A Multicenter, Open-label, Phase 2 Dose Escalation and Confirmation, and Efficacy Expansion Study of Zilovertamab Vedotin (MK-2140) in Combination with R-CHP in Participants with DLBCL (waveLINE)

The primary objective of this study is to evaluate the **safety** and tolerability of zilovertamab vedotin when used in combination with R-CHP, and to establish a recommended Phase 2 dose (RP2D) for this combination. Additionally, the study aims to assess the complete response rate of zilovertamab vedotin at the RP2D in combination with R-CHP, as per the Lugano response criteria, evaluated by the investigator. This is clinically relevant as it seeks to determine the optimal dosing and potential efficacy of this combination therapy in treating patients with **Diffuse Large B-Cell Lymphoma (DLBCL)**, a common and aggressive form of non-Hodgkin lymphoma.

Secondary objectives include: - Evaluating zilovertamab vedotin at the RP2D in combination with R-CHP with respect to overall response rate (ORR) per Lugano response criteria as assessed by the investigator. - Evaluating zilovertamab vedotin at the RP2D in combination with R-CHP with respect to duration of response (DOR) per Lugano response criteria as assessed by the investigator.

The clinical trial involves a total of **23 participants** diagnosed with **diffuse large B-cell lymphoma (DLBCL)**. 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 criteria, including a histologically confirmed diagnosis of DLBCL, PET-positive disease verified by blinded independent central review, and no prior treatment for DLBCL. Additionally, participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the safety, tolerability, and efficacy of **zilovertamab vedotin** in combination with R-CHP in participants with **diffuse large B-cell lymphoma (DLBCL)**. This is a multicenter, open-label, Phase 2 study that includes dose escalation and confirmation, followed by an efficacy expansion phase. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from June 2022 to August 2029, with participant involvement expected to last up to 24 months, depending on individual response and treatment tolerance.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed DLBCL and a PET-positive disease status. Following successful screening, participants will be enrolled and randomized to receive the investigational treatment. Regular follow-up visits will be scheduled to monitor safety, assess dose-limiting toxicities, and evaluate treatment efficacy using the Lugano response criteria. The primary endpoints include the number of participants experiencing dose-limiting toxicities and adverse events, as well as the complete response rate. Secondary endpoints focus on the objective response rate and duration of response.

The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be necessitated by adverse events, disease progression, or withdrawal of consent. Participants will be closely monitored throughout the study to ensure safety and adherence to the protocol. The trial aims to establish a recommended Phase 2 dose (RP2D) for **zilovertamab vedotin** in combination with R-CHP, providing valuable insights into its potential as a treatment option for DLBCL.

The clinical trial involves the administration of several experimental and non-experimental medications. **Cyclophosphamide** is utilized in the form of a powder for solution for injection. It is administered via **intravenous infusion** with a maximum daily dose of 750 mg/m² and a total maximum dose of 6000 mg/m² over a treatment period of 24 weeks. The active substance is of chemical origin.

**Prednisone** is administered orally, with a pharmaceutical form identified as PHF00245MIG. The maximum daily dose is 100 mg, and the total maximum dose is 4000 mg over 24 weeks. The active substance, **prednisolone**, is of chemical origin.

**Rituximab** is provided as a concentrate for solution for infusion, administered via intravenous infusion. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over 24 weeks. The active substance is a protein of other origin.

**Doxorubicin** is also administered as a concentrate for solution for infusion via intravenous infusion. The maximum daily dose is 50 mg/m², with a total maximum dose of 400 mg/m² over 24 weeks. The active substance is of chemical origin.

**Prednisolone** is administered intravenously, with a pharmaceutical form identified as PHF00059MIG. The maximum daily dose is 100 mg, and the total maximum dose is 4000 mg over 24 weeks. The active substance, **betamethasone sodium phosphate**, is of chemical origin.

**Zilovertamab vedotin** is administered as a solution for infusion via intravenous infusion. The maximum daily dose is 2.5 mg/kg, with a total maximum dose of 20 mg/kg over 24 weeks. The active substance is a protein of other origin.

**Truxima 500 mg concentrate for solution for infusion** is administered via intravenous infusion. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over 24 weeks. The active substance is a protein of other origin.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the safety, tolerability, and efficacy of these medications in combination with R-CHP in participants with Diffuse Large B-Cell Lymphoma (DLBCL).

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Complete Response Rate (CRR)** per Lugano Response Criteria, which will be evaluated by the investigator. Secondary endpoints include the **Objective Response Rate (ORR)** and **Duration of Response (DOR)**, both assessed per Lugano Response Criteria. These endpoints are designed to measure the effectiveness of the treatment regimen involving zilovertamab vedotin in combination with R-CHP in participants with diffuse large B-cell lymphoma (DLBCL).

The assessment of efficacy will be conducted through a series of evaluations at specified timepoints throughout the trial. The complete response rate and other response rates will be determined based on imaging and clinical assessments, following the Lugano response criteria. The trial will utilize a multicenter, open-label, phase 2 design, allowing for dose escalation and confirmation, as well as efficacy expansion. The trial aims to establish a recommended phase 2 dose (RP2D) of zilovertamab vedotin when used in combination with R-CHP, and to evaluate its efficacy in terms of response rates in the target population.