In this study, the efficacy and safety of two nilotinib doses, 300 mg twice daily and 400 mg twice daily, were compared with imatinib 400 mg once daily in newly diagnosed patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP). An extension protocol was included in this study design to allow patients who did not show sufficient response to their assigned treatments the opportunity to receive imatinib 400 mg BID (option available until protocol amendment 7) or nilotinib 400 mg BID, using an abbreviated safety and efficacy assessment schedule.
Name: nilotinib
Name: imatinib
Description: MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Measure: Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation Time: Baseline, 12 monthsDescription: MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Measure: Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation Time: 12 monthsDescription: Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points.
Measure: Rates of Durable MMR at 24 Months Between All 3 Arms Time: 24 monthsDescription: CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as "Nocomplete cytogenetic response".
Measure: Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months Time: 12, 24, 36, 48, 60, 72 months (M)Description: MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months based on 12-month cut-off interim data.
Measure: Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms Time: 12 monthsDescription: MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 6 months and beyond up to 120 months based on final data.
Measure: Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms Time: 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 monthsDescription: Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)
Measure: Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Time: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 monthsDescription: This is the molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
Measure: Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Time: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 monthsDescription: Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP.
Measure: Time to First MMR Time: up to 84 monthsDescription: Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
Measure: Duration of MMR Time: approx. 11 yearsDescription: Time to BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% is defined as: date of first BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% - date of randomization +1.
Measure: Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts Time: up to 84 monthsDescription: It is defined as the time from the date of first documented BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
Measure: Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts Time: approx. 11 yearsDescription: Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 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).
Measure: Rate of Hematologic Response Time: 12 months, 24 months, Overall on Core study (approx. 11 years)Description: Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR
Measure: Time to Complete Cytogenic Response (CCyR) Time: 24 monthsDescription: Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.
Measure: Duration of CCyR Time: up to 72 monthsDescription: Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study
Measure: Progression-free Survival (PFS) Time: approx. 11 yearsDescription: Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR
Measure: Event-free Survival (EFS) Time: approx. 11 yearsDescription: OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP.
Measure: Overall Survival (OS) Time: approx. 11 yearsDescription: Actual dose intensity is defined as total dose over time on treatment
Measure: Actual Dose-intensity Time: approx. 11 yearsDescription: Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death.
Measure: Time to Progression to AP/BC Time: approx. 11 yearsDescription: Cmax is defined as the maximum serum concentration after dose
Measure: Pharmacokinetics: Cmax Time: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administrationDescription: Cmin is defined as the minimum serum concentration after dose
Measure: Pharmacokinetics: Cmin Time: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administrationDescription: Tmax is defined as the sampling time when maximum measured serum concentration occurs
Measure: Pharmacokinetics: Tmax Time: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administrationDescription: AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method
Measure: Pharmacokinetics: AUC0-last Time: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administrationDescription: Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 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).
Measure: Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) Time: Overall for Extension study for approx. 10 yearsDescription: Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow.
Measure: Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) Time: Overall for Extension study for approx. 10 yearsDescription: Rate of MMR is defined as the percentage pf participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR))
Measure: Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) Time: Overall for Extension study for approx. 10 yearsDescription: Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)
Measure: Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) Time: Overall for Extension study for approx. 10 yearsDescription: Molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
Measure: Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) Time: Overall for Extension study for approx. 10 yearsDescription: This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib.
Measure: Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension) Time: Overall for Extension study for approx. 10 yearsAllocation: Randomized
Single Group Assignment
There is one SNP
- Diagnosis of chronic myelogenous leukemia in chronic phase with confirmation of Philadelphia chromosome of (9:22) translocations Key Exclusion criteria: - Previously documented T315I mutation - Treatment with a tyrosine kinase inhibitor prior to study entry is not allowed except for no more than 2 weeks in duration of imatinib - Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide - Impaired cardiac function. --- T315I ---