Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia
Conditions
Keywords
Tasigna, nilotinib treatment, chronic phase, Ph+ CML, accelerated phase, newly diagnosed Ph+ CML, pediatric, leukemia, leukemia, pediatric, leukemia, myleiod, leukemia, mylegenous, chronic, leukemia, mylegenous, accelerated, BCR-ABL positive, myeloproliferative disorder, bone marrow disease, hematologic diseases, neoplastic processes, imatinib, dasatinib, enzyme inhibitor, protein kinase inhibitor
Brief summary
To evaluate the safety, efficacy and pharmacokinetics of nilotinib over time in the Ph+ chronic myelogenous leukemia (CML) in pediatric patients (from 1 to \<18 years).
Detailed description
The study was designed as a multi-center, open-label, non-controlled phase II study to assess efficacy, safety and PK parameters of 230 mg/m2 twice daily nilotinib in pediatric patients (1 to \<18 years old). The study population consisted of three cohorts of Ph+ CML pediatric patients: * Cohort 1: Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib * Cohort 2: Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib * Cohort 3: Newly-diagnosed Ph+ CML-CP patients in first chronic phase A minimum number of 50 pediatric patients (from 1 to \<18 years) were enrolled in the study. Of them, at least 15 patients were Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib, and at least 15 were newly-diagnosed Ph+ CML-CP patients in first chronic phase patients. There was no minimum number of patients required for Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib. Based on enrollment forecasts as of Jan 2015, and to reflect the agreements with the US FDA and the PDCO, the study remained open for enrollment until the targeted number of 50 patients with at least 15 newly diagnosed Ph+CML patients was achieved or until 31May2015, whichever was later. Patients who completed the study were treated with nilotinib for a total of 66 cycles of 28 days unless the patient prematurely discontinued study treatment. The primary analysis cut-off date was the date when all patients enrolled in the trial either completed their visit for treatment cycle 12 or had discontinued study treatment early (EoT/early discontinuation visit). These analyses were reported in the 12-cycle clinical study report (CSR). A 24-cycle analysis was done when all patients had either completed their 24-cycle treatment visit or had discontinued study treatment early. At trial end, a final comprehensive CSR of all data collected during the trial was produced.
Interventions
DRUGnilotinib
Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered orally at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Newly diagnosed and untreated Ph+ CML CP or Ph+ CML CP or AP resistant or intolerant to either imatinib or dasatinib * Karnofsky ≥ 50% for patients \> 10 years of age and Lansky ≥ 50 for patients ≤ 10 years of age * Adequate renal, hepatic and pancreatic function * Potassium, magnesium, phosphorus and total calcium values ≥ LLN (lower limit of normal) * Written informed consent Key
Exclusion criteria
* Treatment with strong CYP3A4 inhibitors or inducers * Use or planned use of any medications that have a known risk or possible risk to prolong the QT interval * Acute or chronic liver, pancreatic or severe renal disease * History of pancreatitis or chronic pancreatitis. * Impaired cardiac function * No evidence of active graft vs host and \<3mo since Stem Cell Transplant * Total body irradiation (TBI) or craniospinal radiation therapy \<6months * Hypersensitivity to the active ingredient or any of the excipients including lactose. * the criteria regarding pregnancy and contraception * Active or systemic bacterial, fungal, or viral infection * known Hepatitis B, Hepatitis C, or HIV infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients | 12 cycles | Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as CCyR at 12 cycles if the patient met the CCyR criteria at the Cycle 12 Visit. |
| Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib | 6 cycles | MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR at 6 cycles if the patient met the MMR criteria at the Cycle 6 Visit. |
| MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients | 12 cycles | MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR by 12 cycles if the patient met the MMR criteria at least once at any time between first study drug intake and Cycle 12 visit included. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | up to 66 cycles (1 cycle = 28 days) | MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: \> 0.0032 to ≤ 0.01% is equal to a log reduction category of \>= 4 to \<4.5 -log reduction (MR4); BCR-ABL ratio by percentage: \<=0.0032% is equal to a log reduction category of \>= 4.5-log reduction (MMR4.5) |
| Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | up to 66 cycles (1 cycle = 28 days) | MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: \> 0.0032 to ≤ 0.01% is equal to a log reduction category of \>= 4 to \<4.5 -log reduction (MR4); BCR-ABL ratio by percentage: \<=0.0032% is equal to a log reduction category of \>= 4.5-log reduction (MMR4.5) |
| Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR | From first dosing to the first MMR within 66 cycles period | Time from first study drug intake to first MMR amongst imatinib or dasatinib resistant or intolerant patients with CML-CP computed only for patients who achieved MMR. |
| Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR | From first dosing to the first MMR within 66 cycles period | Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR. |
| Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR | from MMR until confirmed loss of MMR (Assessed up to 66 cycles) | Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date. |
| Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR | from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es) | Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date. |
| Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall | up to 66 cycles | * Complete cytogenetic response (CCyR) - 0% Ph+ metaphases * Partial cytogenetic response (PCyR) - \>0 to 35% Ph+ metaphases * Minor cytogenetic response (mCyR) - \>35 to 65% Ph+ metaphases * Minimal - \>65 to 95% Ph+ metaphases * None - \>95 to 100% Ph+ metaphases * Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses. |
| Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall | up to 66 cycles | Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - \>95 to 100% Ph+ metaphases |
| Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients | From first dosing to the first CCyR up to 66 cycles | Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included. |
| Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients | From first dosing to the first CCyR up to 66 cycles | Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included. |
| Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients | From CCyR to loss of CCyR up to 66 cycles | Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included. |
| Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | 6, 12, 18, 24, 36, 48, 66 cycles | Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses. |
| Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients | up to 66 cycles | Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses. |
| Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients | up to 66 cycles | Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses. |
| Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients | from first dosing to CHR, UP TO 66 CYCLES | Complete Hematological Response (CHR) was defined as * WBC count \<10×109/L * platelet count \<450×109/L * basophils \<5% * no blasts and promyelocytes in peripheral blood * myelocytes+metamyelocytes \<5% in peripheral blood * no evidence of extramedullary disease, including spleen and liver * Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP |
| Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients | from first dosing to CHR, UP TO 66 CYCLES | Complete Hematological Response (CHR) was defined as * WBC count \<10×109/L * platelet count \<450×109/L * basophils \<5% * no blasts and promyelocytes in peripheral blood * myelocytes+metamyelocytes \<5% in peripheral blood * no evidence of extramedullary disease, including spleen and liver * Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP |
| Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates | From first dosing to the disease progression within 66 cycles | Time to disease progression is the time from the date of first study drug intake to the date of event defined as the first progression to AP or BC (from CP) or to BC (from AP) or the date of CML-related death occurring on treatment, whichever was earlier. |
| Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients | From first dosing to the disease progression or death up to 66 cycles | Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment) |
| Event Free Survival in Newly Diagnosed CML-CP Patients | From first dosing to the disease progression or death up to 66 cycles | Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment) |
| Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates | from first dosing to death up to 66 cycles | Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up. |
| Overall Survival (OS) in Newly Diagnosed CML-CP Patients | from first dosing to death up to 66 cycles | Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up. |
| Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles | BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL transcript levels were summarized by cohort and time point. MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR. |
| Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients | Cycle 1 Day 8 | PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early. |
| Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients | Cycle 1 Day 8 | PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early. |
| Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | from first dosing to 66 cycles | To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML in participants with both a baseline and post-baseline value. |
| Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | up to Cycle 12 | Acceptability of the study drug was evaluated from a questionnaire completed by patients, with the help from parents or caregivers at visits. The Questionnaire to capture patient assessment of palatability (very good to very bad) and acceptability of taking the medication (very easy to very hard to administration). |
| Mutational Assessment of BCR-ABL | up to 66 cycles | Emerging signs of resistance to nilotinib |
| Best Complete Hematological Response (CHR) by Time Point | cycle 3, 6, 9, 12, 18, 24, 36, 48, 66 | Complete Hematological Response (CHR) was defined as * WBC count \<10×109/L * platelet count \<450×109/L * basophils \<5% * no blasts and promyelocytes in peripheral blood * myelocytes+metamyelocytes \<5% in peripheral blood * no evidence of extramedullary disease, including spleen and liver * Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP |
| MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days) | Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample. |
| MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days) | Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Long Term Effect of Nilotinib on Bone Metabolism | Cycle 66 | The summary of bone age and Dual-energy X-ray absorptiometry (DEXA) by cohort. Alteration of bone biochemical markers of hand and wrist X-Ray evaluation was observed in bone age standard deviation scores (SDS) and for bone mineral density for DEXA before and after treatment with nilotinib. |
Countries
France, Hungary, Italy, Japan, Malaysia, Netherlands, Russia, South Korea, Spain, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
3 cohorts were planned based on disease classification. In 1 cohort no patients (pts) were enrolled so results presented are based on 2 cohorts. 34 imatinib/dasatinib resistant/intolerant CML-CP pts & 25 newly diagnosed CML-CP pts were enrolled. 1 imatinib/dasatinib resistant/intolerant pt did not receive study drug & was excluded from analysis.
Pre-assignment details
Minimum 50 pediatric patients (pts) to be enrolled in the study. At least 15 were to be Ph+ CML-CP pts resistant/intolerant to either imatinib or dasatinib, & at least 15 newly diagnosed Ph+ CML-CP pts. There was no requirement on the minimum number of pts to be enrolled in the Cohort of CML-AP resistant/intolerant to either imatinib or dasatinib.
Participants by arm
| Arm | Count |
|---|---|
| Resistant/Intolerant Ph+ CML in CP Patients resistant or intolerant to either imatinib or dasatinib | 33 |
| Newly Diagnosed and Untreated Ph+ CML in First CP Patients newly diagnosed in Chronic phase. Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis | 25 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 3 | 4 |
| Overall Study | Adverse Event | 6 | 8 |
| Overall Study | Disease progression | 1 | 0 |
| Overall Study | Protocol deviation | 2 | 0 |
| Overall Study | Untreated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Resistant/Intolerant Ph+ CML in CP | Newly Diagnosed and Untreated Ph+ CML in First CP | Total |
|---|---|---|---|
| Age, Customized 12 to < 18 years | 21 Participants | 19 Participants | 40 Participants |
| Age, Customized 1 to < 12 years | 12 Participants | 6 Participants | 18 Participants |
| Race/Ethnicity, Customized Asian | 16 Participants | 7 Participants | 23 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 12 Participants | 18 Participants | 30 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Male | 21 Participants | 13 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 25 | 0 / 58 |
| other Total, other adverse events | 33 / 33 | 25 / 25 | 58 / 58 |
| serious Total, serious adverse events | 11 / 33 | 4 / 25 | 15 / 58 |
Outcome results
Primary
MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR by 12 cycles if the patient met the MMR criteria at least once at any time between first study drug intake and Cycle 12 visit included.
Time frame: 12 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients | 64.0 Percentage of participants |
Primary
Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as CCyR at 12 cycles if the patient met the CCyR criteria at the Cycle 12 Visit.
Time frame: 12 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients | 64.0 Percentage of participants |
Primary
Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR at 6 cycles if the patient met the MMR criteria at the Cycle 6 Visit.
Time frame: 6 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib | 39.4 Percentage of participants |
Secondary
Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation
Acceptability of the study drug was evaluated from a questionnaire completed by patients, with the help from parents or caregivers at visits. The Questionnaire to capture patient assessment of palatability (very good to very bad) and acceptability of taking the medication (very easy to very hard to administration).
Time frame: up to Cycle 12
Population: Safety Set (SAF): All patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | Cycle (C) 1 Day (D) 1: Completed questionnaire - Patients | 75.9 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Completed questionnaire - Parents/Caregivers | 22.4 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Patients who swallowed capsule whole | 91.4 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Patients had capsule mixed with apple sauce | 6.9 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Patients who reported no taste/unable to answer question | 43.1 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Patients who reported taste as good/very good | 12.1 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Patients who reported taste as not good/not bad | 34.5 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D1: Reported capsule to be very easy/easy to administer | 79.3 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D28: Completed questionnaire - Patients | 55.2 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C1D28: Completed questionnaire - Parents/Caregivers | 22.4 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C12D28: Completed questionnaire - Patients | 55.2 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation | C12D28: Completed questionnaire - Parents/Caregivers | 22.4 Percentage of participants |
Secondary
Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: \> 0.0032 to ≤ 0.01% is equal to a log reduction category of \>= 4 to \<4.5 -log reduction (MR4); BCR-ABL ratio by percentage: \<=0.0032% is equal to a log reduction category of \>= 4.5-log reduction (MMR4.5)
Time frame: up to 66 cycles (1 cycle = 28 days)
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | ≤ 0.0032% | 44.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | >0.0032% - ≤ 0.01% | 12.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | >0.01% - ≤ 0.1% | 20.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | >0.1% - ≤ 1% | 8.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | >1% - ≤ 10% | 8.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall | >10% | 8.0 Percentage of participants |
Secondary
Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: \> 0.0032 to ≤ 0.01% is equal to a log reduction category of \>= 4 to \<4.5 -log reduction (MR4); BCR-ABL ratio by percentage: \<=0.0032% is equal to a log reduction category of \>= 4.5-log reduction (MMR4.5)
Time frame: up to 66 cycles (1 cycle = 28 days)
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | <=0.0032% | 12.1 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | > 0.0032% - ≤ 0.01% | 15.2 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | >0.01% - ≤ 0.1% | 33.3 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | >0.1% - ≤ 1% | 21.2 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | >1% - ≤ 10% | 9.1 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | > 10% | 6.1 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall | Atypical transcripts at baseline | 3.0 Percentage of participants |
Secondary
Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall
* Complete cytogenetic response (CCyR) - 0% Ph+ metaphases * Partial cytogenetic response (PCyR) - \>0 to 35% Ph+ metaphases * Minor cytogenetic response (mCyR) - \>35 to 65% Ph+ metaphases * Minimal - \>65 to 95% Ph+ metaphases * None - \>95 to 100% Ph+ metaphases * Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time frame: up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall | Major cytogenetic response: Complete | 81.1 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall | Major cytogenetic response: Partial | 3.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall | Minimal | 3.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall | None | 3.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall | Missing | 9.1 Percentage of participants |
Secondary
Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall
Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - \>95 to 100% Ph+ metaphases
Time frame: up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall | 84.0 Percentage of participants |
Secondary
Best Complete Hematological Response (CHR) by Time Point
Complete Hematological Response (CHR) was defined as * WBC count \<10×109/L * platelet count \<450×109/L * basophils \<5% * no blasts and promyelocytes in peripheral blood * myelocytes+metamyelocytes \<5% in peripheral blood * no evidence of extramedullary disease, including spleen and liver * Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP
Time frame: cycle 3, 6, 9, 12, 18, 24, 36, 48, 66
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 3 | 76.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 6 | 84.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 9 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 12 | 92.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 18 | 92.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 24 | 92.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 36 | 92.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 48 | 92.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Complete Hematological Response (CHR) by Time Point | by cycle 66 | 92.0 Percentage of participants |
Secondary
Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients
Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time frame: 6, 12, 18, 24, 36, 48, 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 6 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 12 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 18 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 24 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 36 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 48 | 88.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients | by cycle 66 | 88.0 Percentage of participants |
Secondary
Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR
Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.
Time frame: from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es)
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR | NA months |
Secondary
Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR
Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.
Time frame: from MMR until confirmed loss of MMR (Assessed up to 66 cycles)
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR | NA months |
Secondary
Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)
Time frame: From first dosing to the disease progression or death up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients | NA months |
Secondary
Event Free Survival in Newly Diagnosed CML-CP Patients
Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)
Time frame: From first dosing to the disease progression or death up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Event Free Survival in Newly Diagnosed CML-CP Patients | NA months |
Secondary
Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort
To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML in participants with both a baseline and post-baseline value.
Time frame: from first dosing to 66 cycles
Population: Safety Set (SAF): All patients who received at least one dose of study medication in participants with both a baseline and post-baseline value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | Decrease from baseline of 1 SDS category (n=32,24) | 27.3 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | Decrease from baseline of 2 SDS categories (n=32, 24) | 3.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | Decrease from baseline of 3 SDS categories(n= 32, 24) | 6.1 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | Decrease from baseline of 3 SDS categories(n= 32, 24) | 4.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | Decrease from baseline of 1 SDS category (n=32,24) | 32.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort | Decrease from baseline of 2 SDS categories (n=32, 24) | 16.0 Percentage of participants |
Secondary
Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients
Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.
Time frame: From CCyR to loss of CCyR up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients | NA months |
Secondary
Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.
Time frame: From first dosing to the first CCyR up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients | 5.6 months |
Secondary
Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients
Complete Hematological Response (CHR) was defined as * WBC count \<10×109/L * platelet count \<450×109/L * basophils \<5% * no blasts and promyelocytes in peripheral blood * myelocytes+metamyelocytes \<5% in peripheral blood * no evidence of extramedullary disease, including spleen and liver * Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP
Time frame: from first dosing to CHR, UP TO 66 CYCLES
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients | 1.0 months |
Secondary
Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients
Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time frame: up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients | 5.55 months |
Secondary
MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients
Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.
Time frame: by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days)
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 36 | 76.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 3 | 12.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 6 | 52.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 9 | 56.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 12 | 64.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 18 | 68.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 24 | 68.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 48 | 76.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients | By cycle 66 | 76.0 Percentage of participants |
Secondary
MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib
Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.
Time frame: By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days)
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 3 | 36.4 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 6 | 45.5 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 9 | 51.5 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 12 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 18 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 24 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 36 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 48 | 60.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib | By cycle 66 | 60.6 Percentage of participants |
Secondary
Mutational Assessment of BCR-ABL
Emerging signs of resistance to nilotinib
Time frame: up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Mutational Assessment of BCR-ABL | Patients with >=1 evaluable post-baseline mutational analysis | 39.4 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Mutational Assessment of BCR-ABL | Patients with any emergent mutation on treatment | 0.0 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Mutational Assessment of BCR-ABL | Patients with multiple emergent mutations on treatment | 0.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Mutational Assessment of BCR-ABL | Patients with multiple emergent mutations on treatment | 0.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Mutational Assessment of BCR-ABL | Patients with >=1 evaluable post-baseline mutational analysis | 32.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Mutational Assessment of BCR-ABL | Patients with any emergent mutation on treatment | 0.0 Percentage of participants |
Secondary
Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates
Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.
Time frame: from first dosing to death up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates | NA months |
Secondary
Overall Survival (OS) in Newly Diagnosed CML-CP Patients
Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.
Time frame: from first dosing to death up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Overall Survival (OS) in Newly Diagnosed CML-CP Patients | NA months |
Secondary
Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle
BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL transcript levels were summarized by cohort and time point. MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR.
Time frame: By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 6 | 45.5 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 24 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 12 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 36 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 9 | 51.5 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 48 | 60.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 18 | 57.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 66 | 60.6 Percentage of participants |
| Resistant/Intolerant Ph+ CML in CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 3 | 36.4 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 66 | 76.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 3 | 12.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 6 | 52.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 9 | 56.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 12 | 64.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 18 | 68.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 24 | 68.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 36 | 76.0 Percentage of participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle | By Cycle 48 | 76.0 Percentage of participants |
Secondary
Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early.
Time frame: Cycle 1 Day 8
Population: Pharmacokinetics Analysis Set (PAS): All patients with at least one evaluable PK blood sample. Of the 32 patients included in the PAS, only 30 had evaluable Ctrough.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients | 1407.89 ng/mL | Geometric Coefficient of Variation 41.67 |
Secondary
Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients
PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early.
Time frame: Cycle 1 Day 8
Population: Pharmacokinetics Analysis Set (PAS): All patients with at least one evaluable PK blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients | 1274.30 ng/mL | Geometric Coefficient of Variation 46.21 |
Secondary
Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.
Time frame: From first dosing to the first CCyR up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients | 5.55 months |
Secondary
Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients
Complete Hematological Response (CHR) was defined as * WBC count \<10×109/L * platelet count \<450×109/L * basophils \<5% * no blasts and promyelocytes in peripheral blood * myelocytes+metamyelocytes \<5% in peripheral blood * no evidence of extramedullary disease, including spleen and liver * Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP
Time frame: from first dosing to CHR, UP TO 66 CYCLES
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients | 0.95 months |
Secondary
Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients
Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time frame: up to 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients | 5.55 months |
Secondary
Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates
Time to disease progression is the time from the date of first study drug intake to the date of event defined as the first progression to AP or BC (from CP) or to BC (from AP) or the date of CML-related death occurring on treatment, whichever was earlier.
Time frame: From first dosing to the disease progression within 66 cycles
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates | NA months |
Secondary
Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR
Time from first study drug intake to first MMR amongst imatinib or dasatinib resistant or intolerant patients with CML-CP computed only for patients who achieved MMR.
Time frame: From first dosing to the first MMR within 66 cycles period
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR | 2.79 months |
Secondary
Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR
Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.
Time frame: From first dosing to the first MMR within 66 cycles period
Population: Full Analysis Set (FAS): All patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR | 5.59 Months |
Post Hoc
All Collected Deaths
On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 64.5 months (treatment duration ranged from 0.7 to 63.5 months). Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 7 years.
Time frame: approx. 64.5 months, approx. 7 years
Population: Clinical Database Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | All Collected Deaths | On-treatment deaths | 0 Participants |
| Resistant/Intolerant Ph+ CML in CP | All Collected Deaths | Total Deaths | 1 Participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | All Collected Deaths | On-treatment deaths | 0 Participants |
| Newly Diagnosed and Untreated Ph+ CML in First CP | All Collected Deaths | Total Deaths | 3 Participants |
Other Pre-specified
Long Term Effect of Nilotinib on Bone Metabolism
The summary of bone age and Dual-energy X-ray absorptiometry (DEXA) by cohort. Alteration of bone biochemical markers of hand and wrist X-Ray evaluation was observed in bone age standard deviation scores (SDS) and for bone mineral density for DEXA before and after treatment with nilotinib.
Time frame: Cycle 66
Population: Safety Set (SAF): All patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Resistant/Intolerant Ph+ CML in CP | Long Term Effect of Nilotinib on Bone Metabolism | X-ray (n= 6, 0) | -0.61 Percentage of participants | Standard Deviation 1.703 |
| Resistant/Intolerant Ph+ CML in CP | Long Term Effect of Nilotinib on Bone Metabolism | DEXA (n = 14, 10) | -0.35 Percentage of participants | Standard Deviation 1.243 |
| Newly Diagnosed and Untreated Ph+ CML in First CP | Long Term Effect of Nilotinib on Bone Metabolism | DEXA (n = 14, 10) | -0.70 Percentage of participants | Standard Deviation 1.043 |