Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Study Overview
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Brief Summary
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To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib versus asciminib 80mg in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP)

Detailed Description
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The study is a Phase 2, multi-center, open-label, randomized study of asciminib in two different doses (40 mg or 60 mg) in combination with imatinib 400 mg versus continued imatinib versus switch to nilotinib, versus asciminib 80mg single agent in subjects with chronic myeloid leukemia in chronic phase (CML-CP) who have been previously treated with imatinib first line therapy for at least one year and have not achieved deep molecular response (DMR). Eighty-four eligible subjects were randomized 1:1:1:1 to receive asciminib 60 mg once daily (QD) as add-on therapy to imatinib 400 mg QD, or 40 mg QD as add-on therapy to imatinib 400 mg QD, or to continue imatinib 400 mg QD, or to switch to nilotinib 300 mg twice a day (BID). The asciminib single agent cohort will be conducted as an open label cohort. Approximately 20 eligible subjects will be enrolled to receive asciminib 80 mg QD. Amendment 3 aims to add the asciminib single agent cohort to assess whether asciminib single agent at the recommended dose of 80mg QD leads to similar efficacy and safety as observed in the add-on arms of asciminib and imatinib. This additional cohort will help to evaluate if the combination of asciminib with imatinib is needed to increase the likelihood of achieving DMR, or if this can be achieved by asciminib alone. An interim analysis was performed to gain an early insight into the safety and efficacy of the asciminib add-on combination. The interim analysis was planned to be performed when at least 40 (50%) patients have been randomized and have been followed for their 24 weeks visit assessment or have discontinued treatment. The interim analysis cut-off was on 22-July-2020. No change in study conduct were performed based on the benefit/risk balance. The primary analysis cut-off was on 10-Jan-2022. Eighty-four patients have been randomized in the study. Subjects on the imatinib continuation arm who had not achieved MR4.5 at 48 weeks were allowed to cross-over (CO) to receive the add-on treatment within 4 weeks after week 48 visit. to receive the asciminib 60 mg combination add-on treatment, as this dose provided higher exposure. The cross-over is at the discretion of the investigator and the patient. Apart from a polymerase chain reaction (PCR) result of below MR4.5 at Week 48 visit, there are no other entry criteria for the cross-over part. Subjects on nilotinib are not allowed to cross- over to receive the add-on treatment. Subjects on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) / or 48 weeks (in asciminib single agent cohort) after the last randomized subject received the first dose of treatment. After the last dose received, every subject will be followed up for safety for 30 days.

Official Title
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A Phase 2, Multi-center, Open-label, Randomized Study of Oral Asciminib Added to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients With CML-CP Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response

Conditions
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CML, Chronic Myelogenous Leukemia, Leukemia, Myeloid Chronic, Hematologic Diseases

Intervention / Treatment
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* Drug: Asciminib add-on
* Drug: Imatinib
* Drug: Nilotinib
* Drug: Asciminib single agent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18 years of age with a confirmed diagnosis of Chronic Myeloid Leukemia in chronic phase (CML-CP). Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 300mg or 400 mg QD at randomization For Korea only: (i)a minimum of one year (12 calendar months) of prior treatment with imatinib for patients with BCR-ABL levels > 0.1%, ≤ 1% IS at the time of randomization. (ii) a minimum of two years (24 calendar months) of prior treatment with imatinib for patients with BCR-ABL levels > 0.01%, ≤ 0.1% IS at the time of randomization. BCR-ABL1 levels > 0.01% IS (International Scale) and ≤ 1% IS at the time of randomization as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MR4 IS) confirmed by 2 consecutive tests at any time during prior imatinib treatment. An isolated, single test result with BCR-ABL1 levels < 0.01 % (MR4 IS) is allowed, however, it should not have been observed within the 9 months prior to randomization Patient must meet the following laboratory values before randomization: Absolute Neutrophil Count ≥ 1.5 x 10E9/L Platelets ≥ 75 x 10E9/L Hemoglobin ≥ 9 g/dL Serum creatinine < 1.5 mg/dL Total bilirubin ≤ 1.5 x ULN (Upper Limit of Normal) except for patients with Gilbert's syndrome who may only be included with total bilirubin ≤ 3.0 x ULN Aspartate transaminase (AST) ≤ 3.0 x ULN Alanine transaminase (ALT) ≤ 3.0 x ULN Alkaline phosphatase ≤ 2.5 x ULN Serum lipase ≤ 1.5 x ULN Patients must have the following laboratory values ≥ Lower Limit of Normal or corrected to within normal limits with supplements prior to randomization: potassium increase of up to 6.0 mmol/L is acceptable if associated with creatinine clearance within normal limits ; calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with creatinine clearance* within normal limits) ; magnesium increase up to 3.0 mg/dL or 1.23 mmol/L if associated with creatinine clearance within normal limits. Key Exclusion Criteria: Treatment failure according to European Leukemia Network (ELN) criteria 2013 during imatinib treatment. Known second chronic phase of CML after previous progression to Accelerated Phase (AP)/Blast Crisis (BC). Previous treatment with any tyrosine kinese inhibitors (TKIs) other than imatinib. History or current diagnosis of ECG abnormalities indicating significant risk or safety for subjects participating in the study such as: History of myocardial infarction, angina pectoris, coronary artery bypass graft within 6 months prior to randomization Concomitant clinically significant arrhythmias Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization 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 Concomitant medications with a known risk of Torsades de Pointes 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 clinically significant hyperlipidemia and high serum amylase) History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis; on-going acute liver disease or history of chronic liver disease History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively. Other protocol defined inclusion/exclusion may 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
Interventional Model Description: Treatment arms 1 - 4 randomized; New Treatment arm 5 (asciminib single agent cohort) not randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asciminib 60mg QD + Imatinib 400mg QD<br>Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily | Drug: Asciminib add-on<br>* Asciminib 60 mg or 40 mg taken orally once daily.<br>* Other names: ABL001 (asciminib);Drug: Imatinib<br>* Imatinib 400 mg taken orally once daily<br>* Other names: STI571;|
| Experimental: Asciminib 40mg QD + Imatinib 400mg QD<br>Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily | Drug: Asciminib add-on<br>* Asciminib 60 mg or 40 mg taken orally once daily.<br>* Other names: ABL001 (asciminib);Drug: Imatinib<br>* Imatinib 400 mg taken orally once daily<br>* Other names: STI571;|
| Active Comparator: Imatinib 400mg QD<br>Imatinib 400 mg taken once daily | Drug: Imatinib<br>* Imatinib 400 mg taken orally once daily<br>* Other names: STI571;|
| Active Comparator: Nilotinib 300mg BID<br>Nilotinib 300 mg taken twice daily | Drug: Nilotinib<br>* Nilotinib 300 mg taken orally twice daily (total daily dose of 600 mg)<br>* Other names: AMN107;|
| Experimental: Asciminib 80mg QD<br>Asciminib 80 mg taken once daily | Drug: Asciminib single agent<br>* Asciminib 80 mg taken orally once daily<br>* Other names: ABL001 (asciminib);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular Response (MR)^4.5 rate between asciminib+imatinib and imatinib alone | Percentage of subjects still treated with the randomized treatment at 48 weeks and are in MR4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all subjects randomized to the respective treatment arm. | at 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MR^4.5 rate at 48 weeks | Percentage of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib | at 48 weeks | 
| Difference in rate of MR^4.5 at 48 weeks | Difference in the percentage of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib | at 48 weeks | 
| Rate of MR^4.5 at 96 weeks | Percentage of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks | at 96 weeks | 
| Rate of MR^4.5 by 48 and 96 weeks | Best observed rate of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) under randomized treatment up to the specific time point | by 48 weeks and 96 weeks | 
| Sustained MR^4.5 from 48 weeks until 96 weeks | Percentage of participants who are in MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks and who have no loss of MR^4.5. | at 96 weeks | 
| Time to MR^4.5 | Time to MR^4.5 is the time from randomization to first MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) computed only for subjects who achieved MR^4.5 | up to 96 weeks | 
| Duration of MR^4.5 | Time from first MR^4.5 until loss of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%). | end of treatment | 
| Incidence and severity of adverse events, changes in laboratory values, clinically notable ECG abnormalities and vital signs | To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib vs continued imatinib or switch to nilotinib or asciminib 80mg QD | end of study | 
| Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmax | The maximum (peak) observed drug concentration after dose administration | up to 96 weeks | 
| Pharmacokinetic profile of asciminib and imatinib when administered in combination - Tmax | The time to reach maximum (peak) drug concentration after dose administration | up to 96 weeks | 
| Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmin | Minimum drug concentration | up to 96 weeks | 
| Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUClast | The AUC from time zero to the last measurable concentration sampling time (Tlast) | up to 96 weeks | 
| Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUCtau | The AUC calculated to the end of a dosing interval (tau) at steady-state | up to 96 weeks | 
| MR^4.5 rate at 48 weeks | The percentage of subjects on asciminib 80mg QD with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks | at 48 weeks | 
| Time to MR^4.5 | For subjects on asciminib 80mg QD: Time to MR^4.5 is the time from randomization to first MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) computed only for subjects who achieved MR^4.5 | up to 48 weeks | 
| Duration of MR^4.5 | Time from first MR^4.5 until loss of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) for subjects on asciminib 80mg QD | end of treatment | 
| Pharmacokinetic profile of asciminib 80mg QD - Cmax | The maximum (peak) observed drug concentration after dose administration | up to 48 weeks | 
| Pharmacokinetic profile of asciminib 80mg QD - Tmax | The time to reach maximum (peak) drug concentration after dose administration | up to 48 weeks | 
| Pharmacokinetic profile of asciminib 80mg QD - Cmin | Minimum drug concentration | up to 48 weeks | 
| Pharmacokinetic profile of asciminib 80mg QD - AUClast | The AUC from time zero to the last measurable concentration sampling time (Tlast) | up to 48 weeks | 
| Pharmacokinetic profile of asciminib 80mg QD - AUCtau | The AUC calculated to the end of a dosing interval (tau) at steady-state | up to 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, Chronic Myelogenous Leukemia, leukemia, myeloid chronic, Hematologic Diseases, Asciminib, ABL001, Imatinib, Nilotinib, deep molecular response, DMR, Ph+ CML, chronic phase, cancer of the white blood cells, tyrosine kinase inhibitor, leukemia, myeloid, leukemia, CML without Ph+