Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response.

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). An asciminib single agent arm (80 mg daily) was added after the primary analysis to evaluate if asciminib alone could lead to MR4.5 patients in Imatinib for at least one year who have never achieved deep molecular response (DMR).

The study was 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 in participants with chronic myeloid leukemia in chronic phase (CML-CP) who had been previously treated with imatinib first line therapy for at least one year and had not achieved deep molecular response (DMR). Eligible participants 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). During the trial, there was no switch allowed. It was just at the moment of the randomization that the participants were selected to asciminib add-on arms or nilotinib.

Participants 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 was at the discretion of the investigator and the participant. Apart from a polymerase chain reaction (PCR) result of below MR4.5 at Week 48 visit, there were no other entry criteria for the cross-over part. Participants on nilotinib were not allowed to cross-over to receive the add-on treatment.

Participants on the study continued on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) after the last participant had received the first dose of treatment. After the last dose was received, every participant was followed up for safety for 30 days.

Inclusion Criteria:

• Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-CP.
• 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::ABL1 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 1 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
• Participants 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 kinase inhibitors (TKIs) other than imatinib.

• History or current diagnosis of ECG abnormalities indicating significant risk or safety for participants 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.