The purpose of the study is to optimize the treatment of asciminib in patients with chronic myelogenous leukemia in chronic phase (CML-CP) previously treated with 2 or more Tyrosine Kinase Inhibitors (TKIs).
This study consists of a screening period of up to 28 days, a treatment period of 144 weeks and a post-treatment safety follow-up period of 4 weeks. Patients will receive asciminib as study treatment continuously for up to 144 weeks or until disease progression, treatment failure or intolerance to treatment. At treatment initiation, asciminib will be provided to all trial patients at a total daily dose of 80 mg. All patients will be randomly assigned 1:1 to 2 groups with 80 mg given either as 40 mg b.i.d. or 80 mg q.d., using IRT to avoid any selection bias. In patients not achieving Major Molecular Responses (MMR) at 48 weeks or losing the response after the week 48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator's opinion the patient may benefit from the escalation. In addition, there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and unresponsive to optimal management. The trial will enroll a total of approximately 186 patients: * 156 patients with CML-CP not in MMR at baseline who were treated with two or more TKIs and who were either resistant (ELN 2020 warning or failure) or intolerant to the last treatment will be enrolled. For this population, the primary endpoint for MMR at 48 weeks will be assessed. * Up to 30 additional patients intolerant only to their last TKI treatment and in MMR at baseline will also be enrolled. This patient population will not be part of primary endpoint analysis; however, all assessments will be done as with the 156 patients from the population of the primary endpoint analysis.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
199
One tablet of 40 mg will be taken orally twice a day (BID)
Two tablets of 40 mg will be taken orally once a day (QD)
Five tablets of 40 mg will be taken orally once a day (QD)
Major Molecular Response (MMR) Rate at Week 48 for All Patients With no Evidence of MMR at Baseline
Major Molecular Response (MMR) is defined as a significant reduction in the level of BCR::ABL1 transcripts, which are the genetic markers of chronic myeloid leukemia (CML). Specifically, MMR is achieved when there is a ≥ 3.0 log reduction in BCR::ABL1 transcripts compared to a standardized baseline, which corresponds to a BCR::ABL1/ABL1 ratio of ≤ 0.1% on the international scale (IS). The Major Molecular Response (MMR) rate at Week 48 for all patients with no evidence of MMR at baseline refers to the percentage of patients who achieve MMR after 48 weeks of treatment, despite not having MMR at the start.
Time frame: Week 48
MMR Rate at Week 12, 24, 36, 72, 96 and 144 for Patients With no MMR at Baseline
The Major Molecular Response (MMR) rate at alternative time points (weeks 12, 24, 36, 72, 96 and 144) for all patients with no evidence of MMR at baseline refers to the percentage of patients who achieve MMR after those respective weeks of treatment, despite not having MMR at the start. MMR itself is defined as achieving a BCR::ABL1 ratio of ≤ 0.1%.
Time frame: Week 12, 24, 36, 72, 96 and 144
Major Molecular Response (MMR) Rate at Week 48 for Patients With MMR at Baseline
The Major Molecular Response (MMR) rate at Week 48 for patients with MMR at baseline refers to the percentage of patients who maintain or achieve MMR after 48 weeks of treatment. MMR itself is defined as achieving a BCR::ABL1 ratio of ≤ 0.1%.
Time frame: Week 48.
Time to MMR for Subjects Without MMR at Baseline
Time to MMR defined as the time from the date of randomization to the date of the first documented MMR. MMR itself is defined as achieving a BCR::ABL1 ratio of ≤ 0.1%.
Time frame: From the date of enrollment to the date of first documented MMR, assessed up to 144 weeks
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Novartis Investigative Site
CABA, Buenos Aires, Argentina
Novartis Investigative Site
Buenos Aires, Argentina
Novartis Investigative Site
Graz, Austria
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Linz, Austria
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Vienna, Austria
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Rio de Janeiro, Rio de Janeiro, Brazil
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São Paulo, Brazil
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Vancouver, British Columbia, Canada
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Toronto, Ontario, Canada
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Bordeaux, France
...and 38 more locations
Rate of BCR::ABL1 ≤ 10% for Subjects Without MMR at Baseline
The rate of BCR::ABL1 ≤ 10% refers to the percentage of patients who achieve a BCR::ABL1 level of 10% or lower within the first 48 weeks of treatment.
Time frame: Week 12, 24, 36 and 48
Rate of BCR::ABL1 ≤ 1% for Subjects Without MMR at Baseline
The rate of BCR::ABL1 ≤ 1% refers to the percentage of patients who achieve a BCR::ABL1 level of 1% or lower within the first 48 weeks of treatment.
Time frame: Week 12, 24, 36 and 48.
Deep Molecular Responses (MR4) Rate for Subjects Without MMR at Baseline
Deep molecular responses (MR4) is defined as a ≥ 4 log reduction in BCR::ABL1 transcripts compared to the standardized baseline, equivalent to 0.01% BCR::ABL1/ABL1 by the international scale (IS).
Time frame: Week 12, 24, 36, 48, 72, 96 and 144.
Deep Molecular Responses (MR4.5) Rate for Subjects Without MMR at Baseline
Deep molecular responses (MR4.5) is defined as a ≥ 4.5 log reduction in BCR::ABL1 transcripts compared to the standardized baseline, equivalent to 0.0032% BCR::ABL1/ABL1 by the international scale (IS).
Time frame: Week 12, 24, 36, 48, 72, 96 and 144.
Rate of Complete Cytogenetic Response (CCyR) for Subjects Without MMR at Baseline
Cytogenetic Response is assessed based on the percentage of Philadelphia chromosome-positive (Ph+) metaphases in the bone marrow, with a review of at least 20 metaphases required. Complete Cytogenetic Response (CCyR) is defined as 0% Ph+ metaphases in the bone marrow.
Time frame: Week 48 and end of treatment (up to 144 weeks)
Occurrence of High-risk Additional Chromosomal Abnormalities (ACA) for Subjects Without MMR at Baseline
High-risk additional chromosomal abnormalities (ACAs) are specific chromosomal abnormalities that are considered to increase the risk in Philadelphia chromosome-positive (Ph+) cells.
Time frame: Up to 144 weeks
Cumulative Molecular Response Rate of BCR::ABL1 ≤ 10% for Subjects Without MMR at Baseline
The cumulative molecular response rate refers to the proportion of subjects achieving a BCR::ABL1 level of ≤ 10% on the international scale (IS) over a specified period.
Time frame: From enrollment to end of treatment up to 144 weeks.
Cumulative Molecular Response Rate of BCR::ABL1 ≤1% for Subjects Without MMR at Baseline
The cumulative molecular response rate refers to the proportion of subjects achieving a BCR::ABL1 level of ≤ 1% on the international scale (IS) over a specified period.
Time frame: From enrollment to end of treatment up to 144 weeks.
Cumulative Molecular Response Rate of MMR for Subjects Without MMR at Baseline
The cumulative molecular response rate refers to the proportion of subjects achieving MMR, defined as a BCR::ABL1 ratio of ≤ 0.1% on the international scale (IS), over a specified period.
Time frame: From enrollment to end of treatment up to 144 weeks.
Cumulative Molecular Response Rate of MR4 for Subjects Without MMR at Baseline
The cumulative molecular response rate refers to the proportion of subjects achieving MR4, defined as a ≥ 4 log reduction in BCR::ABL1 transcripts compared to the standardized baseline, equivalent to 0.01% BCR::ABL1/ABL1 by the international scale (IS), over a specified period.
Time frame: From enrollment to end of treatment up to 144 weeks.
Cumulative Molecular Response Rate of MR4.5 for Subjects Without MMR at Baseline
The cumulative molecular response rate refers to the proportion of subjects achieving MR4.5, defined as a ≥ 4.5 log reduction in BCR::ABL1 transcripts compared to the standardized baseline, equivalent to 0.0032% BCR::ABL1/ABL1 by the international scale (IS), over a specified period.
Time frame: From enrollment to end of treatment up to 144 weeks.
Duration of MMR
Duration of MMR is defined as the time from the date of first documented MMR to the earliest date of loss of MMR, progression to accelerated phase (AP) or blast crisis (BC), or CML-related death. The duration of MMR is analyzed for the subjects in FAS who achieved MMR at any time.
Time frame: From the date of the first documented molecular response at MMR level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to 144 weeks.
Duration of MR4 Without Loss of MMR
Duration of MR4 without loss of MMR refers to the period during which a patient maintains a deep molecular response (MR4) without experiencing a loss of Major Molecular Response (MMR).
Time frame: From the date of first documented MR4 without loss of MMR to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to 144 weeks.
Progression-Free Survival (PFS) for Subjects Without MMR at Baseline
Progression-Free Survival (PFS) is defined as the time from the date of randomization to the earliest occurrence of documented disease progression to AP/BC or the date of death from any cause, assessed up to approximately 144 weeks. The time will be censored at the date of last study assessment (PCR, cytogenetic, hematologic or extramedullary) or last post-treatment follow-up for subjects without event. PFS (in months) is calculated as: (date of disease progression/death or censoring date - date of randomization +1)/30.4375.
Time frame: Up to 144 weeks.
Overall Survival (OS) for Subjects Without MMR at Baseline
Overall Survival (OS) is defined as the time from treatment assignment to death due to any cause during study, assessed up to 144 weeks. Subjects who are alive at the time of the analysis data cutoff date will be censored at the date of last contact before the cut-off date. OS (in months) is calculated as: (date of death or censoring date - date of randomization + 1)/30.4375.
Time frame: Up to 144 weeks.
Time to Treatment Failure (TTF) for Subjects Without MMR at Baseline
Time from treatment assignment to treatment failure is defined as BCR-ABL1\>10%, assessed up to 144 weeks. For subjects who have not reached treatment failure, their TTFs will be censored at the time of last study assessment (PCR, cytogenetic, hematologic or extramedullary) before the cut-off date. TTF (in months) is calculated as: (date of treatment failure or censoring date - date of randomization + 1)/30.4375.
Time frame: Up to 144 weeks.
Change in Symptom Burden and Interference From Baseline Over Time According to the MDASI-CML PRO Instrument
The MD Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) is a 26 item self-administered questionnaire for adult CML patients. Twenty of the items measure the severity of disease-related symptoms (symptom burden) and are scored from 0 (not present) to 10 (as bad as you can imagine) and 6 items that measure symptom interference with daily life (interference) scored from 0 (did not interfere) to 10 (interfered completely). For symptom burden, total scores range from 0 to 200 and for interference range from 0 to 60, with higher scores indicates high impact on severity of chronic myeloid leukemia-related symptoms and on impact of these symptoms on daily functioning for the patient.
Time frame: Week 4, 12, 24, 48, 72, 96, 120 and at end of treatment (up to 144 weeks).