Efficacy and Safety of Glofitamab with Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Untreated Large B-Cell Lymphoma

The primary objective of this study is to evaluate the **efficacy** of glofitamab in combination with Pola-R-CHP compared with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) based on progression-free survival (PFS) in patients with previously untreated large B-cell lymphoma. This is clinically relevant as PFS is a critical endpoint in assessing the effectiveness of cancer therapies, indicating the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include:

• Evaluating the efficacy of glofitamab in combination with Pola-R-CHP compared with Pola-R-CHP on the basis of PFS, event-free survival–efficacy causes (EFSeff), complete response (CR) rate at the end of treatment by fluorodeoxyglucose positron emission tomography (FDG-PET), objective response rate (ORR) at treatment completion or discontinuation, overall survival (OS), duration of response (DOR), duration of complete response (DOCR), and disease-free survival (DFS).
• Evaluating the efficacy of glofitamab in combination with Pola-R-CHP compared with Pola-R-CHP in patients with an international prognostic index (IPI) of 3-5 based on PFS.
• Evaluating the safety of glofitamab in combination with Pola-R-CHP compared with Pola-R-CHP.
• Characterizing the glofitamab pharmacokinetic (PK) profile in combination with Pola-R-CHP.
• Evaluating the immunogenicity of glofitamab in combination with Pola-R-CHP.
• Evaluating the health-related quality of life (HRQoL) of participants treated with glofitamab in combination with Pola-R-CHP.

The clinical trial involves a total of **727 participants** diagnosed with **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 diagnosis of CD20-positive large B-cell lymphoma, an International Prognostic Index (IPI) score between 2 and 5, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. All participants are required to have a life expectancy of at least six months and adequate hematologic function. The trial also includes individuals from vulnerable populations. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study aims to evaluate the efficacy of glofitamab in combination with Pola-R-CHP compared to polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone, focusing on progression-free survival as the primary outcome measure.

The clinical trial is a **randomized**, open-label, multicenter study designed to evaluate the efficacy and safety of **glofitamab** in combination with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) compared to Pola-R-CHP alone in patients with previously untreated **large B-cell lymphoma**. The primary objective is to assess progression-free survival (PFS) as determined by an independent review facility (IRF). Secondary endpoints include PFS as determined by the investigator, overall survival (OS), and incidence and severity of adverse events, among others. The trial is expected to conclude by January 30, 2031, with recruitment starting on September 15, 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a confirmed diagnosis of CD20-positive large B-cell lymphoma, an International Prognostic Index (IPI) score of 2-5, and adequate hematologic function. The inclusion visit will also involve the collection of tumor tissue and a negative HIV test. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events, with assessments including FDG-PET scans and laboratory tests. The end-of-study visit will evaluate the overall treatment outcomes and any long-term effects.

The expected duration of participant involvement is contingent upon individual response to treatment and the occurrence of any adverse events. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial is structured to ensure rigorous monitoring and data collection to support the evaluation of the investigational treatment's efficacy and safety profile.

The clinical trial involves the use of several experimental and non-experimental treatments. The primary experimental medication is **glofitamab**, a recombinant anti-human CD20 and anti-human CD3 monoclonal antibody, developed by F. Hoffmann-La Roche Ltd. This medication is administered in combination with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, collectively referred to as Pola-R-CHP. The pharmaceutical form, dosage, route, and frequency of administration for glofitamab are not specified in the provided data. Participant compliance with the administration schedule will be monitored throughout the trial.

Polatuzumab vedotin, an **antibody-drug conjugate**, is another key component of the treatment regimen. It is produced by Roche Registration GmbH and is used in combination with other agents in the Pola-R-CHP regimen. The specific details regarding its pharmaceutical form, dosage, and administration are not detailed in the provided data.

Rituximab, a **chimeric murine/human monoclonal antibody**, is included as a comparator treatment. It is also produced by Roche Registration GmbH and is part of the Pola-R-CHP regimen. The administration details are not provided in the data.

Additional non-experimental treatments used in the study include **antihistamines**, **granulocyte colony-stimulating factor**, **inhibitors of uric acid production**, and **chemotherapy agents**. These auxiliary treatments are used to manage side effects and support the primary treatment regimen. Specific details regarding their administration are not provided.

Other auxiliary treatments include **corticoides**, **antivirals**, **uricolytic agents**, **analgesics and antipyretics**, and **immunoglobulins**. These are used as supportive care to manage symptoms and enhance patient comfort during the trial. The exact dosing schedules and administration routes for these treatments are not specified in the data.

Participant compliance with the treatment regimen will be closely monitored to ensure adherence to the study protocol. The trial aims to evaluate the efficacy of glofitamab in combination with Pola-R-CHP compared to the standard Pola-R-CHP regimen in patients with large B-cell lymphoma, focusing on progression-free survival as the primary outcome measure.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**, as determined by the Independent Review Facility (IRF). Secondary endpoints include PFS as determined by the investigator, event-free survival (EFSeff), complete response (CR) rate at the end of treatment as assessed by FDG-PET, overall response rate (ORR) at treatment completion or discontinuation, overall survival (OS), duration of response (DOR), duration of complete response (DOCR), disease-free survival (DFS), and PFS in participants with an International Prognostic Index (IPI) score of 3-5. The incidence and severity of adverse events will also be monitored, with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) and the American Society for Transplantation and Cellular Therapy (ASTCT) cytokine release syndrome (CRS) grading criteria.

Additional assessments will include changes from baseline in targeted vital signs and clinical laboratory test results, tolerability as assessed by dose interruptions, dose reductions, dose intensity, and study treatment discontinuation due to adverse events. Serum concentration of glofitamab at specified timepoints and the prevalence and incidence of anti-drug antibodies (ADAs) of glofitamab will be evaluated. Patient-reported outcomes will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy Lymphoma Subscale (FACT-Lym LymS), focusing on physical functioning, fatigue, and lymphoma symptoms. The time to deterioration in these parameters will also be assessed.