Phase 3 Study of Zilovertamab Vedotin Plus R-CHP Versus R-CHOP in Untreated Diffuse Large B-Cell Lymphoma Patients

The primary objective of this study is to compare **zilovertamab vedotin** plus R-CHP with R-CHOP in terms of progression-free survival (PFS) according to the Lugano response criteria, as assessed by blinded independent central review (BICR). This is clinically relevant as PFS is a critical endpoint in evaluating the efficacy of treatments for **Diffuse Large B-Cell Lymphoma (DLBCL)**, providing insights into the duration patients remain free from disease progression.

Secondary objectives include:

• Comparing zilovertamab vedotin plus R-CHP with R-CHOP regarding the complete response (CR) rate at the end of treatment (EOT) per Lugano response criteria as assessed by BICR.
• Comparing overall survival (OS) between the two treatment regimens.
• Evaluating event-free survival (EFS) with zilovertamab vedotin plus R-CHP versus R-CHOP per Lugano response criteria as assessed by BICR.
• Assessing the duration of CR with zilovertamab vedotin plus R-CHP versus R-CHOP.
• Evaluating the safety and tolerability of zilovertamab vedotin plus R-CHP.
• Assessing changes from baseline in health-related quality of life (HRQoL) using the FACT-Lym and FACT/GOG-NTX instruments.

The clinical trial involves a total of **867 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 at screening, and no prior treatment for DLBCL. The general health status of participants is assessed through an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and an ejection fraction of 45% or higher. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. Participants with controlled HIV on antiretroviral therapy, those with undetectable hepatitis B or C viral loads, are eligible for the study. The selection process ensures a representative sample of the DLBCL patient population, facilitating the evaluation of the trial's main objective to compare zilovertamab vedotin plus R-CHP with R-CHOP in terms of progression-free survival (PFS) as assessed by BICR.

The clinical trial is a **randomized**, open-label, multicenter, Phase 3 study designed to evaluate the efficacy and safety of zilovertamab vedotin in combination with R-CHP compared to R-CHOP in participants with previously untreated **Diffuse Large B-Cell Lymphoma (DLBCL)**. The primary objective is to compare progression-free survival (PFS) per Lugano response criteria as assessed by blinded independent central review (BICR). The trial is expected to commence recruitment on January 17, 2025, and conclude by March 29, 2032, with an estimated participant involvement duration of up to 18 months.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed DLBCL, PET-positive disease, and an ECOG performance status of 0 to 2. Following randomization, participants will receive treatment and attend regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will assess the overall treatment response and collect final data on secondary endpoints, including complete response rate, overall survival, and health-related quality of life changes.

Involvement in the study may be terminated early if participants experience unacceptable adverse events, disease progression, or withdrawal of consent. The trial will utilize intravenous administration of the investigational product and comparator drugs, with dosing regimens tailored to each participant's body surface area or weight. The study will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity throughout the trial duration.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Zilovertamab vedotin**, a biological agent, is administered as a solution for infusion. The dosage is calculated based on body weight, with a maximum daily dose of 1.75 mg/kg and a total maximum dose of 10.5 mg/kg over a treatment period of 18 months. The route of administration is intravenous.

**Rituximab**, another biological agent, is administered intravenously. The dosage is based on body surface area, with a maximum daily dose of 375 mg/m² and a total maximum dose of 3000 mg/m² over a 24-month treatment period. This agent is used as part of the standard-of-care therapy in the study.

**Cyclophosphamide** is a chemical agent administered intravenously. The dosage is also based on body surface area, with a maximum daily dose of 750 mg/m² and a total maximum dose of 4500 mg/m² over 18 months. This agent is part of the comparator treatment regimen.

**Doxorubicin hydrochloride** is administered intravenously, with a dosage based on body surface area. The maximum daily dose is 50 mg/m², and the total maximum dose is 300 mg/m² over 18 months. This chemical agent is included in the comparator treatment.

**Vincristine** is administered intravenously as a solution for injection. The dosage is based on body surface area, with a maximum daily dose of 2 mg/m² and a total maximum dose of 12 mg/m² over 18 months. This agent is part of the auxiliary treatment in the study.

**Prednisolone** and **prednisone** are administered orally. Both are chemical agents with a maximum daily dose of 100 mg and a total maximum dose of 3000 mg over 18 months. These agents are part of the comparator treatment regimen.

**Betamethasone sodium phosphate** is administered orally, with a maximum daily dose of 100 mg and a total maximum dose of 3000 mg over 18 months. This chemical agent is included in the experimental treatment regimen.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to compare the efficacy of zilovertamab vedotin in combination with R-CHP versus R-CHOP in participants with previously untreated diffuse large B-cell lymphoma.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-free Survival (PFS)**, evaluated according to the Lugano Response Criteria and assessed by a Blinded Independent Central Review (BICR). Secondary endpoints include Complete Response (CR) at the End of Treatment (EOT) per Lugano Response Criteria, Overall Survival (OS), Event-free Survival (EFS) per Lugano Response Criteria, Duration of CR, and various health-related quality of life (HRQoL) measures. These HRQoL measures will be assessed using the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Trial Outcome Index (TOI), FACT-Lym Total Score, Physical Wellbeing items, and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Neurotoxicity Subscale Score.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, including baseline and at the end of treatment. The trial will utilize validated scales and criteria, such as the Lugano Response Criteria, to ensure consistent and reliable measurement of outcomes. The trial is designed to compare the efficacy of zilovertamab vedotin in combination with R-CHP versus R-CHOP in participants with previously untreated Diffuse Large B-Cell Lymphoma (DLBCL). The study aims to provide comprehensive data on the efficacy of the treatment regimens, contributing to the understanding of their potential benefits in this patient population.