A Phase III, Randomized, Open-label, Clinical Trial to Compare Pembrolizumab with Brentuximab Vedotin in Subjects with Relapsed or Refractory Classical Hodgkin Lymphoma

The primary objective of this Phase III, randomized, open-label clinical trial is to compare **progression-free survival** (PFS) as assessed by blinded independent central review, according to the International Working Group (IWG) response criteria [Cheson, 2007], between treatment arms in subjects with relapsed or refractory classical **Hodgkin lymphoma**. This includes clinical and imaging data following autologous stem-cell transplantation (auto-SCT) or allogeneic stem-cell transplantation (allo-SCT). Additionally, the trial aims to compare overall survival (OS) between the treatment arms. These objectives are clinically relevant as they assess the efficacy of pembrolizumab compared to brentuximab vedotin, potentially influencing treatment strategies for this patient population.

Secondary objectives include:

• Comparing PFS, excluding clinical and imaging data following auto-SCT or allo-SCT, as assessed by blinded independent central review.
• Comparing the objective response rate (ORR) as assessed by blinded independent central review.
• Evaluating the complete remission rate (CRR) as assessed by blinded independent central review.
• Evaluating PFS, CRR, and ORR as assessed by the investigator.
• Evaluating the safety and tolerability of pembrolizumab.

The clinical trial involves a total of **460 participants** diagnosed with **Hodgkin 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 their health status, specifically those with relapsed or refractory classical Hodgkin lymphoma who have shown a response to previous treatments involving brentuximab vedotin (BV) or BV-containing regimens. The trial includes individuals who have measurable disease and are capable of providing a lymph node biopsy for biomarker analysis. Participants are required to have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale and must demonstrate adequate organ function. Both male and female participants of childbearing potential are required to use adequate contraception during the study and for a specified period after the last dose of the study drug. The trial population includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being throughout the study.

The clinical trial is a **Phase III**, randomized, open-label study designed to compare the efficacy and safety of **pembrolizumab** with **brentuximab vedotin** in subjects with relapsed or refractory classical **Hodgkin lymphoma**. The trial aims to evaluate progression-free survival (PFS) and overall survival (OS) as primary endpoints, with objective response rate (ORR) as a secondary endpoint. The study is expected to run from November 2022 to July 2025, with a maximum treatment period of 24 months for participants.

Participants will be randomly assigned to receive either pembrolizumab or brentuximab vedotin, both administered via **intravenous infusion**. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have relapsed or refractory classical Hodgkin lymphoma, measurable disease, and adequate organ function, among other conditions. Participants must also adhere to specific contraceptive requirements during and after the study period.

The expected duration of participant involvement is up to 24 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial is not classified as low intervention, and it is conducted to confirm the safety and efficacy of the treatments in the target population. The study is conducted under the sponsorship of Merck Sharp & Dohme BV and Takeda Pharma A/S, with the investigational products being Keytruda and Adcetris, respectively.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is provided as a 25 mg/mL **concentrate for solution for infusion**. This experimental medication is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 7000 mg over a treatment period of up to 24 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified as "Protein - Other," and is produced by Merck Sharp & Dohme BV. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

The comparator treatment in this study is **brentuximab vedotin**, marketed as ADCETRIS, which is supplied as a 50 mg **powder for concentrate for solution for infusion**. Similar to pembrolizumab, brentuximab vedotin is administered through **intravenous infusion**. The maximum daily dose for this medication is 180 mg, with a total maximum dose of 6300 mg over a 24-month treatment period. Brentuximab vedotin is categorized as a "Structurally Diverse Substance - Immunoglobulin" and is manufactured by Takeda Pharma A/S. The trial ensures that the administration of this comparator treatment follows the specified dosing schedule, with compliance being closely monitored throughout the study duration.

Efficacy in this clinical trial will be assessed using the primary endpoints of **Progression-free Survival (PFS)** and **Overall Survival (OS)**. These endpoints will be evaluated to compare the efficacy of Pembrolizumab with Brentuximab Vedotin in subjects with relapsed or refractory classical Hodgkin Lymphoma. The PFS will be assessed by blinded independent central review, following the International Working Group (IWG) response criteria as outlined by Cheson in 2007. This assessment will include clinical and imaging data post-autologous or allogeneic stem-cell transplantation.

Secondary efficacy assessment will include the **Objective Response Rate (ORR)**. The trial is designed as a Phase III, randomized, open-label study, and the efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration. The trial aims to provide a comprehensive evaluation of the treatment effects on survival and response rates in the target population.