Phase III Randomized Study of Volrustomig with Carboplatin and Pemetrexed Versus Standard Care in Unresectable Pleural Mesothelioma

The primary objective of this study is to demonstrate the superiority of **volrustomig** in combination with carboplatin plus pemetrexed compared to the investigator's choice of nivolumab in combination with ipilimumab or platinum plus pemetrexed. This will be assessed by evaluating overall survival (OS) in participants with unresectable pleural mesothelioma. The clinical relevance of this objective lies in potentially improving survival outcomes for patients with this aggressive and difficult-to-treat cancer.

Secondary objectives include:

• Demonstrating the effectiveness of volrustomig combined with carboplatin and pemetrexed relative to the investigator's choice of nivolumab plus ipilimumab or platinum plus pemetrexed by assessing OS, progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and second progression-free survival (PFS2).
• Assessing patient-reported physical functioning, disease-related symptoms, role functioning, and health-related quality of life (HRQoL) in participants receiving volrustomig with carboplatin and pemetrexed compared to the investigator's choice.
• Investigating the immunogenicity of volrustomig.
• Assessing the pharmacokinetics of volrustomig.
• Evaluating the safety and tolerability of volrustomig combined with carboplatin and pemetrexed compared to the investigator's choice of nivolumab plus ipilimumab or platinum plus pemetrexed.

The clinical trial involves a total of **304 participants** diagnosed with **unresectable pleural mesothelioma**. The study population includes both male and female subjects, aged 18 years and older, with a histologically confirmed diagnosis of pleural mesothelioma, either epithelioid or non-epithelioid. Participants were selected based on their advanced disease status, which is not amenable to curative surgery, and their ability to maintain a WHO/ECOG performance status of 0 or 1 without deterioration over the two weeks prior to the first dosing. The trial includes individuals with measurable disease as per modified RECIST1.1 criteria and those with adequate bone marrow reserve and organ function at baseline. The study population is inclusive of vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is a **Phase III**, randomized, open-label, multicenter study designed to evaluate the efficacy of **volrustomig** in combination with **carboplatin** and **pemetrexed** compared to the investigator's choice of **nivolumab** with **ipilimumab** or platinum with pemetrexed in participants with **unresectable pleural mesothelioma**. The primary objective is to assess overall survival (OS) in this patient population. The trial is expected to commence recruitment on March 1, 2024, and conclude by April 3, 2028. Participants will be randomly assigned to one of the treatment arms, ensuring a balanced distribution of baseline characteristics.

The study involves several key visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, histological diagnosis, and performance status. Following randomization, participants will undergo regular follow-up visits to monitor treatment response, safety, and tolerability. These visits will include assessments of disease progression, adverse events, and laboratory evaluations. The end-of-study visit will occur after the final treatment cycle or upon early termination, which may result from disease progression, unacceptable toxicity, or withdrawal of consent. The expected duration of participant involvement varies depending on the treatment arm and individual response, with a maximum treatment period of 36 months for certain drugs.

Throughout the trial, data on secondary endpoints such as progression-free survival (PFS), overall response rate, and duration of response will be collected. Safety assessments will include monitoring for adverse events, dose modifications, and discontinuations. The trial will also evaluate the incidence of anti-drug antibodies (ADAs) against volrustomig and pharmacokinetic parameters as data allow. Participants will be closely monitored to ensure adherence to the protocol and to address any safety concerns promptly. The study's design and procedures aim to provide robust data on the comparative efficacy and safety of the investigational treatment regimens in this challenging patient population.

The clinical trial involves several treatments, including both experimental and comparator medications. **Volrustomig** (MEDI5752) is an experimental medication used in this study. It is a **solution for infusion** and is administered via **intravenous use**. The active substance, volrustomig, is a protein-based therapeutic agent, specifically a human IgG1 monoclonal antibody engineered to target PD-1 and CTLA-4. The dosing schedule for volrustomig is determined by the study protocol, with a maximum treatment period extending indefinitely, as indicated by the time unit code of 999999.

**Pemetrexed** is utilized in two forms within the trial: as a **solution for infusion** and as a **concentrate for solution for infusion**. Both forms are administered intravenously. The maximum daily dose of pemetrexed is 1500 mg, with a treatment period of up to 36 weeks. Pemetrexed is a chemical compound used in combination with other agents in this study.

**Carboplatin** is also used in two forms: as a **solution for infusion** and as a **concentrate for solution for infusion**. It is administered intravenously, with a maximum daily dose of 750 mg and a treatment period of up to 36 weeks. Carboplatin is a chemical compound and serves as a comparator in the study.

**Nivolumab** is another treatment used in the trial, provided as a **solution for infusion** and administered intravenously. The maximum daily dose is 360 mg, with a treatment period of up to 24 weeks. Nivolumab is a biologic agent used in combination with other treatments.

**Ipilimumab** is administered as a **solution for infusion** via intravenous use. The maximum daily dose is 150 mg, with a treatment period of up to 24 weeks. Ipilimumab is a comparator treatment in the study.

**Cisplatin** is provided as a **solution for injection** and administered intravenously. The maximum daily dose is 210 mg, with a treatment period of up to 36 weeks. Cisplatin is a chemical compound used as a comparator in the study.

**Mycophenolate mofetil** is included in the study as **hard capsules** and is administered orally. The maximum daily dose is 3 g, with an indefinite treatment period. Mycophenolate mofetil is a chemical compound used as a comparator in the study.

**Infliximab** is administered as a **solution for infusion** via intravenous use. The dosing is based on body weight, with a maximum daily dose of 5 mg/kg and an indefinite treatment period. Infliximab is a biologic agent used as a comparator in the study.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **overall survival** (OS) in participants with unresectable pleural mesothelioma. The primary endpoint is to demonstrate the superiority of volrustomig in combination with carboplatin plus pemetrexed compared to the investigator's choice of nivolumab in combination with ipilimumab or platinum plus pemetrexed. Secondary endpoints include overall survival and progression-free survival (PFS) at various time points (12, 18, 24, and 36 months for OS; 6, 12, 18, and 24 months for PFS), overall response rate, duration of response, and PFS2, which is the time from randomization to the second progression event. Additional secondary endpoints involve time to deterioration (TTD) in physical functioning, changes from baseline in disease-related symptoms and functioning, incidence of anti-drug antibodies (ADAs) against volrustomig, and concentrations of volrustomig with pharmacokinetic (PK) parameters as data allow. Safety and tolerability will also be monitored through adverse events (AEs), rates of AE-related dose discontinuations/modifications, vital signs, clinical laboratory assessments, physical examinations, and electrocardiograms (ECGs).