Efficacy and Safety Evaluation of Glofitamab with Gemcitabine and Oxaliplatin Versus Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

The primary objective of this study is to evaluate the **efficacy** of glofitamab (Glofit) in combination with gemcitabine plus oxaliplatin (GemOx) compared to rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) based on overall survival in patients with relapsed or refractory diffuse large B-cell lymphoma. This is clinically relevant as improving overall survival is a critical endpoint in the treatment of this aggressive form of lymphoma, providing insights into the potential benefits of the Glofit-GemOx regimen over the standard R-GemOx treatment.

Secondary objectives include:

• Evaluating the efficacy of Glofit-GemOx compared with R-GemOx based on progression-free survival, complete response rate, objective response rate, duration of objective response, duration of complete response, and time to deterioration in physical functioning and fatigue.
• Assessing the safety and tolerability of Glofit-GemOx compared with R-GemOx.
• Investigating the pharmacokinetics of Glofit when administered as a component of Glofit-GemOx.
• Evaluating the pharmacokinetics of obinutuzumab.
• Assessing the immune response to Glofit-GemOx.

The clinical trial involves a total of **160 participants** diagnosed with **relapsed or refractory diffuse large B-cell lymphoma**. 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 life expectancy of at least 12 weeks and a histologically confirmed diagnosis of diffuse large B-cell lymphoma, not otherwise specified. Eligible individuals must have experienced relapsed or refractory disease and have undergone at least one prior line of systemic therapy. Those who have failed only one prior line of therapy are excluded if they are candidates for high-dose chemotherapy followed by autologous stem cell transplant. Additionally, participants must have at least one bi-dimensionally measurable nodal or extranodal lesion as determined by CT scan. The trial population includes a vulnerable group, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **glofitamab** in combination with gemcitabine plus oxaliplatin compared to **rituximab** in combination with gemcitabine and oxaliplatin in patients with relapsed or refractory diffuse large B-cell lymphoma. This is a Phase III, open-label, multicenter, randomized study. The trial aims to assess the primary endpoint of overall survival, with secondary endpoints including progression-free survival, complete response rate, and incidence of adverse events, among others. The study is expected to run from April 2021 to March 2027, with participant involvement anticipated to last until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a life expectancy of at least 12 weeks and histologically confirmed diffuse large B-cell lymphoma. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted. Conditions that may lead to early termination from the study include significant adverse events or disease progression that necessitates alternative treatment. The trial is structured to ensure rigorous data collection and analysis, maintaining the integrity and scientific validity of the results.

The clinical trial involves the administration of several experimental medications, each re-labeled and re-packaged for clinical trial use. **Rituximab** is one of the experimental medications used in this study. It is a protein-based therapeutic agent, classified under the category "Protein - Other." The pharmaceutical form, dosage, route, and frequency of administration are not specified in the provided data. Rituximab is utilized in combination with gemcitabine and oxaliplatin, forming the R-GemOx regimen, which serves as a comparator treatment in the study.

Another experimental medication in the trial is **Obinutuzumab**, also a protein-based therapeutic agent. Like rituximab, it is categorized under "Protein - Other." The specific details regarding its pharmaceutical form, dosage, route, and frequency of administration are not provided. Obinutuzumab is re-labeled and re-packaged for clinical trial use, similar to the other medications in the study.

The trial also includes a product identified by the sponsor product code "RO 708-2859/F03-01," which is a protein-based therapeutic agent. The active substance descriptive name is not provided. This product is also re-labeled and re-packaged for clinical trial use. Details regarding its pharmaceutical form, dosage, route, and frequency of administration are not specified in the data.

**Tocilizumab** is another experimental medication used in the trial. It is a protein-based therapeutic agent, categorized under "Protein - Other." The pharmaceutical form, dosage, route, and frequency of administration are not detailed in the provided information. Tocilizumab is re-labeled and re-packaged for clinical trial use, consistent with the other medications in the study.

The trial aims to evaluate the efficacy of glofitamab in combination with gemcitabine plus oxaliplatin (GemOx) compared to rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) in patients with relapsed/refractory diffuse large B-cell lymphoma. The study's main objective is to assess overall survival as the primary endpoint. Participant compliance monitoring and additional relevant information about drug administration and dosing schedules are not specified in the provided data.

The efficacy of the clinical trial will be assessed primarily through the endpoint of **Overall Survival**. This endpoint will serve as the main measure to evaluate the effectiveness of the treatment regimens being compared: glofitamab in combination with gemcitabine plus oxaliplatin (GemOx) versus rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) in patients with relapsed/refractory diffuse large B-cell lymphoma.

Secondary endpoints will provide additional insights into the efficacy of the treatments. These include **Progression-Free Survival** as assessed by both Independent Review Committee (IRC) and investigators, **Complete Response Rate**, and **Objective Response Rate**. The duration of both objective and complete responses will also be evaluated. Patient-reported outcomes will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-Lymphoma subscale (FACT-Lym LymS) to assess time to deterioration in physical functioning, fatigue, and lymphoma symptoms.

Additional parameters include the incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0 and the American Society for Transplantation and Cellular Therapy (ASTCT) CRS grading criteria. Changes from baseline in targeted vital signs and clinical laboratory test results will be monitored. Tolerability will be assessed by examining dose interruptions, reductions, intensity, and treatment discontinuation due to adverse events. Pharmacokinetic parameters such as minimum and maximum serum concentrations of glofitamab and obinutuzumab, as well as the area under the curve (AUC) for serum concentration-time profiles, will be estimated using a population-PK model. The prevalence and incidence of anti-drug antibodies (ADAs) against glofitamab will also be evaluated at baseline and during the study.