A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Novartis Pharmaceuticals846 enrolled

Overview

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.

Primary objectives of this study: * Compared the efficacy (major molecular response (MMR) rate at 12 months) of nilotinib at 400 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. * Compared the efficacy (MMR rate at 12 months) of nilotinib at 300 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. The Primary objectives of Extension Phase of the study: \- Characterized the safety and tolerability profile of nilotinib 400 mg BID after failure of imatinib or insufficiently responded to nilotinib 300 mg BID therapy and the safety and tolerability profile of imatinib therapy after failure of nilotinib therapy. The study was designed to determine whether the treatment of newly diagnosed, previously untreated Ph+ CML-CP patients with either nilotinib 300 mg bid or 400 mg bid demonstrated improved efficacy compared to imatinib 400 mg qd. The primary efficacy endpoint was the rate of MMR defined as the proportion of patients who achieved ≥ 3 log reduction in BCR-ABL transcripts compared to either the standardized Baseline established in the IRIS trial (International Randomized Interferon versus STI571) (Cortes et al 2005) or to the BCR-ABL ratio ≤ 0.1% by International Scale, as detected by real-time quantitative polymerase chain reaction (RQ-PCR) at 12 months. The key secondary endpoint was to compare the rate of durable MMR between nilotinib 300 mg bid with that of imatinib, and of nilotinib 400 mg bid with that of imatinib at 24 months. This report presents the final results of efficacy and safety at the LPLV (21-Aug-2019). The main data analysis was done at the time when all patients completed 12 cycles of treatment (or discontinued earlier). There were two primary comparisons at this time point: the MMR rate of nilotinib 400 mg versus the MMR rate of imatinib 400 mg, and the MMR rate of the nilotinib 300 mg versus the MMR rate of the imatinib 400 mg. Comparisons were done sequentially, i.e. the MMR rate of nilotinib 400 mg versus the MMR rate of imatinib 400 mg was to be compared first; if it was significant at 5% level, the MMR rate of the nilotinib 300 mg versus the MMR rate of the imatinib 400 mg was to be compared. The study had a 90% power to detect a 15% difference between the nilotinib 400 mg arm versus imatinib 400 mg arm assuming that the MMR rate of imatinib is 40% and the MMR rate of nilotinib is 55%. The study also had a 90% power to detect a 15% difference between the nilotinib 300 mg and the imatinib 400 mg arms, if the comparison between the nilotinib 400 mg and the imatinib 400 mg was significant. The second main data analysis was done at the time when all patients completed 24 cycles of treatment (or discontinued earlier). There were two key comparisons at this time point: the rate of durable MMR at 24 months of the nilotinib 400 mg versus the imatinib 400 mg, and the rate of durable MMR at 24 months of the nilotinib 300 mg versus the imatinib 400 mg. In order to control the overall type I error rate at or below 5%, only when the corresponding comparison on the primary efficacy endpoint(s) was (were) significant, the key secondary comparison(s) of the respective nilotinib doses (400 mg bid and/or 300 mg bid) versus imatinib 400 mg qd were tested at two-sided 5% significance level. Patients participating after demonstrating suboptimal response/treatment failure to their assigned study treatment in the core study were offered the option to continue in the extension study and to receive imatinib 400 mg bid (option available only until protocol amendment 7) or nilotinib therapy at a dose of 400 mg bid.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion criteria: * Chronic myelogenous leukemia in chronic phase patients within the first 6 months of diagnosis. * 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. * Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection). * Use of therapeutic coumarin derivatives (i.e., warfarin, acenocoumarol, phenprocoumon) * Currently receiving treatment with any medications that have the potential to prolong the QT interval.

Locations (213)

University of California at Los Angeles Dept. of Hematology Clinic

Los Angeles, California, United States

Kaiser Permanente - California Southern Dept of Kaiser South 3

San Diego, California, United States

Kaiser Permanente - California Northern Vallejo Med Center/Med Offices

Vallejo, California, United States

Kaiser Permanente - California Northern Kaiser Med

Vallejo, California, United States

Rocky Mountain Cancer Centers RMCC - Colorado Springs

Greenwood Village, Colorado, United States

Outcomes

Primary Outcomes

Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation

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.

Time frame: Baseline, 12 months

Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation

Time frame: 12 months

Secondary Outcomes

Rates of Durable MMR at 24 Months Between All 3 Arms

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.

Time frame: 24 months

Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months

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".

Time frame: 12, 24, 36, 48, 60, 72 months (M)

Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms

Time frame: 12 months

Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms

Time frame: 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib

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)

Time frame: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib

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)

Time frame: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Time to First MMR

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.

Time frame: up to 84 months

Duration of MMR

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.

Time frame: approx. 11 years

Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts

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.

Time frame: up to 84 months

Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts

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.

Time frame: approx. 11 years

Rate of Hematologic Response

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).

Time frame: 12 months, 24 months, Overall on Core study (approx. 11 years)

Time to Complete Cytogenic Response (CCyR)

Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR

Time frame: 24 months

Duration of CCyR

Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.

Time frame: up to 72 months

Progression-free Survival (PFS)

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

Time frame: approx. 11 years

Event-free Survival (EFS)

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

Time frame: approx. 11 years

Overall Survival (OS)

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.

Time frame: approx. 11 years

Actual Dose-intensity

Actual dose intensity is defined as total dose over time on treatment

Time frame: approx. 11 years

Time to Progression to AP/BC

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.

Time frame: approx. 11 years

Pharmacokinetics: Cmax

Cmax is defined as the maximum serum concentration after dose

Time frame: 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 administration

Pharmacokinetics: Cmin

Cmin is defined as the minimum serum concentration after dose

Pharmacokinetics: Tmax

Tmax is defined as the sampling time when maximum measured serum concentration occurs

Pharmacokinetics: AUC0-last

AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method

Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)