Phase III Evaluation of Polatuzumab Vedotin with Rituximab, Gemcitabine, and Oxaliplatin in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

The primary objective of this study is to evaluate the **efficacy** of Polatuzumab Vedotin in combination with Rituximab, Gemcitabine, and Oxaliplatin (Pola-R-GemOx) compared to R-GemOx alone in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This evaluation is based on overall survival (OS) in Stage 2. Additionally, the study aims to assess the safety and tolerability of Pola-R-GemOx as a combination therapy, focusing on the incidence, nature, and severity of adverse events (AEs), particularly peripheral neuropathy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0) in Stage 1. These objectives are clinically relevant as they address both the potential survival benefit and the safety profile of the treatment regimen, which are critical factors in the management of DLBCL.

Secondary objectives include:

• Evaluating the safety and tolerability of Pola-R-GemOx compared to R-GemOx, focusing on peripheral neuropathy, tolerability, prevalence of anti-drug antibodies (ADA), and the incidence, nature, and severity of AEs in Stages 1 and 2.
• Assessing the efficacy of Pola-R-GemOx compared to R-GemOx alone, based on complete response (CR), objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), event-free survival (EFS) in Stages 1 and 2, OS in Stage 1, and duration of response (DOR) in Stage 2.
• Evaluating the immunogenicity of polatuzumab vedotin based on the prevalence of ADAs in Stages 1 and 2.
• Assessing the impact of treatment and disease on aspects of health-related quality of life in Stage 2.

The clinical trial involves a total of **235 participants** diagnosed with **relapsed/refractory diffuse large B-cell lymphoma (DLBCL)**. The study population includes both male and female subjects, with an age range that corresponds to categories 3 and 4, indicating adult and elderly participants. The selection criteria for the trial population required individuals to have histologically-confirmed DLBCL, either not otherwise specified or with a history of transformation from indolent disease to DLBCL. Participants must have relapsed or refractory disease, have undergone at least one prior line of systemic therapy, and possess at least one bi-dimensionally measurable lesion. Additionally, an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and adequate hematological function were necessary for inclusion. The trial also considers vulnerable populations, although specific lifestyle factors such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the safety and efficacy of **polatuzumab vedotin** in combination with **rituximab**, **gemcitabine hydrochloride**, and **oxaliplatin** (R-GemOx) compared to R-GemOx alone in patients with relapsed/refractory **diffuse large B-cell lymphoma** (DLBCL). The trial is structured in two stages, with the primary objectives being the assessment of overall survival and the safety profile, particularly focusing on peripheral neuropathy. The trial is expected to last until February 2025, with participant recruitment having commenced in April 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed DLBCL, relapsed or refractory disease, and adequate hematological function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events, with a specific focus on the incidence and severity of peripheral neuropathy. The end-of-study visit will conclude the participant's involvement, assessing the overall treatment outcomes and any long-term effects.

The expected duration of participant involvement is approximately 168 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial's methodology ensures rigorous data collection and analysis, with endpoints including overall survival, incidence of adverse events, and response rates as determined by both independent review and investigator assessment. The study's design and procedures are aligned with the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0), ensuring a standardized approach to safety and efficacy evaluation.

The clinical trial involves the administration of **MabThera**, a 500 mg concentrate for solution for infusion, containing the active substance **rituximab**. This pharmaceutical form is a solution for infusion, administered via the **intravenous route**. The dosage is calculated based on body surface area, with a maximum daily dose of 375 mg/m² and a total maximum dose of 3000 mg over the treatment period. The treatment duration is set for a maximum of 168 days. Participant compliance is monitored through regular assessments of infusion administration and adherence to the dosing schedule.

**Polivy**, a 140 mg powder for concentrate for solution for infusion, is also used in the trial. The active substance is **polatuzumab vedotin**, and it is administered intravenously. The dosage is based on body weight, with a maximum daily dose of 1.8 mg/kg and a total maximum dose of 14.4 mg/kg over the treatment period. The administration schedule is designed to ensure optimal therapeutic levels while monitoring for adverse events, particularly peripheral neuropathy.

**Gemcitabine hydrochloride** is included as a non-experimental treatment in the study. It is administered as a chemical compound via intravenous infusion. The dosage is determined by body surface area, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 8000 mg over the treatment period. Compliance is assessed through infusion records and patient monitoring.

**Oxaliplatin** is another non-experimental treatment used in the study, administered intravenously as a chemical compound. The dosage is based on body surface area, with a maximum daily dose of 100 mg/m² and a total maximum dose of 800 mg over the treatment period. The administration is closely monitored to ensure adherence to the protocol and to manage any potential side effects.

The efficacy of the investigational treatment in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the incidence, nature, and severity of physical findings and adverse events (AEs), with a specific focus on **peripheral neuropathy**, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0) in Stage 1, and overall survival (OS) in Stage 2. Secondary endpoints encompass a range of measures, including the incidence and assessment of peripheral neuropathy using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-/GOG-NTX-12) in Stage 1, and the incidence, nature, and severity of AEs according to NCI CTCAE v5.0 in Stage 2.

Additional secondary endpoints include tolerability, as measured by dose interruptions, dose reductions, and dose intensity across both stages, and the prevalence and incidence of anti-drug antibodies (ADAs) to polatuzumab vedotin. The complete response (CR) and overall response rate (ORR) will be determined by both an independent review committee (IRC) and investigators. Progression-free survival (PFS), event-free survival (EFSeff), duration of response (DOR), and time to deterioration in physical functioning and fatigue, as well as time to progression in lymphoma symptoms, will also be evaluated. These assessments will be conducted using validated scales and instruments, such as the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30, and the FACT/GOG-NTX-12 subscale score, at various timepoints throughout the trial duration.