Phase III Randomized Double-Blind Trial of Polatuzumab Vedotin, Rituximab, and CHP vs. Rituximab and CHOP in Untreated Diffuse Large B-Cell Lymphoma

The primary objective of this Phase III, multicenter, randomized, double-blind, placebo-controlled trial is to evaluate the **efficacy** of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated patients with diffuse large B-cell lymphoma (DLBCL), specifically focusing on progression-free survival (PFS). This is clinically relevant as improving PFS can significantly impact patient outcomes by delaying disease progression and potentially improving overall survival.

Secondary objectives include:

• Evaluating the efficacy of polatuzumab vedotin plus R-CHP compared with R-CHOP concerning secondary efficacy endpoints.
• Assessing the **safety** of polatuzumab vedotin plus R-CHP compared with R-CHOP.
• Characterizing the **pharmacokinetics** of polatuzumab vedotin.
• Evaluating the **immune response** to polatuzumab vedotin.

The clinical trial involves a total of **644 participants** diagnosed with **previously untreated diffuse large B-cell lymphoma (DLBCL)**. The study population includes both male and female subjects, with an age range corresponding to adults and older adults. Participants were selected based on specific criteria, including a diagnosis of CD20-positive DLBCL as per the 2016 WHO classification of lymphoid neoplasms, an International Prognostic Index (IPI) score of 2-5, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. Additionally, participants are required to have a life expectancy of at least 12 months and at least one bi-dimensionally measurable lesion. The trial also considers lifestyle factors such as general health status, with a requirement for a left ventricular ejection fraction (LVEF) of 50% or higher. The study includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse patient groups.

The clinical trial is a **Phase III**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **polatuzumab vedotin** in combination with **rituximab** and CHP (R-CHP) versus rituximab and CHOP (R-CHOP) in patients with previously untreated **diffuse large B-cell lymphoma** (DLBCL). The primary objective is to assess progression-free survival, while secondary endpoints include event-free survival, complete response rate, overall survival, and incidence of adverse events, among others. The trial is expected to conclude by June 2026, with recruitment having commenced in November 2017.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as CD20-positive DLBCL diagnosis, International Prognostic Index score, and measurable lesions. Following randomization, participants will receive treatment over a maximum period of 126 to 168 days, depending on the specific regimen. Follow-up visits will be scheduled to monitor treatment response and safety, utilizing assessments like FDG-PET scans and cardiac evaluations. The end-of-study visit will finalize data collection and assess long-term outcomes.

Participant involvement is anticipated to last until the end of the trial, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial's design ensures rigorous evaluation of the investigational treatment's impact on DLBCL, contributing valuable data to the field of oncology.

The clinical trial involves the administration of several **experimental medications**. **Vinorelbine**, marketed under the name **Vincristine**, is utilized in this study. It is a chemical substance administered in the form of a **PHF00007MIG** pharmaceutical formulation. The medication is delivered via **intravenous use**. The maximum daily dose is set at 2.0 mg, with a total maximum dose of 12.0 mg over a treatment period of 126 days. The product has been re-packed and re-labeled specifically for clinical trial use.

Another experimental medication used in the trial is **Polatuzumab Vedotin**, marketed as **Polivy 140 mg powder for concentrate for solution for infusion**. This protein-based substance is administered as a **solution for infusion** through **intravenous use**. The dosing regimen allows for a maximum daily dose of 1.8 mg/kg, with a total maximum dose of 10.8 mg/kg over a 126-day treatment period. The product is also re-packed and re-labeled for the purposes of the clinical trial.

**Rituximab**, marketed as **MabThera 500 mg concentrate for solution for infusion**, is another protein-based experimental medication included in the study. It is administered as a **solution for infusion** via **IV infusion**. The dosing schedule permits a maximum daily dose of 375 mg/m², with a total maximum dose of 3000 mg/m² over a treatment period of 168 days. Similar to the other medications, it has been re-packed and re-labeled for clinical trial use.

In addition to the experimental medications, the trial includes a standard-of-care therapy regimen known as R-CHOP, which consists of **Rituximab**, **Cyclophosphamide**, **Doxorubicin**, **Vincristine**, and **Prednisone**. This regimen serves as a comparator treatment to evaluate the efficacy of the experimental combination of **Polatuzumab Vedotin**, **Rituximab**, and CHP (Cyclophosphamide, Doxorubicin, and Prednisone). Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.

The efficacy of the clinical trial will be assessed by evaluating the **progression-free survival (PFS)**, which is defined as the time from randomization to the first occurrence of disease progression or relapse, as assessed by the investigator using the Lugano Response Criteria for Malignant Lymphoma, or death from any cause, whichever occurs earlier. Secondary endpoints include event-free survival, complete response rate at the end of treatment by fluorodeoxyglucose positron emission tomography (FDG-PET) as determined by blinded independent central review (BICR), overall survival, and 2-year progression-free survival rate (PFS24) as determined by the investigator. Additional secondary endpoints involve disease-free survival, duration of response, and time to deterioration in quality of life as measured by 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 (FACT-Lym) subscale.

The trial will also assess the incidence, nature, and severity of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0). The incidence of peripheral neuropathy rates and severity, as well as the incidence and nature of study drug discontinuation, dose reduction, and dose delay due to adverse events, will be monitored. Dose intensities of study drugs and plasma and/or serum concentration of polatuzumab vedotin-related analytes at specified time points will be measured. The incidence of anti-drug antibodies (ADAs) to polatuzumab vedotin during the study relative to the prevalence of ADAs at baseline will also be evaluated.