A Phase 2/3 Multicenter, Open-label, Randomized, Active-Control Study of Zilovertamab Vedotin (MK-2140) in Combination With Standard of Care in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (waveLINE-003)

The primary objective of this study is to evaluate the **safety** and tolerability of zilovertamab vedotin when used in combination with R-GemOx and BR, and to establish a recommended Phase 2 dose (RP2D). Additionally, the study aims to compare zilovertamab vedotin in combination with R-GemOx to R-GemOx alone with respect to progression-free survival (PFS) per Lugano response criteria as assessed by blinded independent central review (BICR) in part 2 of the study. This is clinically relevant as it may provide insights into the potential efficacy and safety of zilovertamab vedotin in treating relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL), potentially leading to improved therapeutic strategies.

Secondary objectives include:

• Comparing zilovertamab vedotin in combination with R-GemOx to R-GemOx with respect to overall survival (OS) in part 2 of the study.
• Comparing zilovertamab vedotin in combination with BR to BR with respect to OS in part 2 of the study.
• Comparing zilovertamab vedotin in combination with R-GemOx to R-GemOx with respect to overall response rate (ORR) per Lugano response criteria as assessed by BICR in part 2 of the study.
• Comparing zilovertamab vedotin in combination with BR to BR with respect to ORR per Lugano response criteria by BICR in part 2 of the study.
• Evaluating zilovertamab vedotin in combination with R-GemOx and R-GemOx with respect to duration of response (DOR) per Lugano response criteria as assessed by BICR in part 2 of the study.
• Evaluating zilovertamab vedotin in combination with BR and BR with respect to DOR per Lugano response criteria as assessed by BICR in part 2 of the study.

The clinical trial involves a total of **37 participants** diagnosed with **Relapsed or Refractory Diffuse Large B-Cell Lymphoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed diagnosis of Diffuse Large B-Cell Lymphoma, measurable disease per Lugano response criteria, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Additionally, participants must have adequate organ function and be able to provide a new or archival tumor tissue sample. The trial includes individuals who have relapsed or refractory disease and are ineligible for or have failed autologous stem-cell transplant (ASCT) and at least one line of prior therapy. The study also considers those with post-chimeric antigen receptor T (CAR-T) cell therapy failure or ineligibility. The trial population is noted to include a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, open-label, active-controlled study to evaluate the safety and efficacy of **Zilovertamab Vedotin** in combination with standard care in participants with **relapsed or refractory diffuse large B-cell lymphoma**. The trial is structured in two phases, Phase 2 and Phase 3, and is expected to conclude by December 2029. Participants will be randomly assigned to receive either Zilovertamab Vedotin in combination with R-GemOx or Bendamustine Rituximab (BR), or the standard care regimen alone. The primary objectives include assessing dose-limiting toxicities, adverse events, and progression-free survival, while secondary endpoints focus on overall survival, objective response rate, and duration of response.

The trial will commence with a screening visit to confirm eligibility based on criteria such as a confirmed diagnosis of diffuse large B-cell lymphoma, measurable disease per Lugano response criteria, and adequate organ function. Participants must have failed at least one prior therapy line and be ineligible for or have failed autologous stem-cell transplant. Following the screening, eligible participants will undergo a series of study visits, including treatment administration and regular follow-up assessments to monitor safety and efficacy outcomes. The end-of-study visit will occur after the final treatment cycle or upon early termination.

Participant involvement is anticipated to last up to 15 treatment cycles, with each cycle spanning approximately 21 days. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. The trial will ensure rigorous monitoring and adherence to ethical standards throughout its duration, with all interventions administered via **intravenous infusion**. The study aims to provide valuable insights into the therapeutic potential of Zilovertamab Vedotin in this patient population.

The clinical trial involves the administration of several **experimental medications** and standard-of-care therapies. The primary experimental medication is **Zilovertamab vedotin**, which is administered as a solution for injection or infusion. The pharmaceutical form is a solution for injection, and the route of administration is via **intravenous infusion**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 2.5 mg/kg and a total maximum dose of 15 mg/kg over a treatment period of 15 days. The administration schedule is designed to ensure optimal therapeutic levels while monitoring for safety and tolerability.

In addition to Zilovertamab vedotin, the study includes the use of **Bendamustine hydrochloride** as a comparator treatment. This medication is provided in the form of a powder for concentrate for solution for infusion, administered intravenously. The dosing regimen involves a maximum daily dose of 90 mg/m² and a total maximum dose of 1080 mg/m² over the same 15-day treatment period. Participant compliance and response to treatment are closely monitored throughout the trial.

Another comparator treatment used in the study is **Oxaliplatin**, which is administered as a concentrate for solution for infusion. The route of administration is intravenous infusion, with a maximum daily dose of 100 mg/m² and a total maximum dose of 600 mg/m² over 15 days. The administration of Oxaliplatin is carefully scheduled to align with the study protocol and ensure participant safety.

The trial also incorporates the use of **Rituximab**, available under different brand names such as MabThera, Ruxience, and Truxima. Rituximab is administered as a concentrate for solution for infusion, with the route of administration being intravenous infusion. The dosing schedule allows for a maximum daily dose of 375 mg/m² and a total maximum dose of 2250 mg/m² over the 15-day treatment period. The administration of Rituximab is conducted in accordance with established guidelines to ensure efficacy and safety.

**Gemcitabine** is another standard-of-care therapy included in the study. It is administered as a concentrate for solution for infusion, with the route of administration being intravenous infusion. The dosing regimen involves a maximum daily dose of 1000 mg/m² and a total maximum dose of 6000 mg/m² over the 15-day treatment period. The administration schedule is designed to optimize therapeutic outcomes while minimizing potential adverse effects.

Throughout the trial, participant compliance with the dosing schedules is monitored through regular assessments and documentation. The study protocol includes provisions for adjusting dosages based on individual participant responses and tolerability. All treatments are administered under the supervision of qualified healthcare professionals, ensuring adherence to the study protocol and maintaining participant safety.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Progression-Free Survival (PFS)**, which will be evaluated according to the Lugano response criteria by a Blinded Independent Central Review (BICR). Additionally, the percentage of participants experiencing dose-limiting toxicities (DLTs), adverse events (AEs), and those who discontinue study treatment due to AEs will be monitored. Secondary endpoints will include Overall Survival (OS), Objective Response Rate (ORR), and Duration of Response (DOR).

Measurements for these endpoints will be collected at specified intervals throughout the trial, with the final assessment occurring at the end of the treatment period. The trial is designed to compare the efficacy of Zilovertamab Vedotin in combination with R-GemOx against R-GemOx alone, as well as Zilovertamab Vedotin in combination with Bendamustine Rituximab (BR) against BR alone. The trial will involve participants with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) who meet the inclusion criteria, such as having a histologically confirmed diagnosis and measurable disease per the Lugano criteria.