Phase 3 Randomized Study of Pirtobrutinib vs. Idelalisib + Rituximab or Bendamustine + Rituximab in BTK Inhibitor-Pretreated CLL/SLL Patients

The primary objective of this Phase 3 open-label, randomized study is to evaluate the **progression-free survival** (PFS) of **pirtobrutinib** as monotherapy compared to the investigator's choice of **idelalisib** plus **rituximab** or **bendamustine** plus rituximab in patients with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma** who have been pretreated with a **BTK inhibitor**. This objective is clinically relevant as it aims to determine the efficacy of pirtobrutinib in extending the time patients live without disease progression, which is a critical measure of treatment success in this patient population.

The clinical trial involves a total of **130 participants** diagnosed with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma**. The study population includes both male and female subjects aged 18 years and older, as per local regulations. Participants were selected based on specific inclusion criteria, including an estimated creatinine clearance of ≥ 30 mL/min, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a confirmed diagnosis of CLL/SLL requiring therapy according to iwCLL 2018 criteria. All participants have been previously treated with a covalent BTK inhibitor. The trial population is characterized by a general health status that allows for participation, with specific hematological and biochemical parameters required for eligibility. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring that all participants are willing and capable of providing informed consent. Key laboratory values such as absolute neutrophil count, hemoglobin, platelets, AST, ALT, and total bilirubin are considered for inclusion, with specific thresholds set to ensure participant safety and trial integrity.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy of **pirtobrutinib** as monotherapy compared to the investigator's choice of **idelalisib** plus **rituximab** or **bendamustine hydrochloride** plus rituximab in patients with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma** (CLL/SLL) who have been pretreated with a covalent BTK inhibitor. The primary objective is to assess progression-free survival (PFS) as determined by an Independent Review Committee (IRC) according to iwCLL 2018 criteria. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on June 16, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, creatinine clearance, and hematological parameters. Following randomization, participants will be assigned to either the pirtobrutinib monotherapy arm or the investigator's choice arm. The trial includes regular follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 55 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial is structured to ensure rigorous data collection and analysis, with the aim of providing robust evidence on the comparative effectiveness of the treatment regimens in this patient population.

**Rituximab** is utilized in this clinical trial as a **concentrate for solution for infusion**. The active substance, rituximab, is administered via **intravenous use**. The maximum daily dose is 500 mg/ml, with a total maximum dose of 3875 mg/ml over a treatment period of up to 6 months. The product is specifically relabeled and repackaged for clinical trial use only.

**Pirtobrutinib** is administered in the form of a **tablet**. The active substance, pirtobrutinib, is taken **orally**. The maximum daily dose is 200 mg, with a total maximum dose of 334600 mg over a treatment period of up to 55 months. This product is not subject to relabeling or repackaging for the trial.

**Idelalisib** is provided as a **film-coated tablet**. The active substance, idelalisib, is administered **orally**. The maximum daily dose is 300 mg, with a total maximum dose of 501600 mg over a treatment period of up to 55 months. The product is relabeled and repackaged for clinical trial use only.

**Bendamustine Hydrochloride** is used in the form of a **powder for concentrate for solution for infusion**. The active substance, bendamustine hydrochloride, is administered via **intravenous use**. The maximum daily dose is 70 mg/m², with a total maximum dose of 840 mg/m² over a treatment period of up to 6 months. This product is also relabeled and repackaged for clinical trial use only.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial involves a comparison between the investigational product, pirtobrutinib, and the standard-of-care therapies, which include combinations of idelalisib plus rituximab or bendamustine plus rituximab.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. This will be measured by an Independent Review Committee (IRC) according to the iwCLL 2018 criteria. The trial involves a comparison between **pirtobrutinib** as monotherapy and the investigator's choice of **idelalisib** plus **rituximab** or **bendamustine** plus **rituximab**. The primary endpoint is the PFS, which is a critical measure of the time during and after treatment that a patient lives with the disease without it getting worse.