Phase IIIb Multicenter Open-Label Study of Asciminib Hydrochloride in Chronic Myelogenous Leukemia Patients in Chronic Phase Post-Two or More Tyrosine Kinase Inhibitors

The primary objective of this study is to estimate the **molecular response rate (MMR)** at week 48 in patients with **Chronic Myelogenous Leukemia in chronic phase (CML-CP)** who have been treated with two or more prior tyrosine kinase inhibitors (TKIs) and have no evidence of MMR at baseline. This objective is clinically relevant as achieving MMR is a critical milestone in the management of CML-CP, indicating a significant reduction in disease burden and potentially improving long-term outcomes.

Secondary objectives include:

• Evaluating the safety and tolerability of asciminib in patients with CML-CP following two or more prior TKI treatments.
• Assessing the rate of MMR in patients without MMR at baseline at various time points (weeks 12, 24, 36, 72, 96, and 144).
• Assessing the rate of MMR at week 48 for patients with MMR at baseline.
• Assessing the time to MMR.
• Assessing the rate of early responses of BCR-ABL1 ≤10% and ≤1% at weeks 12, 24, 36, and 48.
• Assessing the rate of deep molecular responses (MR4 and MR4.5) at weeks 12, 24, 36, 48, 72, 96, and 144.
• Assessing cytogenetic response (% Ph+ metaphases) at week 48 and end of treatment (EOT).
• Characterizing the impact of additional cytogenetic abnormalities on efficacy.
• Assessing cumulative molecular responses by all-time points.
• Assessing the duration of MMR.
• Assessing sustained deep molecular responses as a prerequisite for Treatment Free Remission (TFR).
• Assessing the rate of progressions (PFS).
• Assessing overall survival (OS).
• Assessing time to treatment failure (TTF).
• Evaluating patient-reported outcomes and quality of life using MDASI-CML.

The clinical trial involves a total of **95 participants** diagnosed with **Chronic Myelogenous Leukemia in chronic phase (CML-CP)**. The study population includes both male and female patients aged 18 years and older. Participants have undergone treatment with a minimum of two or more prior tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, radotinib, or ponatinib. The selection criteria required participants to have no evidence of major molecular response (MMR) at baseline and to have experienced warning or failure, or intolerance to the most recent TKI therapy, as adapted from the 2020 European LeukemiaNet (ELN) Recommendations. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating a range from fully active to ambulatory and capable of all self-care but unable to carry out any work activities. Participants are required to have adequate end organ function as determined by central laboratory tests. The trial population is considered vulnerable, and informed consent was obtained from all participants prior to their inclusion in the study.

The clinical trial is designed to evaluate the efficacy of **asciminib hydrochloride** in patients with **Chronic Myelogenous Leukemia in chronic phase (CML-CP)** who have been previously treated with two or more tyrosine kinase inhibitors (TKIs). This is a phase IIIb, multi-center, open-label study with a primary objective to estimate the molecular response rate (MMR) at week 48. The trial will involve oral administration of asciminib hydrochloride, with a maximum daily dose of 200 mg and a total treatment period of up to 144 weeks. The study is expected to conclude by January 2025, with recruitment having started in October 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), prior TKI treatment, and adequate end organ function. Follow-up visits will be scheduled at regular intervals to monitor the primary and secondary endpoints, including MMR rates at various time points, adverse events, and changes in laboratory values. The end-of-study visit will assess the overall treatment outcomes and any long-term effects.

The expected length of participant involvement is up to 144 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, lack of efficacy, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Asciminib Hydrochloride**, a chemical compound used in the treatment of patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP). The pharmaceutical form of this experimental medication is a film-coated tablet. The active substance, **Asciminib Hydrochloride**, is administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 23,040 mg over the treatment period. The treatment duration is set for a maximum of 144 weeks. Asciminib Hydrochloride is sourced locally from the commercial market and may be over-labeled if available. The medication is not formulated for pediatric use and has been designated as an orphan drug under the designation number EU/3/20/2261.

In addition to Asciminib Hydrochloride, the trial also includes the administration of **Asciminib**, another chemical compound with the same active substance name. This medication is also provided in the form of a film-coated tablet and is administered orally. The dosing regimen mirrors that of Asciminib Hydrochloride, with a maximum daily dose of 200 mg and a total maximum dose of 23,040 mg over the course of the study. The treatment period is similarly capped at 144 weeks. Asciminib is also sourced locally from the commercial market and may be over-labeled. Like Asciminib Hydrochloride, it is not intended for pediatric use and holds the same orphan drug designation number.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The primary objective of the trial is to estimate the molecular response rate at week 48 in patients with CML-CP who have been previously treated with two or more tyrosine kinase inhibitors and have no evidence of molecular response at baseline.

The efficacy of the clinical trial will be assessed primarily through the measurement of the **molecular response rate (MMR)** at 48 weeks in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP) who have been previously treated with two or more tyrosine kinase inhibitors (TKIs) and show no evidence of MMR at baseline. Secondary endpoints include the evaluation of MMR rates at various timepoints, specifically at weeks 12, 24, 36, 72, 96, and 144, as well as the rate of BCR-ABL1 ≤ 10% and ≤1% at weeks 12, 24, 36, and 48. Additional assessments will include the rate of MR4 and MR4.5 at specified intervals, the rate of complete cytogenetic response (CCyR) at week 48 and end-of-treatment, and the duration of MMR and MR4 without loss of MMR.

The trial will also monitor the time from randomization to the first documented MMR, the time to treatment failure defined as BCR-ABL1 > 1%, and the time from randomization to death. Changes in symptom burden and interference from baseline over time will be evaluated using the MDASI-CML patient-reported outcome instrument. The type, frequency, and severity of adverse events, along with changes in laboratory values and clinically notable ECG and other safety data, will be recorded to ensure comprehensive safety monitoring. These efficacy parameters will be collected and analyzed at predetermined intervals throughout the trial to provide a robust assessment of the treatment's impact on the patient population.