Evaluation of Mosunetuzumab and Polatuzumab Vedotin Combination in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Patients

The primary objective of this study is to evaluate the **safety** and tolerability of mosunetuzumab (Mosun) in combination with polatuzumab vedotin (Pola) in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). This includes estimating the maximum tolerated dose, determining the recommended Phase II dose (RP2D), and characterizing dose-limiting toxicity (DLT). Additionally, a preliminary assessment of the anti-tumor activity of Mosun + Pola will be conducted. The clinical relevance of this objective lies in its potential to establish a new therapeutic regimen for patients with R/R B-cell non-Hodgkin lymphoma, a condition with limited treatment options.

Secondary objectives include: - Characterizing the pharmacokinetics of Mosun (subcutaneous and intravenous) as a single agent and in combination with Pola. - Assessing the incidence of anti-drug antibodies (ADAs) to Mosun and Pola. - Evaluating the efficacy of Mosun + Pola in R/R DLBCL, R/R FL, and R/R mantle cell lymphoma (MCL) based on best objective response rate (ORR), best complete response (CR) rate, CR rate at primary response assessment (PRA), ORR at PRA, duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS). - Evaluating the safety of Mosun + Pola in R/R DLBCL, R/R FL, and R/R MCL.

The clinical trial involves a total of **218 participants** diagnosed with **B-cell non-Hodgkin lymphoma (NHL)**, specifically focusing on relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2, indicating a range from fully active to ambulatory and capable of all self-care but unable to carry out any work activities. Participants were selected based on their histologically confirmed diagnosis of R/R FL, DLBCL, or MCL, and their prior treatment history, which for DLBCL or FL includes at least one prior systemic treatment regimen containing an anti-cluster of differentiation 20 (CD20)-directed therapy, and for MCL, at least two prior systemic treatment regimens including agents from all three specified classes. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study aims to evaluate the safety, tolerability, and efficacy of the combination of mosunetuzumab and polatuzumab vedotin in this patient population.

The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and efficacy of **mosunetuzumab** in combination with **polatuzumab vedotin** in patients with B-cell non-Hodgkin lymphoma (NHL). This trial is structured as a Phase Ib/II, open-label, multicenter study. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from March 29, 2021, to July 31, 2025, allowing for comprehensive assessment of the investigational treatments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), or mantle cell lymphoma (MCL), and previous treatment history. Following the screening, participants will be randomized to receive the investigational treatments. The trial includes multiple follow-up visits to monitor safety, adverse events, and treatment efficacy, with assessments conducted by both investigators and an Independent Review Committee (IRC). The end-of-study visit will conclude the participant's involvement, with final evaluations of treatment outcomes and any long-term effects.

The expected length of participant involvement varies depending on individual response and tolerance to the treatment, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The primary endpoints focus on the occurrence and severity of adverse events, changes in vital signs and laboratory test results, and the best overall response rate (ORR) as determined by the investigator and IRC. Secondary endpoints include progression-free survival (PFS), event-free survival (EFS), and overall survival (OS), among others. The trial aims to establish the maximum tolerated dose and recommended Phase II dose, while also making preliminary assessments of anti-tumor activity.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Mosunetuzumab** is a humanized bispecific antibody used as an experimental treatment in this study. It is available in two pharmaceutical forms: a **solution for infusion** and a **solution for injection**. The administration routes include both **intravenous infusion** and **subcutaneous injection**. The dosing schedule and frequency are determined based on the phase of the trial and the specific protocol requirements.

**Polatuzumab vedotin** is another experimental treatment, classified as an antibody-drug conjugate (ADC). It is provided as a **powder for concentrate for solution for infusion** and administered via **intravenous infusion**. The dosing regimen is tailored to the study's objectives, focusing on safety and efficacy in combination with mosunetuzumab.

**Tocilizumab**, a recombinant humanized anti-human monoclonal antibody, is used as a non-experimental treatment. It is available as a **concentrate for solution for infusion** and administered through **intravenous infusion**. This treatment is included to manage potential inflammatory responses during the trial.

**Rituximab**, a human monoclonal antibody, is provided as a **concentrate for solution for infusion** and administered via **intravenous infusion**. It serves as a standard-of-care therapy in the study, particularly for patients with B-cell non-Hodgkin lymphoma.

**Prednisolone** and **methylprednisolone** are corticosteroids used as auxiliary treatments. Prednisolone is administered as a **solution for infusion** via **intravenous infusion**, while methylprednisolone is also provided as a **solution for infusion** with the same route of administration. These medications are used to manage inflammation and other symptoms associated with the disease or treatment.

**Paracetamol** is included as an analgesic to manage pain and discomfort. It is administered orally in **tablet** form. The dosing schedule is adjusted based on the patient's needs and the trial protocol.

**Diphenhydramine hydrochloride** and **benzocaine** are combined as an antihistamine treatment, provided in a **pharmaceutical form** suitable for **intravenous infusion**. This combination is used to manage allergic reactions or side effects during the trial.

**Allopurinol** is used as a xanthine oxidase inhibitor to manage uric acid levels. It is administered orally, and the dosing is adjusted according to the patient's condition and trial requirements.

**Fludeoxyglucose (18F)** is a radiopharmaceutical used for imaging purposes in the trial. It is administered via **intravenous infusion** to facilitate the assessment of treatment efficacy through imaging techniques.

Participant compliance with the dosing schedules and administration routes is monitored throughout the trial to ensure adherence to the protocol and to evaluate the safety and efficacy of the treatments. The trial's design includes regular assessments and adjustments to the treatment regimens based on the participants' responses and any observed adverse effects.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the occurrence and severity of adverse events, including dose-limiting toxicities (DLTs) in Phase Ib, and the best objective response rate (ORR) as determined by the Independent Review Committee (IRC) in Phase II. Additionally, the complete response (CR) rate at the time of primary response assessment (PRA) and the duration of response (DOR) will be evaluated in Phase Ib.

Secondary endpoints will further assess efficacy by determining the best ORR and CR rate as evaluated by both the investigator and IRC in Phase II. Other secondary endpoints include progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) in Phase II. The trial will also monitor changes from baseline in targeted vital signs and clinical laboratory test results, as well as pharmacokinetic parameters such as maximum serum concentration (Cmax), minimum serum concentration (Cmin), total exposure area under the concentration-time curve (AUC), clearance, and volume of distribution for **Mosunetuzumab** in both Phase Ib and II.

The efficacy assessments will be conducted at various timepoints throughout the trial, with specific measurements and analyses performed by the investigator and IRC. The trial aims to provide a comprehensive evaluation of the efficacy of **Mosunetuzumab** in combination with **Polatuzumab Vedotin** in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).