A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP

Study Overview
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Brief Summary
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The study is designed to compare the efficacy of asciminib 80 mg QD versus Investigator selected 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.

Detailed Description
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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. The study is designed to compare the efficacy of asciminib 80 mg QD with Investigator selected TKI for the treatment of newly diagnosed, previously untreated patients with Ph+ CML-CP. The Investigator selected TKI will be one of the treatment options approved by major Health Authorities 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. Approximately 402 patients will be randomized in a 1:1 ratio to asciminib and Investigator selected TKI. 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. 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. No crossover of study treatment across arms and no change of study treatment within the Investigator selected TKI will be allowed. Duration of Study treatment: Patients on the study will continue to receive the assigned treatment until the End of Study, or until premature discontinuation due to treatment failure, disease progression or intolerance or due to Investigator or participant decision. Duration of study: The End of Study will occur 5 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.

Official Title
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A Phase III, Multi-center, Open-label, Randomized Study of Oral Asciminib Versus Investigator Selected TKI in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase

Conditions
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Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive

Intervention / Treatment
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* Drug: Imatinib
* Drug: Nilotinib
* Drug: Bosutinib
* Drug: Dasatinib
* Drug: Asciminib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants eligible for inclusion in this study must meet all of the following criteria: Male or female patients ≥ 18 years of age. Participants with CML-CP within 3 months of diagnosis. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of Philadelphia chromosome Documented chronic phase CML will meet all the below criteria (Hochhaus et al 2020): < 15% blasts in peripheral blood and bone marrow, < 30% blasts plus promyelocytes in peripheral blood and bone marrow, < 20% basophils in the peripheral blood, Platelet count ≥ 100 x 109/L (≥ 100,000/mm3), No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0,or 1. 5. Adequate end organ function as defined by: Total bilirubin < 3 x ULN; patients with Gilbert's syndrome may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN Creatinine clearance (CrCl) ≥ 30 mL/min as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis 6. Participants must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization: Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min) Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min) Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min) For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be ≥ LLN or corrected to within normal limits with supplements prior to randomization. *CrCl as calculated using Cockcroft-Gault formula 7. Ability to provide written informed consent prior to any study related screening procedures being performed. 8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening which is amenable to standardized Real time quantitative polymerase chain reaction (RQ-PCR) quantification. Exclusion Criteria: Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide. Treatment with either imatinib, or nilotinib, or dasatinib or bosutinib for ≤2 weeks is allowed, but no other treatment with other tyrosine kinase inhibitors prior to randomization is permitted. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required). Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following: History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) QTc ≥ 450 ms (male patients), ≥460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia Concomitant medication(s) with a Known risk of Torsades de Pointes per www.crediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.•Inability to determine the QTcF interval Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia). Please refer to Section 6.3.1 History of significant congenital or acquired bleeding disorder unrelated to cancer. Major surgery within 4 weeks prior to study entry or who have not recovered from prior surgery. History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis. History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease. Other protocol-defined Inclusion/exclusion criteria will apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asciminib<br>Patients will take asciminib 80 mg QD under fasting conditions on ongoing basis; Patients will be randomized 1:1 asciminib versus Investigator selected TKIs | Drug: Asciminib<br>* Comes in 40 mg tablets and taken orally<br>* Other names: ABL001;|
| Active Comparator: Investigator selected TKIs<br>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 | Drug: Imatinib<br>* Comes in 100 mg and 400 mg tablets and taken orally<br>* Other names: STI571;Drug: Nilotinib<br>* Comes in 150 mg capsules and taken orally<br>* Other names: AMN107;Drug: Bosutinib<br>* Comes in 100 mg and 400 mg tablets and taken orally<br>Drug: Dasatinib<br>* Comes in 70 mg and 100 mg tablets and taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Molecular Response (MMR) at week 48 | 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). | at 48 weeks (48 weeks after last patient first dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Molecular response at week 96 | 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). | at 96 weeks (96 weeks after last patient first dose) | 
| Time to discontinuation of study treatment due to Adverse Events (TTDAE) | 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. | 96 weeks after last patient first dose | 
| Major Molecular response at scheduled data collection time points | 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). | Planned total follow-up duration of 5 years | 
| Major Molecular response by scheduled data collection time points | 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). | Planned total follow-up duration of 5 years | 
| MR4.0 at scheduled data collection time points | 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). | Planned total follow-up duration of 5 years | 
| MR4.5 at all scheduled data collection time points | 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). | Planned total follow-up duration of 5 years | 
| MR4.0 by scheduled data collection time points | 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). | Planned total follow-up duration of 5 years | 
| MR4.5 by all scheduled data collection time points | 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). | Planned total follow-up duration of 5 years | 
| Complete Hematological response (CHR) at all scheduled data collection time points | 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 liver | Planned total follow-up duration of 5 years | 
| Complete Hematological response (CHR) by all scheduled data collection time points | 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 liver | Planned total follow-up duration of 5 years | 
| Complete Cytogenic response (CCyR) at Week 48 & Week 96 | The CCyR response status will be based on bone marrow assessment, in any patients who have this done due to a clinical indication | at 48 weeks and at 96 weeks (48 weeks and 96 weeks after last patient first dose) | 
| Complete Cytogenic response (CCyR) by Week 48 & Week 96 | The CCyR response status will be based on bone marrow assessment, in any patients who have this done due to a clinical indication | at 48 weeks and at 96 weeks (48 weeks and 96 weeks after last patient first dose) | 
| Duration of MMR | 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 | Planned total follow-up duration of 5 years | 
| Duration of MR4.0 | 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 | Planned total follow-up duration of 5 years | 
| Duration of MR4.5 | 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 | Planned total follow-up duration of 5 years | 
| Time to first MMR | 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. | Planned total follow-up duration of 5 years | 
| Time to first MR4.0 | 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. | Planned total follow-up duration of 5 years | 
| Time to first MR4.5 | 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. | Planned total follow-up duration of 5 years | 
| BCR-ABL1≤1% at scheduled data collection time points | Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. | Planned total follow-up duration of 5 years | 
| BCR-ABL1≤1% by scheduled data collection time points | Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. | Planned total follow-up duration of 5 years | 
| Time to treatment failure (TTF) | 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) . | Planned total follow-up duration of 5 years | 
| Failure Free Survival (FFS) | 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. | Planned total follow-up duration of 5 years | 
| Event Free Survival (EFS) | 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. | Planned total follow-up duration of 5 years | 
| Progression Free Survival (PFS) | 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. | Planned total follow-up duration of 5 years | 
| Overall Survival (OS) | 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. | Planned total follow-up duration of 5 years | 
| Trough plasma concentrations. | Trough plasma concentration will measure the concentration of asciminib in the blood immediately before the next dose is administered. | 48 weeks after last patient first dose | 
| Pharmacokinetics (PK) of Asciminib: Cmax | Cmax is the maximum serum concentration of asciminib during a dosing interval (mass x volume-1). | 48 weeks after last patient first dose | 
| PK of Asciminib: Tmax | Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (time) | 48 weeks after last patient first dose | 
| PK of Asciminib: AUCtau and AUClast | 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) | 48 weeks after last patient first dose | 
| PK of Asciminib: CL/F | CL/F is the apparent total body clearance of asciminib from plasma after oral administration (volume x time-1). | 48 weeks after last patient first dose | 
| Change from baseline in overall scores and individual scales of the EORTC QLQ-C30 | The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) consists of functioning scales, symptoms' scales, single-item 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. | baseline, 48 weeks after last patient first dose, 96 weeks after last patient first dose | 
| Change from baseline in overall scores and individual scales of the EORTC QLQ-CML24 | The QLQ-CML24 consists of (i) 22 multi-scale items: impact on daily life, symptom burden, impact on worry/mood, satisfaction with care and information, (ii) 2 single items: body image problems, 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. | baseline, 48 weeks after last patient first dose, 96 weeks after last patient first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asciminib, Chronic Myeloid Leukemia, CML, Philadelphia Chromosome, TKIs, Bosutinib, Dasatinib, Nilotinib, Imatinib