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
To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP)
Subjects on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks after the last randomized subject received the first dose of treatment (the end of treatment (EOT) will be the same day for all the ongoing subjects). After the last dose received, every subject will be followed up for safety for 30 days.
An interim analysis will 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. At the time of the interim analysis, if excessive toxicity without added benefit is observed in one of the investigational arms, discontinuation of that treatment arm will be considered. The decision to discontinue an investigational arm in the study will be taken based on the risk benefit balance of the two investigational arms, and in context of the other two treatment options available for the patients in the study, namely: continue on imatinib with no potential improvement of efficacy; or switch to nilotonib with a potential to improve efficacy however, with a relatively adverse safety profile as compared to imatinib. If a decision is taken to discontinue asciminib 60 mg + imatinib treatment arm at interim analysis, subjects ongoing on that treatment arm will be provided an opportunity to continue on the study at a lower dose (asciminib 40 mg + imatinib) if the investigator considers that is in the best interest of the patient.
Subjects on the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross-over (CO) to receive the add-on treatment within 4 weeks after week 48 visit. It is planned that these subjects cross-over to receive the asciminib 60 mg combination add-on treatment, as this dose provides higher exposure. Based on the results of the interim analysis or emerging data, cross-over may be changed to the asciminib 40 mg add-on treatment. 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.
18 Years and up
Accepting Healthy Volunteers?
1. Male or female patients ≥ 18 years of age with a confirmed diagnosis of Chronic Myeloid Leukemia in chronic phase (CML-CP).
2. Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 400 mg QD at randomization and had no dose change in the past three months).
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.
3. 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
4. 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
5. 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:
1. Treatment failure according to European Leukemia Network (ELN) criteria 2013 during imatinib treatment.
2. Known second chronic phase of CML after previous progression to Accelerated Phase (AP)/Blast Crisis (BC).
3. Previous treatment with any tyrosine kinese inhibitors (TKIs) other than imatinib.
4. 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
5. 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)
6. 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
7. 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.