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

Phase 2

Completed

Conditions: CML

Interventions: Drug: nilotinib

Registration Number: NCT01744665

Lead Sponsor: Novartis Pharmaceuticals

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

Detailed Description: 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..

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 59

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment Free Remission	nilotinib	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Without Molecular Relapse Within 6 Months After Starting the TFR Phase	6 months after stopping nilotinib therapy	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).

Secondary Outcome Measures

Name	Time	Method
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).	7 years	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.
Percentage of Participants Without Molecular Relapse Within 12 and 24 Months After Starting the Treatment -Free Remission (TFR) Phase	12 and 24 months after starting the TFR	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.
Percentage of Participants Who Regained MR4.5 After Restarting Nilotinib Due to Molecular Relapse	Restart of nilotinib up to month 6, 12 and 24	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.
Number of Participants Who Progressed to Accelerated Phase/Blastic Crisis (AP/BC) or Died From From Any Cause.	Baseline up to approximately 5 years	Progression to AP/BC and death where the "failure" event is the earliest occurrence of the following event: progression to AP/BC date.
Overall Survival (OS)	Baseline up to approximately 5 years	OS was defined as the time from the date of cessation of nilotinib therapy to the date of death from any cause.
Change in Symptom-burden Scores by the M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) Assessment	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	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
Change in Health Utility Assessed by EuroQol Group-5D-3L (EQ-5D-3L) Visual Analogue - Safety Set	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	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).
Change in Observed Scores for Patient Quality of Life Assessed by SF-8 - Safety Set	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	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
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 3 in Consolidation Phase - Safety Set	At month 3 in Consolidation Phase	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
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Consolidation Phase - Safety Set	Month 12 in Consolidation Phase	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
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 24 in Consolidation Phase - Safety Set	Month 24 in Consolidation Phase	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
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 6 in Treatment Free Remission Phase - Safety Set	Month 6 in in Treatment Free Remission Phase	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
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Treatment Free Remission Phase - Safety Set	Month 12 in in Treatment Free Remission Phase	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

Trial Locations

Locations (54): University of Alabama Comprehensive Cancer Center University of Alabama (8)
🇺🇸
Birmingham, Alabama, United States
Banner MD Anderson Cancer Center Banner MD Anderson (2)
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Gilbert, Arizona, United States
Scottsdale Healthcare/TGen Clinical Research Service SC
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Scottsdale, Arizona, United States
Highlands Oncology Group
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Fayetteville, Arkansas, United States
City of Hope National Medical Center Dept of Oncology
🇺🇸
Duarte, California, United States
Compassionate Care Research Group Inc CCCMG
🇺🇸
Fountain Valley, California, United States
UC San Diego UC San Diego Cancer Ctr
🇺🇸
La Jolla, California, United States
Wilshire Oncology Medical Group Corona Cancer Center
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Multiple Locations, California, United States
Epic-Care
🇺🇸
Pleasant Hill, California, United States
Sutter Institute for Medical Research Oncology/Hematology
🇺🇸
Sacramento, California, United States
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University of Alabama Comprehensive Cancer Center University of Alabama (8)
🇺🇸Birmingham, Alabama, United States