Phase 3 Randomized Study of Pirtobrutinib vs. Investigator-Selected BTK Inhibitor in Previously Treated BTK Inhibitor-Naïve Mantle Cell Lymphoma

The primary objective of this Phase 3 open-label, randomized study is to compare **progression-free survival (PFS)** of **pirtobrutinib** as monotherapy (Arm A) to the Investigator's choice of covalent Bruton’s tyrosine kinase (BTK) inhibitor monotherapy (Arm B) in patients with previously treated **Mantle Cell Lymphoma (MCL)**. This objective is clinically relevant as it aims to determine the efficacy of pirtobrutinib in extending the time patients live without disease progression compared to standard BTK inhibitors, which is crucial for improving treatment outcomes in MCL.

The clinical trial involves a total of **352 participants** diagnosed with **mantle cell lymphoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific health criteria, including a confirmed diagnosis of mantle cell lymphoma and previous treatment with at least one prior line of systemic therapy for the condition. The general health status of participants is assessed through various parameters, such as creatinine clearance, measurable disease per Lugano criteria, and specific blood count levels. The trial population includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are fully active or capable of self-care. Lifestyle considerations such as diet and physical activity are not specified, but the inclusion criteria ensure participants have adequate organ function and blood counts. The trial does not exclude vulnerable populations, indicating a broad inclusion strategy to assess the efficacy of the treatment across diverse patient groups.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy and safety of **pirtobrutinib** compared to investigator's choice of a covalent Bruton’s tyrosine kinase (BTK) inhibitor in patients with previously treated **mantle cell lymphoma**. The trial aims to assess progression-free survival as the primary endpoint, with evaluations conducted by an independent review committee using the Lugano criteria. The study involves two arms: Arm A, where participants receive pirtobrutinib, and Arm B, where participants receive a BTK inhibitor chosen by the investigator. The trial is expected to last until March 2026, with recruitment having commenced in April 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of mantle cell lymphoma, adequate organ function, and previous treatment history. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of disease progression, laboratory tests, and adverse event monitoring. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 48 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants will receive oral doses of the investigational products, with pirtobrutinib administered at a maximum daily dose of 200 mg and the comparator BTK inhibitor at a maximum daily dose of 560 mg. The trial is conducted in compliance with EU labeling requirements, with secondary relabeling implemented as necessary.

The clinical trial involves the administration of **PIRTOBRUTINIB**, an experimental medication, in the form of a tablet. The active substance, pirtobrutinib, is of chemical origin and is identified by the code LY3527727. The maximum daily dose of pirtobrutinib is 200 mg, with a total maximum dose of 292,000 mg over a treatment period of 48 weeks. The medication is administered orally, and secondary relabeling will occur to comply with EU labeling requirements. Pirtobrutinib is designated as an orphan drug under the number EU/3/21/2450.

In addition to the experimental treatment, the study includes a comparator treatment with **IBRUTINIB**, also in the form of a film-coated tablet. Ibrutinib is a chemical substance, and its maximum daily dose is 560 mg, with a total maximum dose of 817,600 mg over the same 48-week treatment period. This medication is also administered orally, and similar to pirtobrutinib, it will undergo secondary relabeling to meet EU labeling standards. Ibrutinib serves as the investigator's choice of covalent Bruton’s tyrosine kinase (BTK) inhibitor monotherapy in the study.

The efficacy of the investigational medicinal product **pirtobrutinib** will be assessed in a Phase 3 open-label, randomized clinical trial involving patients with previously treated Mantle Cell Lymphoma (MCL). The primary endpoint for evaluating efficacy is progression-free survival (PFS), which will be assessed by an independent review committee (IRC) using the Lugano criteria. This endpoint will compare the efficacy of pirtobrutinib monotherapy (Arm A) against the investigator's choice of covalent Bruton’s tyrosine kinase (BTK) inhibitor monotherapy (Arm B).