Chronic Myelogenous Leukemia
Conditions
Keywords
AMN107, Ph+ CML-CP, chronic phase, nilotinib treatment, 2 years treatment, MR 4.5, Loss of MR 4, Loss of MMR, CML
Brief summary
The main purpose of the study was to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment
Detailed description
The Primary objective of this study was to determine the percentage of patients who were in Major Molecular Response (MMR) at 48 weeks after starting the Treatment-Free Remission (TFR) phase (patients who required re-initiation of treatment were considered as non-responders). Nilotinib treatment consolidation phase (NTCS): Patients who satisfied all inclusion/exclusion criteria were enrolled in the consolidation phase and continued to receive nilotinib for 52 weeks. All patients were treated with the planned nilotinib dose 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of toxicity). In order for patients to be eligible for the TFR phase, they had to fulfill the protocol specific definition of durable MRD. The four last quarterly performed PCR assessments must have fulfilled the following criteria: * The last assessment was MR4.5 (BCR-ABL ≤ 0.0032% IS) * No assessment worse than MR4.0 (BCR-ABL \>0.01% IS) and * No more than two assessments between MR4.0 and MR4.5 (0.0032% IS\<BCR-ABL ≤ 0.01% IS) Nilotinib Treatment-Free Remission (TFR) phase: Patients who were eligible to enter in the TFR phase after completing the 52 weeks consolidation phase, stopped taking nilotinib on the first day of the TFR phase. Duration of this phase was up to 10 years after the last patient enters in the TFR phase. BCR-ABL levels were monitored every four weeks during the first 48 weeks, every six weeks for the following 48 weeks and every 12 weeks during the last period. Nilotinib treatment re-initiation (NTRI) phase: If a patient had a loss of MMR (BCR-ABL \>0.1% IS) in the TFR phase, the patient restarted nilotinib treatment. Patients were on nilotinib treatment for up to 10 years after the last patient entered the nilotinib TFR phase. Patients who required re-initiation of nilotinib treatment were monitored for the BCR-ABL level every four weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR. The frequency of BCR-ABL monitoring in patients not regaining MMR within the first 24 weeks after re-initiation of treatment was at least every 12 weeks or more frequently as clinically indicated.
Interventions
DRUGNilotinib followed by treatment-free
Nilotinib is being used as commercial available capsules (except in Japan where clinical supplies is used) of 150 mg and 200 mg strength. Treatment occurs during consolidation, continuation, prolonged continuation, re-initiation and re-initiation-2 phases of the study.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥ 18 years of age * Minimum of 2 calendar years of nilotinib treatment with at least the last 12 months of nilotinib treatment prior to pre-screening at approved total daily dose of 600 mg BID or at a reduced dose of 400 mg QD if required from the perspective of tolerance for BCR-ABL positive CML in documented chronic phase at the time of diagnosis * Evidence of typical BCR-ABL transcripts (b3a2 and/or b2a2) at the time of CML-CP diagnosis i.e. prior to first start of TKI treatment which are amenable to standardized RT-PCR quantification" * Patient in MR4.5 at prescreening at Novartis designated lab * ECOG performance status of 0-2 * Adequate end organ function as defined by: * Direct bilirubin ≤ 1.5 x ULN except for i) patients with documented Gilbert's syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range). * SGOT(AST) and SGPT(ALT) ≤ 3 x ULN i.e. equivalent to ≤ Grade 1 NCI-CTCAE v.4.03 * Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03 * Alkaline phosphatase ≤ 2.5 x ULN * Serum creatinine \< 1.5 x ULN * Patients must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication: * Potassium (suggested keep to prevent issues with QT and/or rhythm abnormalities) * Magnesium (suggested keep to prevent issues with QT and/or rhythm abnormalities) * Total calcium (corrected for serum albumin) * Patients must have normal marrow function as defined: * Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L * Hemoglobin ≥ 9.0 g/dL * Platelets ≥ 100 x 10E9/L * Documented chronic phase CML must meet all the criteria defined by: * \< 15% blasts in peripheral blood and bone marrow, * \< 30% blasts plus promyelocytes in peripheral blood and bone marrow, * \< 20% basophils in the peripheral blood, * ≥ 100 x 109/L (≥ 100,000/mm3) platelets, * No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly * Patients must tolerate a minimum total daily dose of nilotinib of 400 mg
Exclusion criteria
* Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total cumulative duration of 4 weeks * Previous treatment with alpha-interferon of any duration * Previous anticancer agents for CML other than nilotinib except for cytoreduction after CML diagnosis until up to 4 weeks after first dose of nilotinib * Known second chronic phase of CML after previous progression to AP/BC * Poorly controlled diabetes mellitus (defined as HbA1c \> 9%) * Impaired cardiac function including any one of the following: * LVEF \< 45% or below the institutional lower limit of the normal range (whichever is higher) * Inability to determine the QT interval on ECG, except for patients with evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality. * Complete left bundle branch block * Right bundle branch block plus left anterior or posterior hemiblock * Use of a ventricular-paced pacemaker * Congenital long QT syndrome or a known family history of long QT syndrome * History of or presence of clinically significant ventricular or atrial tachyarrhythmias * Clinically significant resting bradycardia * QTc \> 450 msec on the average of three serial baseline ECG (using the QTcF formula). If QTcF \> 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-tested for QTc.This exclusion criterion is not applicable for patients with non-measurable QT interval who have evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality. * History or clinical signs of myocardial infarction within 1 year of study entry * History of unstable angina within 1 year of study entry * Other clinically significant heart disease (e.g. congestive heart failure, cardiomyopathy or uncontrolled hypertension) * History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis * Known presence of significant congenital or acquired bleeding disorder unrelated to cancer * Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, uncontrolled infection) * History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively * Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1 * Patients who have not recovered from prior surgery * Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. * Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo. * Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug. (see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval) * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 14 days after the final dose of nilotinib. Highly effective contraception is defined as either: * Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. * Male sterilization (at least 6 months prior to enrolling). For female patients on the study the vasectomized male partner should be the sole partner for that patient. * Use of a combination of any two of the following: 1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. If a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of nilotinib, the Study Doctor needs to be informed immediately and ongoing study treatment with nilotinib has to be stopped immediately.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Major Molecular Response at 48 Weeks After Start of Treatment-Free Remission (TFR) Phase | 48 weeks in TFR | The primary endpoint was the percentage of participants in major molecular response (MMR) at 48 weeks after initiation of the treatment-free remission (TFR) phase. Participants who required re-initiation of treatment were considered as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 Weeks After Start of TFR Phase | 48 weeks in TFR | The outcome measure was the percentage of participants in molecular response 4.5 (MR4.5) at 48 weeks after initiation of the treatment-free remission (TFR) phase. Participants who required reinitiation of treatment were considered non-responders. MR4.5 corresponds to a BCR-ABL transcript level ≤0.0032% on the International Scale (IS), representing a deep molecular response. |
| Percentage of Participants in Major Molecular Response (MMR) at Multiple Time Points After Start of the Treatment-Free Remission (TFR) Phase | Weeks 96, 144, 192, and 264, and End of Years 6, 7, 8, 9, and 10 | This outcome measure was the percentage of participants in major molecular response (MMR) assessed at multiple timepoints after initiation of the treatment-free remission (TFR) phase. Participants who required re-initiation of treatment at any time prior to the respective assessment were considered non-responders. |
| Percentage of Participants in Molecular Response 4.5 (MR4.5) at Multiple Time Points After Start of the Treatment-Free Remission (TFR) Phase | Weeks 96, 144, 192, and 264, and End of Years 6, 7, 8, 9, and 10 | This secondary outcome measure was the percentage of participants in molecular response 4.5 (MR4.5) assessed at multiple timepoints after initiation of the treatment-free remission (TFR) phase. Participants who required reinitiation of treatment at any time prior to the respective assessment were considered non-responders. MR4.5 corresponds to a BCR-ABL transcript level ≤0.0032% on the International Scale (IS). |
| Number of Participants in Major Molecular Response (MMR) at Multiple Time Points After Start of the Treatment-Free Remission (TFR) Phase | Weeks 48, 96, 144, 192, and 264, and End of Years 6, 7, 8, 9, and 10 | This outcome measure was the number of participants in major molecular response (MMR) assessed at multiple timepoints after initiation of the treatment-free remission (TFR) phase of nilotinib. At each assessment time point, participants with available MMR data were counted. Participants who reinitiated nilotinib treatment for less than 12 weeks prior to the respective assessment time point were excluded from the analysis at that time point. |
| Number of Participants in Molecular Response 4.5 (MR4.5) at Multiple Time Points After Start of the Treatment-Free Remission (TFR) Phase | Weeks 48, 96, 144, 192, and 264, and End of Years 6, 7, 8, 9, and 10 | This outcome measure was the number of participants in molecular response 4.5 (MR4.5) assessed at multiple timepoints after initiation of the treatment-free remission (TFR) phase of nilotinib. At each assessment time point, participants with available MR4.5 data were counted. Participants who reinitiated nilotinib treatment for less than 12 weeks prior to the respective assessment time point were excluded from the analysis at that time point. MR4.5 corresponds to a BCR-ABL transcript level ≤0.0032% on the International Scale (IS). |
| Percentage of Participants Who Achieved Major Molecular Response (MMR) Within 12 Weeks of Reinitiation of Nilotinib Treatment | 12 weeks after reinitiation of nilotinib treatment | Percentage of patients who achieved MMR within 12 weeks of re-initiation of treatment with nilotinib defined as the number of patients who were in MMR at least at 1 assessment within 12 weeks after re-start of nilotinib treatment divided by the number of patients who were re-initiated for at least 12 weeks. |
| Percentage of Participants With Stable Major Molecular Response (MMR) at Multiple Time Points After First Achievement of MMR During Nilotinib Re-Initiation | Weeks 48, 96, 144, 192, 240, 288, 336, 384, and 432 after first achievement of MMR during the nilotinib re-initiation phase | The percentage of patients who were in stable MMR after achieving a response in the NTRI phase at multiple timepoints was calculated by dividing the number of participants achieving MMR any time during the NTRI phase and having the same response at those timepoints after the first achievement of MMR, irrespective of whether there was loss of MMR in between, by the number of patients who achieved MMR at any time during the NTRI phase. |
| Percentage of Participants With Stable Molecular Response 4.5 (MR4.5) at Multiple Time Points After First Achievement During Nilotinib Re-Initiation | Weeks 48, 96, 144, 192, 240, 288, 336, 384, and 432 after first achievement of MR4.5 during the nilotinib re-initiation phase | The proportion of patients who were in stable MR4.5 after achieving a response in the NTRI phase at multiple timepoints was calculated by dividing the number of participants achieving MR4.5 any time during the NTRI phase and having the same response at those timepoints after the first achievement of MR4.5, irrespective of whether there was loss of MR4.5 in between, by the number of patients who achieved MR4.5 at any time during the NTRI phase. |
| BCR-ABL Ratio (%) Over Time in Nilotinib Treatment Re-initiation Phase (NTRI) | Baseline; every 4 weeks up to Week 24; and every 12 weeks thereafter, up to Week 528 | The BCR-ABL ratio (%) represents the level of BCR-ABL fusion gene transcripts relative to a control gene (ABL) measured in peripheral blood samples using quantitative reverse transcription polymerase chain reaction (RT-PCR). Results are expressed as a percentage on the International Scale (IS), a standardized reporting method that allows comparison across laboratories. The BCR-ABL ratio is used to assess the molecular response to treatment, with lower values indicating a reduced disease burden. |
| Duration of Re-Initiated Nilotinib Treatment Required to Regain Major Molecular Response (MMR) After Loss of MMR | Every 4 weeks up to Week 24, and every 12 weeks thereafter, up to Week 528 | This outcome measure was defined as the time from the date of reinitiation of nilotinib treatment following loss of major molecular response (MMR) to the date of first documented achievement of MMR. Participants who did not regain MMR after reinitiation of treatment on or before the data cut-off date were censored at the date of their last available BCR-ABN PCR assessment. |
| Duration of Re-Initiated Nilotinib Treatment Required to Regain Molecular Response 4.5 (MR4.5) After Loss of MMR | From start of Nilotinib treatment re-initiation up to Week 528 | This outcome measure was defined as the time from the date of reinitiation of nilotinib treatment following loss of major molecular response (MMR) to the date of first documented achievement of molecular response 4.5 (MR4.5). Participants who did not regain MR4.5 after reinitiation of treatment on or before the data cut-off date were censored at the date of their last available BCR-ABN PCR assessment. MR4.5 corresponds to a BCR-ABN transcript level ≤0.0032% on the International Scale (IS). |
| Treatment-Free Survival (TFS) After Start of the Treatment-Free Remission (TFR) Phase | From start of the treatment-free remission (TFR) phase up to Week 528 | Treatment-free survival (TFS) was defined as the time from the start of the treatment-free remission (TFR) phase to the earliest occurrence of loss of major molecular response (MMR), reinitiation of treatment for any reason, progression to accelerated phase (AP) or blast crisis (BC), or death due to any cause. Participants without an event on or before the data cut-off date were censored at the date of their last available disease assessment (polymerase chain reaction, cytogenetic, hematologic, or extramedullary assessment). |
| Progression-Free Survival (PFS) After Start of the Treatment-Free Remission (TFR) Phase | From start of the treatment-free remission (TFR) phase up to Week 528 | Progression-free survival (PFS) was defined as the time from the start of the treatment-free remission (TFR) phase to the earliest occurrence of disease progression to accelerated phase (AP) or blast crisis (BC), or death due to any cause. Participants without an event on or before the data cut-off date were censored at the date of their last available disease assessment (cytogenetic, hematologic, or extramedullary assessment) or last contact for participants in follow-up. |
| Overall Survival (OS) After Start of the Treatment-Free Remission (TFR) Phase | From start of the treatment-free remission (TFR) phase up to Week 528 | Overall survival (OS) was defined as the time from the start of the treatment-free remission (TFR) phase to death due to any cause. Participants who were alive on or before the data cut-off date were censored at the date of their last assessment or last known alive date for participants in follow-up. |
| Percentage of Participants With Treatment-emergent Adverse Events During the Entire Study | From first dose of nilotinib through up to approximately 11 years of study participation, including the NTCS, TFR, and NTRI phases | This outcome measure summarized the overall occurrence of adverse events related to nilotinib during the study. A study drug-related adverse event was defined as any adverse event assessed by the investigator as related to nilotinib and reported during the nilotinib treatment consolidation (NTCS) phase, the treatment-free remission (TFR) phase, or the nilotinib treatment re-initiation (NTRI) phase. |
| Number of Participants With BCR-ABL1 Mutations Associated With Resistance to Nilotinib After Loss of Major Molecular Response | From loss of major molecular response after nilotinib suspension through up to 528 weeks of study participation | This outcome measure was the number of participants who developed BCR-ABL1 mutations associated with resistance to nilotinib following loss of major molecular response (MMR) after suspension of nilotinib treatment. Mutations assessed included, but were not limited to, T315I, E255K, Y253H, F359V, F359C, and F359I. The endpoint was calculated as the number of participants with at least one detected BCR-ABL1 mutation divided by the number of participants who experienced loss of MMR after nilotinib suspension. |
Countries
Argentina, Austria, Belgium, Bulgaria, Colombia, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Recruitment for the study comprised a total of 215 participants, who were enrolled at 132 clinical sites distributed across 19 different countries..
Pre-assignment details
Informed consent was obtained from each participant in writing before screening and before any study specific procedure was performed.
Participants by arm
| Arm | Count |
|---|---|
| NTCS Phase Patients who received a minimum of two years of first line nilotinib treatment and with BCR-ABL1 transcript level of MR4.5 entered consolidation phase of the study (52 weeks of nilotinib 300 mg BID) | 215 |
| Total | 215 |
Baseline characteristics
| Characteristic | NTCS Phase |
|---|---|
| Age, Continuous | 54.0 years |
| Race/Ethnicity, Customized Asian | 20 participants |
| Race/Ethnicity, Customized Caucasian | 189 participants |
| Race/Ethnicity, Customized Native American | 1 participants |
| Race/Ethnicity, Customized Other | 2 participants |
| Race/Ethnicity, Customized Unknown | 3 participants |
| Sex: Female, Male Female | 102 Participants |
| Sex: Female, Male Male | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 215 | 2 / 190 | 5 / 91 | 0 / 13 | 0 / 10 | 0 / 5 | 0 / 3 | 9 / 215 |
| other Total, other adverse events | 159 / 215 | 136 / 190 | 86 / 91 | 11 / 13 | 7 / 10 | 5 / 5 | 2 / 3 | 205 / 215 |
| serious Total, serious adverse events | 20 / 215 | 34 / 190 | 40 / 91 | 1 / 13 | 1 / 10 | 3 / 5 | 0 / 3 | 84 / 215 |
Outcome results
Primary
Percentage of Patients Who Are in MMR (Major Molecular Response) at 48 Weeks After Starting the Treatment-free Remission (TFR) Phase
Primary endpoint was the percentage of participants who were in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment were considered as non-responders.
Time frame: 48 weeks
Population: FAS: The FAS included the 190 patients who completed 52 weeks of nilotinib treatment in the NTCS phase and entered TFR phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TFR Phase | Percentage of Patients Who Are in MMR (Major Molecular Response) at 48 Weeks After Starting the Treatment-free Remission (TFR) Phase | 51.6 Percentage of participants |
Secondary
Duration of Re-initiated Treatment Required to Regain MMR After Loss of MMR
Defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment
Time frame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR
Secondary
Duration of Re-initiated Treatment Required to Regain MR4.5 After Loss of MMR
Defined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4.5. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment
Time frame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR
Secondary
Kinetics of BCR-ABL Transcript After Re-start of Nilotinib Therapy
Descriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 528 weks after the last patient has entered TFR
Time frame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after last patient has entered the TFR
Secondary
Overall Survival (OS) After the Start of the TFR Phase
OS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up
Time frame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR
Secondary
Percentage of Patients in MMR at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib
Proportion of patients who are in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis
Time frame: 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years
Secondary
Percentage of Patients in MR4.5 at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib
Proportion of patients who are in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis
Time frame: 48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
Secondary
Percentage of Patients Who Achieve MMR Within 12 Weeks of Re-treatment With Nilotinib
Proportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks
Time frame: 12 weeks
Secondary
Percentage of Patients Who Are in MMR at 96, 144,192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase
Proportion of patients who are in MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders
Time frame: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
Secondary
Percentage of Patients Who Are in MR4.5 at 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase
Proportion of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders
Time frame: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
Secondary
Percentage of Patients Who Are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 Weeks After Starting the TFR Phase
Proportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.
Time frame: 48 weeks
Secondary
Percentage of Patients Who Are in Stable Response (MMR and MR4.5) After Achievement of That Response in Nilotinib Re-initiation Phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 Weeks, Based on Availability of Appropriate Data
Proportion of patients who are in stable MMR/MR4.5 after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data, is calculated by dividing the number of patients achieving MMR/MR4.5 any time during the nilotinib re-initiation phase and having the same response 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks after the first achievement of MMR/MR4.5, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR/MR4.5 at any time during the nilotinib re-initiation phase
Time frame: 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks
Secondary
Progression-free Survival (PFS) After the Start of the TFR Phase
PFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up
Time frame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR
Secondary
Proportion of Patients Who Develop T3151, E255K/V, Y253H, F359V/C/I Mutations on Study or Any Other BCR-ABL Mutations in Patients Who Lost MMR After Nilotinib Suspension
Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR
Time frame: Every 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)
Secondary
Safety Profile During the Nilotinib Treatment Consolidation Phase, During the TFR Phase and During Re-initiation Treatment With Nilotinib
Safety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib
Time frame: Every 4 weeks in treatment consolidation and during the first 24 weeks of the re-initiation phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 432 weeks of the TFR
Secondary
Treatment-free Survival (TFS) After the Start of the TFR Phase
TFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.
Time frame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 432 weeks of the TFR