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

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

Asciminib 60 mg or 40 mg taken orally once daily.

Asciminib add-on

Imatinib

Nilotinib 300 mg taken orally twice daily (total daily dose of 600 mg)

Asciminib single agent

Novartis Pharmaceuticals

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)

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.

Treatment arms 1 - 4 randomized; New Treatment arm 5 (asciminib single agent cohort) not randomized

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

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

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.

Percentage of subjects with MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib

Difference in the percentage of subjects with MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib

Percentage of subjects with MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks

Best observed rate of MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) under randomized treatment up to the specific time point

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.

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

Time from first MR\^4.5 until loss of MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%).

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

The maximum (peak) observed drug concentration after dose administration

The time to reach maximum (peak) drug concentration after dose administration

The AUC from time zero to the last measurable concentration sampling time (Tlast)

The AUC calculated to the end of a dosing interval (tau) at steady-state

The percentage of subjects on asciminib 80mg QD with MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks

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

Time from first MR\^4.5 until loss of MR\^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) for subjects on asciminib 80mg QD

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)	NCT03578367	CML Chronic Myeloge... Leukemia, Myelo... Hematologic Dis...	Asciminib add-o... Imatinib Nilotinib Asciminib singl...	18 Years -	Novartis
Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)	NCT03578367	CML Chronic Myeloge... Leukemia, Myelo... Hematologic Dis...	Asciminib add-o... Imatinib Nilotinib Asciminib singl...	18 Years -	Novartis

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