Phase II Study of Asciminib Hydrochloride Monotherapy or Combined with Nilotinib in First-Line Treatment of BCR-ABL1+ Chronic Myeloid Leukemia

The primary objective of this study is to evaluate the **efficacy** of asciminib, either as a single agent or in combination with nilotinib, in achieving deep molecular response (DMR, MR4) in the first-line treatment of patients with BCR-ABL1+ Chronic Myeloid Leukemia (CML) in early chronic phase (CP). This is clinically relevant as achieving DMR is associated with improved long-term outcomes and may allow for treatment-free remission in patients with CML.

Secondary objectives include:

• Assessing the rate of treatment-free remission.
• Evaluating the molecular response at specific timepoints and the dynamics of molecular response.
• Assessing survival outcomes and the safety profile of the treatment.
• Evaluating baseline and response-related predictors of response.
• Assessing the type and dynamics of emergent BCR::ABL1 mutations and cancer-related somatic mutations.
• Investigating health-related quality of life (HRQoL) differences between treatment arms over time, up to 24 months.

The clinical trial involves participants diagnosed with **BCR-ABL1+ Chronic Myeloid Leukemia** in the early chronic phase, specifically within three months from diagnosis. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a cytogenetic and molecularly confirmed diagnosis of Ph+ and BCR-ABL1+ CML, with evidence of typical BCR-ABL1 RNA transcripts necessary for international scale reporting. The trial does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and demonstrate adequate end organ function as defined by specific laboratory criteria. Prior treatment with any tyrosine kinase inhibitor (TKI) is limited to 30 days or less, although prior treatment with hydroxyurea or anagrelide is permitted. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Participants must provide signed written informed consent and agree to use effective contraception with their sexual partners from enrollment through 30 days after the end of treatment.

The clinical trial is designed to evaluate the efficacy of **asciminib hydrochloride** as a single agent or in combination with **nilotinib** in the first-line treatment of patients with BCR-ABL1+ Chronic Myeloid Leukemia (CML) in the early chronic phase. This is a phase II, randomized, double-blind, controlled study. The trial aims to assess the achievement of deep molecular response (MR4) over a period of 2 years, with additional secondary endpoints evaluated over a 5-year duration. The study will commence with a screening visit to confirm eligibility based on criteria such as cytogenetic and molecular diagnosis, age, and organ function. Participants will be randomly assigned to receive either asciminib alone or in combination with nilotinib, administered orally in the form of film-coated tablets and hard capsules, respectively.

Participants will be involved in the study for a maximum treatment period of 48 months, with regular follow-up visits scheduled to monitor response and safety. These visits will include assessments of molecular response, adverse events, and quality of life. The primary endpoint is the rate of deep molecular response at 2 years, with secondary endpoints including sustained molecular response rates, progression-free survival, and overall survival at 5 years. The study will conclude with an end-of-study visit to evaluate the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial is expected to end by October 29, 2032, with recruitment starting on April 21, 2025. The study is not classified as low intervention, and it adheres to the guidelines for a phase II clinical trial. The trial's design ensures rigorous assessment of the investigational treatments' efficacy and safety in the target population.

The clinical trial involves the use of **asciminib hydrochloride**, marketed under the name Scemblix, as an experimental medication. Scemblix is formulated as **film-coated tablets** containing 40 mg of the active substance. The tablets are administered **orally**. The maximum daily dose is 80 mg, with a total maximum dose of 116.8 mg over a treatment period of up to 48 weeks. The medication is produced by Novartis Europharm Limited and is classified under the ATC code L01EA06. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to Scemblix, the trial also includes the use of **nilotinib**, marketed as Tasigna, as a comparator treatment. Tasigna is available in the form of **hard capsules**, each containing 150 mg of nilotinib. The capsules are also administered **orally**. The maximum daily dose for Tasigna is 600 mg, with a total maximum dose of 594 g over a treatment period of up to 45 weeks. This medication is also manufactured by Novartis Europharm Limited and is classified under the ATC code L01EA03. Compliance with the administration schedule will be closely monitored to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed primarily through the achievement of a **deep molecular response (MR4)** at 2 years. This endpoint will be evaluated by measuring the rate of MR4 in patients treated with asciminib as a single agent or in combination with nilotinib for the first-line treatment of BCR-ABL1+ Chronic Myeloid Leukemia (CML) in the early chronic phase. Patients with non-evaluable molecular analysis may undergo a repeat quantitative polymerase chain reaction (QPCR) analysis one month later, at 25 months from day 1.

Secondary endpoints include the rate of sustained MR4 or MR4.5 at 4 years, the proportion of patients free from relapse 12 months after treatment discontinuation, and the rate of major molecular response (MR3) at various time points up to 24 months. Additional measures include the median time to response, overall survival, progression-free survival, and the incidence of treatment-emergent BCR-ABL1 mutations. The trial will also assess health-related quality of life (HRQoL) using the EORTC QLQ-C30 and QLQ-CML24 questionnaires. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, with outcome measures evaluated at 2 and 5 years.