Evaluation of Tumor Lysis Syndrome Risk in Chronic Lymphocytic Leukemia Patients Treated with Venetoclax, Obinutuzumab, or Acalabrutinib Combinations

The primary objective of this study is to evaluate the incidence of treatment-emergent laboratory **Tumor Lysis Syndrome (TLS)** per Howard criteria or hyperkalemia, requiring clinical intervention as assessed by the Independent Review Committee (IRC), in previously untreated subjects with **Chronic Lymphocytic Leukemia (CLL)**. This evaluation is conducted during the venetoclax ramp-up period, which spans 5, 6, or 7 weeks. The clinical relevance of this objective lies in its potential to inform the optimization of venetoclax initiation, thereby minimizing the risk of TLS, a potentially life-threatening complication, in CLL patients.

Secondary objectives include:

• Evaluating the incidence of treatment-emergent laboratory TLS or hyperkalemia requiring clinical intervention, as well as other TLS-related events, at each dose level and laboratory monitoring point during the ramp-up period.
• Assessing adverse events (AEs) of TLS as reported by the Investigator during the venetoclax ramp-up period.
• Evaluating the reduction of tumor burden from baseline to after debulking in all enrolled subjects who have TLS assessments performed at both baseline and after debulking.

The clinical trial involves a total of **110 participants** diagnosed with **Chronic Lymphocytic Leukemia (CLL)** or small lymphocytic lymphoma (SLL), both requiring treatment as per the 2018 international workshop on CLL criteria. The study population includes both **male and female subjects**, with an age range encompassing adults and older adults. Participants were selected based on specific inclusion criteria, such as having a documented diagnosis of previously untreated CLL or SLL, an **Eastern Cooperative Oncology Group (ECOG) performance status** of 2 or less, and adequate marrow function. The trial also considers individuals with a creatinine clearance of at least 30 mL/min, calculated using the Cockcroft-Gault formula. The study population includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Lifestyle factors such as diet and physical activity are not specified, but participants are required to have a life expectancy of more than six months. The selection process ensures that participants have not received prior treatment for CLL or SLL, maintaining the integrity of the study's objective to evaluate treatment-emergent laboratory tumor lysis syndrome (TLS) or hyperkalemia during the venetoclax ramp-up period.

The clinical trial is designed to evaluate the risk of **tumor lysis syndrome** (TLS) and optimize the initiation of **venetoclax** in combination with **obinutuzumab** or **acalabrutinib** in previously untreated subjects with **chronic lymphocytic leukemia** (CLL). This is a prospective, open-label, Phase IIb/III study. The trial employs a randomized, controlled design with different ramp-up periods for venetoclax administration. The estimated duration of the trial is from December 14, 2024, to December 5, 2026.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented diagnosis of CLL, an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, and adequate marrow function. Following the screening, participants will be randomized to receive venetoclax in combination with either obinutuzumab or acalabrutinib. The trial includes a ramp-up period for venetoclax over 5, 6, or 7 weeks, during which the primary objective is to assess the incidence of treatment-emergent laboratory TLS or hyperkalemia requiring clinical intervention.

Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events, with a focus on the primary and secondary endpoints, including the reduction of tumor burden from baseline and the incidence of TLS-related laboratory abnormalities. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 60 weeks, depending on the treatment arm and response.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial aims to provide valuable insights into the safety and efficacy of venetoclax combinations in the treatment of CLL, contributing to the optimization of therapeutic strategies for this condition.

**Venetoclax** is administered in the form of a **film-coated tablet**. The active substance, venetoclax, is of chemical origin and is provided by ABBVIE DEUTSCHLAND GMBH & CO. KG. The administration route is **oral**, and the treatment period is up to 19 weeks. The specific dosage and frequency of administration are determined based on the study protocol, with a focus on optimizing the initiation of venetoclax in combination with other treatments. The maximum daily and total dose amounts are not specified in the provided data.

**Calquence** (acalabrutinib) is also administered as a **film-coated tablet**. The active substance, acalabrutinib, is chemically derived and supplied by ASTRAZENECA AB. The administration is **oral**, with a maximum daily dose of 200 mg and a total dose of 84,000 mg over a treatment period of 60 days. This medication is used in combination with venetoclax to evaluate its efficacy and safety in the clinical trial.

**Gazyvaro** (obinutuzumab) is provided as a **concentrate for solution for infusion**. The active substance, obinutuzumab, is a protein of other origin, manufactured by ROCHE REGISTRATION GMBH. The administration route is via **infusion**, with a maximum daily dose of 1,000 mg and a total dose of 6,000 mg over a 19-day treatment period. This medication is used in combination with venetoclax to assess the risk of tumor lysis syndrome (TLS) and optimize treatment initiation.

In this clinical trial, the combination of these medications aims to evaluate the incidence of treatment-emergent laboratory TLS or hyperkalemia in previously untreated subjects with chronic lymphocytic leukemia (CLL). The study involves different ramp-up periods for venetoclax, in combination with either obinutuzumab or acalabrutinib, to determine the optimal initiation strategy. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules and to assess the safety and efficacy of the treatment regimens.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of treatment-emergent laboratory **tumor lysis syndrome (TLS)** or hyperkalemia, as defined by Howard criteria, that require clinical intervention per Independent Review Committee (IRC) assessment. Additionally, the reduction of tumor burden from baseline will be evaluated. Secondary endpoints will further explore the incidence of laboratory TLS or hyperkalemia per Howard criteria, both requiring and irrespective of clinical intervention, as well as the incidence of clinical TLS and any single TLS-related laboratory abnormality requiring clinical intervention, such as hyperuricemia, hyperphosphatemia, hyperkalemia, or hypocalcemia. Adverse events related to TLS and the reduction of tumor burden from baseline will also be monitored.

The trial will involve the administration of **Venetoclax** in combination with **Obinutuzumab** or **Acalabrutinib** with different ramp-up periods in previously untreated subjects with chronic lymphocytic leukemia (CLL). The efficacy parameters will be collected and analyzed according to the specified criteria, ensuring a comprehensive evaluation of the treatment's impact on the participants. The trial is designed to optimize the initiation of Venetoclax and assess the risk of TLS, with a focus on achieving a medium tumor burden with a creatinine clearance (CrCl) of at least 80 ml/min or a low tumor burden after debulking therapy during the Venetoclax ramp-up period, which spans 5, 6, or 7 weeks.