are also analyzed.

Official Title
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A Phase 4 Study of Nilotinib in Korean Patients With Philadelphia Chromosome-positive Chronic Myeloid Leukemia in Chronic Phase

Conditions
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Chronic Myeloid Leukemia, Chronic Phase

Intervention / Treatment
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* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 19 or older Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase Exclusion Criteria: CML with atypical BCR-ABL1 transcripts (transcripts other than e13a2 or e14a2) Eastern Cooperative Oncology Group performance status ≥ 3 Cardiac abnormality including a corrected QT interval ≥ 480 milliseconds, complete left bundle branch block, permanent pacemaker implantation, congenital long QT syndrome, history of tachyarrhythmia requiring treatment, clinically significant resting bradycardia, history of acute coronary syndrome within 12 months, and decompensated congestive heart failure Organ dysfunction defined by total serum bilirubin levels ≥ 1.5 × the upper limit of the normal range (ULN), creatinine ≥ 1.5 × ULN, aspartate or alanine aminotransferase ≥ 2.5 × ULN, amylase or lipase ≥ 1.5 × ULN and alkaline phosphatase ≥ 2.5 × ULN not directly related to the CML Uncontrolled hypertension and/or diabetes Active and uncontrolled infection Major surgery within two weeks or incomplete recovery from the previous surgery Congenital or acquired bleeding tendency Impaired gastrointestinal absorption History of small bowel resection or bypass surgery History of acute pancreatitis within 12 months or chronic pancreatitis Concomitant administration of strong irreplaceable CYP3A4 inhibitors or inducers, QT-prolonging agents, or coumarin derivatives Any other uncontrolled medical conditions that would present substantial safety risks or compromise compliance with the study treatment

Ages Eligible for Study
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Minimum Age: 19 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational arm<br>Oral nilotinib 300mg twice daily with a 12-hour interval | Drug: Nilotinib<br>* Nilotinib 300mg twice-daily<br>* Other names: Tasigna;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative rate of molecular response 4.5 by 24 months | Cumulative rate of BCR-ABL1 fusion transcripts ≤ 0.0032%, measured by real-time quantitative polymerase chain reaction and standardized to the international scale | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative rate of molecular response 3 by 24 months | Cumulative rate of BCR-ABL1 fusion transcripts ≤ 0.1%, measured by real-time quantitative polymerase chain reaction and standardized to the international scale | 24 months | 
| Cumulative rate of molecular response 3 by 12 months | Cumulative rate of BCR-ABL1 fusion transcripts ≤ 0.1%, measured by real-time quantitative polymerase chain reaction and standardized to the international scale | 12 months | 
| Cumulative rate of molecular response 4 by 24 months | Cumulative rate of BCR-ABL1 fusion transcripts ≤ 0.01%, measured by real-time quantitative polymerase chain reaction and standardized to the international scale | 24 months | 
| Cumulative rate of molecular response 4 by 12 months | Cumulative rate of BCR-ABL1 fusion transcripts ≤ 0.01%, measured by real-time quantitative polymerase chain reaction and standardized to the international scale | 12 months | 
| Progression-free survival | Time from enrollment to documented disease progression or death from any cause | 24 months | 
| Overall survival | Time from enrollment to death from any cause | 24 months |