A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP
- Conditions
- Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive
- Interventions
- Registration Number
- NCT04971226
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The study is designed to compare the efficacy of asciminib 80 mg QD versus Investigator selected Tyrosine Kinase Inhibitor (TKI) for the treatment of newly diagnosed, previously untreated patients with Ph+ CML-CP. The Investigator selected TKI will be one of the following treatment options for first-line treatment of CML-CP - imatinib 400 mg QD or nilotinib 300 mg BID or dasatinib 100 mg QD or bosutinib 400 mg QD.
This study has three periods: 1. Treatment period for all randomized participants, 2. Optional Treatment-Free Remission (TFR) period only for participants meeting TFR eligibility criteria and 3. Treatment Re-Initiation (TRI) period only for participants who relapsed after TFR attempt.
- Detailed Description
This study is a phase III, multi-center, open-label, randomized study of oral asciminib 80 mg QD versus Investigator selected TKI (imatinib, nilotinib, dasatinib, or bosutinib) in adult patients with newly diagnosed Ph+ CML-CP. All comparator TKIs will be made available, unless not permitted by local regulations or local Health Authority or not approved for the treatment of CML in the country.
Approximately 402 patients will be randomized in a 1:1 ratio to asciminib and Investigator selected TKI to join the treatment period.
Randomization will be stratified based on the following two stratification factors:
* ELTS score (low versus intermediate versus high)
* Pre-randomization selected TKI (imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib)).
Prior to randomization, the Investigator, in consultation with the patient, considering the current treatment paradigm and patient characteristics and comorbidities, will make a selection of preference for imatinib or 2G TKI (nilotinib or dasatinib or bosutinib) if the patient is randomized to the comparator arm. The stratified randomization based on these two stratification factors will help to achieve a balance across the treatment arms for the possible comorbidities and baseline characteristics of patients enrolled in the study.
To further ensure that the distribution of patients, between imatinib and 2G TKIs (nilotinib or dasatinib or bosutinib), in the Investigator selected TKI arm is reflective of the use of these agents in clinical practice, the enrollment into the strata of imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib) based on the pre-randomization selection of TKI will be managed by Interactive Response Technology to be approximately 50% versus 50%.
Treatment arms: The study will have 2 treatment arms:
* Arm 1: asciminib 80 mg QD under fasting conditions
* Arm 2: Investigator selected TKI that will include one of the below treatments:
* Imatinib 400 mg QD administered with food
* Nilotinib 300 mg BID administered under fasting conditions
* Dasatinib 100 mg QD administered with or without meal
* Bosutinib 400 mg QD administered with food.
Apart from the treatment period described above, the present study comprises an optional Treatment-Free Remission (TFR) Period enrolling consenting participants of the treatment period (receiving asciminib or IS-TKI) who will discontinue their randomized treatment if they meet per protocol eligibility criteria. The optional TFR Period will last at least 2 years to assess the feasibility of TFR and TFR outcomes following discontinuation of their randomized treatment (asciminib or IS-TKI).
In addition, during the TFR Period, participants who will lose major molecular response (MMR) must re-initiate treatment and will enter into a Treatment Reinitiation (TRI) Period.
During the treatment period, no crossover of study treatment across arms and no change of study treatment within the Investigator selected TKI will be allowed. For specifically participants who must transition into the TRI Period, at the time of treatment re-initiation: a) participants who were previously treated with asciminib will resume asciminib at the same dose prior to entry into TFR. b) participants who were on IS-TKI may either continue with the same study treatment they were randomized to and at the same dose prior to entry into TFR or may switch to asciminib with a starting dose of 80 mg QD.
Duration of Study treatment: Patients on the study will continue to receive the assigned treatment until the End of Study, premature discontinuation due to treatment failure, disease progression or intolerance, due to Investigator or participant decision. or due to patient going to TFR Period and/or TRI Period.
Duration of study: The End of Study will occur 8 years from the last patient first treatment in the study. Patients who discontinue study treatment prematurely due to any reason, will be followed up for survival and progression (to AP/BC) until the End of Study.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 405
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Asciminib Asciminib Patients will take asciminib 80 mg QD under fasting conditions on ongoing basis; Patients will be randomized 1:1 asciminib versus Investigator selected TKIs Investigator selected TKIs Imatinib Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food Investigator selected TKIs Nilotinib Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food Investigator selected TKIs Bosutinib Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food Investigator selected TKIs Dasatinib Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food
- Primary Outcome Measures
Name Time Method Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Ascimimib vs. Investigator Selected TKI At 48 weeks Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Asciminib (Imatinib Stratum) vs Investigator Selected TKI (Imatinib Stratum) At 48 weeks Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL1/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
- Secondary Outcome Measures
Name Time Method Major Molecular Response at Week 96 at 96 weeks (96 weeks after last patient first dose) Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
Time to Discontinuation of Study Treatment Due to Adverse Events (TTDAE) 96 weeks after last patient first dose TTDAE is defined as the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to Adverse Event (AE). For patients ongoing without study treatment discontinuation, on or prior to the analysis cut-off date, the time will be censored at the at the analysis cut-off date.
Major Molecular Response at Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
Major Molecular Response by Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
MR4.0 at Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.0 is defined as a ratio BCR-ABL/ABL ≤0.01% on the international scale (ie, at least 4 log reduction from a standardized baseline value).
MR4.5 at All Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.5 is defined as a ratio BCR-ABL/ABL ≤0.0032% on the international scale (ie, at least 4.5 log reduction from a standardized baseline value).
MR4.0 by Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.0 is defined as a ratio BCR-ABL/ABL ≤0.01% on the international scale (ie, at least 4 log reduction from a standardized baseline value).
MR4.5 by All Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.5 is defined as a ratio BCR-ABL/ABL ≤0.0032% on the international scale (ie, at least 4.5 log reduction from a standardized baseline value).
Complete Hematological Response (CHR) at All Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Hematologic response will be assessed by CBC and physical examination at each visit.
Complete Hematological Response (CHR) will be defined as all of the following present for ≥ 4 weeks:
white blood cell(s) (WBC) count \< 10 x 10\^9/L PLT count \< 450 x 10\^9/L Basophils \< 5% No blasts and promyelocytes in peripheral blood Myelocytes + metamyelocytes \< 5% in peripheral blood No evidence of extramedullary disease, including spleen and liverComplete Hematological Response (CHR) by All Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Hematologic response will be assessed by CBC and physical examination at each visit.
Complete Hematological Response (CHR) will be defined as all of the following present for ≥ 4 weeks:
white blood cell(s) (WBC) count \< 10 x 10\^9/L PLT count \< 450 x 10\^9/L Basophils \< 5% No blasts and promyelocytes in peripheral blood Myelocytes + metamyelocytes \< 5% in peripheral blood No evidence of extramedullary disease, including spleen and liverPercentage of Participants With Complete Cytogenic Response (CCyR) by Week 48 & Week 96 By week 48 and by week 96 (48 weeks and 96 weeks after last patient first dose); data collection/analysis is ongoing for the 96 week time point, and the data will be reported later The CCyR response status was to be based on bone marrow assessment. Bone marrow examination for cytogenetic assessment was to be performed locally by the Investigator at baseline for all participants. Thereafter, during the course of the study, cytogenetic assessment was not mandatory and only performed if clinically indicated.
Duration of MR4.0 Planned total follow-up duration of 5 years Duration of MR4.0 is defined as the time between the date of the first documented achievement of MR4.0 and the earliest date of loss of MR4.0, treatment failure, progression to Accelerated Phase/Blast Crisis, or CML-related death
Duration of MR4.5 Planned total follow-up duration of 5 years Duration of MR4.5 is defined as the time between the date of the first documented achievement of MR4.5 and the earliest date of loss of MR4.5, treatment failure, progression to Accelerated Phase/Blast Crisis, or CML-related death
Time to First MMR Planned total follow-up duration of 5 years Time to first MMR is defined as the time from the date of randomization to the date of the first documented occurrence of MMR. Time will be censored at the last molecular assessment date while on treatment, or the End Of Treatment (whichever comes first) for patients who have not experienced MMR.
Time to First MR4.0 Planned total follow-up duration of 5 years Time to first MR4.0 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.0. Time will be censored at the last molecular assessment date while on treatment, or the End Of Treatment (whichever comes first) for patients who have not experienced MR4.0.
Time to First MR4.5 Planned total follow-up duration of 5 years Time to first MR4.5 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.5. Time will be censored at the last molecular assessment date while on treatment, or the End Of Treatment (whichever comes first) for patients who have not experienced MR4.5.
BCR-ABL1≤1% at Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.
BCR-ABL1≤1% by Scheduled Data Collection Time Points Planned total follow-up duration of 5 years Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.
Time to Treatment Failure (TTF) Planned total follow-up duration of 5 years TTF is defined as the time from date of randomization to the first/earliest documented date of any of the following events: treatment failure as per ELN, Confirmed loss of MMR while on study treatment, discontinuation from study treatment due to any reason
For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the last study assessment date while on treatment, or the EOT (whichever comes first) .Failure Free Survival (FFS) Planned total follow-up duration of 5 years FFS is defined as the time from the date of randomization to the earliest occurrence of the following events: treatment failure per ELN, confirmed loss of MMR, progression to AP/BC, death from any cause.
For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last study treatment assessment or last post-treatment follow-up.Event Free Survival (EFS) Planned total follow-up duration of 5 years EFS is defined as the time from the date of randomization to the earliest occurrence of the following events: treatment failure as per ELN, confirmed loss of MMR ,discontinuation of study treatment due to AE, progression to AP/BC, death from any cause.
For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last study treatment assessment or last post-treatment follow-up.Progression Free Survival (PFS) Planned total follow-up duration of 5 years PFS is defined as the time from the date of randomization to the earliest occurrence of progression to AP/BC or death from any cause.
For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last study treatment assessment or last post-treatment follow-up.Overall Survival (OS) Planned total follow-up duration of 5 years OS is defined as the time from the date of randomization to the date of death from any cause. For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last contact before the cut-off date.
Pharmacokinetics (PK) of Asciminib: Cmax Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose) Cmax is the maximum serum concentration of asciminib during a dosing interval (mass x volume-1).
PK of Asciminib: Tmax Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose) Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (time)
PK of Asciminib: AUCtau and AUClast Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose) AUCtau is the area under the plasma concentration-time curve over the dosing interval. AUClast is the area under the plasma concentration-time curve from time zero (time of dose administration) to time of last measurable concentration (mass x time x volume-1)
PK of Asciminib: CL/F Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose) CL/F is the apparent total body clearance of asciminib from plasma after oral administration (volume x time-1).
Change From Baseline in Overall Scores (Global Health Status) and Individual Scales of the EORTC QLQ-C30 at Week 48 and Week 96 Baseline, week 48 and week 96 The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assesses the quality of life of cancer patients. It consists of functioning scales, symptom scales, and the global health status quality of life (QoL) scale.
A high score for functional and QoL items/scales from the QLQ-30 represents better function and QOL. A high score in symptoms items from QLQ-30 represents worse symptoms.Duration of MMR Planned total follow-up duration of 5 years Duration of MMR is defined as the time between the date of the first documented achievement of MMR and the earliest date of loss of MMR, treatment failure, progression to Accelerated Phase/Blast Crisis, or CML-related death
Trough Plasma Concentrations. Week 48 Trough plasma concentration will measure the concentration of asciminib in the blood immediately before the next dose is administered.
Change From Baseline in EORTC QLQ-CML24 Scales at Week 48 and Week 96 Baseline, week 48 and week 96. The QLQ-CML24 consists of multi-scale items: symptom burden, impact on worry/mood, impact on daily life, body image problems, satisfaction with care and information and satisfaction with social life.
A higher score on most of the item scales in QLQ-CML24 reflects a larger impairment in the corresponding domain, with the exception of the satisfaction with care and information, and problems and satisfaction with social life, where a higher score reflects a higher level of satisfaction.
Trial Locations
- Locations (13)
Rocky Mountain Cancer Centers
🇺🇸Denver, Colorado, United States
Florida Cancer Specialists
🇺🇸Fort Myers, Florida, United States
Florida Cancer Specialists Pan
🇺🇸Tallahassee, Florida, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Uni of Massachusetts Medical Center
🇺🇸Worcester, Massachusetts, United States
Wake Forest University Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Williamette Cancer Center
🇺🇸Eugene, Oregon, United States
Oregon Health Sciences University
🇺🇸Portland, Oregon, United States
Avera Cancer
🇺🇸Sioux Falls, South Dakota, United States
Chattanooga Onc And Hem Assoc PC
🇺🇸Chattanooga, Tennessee, United States
Scroll for more (3 remaining)Rocky Mountain Cancer Centers🇺🇸Denver, Colorado, United States