A Study That Switched Patients From Imatinib to Nilotinib and Then Was Followed by Treatment Cessation

Study Overview
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Brief Summary
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To evaluate molecular relapse free rates 6 months after stopping nilotinib therapy in patients who achieve MR4.5

Detailed Description
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Study protocol included criteria for study termination that was met when > 2 patients lost CCyR during TFR phase (> 1% BCR-ABL); This study was terminated early as > 2 cases of confirmed loss of complete cytogenetic response were reported despite BCR-ABL monitoring during the TFR Phase. All cases achieved MR4.5 after Nilotinib treatment re-initiation and maintained until end of study; trial did not mandate re-initiation within 4 weeks after loss of MMR_ that was a requirement in other Nilotinib TFR trials Initial sample size was 300 patients with CML-CP; Amendment #2 in June 2015 reduced sample size to 59 due to recruitment challenges; Study endpoint analysis and interpretations of data were challenging due to small sample size for early study closure..

Official Title
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A Phase II Randomized, Multicenter Study of Treatment-free Remission in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients Who Achieve and Sustain MR4.5 After Switching to Nilotinib

Conditions
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CML

Intervention / Treatment
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* Drug: nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of CML Treated with at least 1 year of imatinib Bcr-Abl level by PCR must be less than or equal to 0.1% and greater than 0.0032% by PCR reported on the International scale confirmed during screening Written informed consent obtained prior to any screening procedures performed Exclusion Criteria: T315I mutation Prior imatinib failure or had accelerated phase or blast crisis CML Impaired cardiac function Pregnant or lactating women

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Free Remission<br>Patients entered a monitoring phase for 2 years and received 300 mg nilotinib mg bid. Patients who achieved MR4.5 entered a Consolidation Phase and were treated with nilotinib for 2 years. If MR4.5 was sustained during the Consolidation phase, patients were eligible to stop taking niltoinib during the treatment-free remission (TFR) phase. | Drug: nilotinib<br>* Nilotinib will be provided as 150 mg capsules. Patients will take nilotinib 300mg twice daily on study and dose modifications to 450mg once daily is permitted per protocol.<br>* Other names: AMN107;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Without Molecular Relapse Within 6 Months After Starting the TFR Phase | Percentage of particpants without confirmed loss of MMR within 6 months following nilotinib TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, in the first 6 months after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase. Molecular relapse is defined as having a confirmed BCR-ABL ratio above MMR (2 consecutive BCR-ABL levels >0.1% IS taken approximately 4 weeks apart). | 6 months after stopping nilotinib therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse Free Survival is Defined as Time From the Date of Nilotinib Treatment Discontinuation to the First Documented Molecular Relapse (Confirmed Loss of MR4.5). | Relapse-free survival after the start of the TFR phase was summarized using the product-limit (Kaplan-Meier) estimates. The median for the relapse free survival and its 95% confidence intervals were provided. This analysis was performed on the FAS. Patients who dropped out without relapse were treated as censored observations. | 7 years | 
| Percentage of Participants Without Molecular Relapse Within 12 and 24 Months After Starting the Treatment -Free Remission (TFR) Phase | The percentage of participants without confirmed loss of MRR at 12 and 24 months is calculated by dividing the number of patients with no documented confirmed loss of MR4 at 12 and 24 months after starting the nilotinib TFR phase by the number of patients who entered nilotinib TFR phase. | 12 and 24 months after starting the TFR | 
| Percentage of Participants Who Regained MR4.5 After Restarting Nilotinib Due to Molecular Relapse | The percentage of participants who regained MR4.5 after restarting nilotinib will be calculated as the number of patients who achieved MR4.5 after having lost MR4 divided by the number of patients who lost MR4. | Restart of nilotinib up to month 6, 12 and 24 | 
| Number of Participants Who Progressed to Accelerated Phase/Blastic Crisis (AP/BC) or Died From From Any Cause. | Progression to AP/BC and death where the failure event is the earliest occurrence of the following event: progression to AP/BC date. | Baseline up to approximately 5 years | 
| Overall Survival (OS) | OS was defined as the time from the date of cessation of nilotinib therapy to the date of death from any cause. | Baseline up to approximately 5 years | 
| Change in Symptom-burden Scores by the M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) Assessment | The M.D. Anderson Symptom Inventory for CML patients (MDASI-CML) was used to assess the nature and impact of symptom burden on life. It consisted of 20 validated symptom items and 6 validated interference items. Each item was assessed on an 11 point scale with responses from 0-10, 0=not present and 10=as bad as you can imagine. Symptom score (SS) was calculated when a patient scored at least 8 items of the symptom items using the formula: (sum of scores for the items answered) / number of items answered. If a subject responded to < 8 symptom items, the score was considered missing. Interference score (IS) was calculated when a patient scored at least 4 items using the formula: (sum of scores for the items answered)/number of items answered. If a subject responded to < 4 interference items, the score was considered missing. The total symptom score was 0-200 and total interference score was 0-60. Mean change from baseline was summarized at all post-baseline time points | From baseline to time to when MR4.5 is confirmed, up to 24 months, and from end of Consolidation Phase to 6 and 12 months into the TFR Phase | 
| Change in Health Utility Assessed by EuroQol Group-5D-3L (EQ-5D-3L) Visual Analogue - Safety Set | The EQ-5D-3L questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and visual analog has a scale 0 to 100 (0=worst imaginable health state, 100=best imaginable health state). | From baseline to time to when MR4.5, up to 24 months, is confirmed and from end of Consolidation Phase to 6 and 12 months into the TFR Phase | 
| Change in Observed Scores for Patient Quality of Life Assessed by SF-8 - Safety Set | The SF-8 questionnaire consisted of 8 items (general health, physical functioning, role physical, bodily pain, vitality, social functioning, role-emotional and mental health) and was used to assess the impact of nilotinib treatment discontinuation on the quality of life. Each item had a 1 to 5 or 1 to 6 point response range and the higher number in the raw scores indicated poorer quality of life. The physical and mental component summary measures were calculated using a norm-based scoring method given in the instrument guidelines. These norm-based scores were summarized at baseline and mean change from baseline for post-baseline time points. The norm-based scores (based on the US population) had a mean of 50 and standard deviation of 10. Higher norm-based summary scores indicated better health | From baseline to time to when MR4.5 is confirmed and from end of Consolidation Phase to 6 and 12 months into the TFR Phase | 
| Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 3 in Consolidation Phase - Safety Set | The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point | At month 3 in Consolidation Phase | 
| Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Consolidation Phase - Safety Set | The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point | Month 12 in Consolidation Phase | 
| Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 24 in Consolidation Phase - Safety Set | The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point | Month 24 in Consolidation Phase | 
| Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 6 in Treatment Free Remission Phase - Safety Set | The EuroQol Five Dimensional Three-level questionnaire (EQ-5D-3L) comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point | Month 6 in in Treatment Free Remission Phase | 
| Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Treatment Free Remission Phase - Safety Set | The EuroQol Five Dimensional Three-level questionnaire (EQ-5D-3L) comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point | Month 12 in in Treatment Free Remission Phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, chronic myeloid leukemia, stop, niotinib, discontinue, imatinib, switch, MR4.5, undetectable, bcr-abl