Phase 2 Randomized Study of Zilovertamab Vedotin Plus R-CHP Versus Polatuzumab Vedotin Plus R-CHP in Treatment-Naive GCB-DLBCL Patients

The primary objective of this study is to compare **zilovertamab vedotin** plus R-CHP with **polatuzumab vedotin** plus R-CHP in terms of the complete response (CR) rate at the end of treatment (EOT) according to the Lugano response criteria, as assessed by a blinded independent central review (BICR). This is clinically relevant as achieving a complete response is a critical indicator of treatment efficacy in patients with the germinal center B-cell (GCB) subtype of **Diffuse Large B-Cell Lymphoma (DLBCL)**, potentially leading to improved patient outcomes.

Secondary objectives include: - Comparing the two treatment regimens with respect to progression-free survival (PFS) per Lugano response criteria as assessed by BICR. - Comparing overall survival (OS) between the two treatment groups. - Evaluating event-free survival (EFS) using the Lugano response criteria as assessed by BICR. - Assessing the duration of complete response (DurCR) per Lugano response criteria as assessed by BICR. - Evaluating the safety and tolerability of zilovertamab vedotin plus R-CHP. - Assessing changes from baseline in health-related quality of life (HRQoL) and symptoms using the FACT-Lym and FACT/GOG-NTX instruments.

The clinical trial involves a total of **354 participants** diagnosed with **Diffuse Large B-Cell Lymphoma (DLBCL)**. 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 the germinal center B-cell subtype of DLBCL, as per the World Health Organization classification, and having PET-positive disease at screening. The trial excludes individuals who have received prior treatment for DLBCL. Participants with controlled HIV on antiretroviral therapy, those with hepatitis B who have an undetectable viral load due to antiviral therapy, and individuals with a history of hepatitis C with an undetectable viral load at screening are eligible. The trial does not focus on a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of **zilovertamab vedotin** plus R-CHP compared to **polatuzumab vedotin** plus R-CHP in treatment-naive participants with the germinal center B-cell (GCB) subtype of **diffuse large B-cell lymphoma (DLBCL)**. The trial aims to assess the complete response (CR) rate at the end of treatment (EOT) per Lugano response criteria, as evaluated by a blinded independent central review (BICR). The study is expected to conclude by November 25, 2030, with recruitment starting on April 14, 2025.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as a histologically confirmed diagnosis of GCB subtype DLBCL and PET-positive disease. The trial will include follow-up visits to monitor progression-free survival, overall survival, event-free survival, and duration of CR, among other secondary endpoints. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced by participants.

The expected length of participant involvement is approximately one year, with the treatment period lasting up to one year. Conditions that may lead to early termination from the study include the occurrence of adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial will utilize intravenous infusion and oral administration routes for the investigational products, with dosing based on milligrams per kilogram of body weight. The study will not involve any pediatric formulations, and all medicinal products used are either biological or chemical in nature.

The clinical trial involves the administration of **Zilovertamab vedotin**, an experimental medication provided in the form of a **solution for infusion**. This biological agent is administered via **intravenous infusion**. The dosing schedule is based on a milligram per kilogram (mg/kg) basis, although specific dosage amounts are not provided. The treatment period is limited to a maximum of one cycle, with the time unit code indicating a duration of two weeks. Participant compliance with the administration schedule is monitored throughout the trial.

**Prednisolone** is utilized as a non-experimental treatment in the study. It is administered orally, with the pharmaceutical form designated as PHF00245MIG. The dosing is also calculated on a mg/kg basis, with no specific maximum daily or total dose amounts specified. The treatment period is similarly restricted to one cycle, with a two-week duration.

**Rituximab** is included as a standard-of-care therapy in the trial. It is provided as a concentrate for solution for infusion and administered via intravenous infusion. The dosing follows a mg/kg regimen, with no specified maximum daily or total dose amounts. The treatment period is limited to one cycle, with a two-week duration.

**Doxorubicin hydrochloride** is another standard treatment used in the study. It is administered as a concentrate for solution for infusion through intravenous infusion. The dosing is based on a mg/kg calculation, with no specified maximum daily or total dose amounts. The treatment period is restricted to one cycle, with a two-week duration.

**Cyclophosphamide** is also part of the standard treatment regimen. It is provided as a powder for solution for injection and administered via intravenous infusion. The dosing is calculated on a mg/kg basis, with no specified maximum daily or total dose amounts. The treatment period is limited to one cycle, with a two-week duration.

**Polatuzumab vedotin** serves as a comparator treatment in the trial. It is administered as a biological agent via intravenous infusion, with the pharmaceutical form designated as PHF00230MIG. The dosing follows a mg/kg regimen, with no specified maximum daily or total dose amounts. The treatment period is restricted to one cycle, with a two-week duration.

Additionally, **Colony Stimulating Factors** are used as auxiliary treatments in the study. They are administered as a biological agent via intravenous infusion, with the pharmaceutical form designated as PHF00231MIG. The dosing is based on a mg/kg calculation, with no specified maximum daily or total dose amounts. The treatment period is limited to one cycle, with a two-week duration.

The efficacy of the clinical trial will be assessed by comparing the combination of **zilovertamab vedotin** plus R-CHP with polatuzumab vedotin plus R-CHP in treatment-naive participants with the germinal center B-cell (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). The primary endpoint for evaluating efficacy is the Complete Response (CR) rate at the End of Treatment (EOT) as per the Lugano Response Criteria, assessed by a Blinded Independent Central Review (BICR).

Secondary endpoints include Progression-free Survival (PFS), Overall Survival (OS), Event-free Survival (EFS), and Duration of CR, all evaluated according to the Lugano Response Criteria. Additionally, the trial will assess the number of participants experiencing at least one adverse event (AE) and those who discontinue study treatment due to an AE. Changes from baseline in Health-Related Quality of Life (HRQoL) will be measured using the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Trial Outcome Index (TOI), FACT-Lym Total Score, FACT-Lym Physical Well-being (PWB), and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Neurotoxicity Subscale Score.