De-escalation and TFR Study in CML Patients Treated With Nilotinib Followed by a Second Attempt After Nilotinib and Asciminib Combination
- Conditions
- Chronic Myeloid Leukemia
- Interventions
- Registration Number
- NCT03874858
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
This study is constituted of two stage: Treatment-Free Remission 1 (TFR1) stage and Treatment-Free Remission 2 (TFR2) stage.
The purpose of the TFR1 stage is to assess the effect of nilotinib reduced to half the standard dose for 12 months on treatment-free remission in patients with Chronic Myeloid Leukemia - Chronic Phase (CML-CP) treated with first-line nilotinib who reached a sustained deep molecular response before entering the study.
The purpose of the TFR2 stage is to evaluate whether the use of asciminib in combination with nilotinib after failure of a first attempt at TFR can lead to higher and more durable TFR rates after a second attempt at TKI discontinuation than those reported in other studies.
- Detailed Description
This is a prospective, single arm, phase II study constituted of two stage: Treatment-Free Remission 1 (TFR1) stage and Treatment-Free Remission 2 (TFR2) stage.
The TFR1 stage is made up of 4 periods:
1. Screening (week -4 - week 0)
2. Nilotinib consolidation (week 0 - week 48): Patients will be treated with nilotinib 300 mg QD. At the end or during the consolidation period, patients will proceed as follows:
* Patients with sustained DMR at the end of the consolidation phase will enter the treatment-free remission (TFR1) and nilotinib will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed or results are not available, the patient will not be eligible for TFR1 period and will be treated with nilotinib 300 mg QD until the end of the TFR1 stage (week 144).
* Patients with loss of major molecular response (MMR) at any time during the consolidation phase will enter the follow-up period and will return to the standard nilotinib administration regimen (nilotinib 300 mg BID) until the end of the TFR1 stage (week 144).
* Patients with more than MMR, but without meeting the definition of sustained DMR, will remain in the consolidation phase and will be treated with nilotinib 300 mg QD until the end of the TFR1 stage (week 144).
3. Nilotinib treatment-free remission (TFR1) (week 48 - week 144): During the TFR1 period, BCR-ABL levels will be monitored until the end of the TFR1 stage (week 144)
4. Follow up: Patients who remain on half-dose nilotinib after week 48 and patients with loss of MMR at any time during the study will enter follow-up until week 144.
Patients discontinued from the treatment for any reason will be followed for survival information until week 144. All patients still on study treatment at the end of the study will be transitioned to prescription nilotinib.
The TFR2 stage will include two cohorts; an internal cohort made up of patients who participated in the TFR1 stage of this study, and an external cohort of patients who failed a first attempt at TFR with nilotinib outside of this study. The TFR2 stage is made up of 4 periods:
1. Screening for reinduction
2. Reinduction (week 0-96): Patients will be treated with asciminib 40 mg BID + nilotinib 300 mg BID for 96 weeks. Patients will proceed as follows:
* Patients with sustained DMR at the end of reinduction will enter TFR2 and asciminib + nilotinib will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed or results are not available, the patient will not be eligible for TFR2
* Patients not eligible for TFR2 but with more than an MMR continue treatment with asciminib + nilotinib until the end of reinduction (week 96) and then continue nilotinib monotherapy at 300 mg BID until the end of the TFR2 stage (week 144).
* Patients with loss of MMR at any time during reinduction or during nilotinib monotherapy will be discontinued from the study.
3. Asciminib+nilotinib treatment-free remission (TFR2) (week 96-week 144): During the TFR2 period, BCR-ABL levels will be monitored every month for one year
4. Follow up: Patients with loss of MMR during TFR2 and patients not eligible for TFR2 but with more than an MMR will be treated with nilotinib 300 mg BID and monitored until week 144. If MMR loss occurs during reinduction or during nilotinib monotherapy, patients will be discontinued from the study and treated according to clinical practice.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 124
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description TFR1 stage- Nilotinib Nilotinib During TFR1 stage, all patients will be treated with nilotinib 300 mg QD for up to 48 weeks (consolidation period). * Patients with sustained DMR at the end of the consolidation period will enter the TFR1 period and nilotinib will be discontinued. * Patients with loss of MMR will return to the standard nilotinib administration * Patients with ≥ MMR, but without sustained DMR at the end of the consolidation period will be treated with nilotinib 300 mg QD TFR2 stage- Nilotinib+Asciminib Nilotinib During the TFR2 stage, participants will be treated with nilotinib and asciminib for up to 96 weeks (reinduction period). * Patients with sustained DMR at the end of reinduction will enter TFR2 and asciminib + nilotinib will be discontinued. * Patients with ≥ MMR, but without sustained DMR, at the end of the reinduction, will be treated with nilotinib monotherapy at 300 mg BID until the end of the TFR2 stage. * Patients with loss of MMR at any time during reinduction or during nilotinib monotherapy will be discontinued from the study. TFR2 stage- Nilotinib+Asciminib Asciminib During the TFR2 stage, participants will be treated with nilotinib and asciminib for up to 96 weeks (reinduction period). * Patients with sustained DMR at the end of reinduction will enter TFR2 and asciminib + nilotinib will be discontinued. * Patients with ≥ MMR, but without sustained DMR, at the end of the reinduction, will be treated with nilotinib monotherapy at 300 mg BID until the end of the TFR2 stage. * Patients with loss of MMR at any time during reinduction or during nilotinib monotherapy will be discontinued from the study.
- Primary Outcome Measures
Name Time Method Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation period of TFR1 stage Baseline of consolidation phase up to 96 weeks of TFR1 stage Full Treatment-Free Remission (FTFR) is defined as patients with Major Molecular Response (MMR) or better (i.e. BCR-ABL ≤ 0.1% IS), including those who have totally discontinued treatment during the Treatment-Free Remission (TFR) stage and those who are treated with half the standard dosage.
Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation period of TFR1 stage is calculated by dividing the number of patients with no loss of MMR-Major Molecular Response (BCR-ABL ≤ 0.1% (IS) after 96 weeks by the number of patients who entered consolidation of TFR1 stage.Percentage of patients in treatment-free remission 48 weeks after starting a second attempt at treatment-free remission during TFR2 stage. Baseline TFR2 phase (week 96 of TFR2 stage) up to week 144 of TFR2 stage Treatment-Free Remission (TFR) is defined as patients with MMR or better (i.e. BCR-ABL ≤ 0.1% IS).
Percentage of patients in TFR 48 weeks after the start of TFR2 phase during TFR2 stage is calculated by dividing the number of patients with no loss of MMR after 48 weeks by the number of patients who entered TFR2 during TFR2 stage.
Patients who require re-initiation of nilotinib during TFR2 for loss of MMR, and those discontinued from the study will be considered failures.
- Secondary Outcome Measures
Name Time Method Treatment-free survival (TFS) in TFR2 stage From the start of the TFR period of TFR2 stage up to Week 144 of TFR2 stage. TFS: time from the start of the TFR period in TFR2 stage to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to AP/BC or death due to any cause.
Progression Free Survival (PFS) after the start of TFR2 period of TFR2 stage From the start of the TFR2 period of TFR2 stage up to week 144 of TFR2 stage. PFS: time from the start of the TFR2 period of TFR2 stage to progression to AP/BC or death due to any cause, whichever occurs first.
Overall Survival (OS) in TFR2 stage Baseline of reinduction period up to week 144 of TFR2 stage OS: time from start of the reinduction period (TFR2 stage) to death due to any cause.
Percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of the consolidation period (week 48 TFR1 stage). Baseline of consolidation period up to 48 weeks (TFR1 stage) The percentage of patients in sustained DMR at the end of the consolidation phase (week 48 of TFR1 stage) is calculated by dividing the number of patients in sustained DMR at week 48 of TFR1 stage by the number of patients who entered the consolidation phase of TFR1 stage.
Sustained DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS) in all of the last 4 BCR-ABL RQ-PCR assessmentsPercentage of patients who remain in DMR at the end of the consolidation period (week 48 of TFR1 stage), at 96 weeks and at 144 weeks after the start of the consolidation period of TFR1 stage. Baseline of consolidation period, week 48, week 96 and week 144 (TFR1 stage) The percentage of patients in DMR is calculated by dividing the number of patients in DMR 48, 96 and 144 weeks after the start of the consolidation period in TFR1 stage by the number of patients who entered the consolidation period in TFR1 stage.
DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS)Percentage of patients in full treatment-free remission 144 weeks after the start of consolidation ( end of the TFR1 stage.) Baseline of consolidation period, week 144 of TFR1 stage The percentage of patients in full treatment-free remission at week 144 of TFR1 stage is calculated by dividing the number of patients in full treatment-remission at week 144 (TFR1 stage) by the number of patients who entered the consolidation period (TFR1 stage).
Full Treatment-Free Remission (FTFR) is defined as patients with Major Molecular Response (MMR) or better (i.e. BCR-ABL ≤ 0.1% IS), including those who have totally discontinued treatment during the Treatment-Free Remission (TFR) stage and those who are treated with half the standard dosage.Percentage of patients with MMR or better at 48, 96, 144 weeks after starting the consolidation period of TFR1 stage Baseline of consolidation period, week 48, 96 and 144 of TFR1 stage The percentage of patients with MMR or better (i.e. BCR-ABL ≤ 0.1% IS) at week 48, 96 and 144 is calculated by dividing the number of patients with MMR at week 48, 96 and 144 of TFR1 stage, regardless of whether they required re-initiation of treatment after the start the study, by the number of patients who entered the consolidation period of TFR1 stage.
Change in BCR-ABL transcript levels after re-start of nilotinib therapy in patients who failed Treatment Free Remission Phase during TFR1 stage. Restart of nilotinib therapy up to 144 weeks of TFR1 stage Change in BCR-ABL levels (International scale), measured by quantitative Polymerase Chain Reaction (PCR), over time after re-start of nilotinib therapy up to 144 weeks in patient who failed Treatment Free Remission Phase in TFR1 stage.
Change in BCR-ABL transcript levels after discontinuation of nilotinib therapy in TFR1 period in TFR1 stage. Discontinuation of nilotinib therapy in patients in TFR phase up to 144 weeks of TFR1 stage Change in BCR-ABL levels (IS), measured by quantitative PCR, over time after discontinuation of nilotinib therapy in TFR1 period up to 144 weeks of TFR1 stage.
Change in BCR-ABL transcript levels during the consolidation period of TFR1 stage. Baseline of consolidation period up to 48 weeks of TFR1 stage Change in BCR-ABL levels (IS), measured by quantitative PCR, over time during the consolidation period to 48 weeks of TFR1 stage.
Full Treatment-Free Survival (FTFS) in TFR1 stage Baseline of consolidation period up to 144 weeks of TFR1 stage FTFS: time from the start of the consolidation period to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to accelerated phase (AP)/blast crisis (BC), or death due to any cause.
Treatment-Free Remission rate (TFR rate) after the start of consolidation of TFR1 stage Baseline of consolidation, week 96 and week 144 of TFR1 stage TFR rate at weeks 96 and week 144 of TFR1 stage is calculated by dividing the number of patients with no loss of MMR and no reinitiation of nilotinib after drug discontinuation at weeks 96 and week 144 of TFR1 stage by the number of patients who entered the TFR1 period of TFR1 stage.
Treatment-free survival (TFS) in TFS1 stage From the start of the TFR phase up to 144 weeks of TFR1 stage. TFS: time from the start of the TFR1 period in TFR1 stage to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to AP/BC or death due to any cause.
Progression-free survival (PFS) after the start of the consolidation period of TFR1 stage Baseline of consolidation up to 144 weeks of TFR1 stage PFS: time from the start of the consolidation phase of TFR1 stage to progression to AP/BC or death due to any cause, whichever occurs first.
Progression Free Survival (PFS) after the start of TFR1 period of TFR1 stage From the start of the TFR1 period up to week 144 of TFR1 stage. PFS: time from the start of the TFR1 period of TFR1 stage to progression to AP/BC or death due to any cause, whichever occurs first.
Overall Survival (OS) in TFR1 stage Baseline of consolidation up to 144 weeks of TFR1 stage OS: time from start of the study to death due to any cause.
Correlation between clinical and laboratory factors and clinical outcome Baseline of reinduction up to 144 weeks of TFR2 stage Statistical correlation between clinical and laboratory correlates at diagnosis (e.g. Sokal Risk scale, demography, type of BCR-ABL transcript) or during previous treatment (e.g. Early Molecular Response=BCR-ABL transcript measured by quantitative PCR \<10% after 3 months of first-line treatment with nilotinib at the dose of 300 mg BID) and the achievement of Full Treatment Free Remission, no loss of MMR and no reinitiation of nilotinib therapy at 144 weeks of TFR2 stage
Number of patients stratified by risk of cardiovascular disease through the Framingham risk score (TFR1 stage) Baseline of TFR1 stage The Framingham risk score will be assessed at the start of TFR1 stage. The Framingham risk score is an algorithm for estimating the combined risk of fatal and non-fatal cardiovascular disease events. The Framingham risk score was developed from the Framingham heart study, and uses sex, age, total cholesterol, HDL, smoking status, and systolic blood pressure for calculating the risk factor: that correlates into a risk category: low, moderate, moderate - high risk, very high. Minimum value=0, maximum value 100. Higher score means a worse outcome, i.e. a higher risk of cardiovascular diseases.
Number of patients stratified by risk of cardiovascular disease through the Systemic Coronary Risk Evaluation (SCORE) (TFR1 stage) Baseline of TFR1 stage The SCORE will be assessed at the start of TFR1 stage. The SCORE is an algorithm for estimating the 10-year risk of fatal cardiovascular disease. The SCORE was developed for use in Europe, and uses sex, age, smoking status, systolic blood pressure, total cholesterol, and total cholesterol/HDL ratio for calculating the risk factor. The SCORE differentiates between high-risk and low-risk countries in Europe and provides different risk charts for the regions.
Percentage of patients eligible for the TFR2 period among patients entering reinduction with asciminib + nilotinib in TFR2 stage Baseline of TFR2 stage up to week 96 of TFR2 stage Eligibility is defined as sustained DMR, defined as no loss of MR4.0 (BCR-ABL level ≤ 0.01% IS) in any BCR-ABL RQ-PCR assessment. The proportion of eligible patients is calculated by dividing the number of eligible patients by the number of patients who entered reinduction of TFR2 stage.
Number of patients with loss of MMR in TFR2 who regain MMR/DMR by the end of the TFR2 stage Baseline TFR2 phase (week 96 of TFR2 stage) up to week 144 of TFR2 stage The proportion of patients who regain MMR/DMR is calculated by dividing the number of patients in MMR/DMR 48 weeks after the start of TFR2 by the number of patients with loss of MMR in TFR2.
DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS). MMR: BCR-ABL level ≤0.1% IS.Change in BCR-ABL transcript levels during reinduction of TFR2 stage. Baseline of TFR2 stage up to week 96 of TFR2 stage Change in BCR-ABL levels (IS), measured by quantitative Polymerase Chain Reaction (PCR), over time from baseline of TFR2 stage up to 96 weeks of TFR2 stage.
Change in BCR-ABL transcript levels after restart of nilotinib therapy in patients who failed TFR2 period in TFR2 stage. Restart of nilotinib therapy up to week 144 of TFR2 stage Change in BCR-ABL levels (IS), measured by quantitative PCR, over time after restart of nilotinib therapy in patients who failed TFR2 period up to 144 weeks of TFR2 stage.
Change in BCR-ABL transcript levels after restart of nilotinib therapy in patients who were not eligible for entering the TFR2 period in TFR2 stage. Restart of nilotinib therapy up to week 144 of TFR2 stage Change in BCR-ABL levels (IS), measured by quantitative PCR, over time after restart of nilotinib therapy in patients after restart of nilotinib therapy in patients who were not eligible for entering the TFR2 period up to 144 weeks of TFR2 stage
Change in BCR-ABL transcript levels after discontinuation of asciminib + nilotinib therapy in TFR2 stage. Discontinuation of asciminib + nilotinib (week 96 of TFR2 stage) up to week 144 of TFR2 stage Change in BCR-ABL levels (IS), measured by quantitative PCR, over time after after discontinuation of asciminib + nilotinib therapy up to 144 weeks of TFR2 stage
Number of patients stratified by risk of cardiovascular disease through the Framingham risk score (TFR2 stage) Baseline of TFR2 stage The Framingham risk score will be assessed at the start of TFR2 stage. The Framingham risk score is an algorithm for estimating the combined risk of fatal and non-fatal cardiovascular disease events. The Framingham risk score was developed from the Framingham heart study, and uses sex, age, total cholesterol, HDL, smoking status, and systolic blood pressure for calculating the risk factor: that correlates into a risk category: low, moderate, moderate - high risk, very high. Minimum value=0, maximum value 100. Higher score means a worse outcome, i.e. a higher risk of cardiovascular diseases.
Number of patients stratified by risk of cardiovascular disease through the Systemic Coronary Risk Evaluation (SCORE) (TFR2 stage) Baseline of TFR2 stage The SCORE will be assessed at the start of TFR2 stage. The SCORE is an algorithm for estimating the 10-year risk of fatal cardiovascular disease. The SCORE was developed for use in Europe, and uses sex, age, smoking status, systolic blood pressure, total cholesterol, and total cholesterol/HDL ratio for calculating the risk factor. The SCORE differentiates between high-risk and low-risk countries in Europe and provides different risk charts for the regions.
Trial Locations
- Locations (1)
Novartis Investigative Site
🇮🇹Novara, Italy