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

Novartis

Status and phase: Active, not recruiting; Phase 2

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

Treatments: Drug: Asciminib add-on; Drug: Nilotinib; Drug: Imatinib; Drug: Asciminib single agent

Study type: Interventional

Funder types: Industry

Identifiers

NCT03578367

CABL001E2201

2018-001594-24 (EudraCT Number)

Details and patient eligibility

About

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)

Full description

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.

Enrollment: 104 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

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 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.

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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104 participants in 5 patient groups

Asciminib 60mg QD + Imatinib 400mg QD

Experimental group

Description:

Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily

Treatment:

Drug: Imatinib

Drug: Asciminib add-on

Asciminib 40mg QD + Imatinib 400mg QD

Experimental group

Description:

Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily

Treatment:

Drug: Imatinib

Drug: Asciminib add-on

Imatinib 400mg QD

Active Comparator group

Description:

Imatinib 400 mg taken once daily

Treatment:

Drug: Imatinib

Nilotinib 300mg BID

Active Comparator group

Description:

Nilotinib 300 mg taken twice daily

Treatment:

Drug: Nilotinib

Asciminib 80mg QD

Experimental group

Description:

Asciminib 80 mg taken once daily

Treatment:

Drug: Asciminib single agent