A Phase IV, Multicenter, Open-Label, Randomized Study of Acalabrutinib Monotherapy Versus Investigator's Choice in Chronic Lymphocytic Leukemia with Cardiac Impairment

The primary objective of this study is to evaluate the **safety** and **tolerability** of acalabrutinib monotherapy compared to the investigator’s choice of treatment in patients with treatment-naïve or relapsed/refractory **chronic lymphocytic leukaemia** and moderate to severe cardiac impairment. This is clinically relevant as it aims to determine the suitability of acalabrutinib for patients with significant cardiac conditions, potentially expanding treatment options for this population.

Secondary objectives include:

• Evaluating the extent and duration of **tumour response** and survival following treatment with acalabrutinib versus the investigator’s choice in the specified patient population.

The clinical trial involves a total of **33 participants** diagnosed with **Chronic Lymphocytic Leukaemia** and moderate to severe cardiac impairment. The study population includes both men and women aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 3. Participants were selected based on specific criteria, including a left ventricular ejection fraction (LVEF) of less than 50% as assessed by echocardiogram, and they must be either treatment-naïve or have relapsed/refractory disease with no more than two prior lines of systemic anti-CLL treatment. The trial population is required to have an active disease that necessitates treatment, as per iwCLL 2018 criteria. Participants must meet certain laboratory parameters, including an absolute neutrophil count of at least 500 cells/μL, a platelet count of at least 30,000 cells/μL, and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels not exceeding three times the upper limit of normal. Additionally, total bilirubin levels must be 1.5 times the upper limit of normal or less, unless attributed to Gilbert's syndrome, and estimated creatinine clearance must be at least 40 mL/min. Both male and female participants who are sexually active and capable of reproduction are required to use highly effective contraception methods. The trial excludes vulnerable populations, such as prisoners or institutionalized individuals, in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Participants must be willing to adhere to the study visit schedule and comply with protocol requirements, providing written informed consent and authorization for the use of protected health information.

The clinical trial is designed as a **randomized**, open-label, Phase IV study to evaluate the safety and tolerability of **acalabrutinib** monotherapy compared to the investigator's choice of treatment in adults with **chronic lymphocytic leukemia** (CLL) and moderate to severe cardiac impairment. The trial will involve participants who are either treatment-naïve or have relapsed/refractory CLL, having received no more than two prior lines of systemic anti-CLL treatment. The study will commence with a screening visit to assess eligibility based on criteria such as age, performance status, and specific laboratory parameters. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 and a left ventricular ejection fraction (LVEF) of less than 50% as assessed by echocardiogram.

The trial will be conducted over an estimated duration from October 2024 to May 2031, with the maximum treatment period for participants set at 72 weeks. Participants will be randomly assigned to receive either acalabrutinib or the investigator's choice of treatment, with the primary endpoints focusing on the frequency and time to discontinuation of any study treatment due to cardiovascular function worsening or adverse events. Secondary endpoints include overall survival, event-free survival, overall response rate, duration of response, and progression-free survival.

Study visits will be scheduled at regular intervals to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and any long-term effects of the treatment. Participants are expected to remain in the study for the entire duration unless they experience significant adverse events, disease progression, or choose to withdraw consent. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or any safety concerns as determined by the investigator.

The clinical trial involves the administration of **acalabrutinib**, marketed under the name Calquence, as the experimental medication. Calquence is provided in the form of **film-coated tablets**, each containing 100 mg of the active substance **acalabrutinib**. The tablets are intended for **oral use**. The maximum daily dose is 100 mg, and the treatment period can extend up to 72 weeks. The clinical supply is packaged in HDPE bottles, differing from the blister packaging used in the marketing authorization application, and is sourced from various manufacturing sites. The medication is administered as a monotherapy, and participant compliance is monitored throughout the study.

In addition to the experimental treatment, the study includes a comparator treatment, which is the investigator's choice of therapy for patients with chronic lymphocytic leukemia and moderate to severe cardiac impairment. This allows for a direct comparison of the safety and tolerability of acalabrutinib monotherapy against standard-of-care treatments selected by the investigator. The study is designed to evaluate the efficacy and safety profile of acalabrutinib in a specific patient population, ensuring that all participants receive appropriate care and monitoring throughout the trial duration.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the frequency and time to discontinuation of any study treatment due to worsening cardiovascular function or cardiovascular **adverse events** (AEs), as well as the incidence of Grade 4 and 5 cardiovascular events of interest. Additionally, the incidence and relationship to study treatment of Grade ≥ 3 AEs, serious adverse events (SAEs), adverse events of special interest (AESI) as defined in the acalabrutinib Investigator’s Brochure, non-cardiovascular AEs leading to discontinuation of any study treatment, and events of clinical interest (ECI) as defined in the Statistical Analysis Plan (SAP) will be evaluated.

Secondary endpoints will focus on overall survival (OS), defined as the time from randomization to death from any cause, and event-free survival (EFS) per iwCLL 2018 criteria, defined as the time from randomization to disease progression, initiation of subsequent anti-CLL therapy, or death from any cause. The overall response rate (ORR) will be determined by the proportion of patients achieving a complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (PR). Duration of response (DOR) will be measured from the first documented response to disease progression or death. Progression-free survival (PFS) will be assessed as the time from randomization to disease progression or death.