Evaluation of Glofitamab Combined with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in ctDNA High-Risk Untreated Diffuse Large B-Cell Lymphoma

The primary objective of this study is to evaluate the **efficacy** of glofitamab in combination with R-CHOP in patients with circulating-tumor DNA (ctDNA) high-risk, previously untreated **Diffuse Large B-Cell Lymphoma (DLBCL)**. This evaluation is based on the end of treatment (EOT) complete response (CR) rate as determined by the investigator according to the 2014 Lugano Response Criteria. The clinical relevance of this objective lies in its potential to improve treatment outcomes for high-risk DLBCL patients by assessing the effectiveness of this combination therapy in achieving complete remission.

Secondary objectives include:

• Evaluating the efficacy of glofitamab in combination with R-CHOP in ctDNA high-risk patients with previously untreated DLBCL based on objective response rate (ORR) at the EOT, progression-free survival (PFS), and overall survival (OS) as determined by the investigator according to 2014 Lugano Response Criteria.
• Assessing the safety of glofitamab in combination with R-CHOP in ctDNA high-risk participants with DLBCL.
• Characterizing the serum pharmacokinetics (PK) profile of glofitamab in combination with R-CHOP.
• Evaluating potential effects of anti-drug antibodies (ADAs).

The clinical trial involves a total of **20 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 inclusion criteria, such as being previously untreated and having a cluster of differential (CD20)-positive DLBCL, as per the 2016 World Health Organization classification of lymphoid neoplasms. The trial also considers individuals with an International Prognostic Index (IPI) score between 1 and 5 and a life expectancy of at least six months. Participants are required to have adequate biomarker blood samples and at least one bi-dimensionally fluorodeoxyglucose (FDG)-avid measurable lymphoma lesion on a PET/CT scan. Additionally, a left ventricular ejection fraction (LVEF) of 50% or higher is necessary, as determined by a cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO). The trial includes a vulnerable population, indicating a careful selection process to ensure the safety and efficacy of the treatment under investigation.

The clinical trial is designed to evaluate the **efficacy** and safety of **glofitamab** in combination with R-CHOP in patients with untreated **Diffuse Large B-Cell Lymphoma** (DLBCL) who are considered high-risk based on circulating tumor DNA (ctDNA) levels. This is a Phase II, randomized, double-blind, controlled study. The trial aims to assess the complete response rate at the end of treatment (EOT) as the primary endpoint, with secondary endpoints including overall response rate, progression-free survival, overall survival, and the incidence and severity of adverse events. The trial is expected to conclude by September 2026, with recruitment having started in March 2022.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as a diagnosis of CD20-positive DLBCL, a life expectancy of at least six months, and adequate biomarker blood samples. The trial will include follow-up visits to monitor treatment response and safety, with assessments conducted according to the 2014 Lugano Response Criteria. The end-of-study visit will evaluate the final treatment outcomes and any long-term effects.

The expected duration of participant involvement is up to 168 days, corresponding to the maximum treatment period for **glofitamab**. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. Participants will receive **glofitamab** and R-CHOP via intravenous infusion, with dosing and administration closely monitored to ensure safety and adherence to the study protocol.

The clinical trial involves the administration of **Glofitamab**, an experimental medication formulated as a **solution for infusion**. Glofitamab is administered via **intravenous infusion**. The maximum daily dose is 30 mg, with a total maximum dose of 222.5 mg over a treatment period of 168 days. The active substance, glofitamab, is a protein of non-specific origin, developed by F. Hoffmann-La Roche Ltd. The medication is not a pediatric formulation and is not classified as an orphan drug. Participant compliance with the dosing schedule is monitored throughout the trial.

In addition to Glofitamab, the trial includes the administration of **RoActemra**, a concentrate for solution for infusion containing the active substance **Tocilizumab**. This medication is also administered via intravenous infusion. The maximum daily dose is 8 mg/kg, with a total maximum dose of 800 mg over a treatment period of 2 days. Tocilizumab is a protein of non-specific origin, provided by Roche Registration GmbH. The product has been re-labeled and re-packaged specifically for clinical trial use. RoActemra is not a pediatric formulation and is not classified as an orphan drug. Compliance with the administration schedule is closely monitored to ensure adherence to the trial protocol.

Both experimental medications are evaluated in combination with standard-of-care therapy, which includes Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP). This combination is used to assess the efficacy and safety of the treatment regimen in patients with untreated **Diffuse Large B-Cell Lymphoma** (DLBCL) who are considered high-risk based on circulating tumor DNA (ctDNA) levels. The trial aims to determine the complete response rate at the end of treatment, as assessed by the investigator according to the 2014 Lugano Response Criteria.

The efficacy of the investigational treatment in this clinical trial will be assessed primarily through the **end of treatment (EOT) complete response (CR) rate**. This primary endpoint will be determined by the investigator according to the 2014 Lugano Response Criteria for Malignant Lymphoma. Secondary endpoints include the overall response rate (ORR) at EOT, progression-free survival (PFS), overall survival (OS), and the incidence and severity of adverse events, with severity assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Additional secondary endpoints involve the assessment of tolerability through dose modifications, dose intensity, and study treatment discontinuation due to adverse events.

Pharmacokinetic parameters such as serum concentrations of **glofitamab** at specified timepoints, serum trough concentrations, maximum concentration (Cmax), and area under the concentration–time curve (AUC) will also be evaluated. The relationship between anti-drug antibody (ADA) status and efficacy, safety, or pharmacokinetic endpoints will be explored. These assessments will be conducted at predetermined intervals throughout the trial to ensure comprehensive data collection and analysis.