Phase II Study of Niraparib and Dostarlimab in Advanced NSCLC or Malignant Pleural Mesothelioma with PD-L1 Expression and HRR Gene Mutations

The primary objective of this Phase II, open-label, single-arm, multicenter study is to evaluate the **progression-free survival (PFS)** in patients with advanced non-small cell lung cancer and/or malignant pleural mesothelioma, who are positive for PD-L1 expression and have germline or somatic mutations in the HRR genes. Assessing PFS is clinically relevant as it provides insights into the efficacy of the combination therapy of Niraparib and Dostarlimab in delaying disease progression in this patient population.

Secondary objectives include evaluating the following:

• Objective response rate (ORR)
• Duration of response (DOR)
• Disease control rate (DCR)
• Overall survival (OS)
• Safety and tolerability of the combination therapy

The clinical trial involves participants diagnosed with **pleural mesothelioma** or **non-small cell lung cancer**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to have a performance status of 0-1, indicating they are in relatively good health with adequate organ functions. The trial does not include vulnerable populations. Participants must have experienced disease progression following at least one previous systemic therapy line and exhibit germline and/or somatic mutations in DNA shelter genes, with PD-L1 expression equal to or greater than 1%. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the necessity for measurable disease according to RECIST criteria and consent to biological material analysis, such as tissue biopsy. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

The clinical trial is a **Phase II**, open-label, single-arm, prospective, multicenter study designed to evaluate the efficacy and safety of a combination therapy involving **niraparib** and **dostarlimab** in patients diagnosed with advanced **non-small cell lung cancer** and/or **pleural mesothelioma**. The primary objective is to assess progression-free survival (PFS), while secondary endpoints include evaluating the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), overall survival (OS), and the safety and tolerability of the drug combination. The trial is expected to run from February 1, 2021, to December 31, 2025, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of mesothelioma or non-small cell lung cancer, disease progression after at least one systemic therapy, and the presence of germline or somatic mutations in DNA shelter genes with PD-L1 expression ≥ 1%. Additional criteria include age between 18 and 75, measurable disease per RECIST criteria, and adequate organ function. Following the screening, participants will receive **niraparib** orally and **dostarlimab** via intravenous infusion according to the study protocol.

Regular follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse effects. These visits will include assessments of disease progression, laboratory tests, and imaging studies as required. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by factors such as disease progression, unacceptable toxicity, or withdrawal of consent. The expected length of participant involvement is up to 24 months, contingent upon individual response and tolerability to the treatment regimen.

The clinical trial involves the administration of **NIRAPARIB**, an experimental medication, in the form of a **capsule**. The active substance, **niraparib**, is of chemical origin. The medication is administered **orally** with a maximum daily dose of **300 mg**. The treatment period is set for a maximum of **24 months**. Participants' compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to **niraparib**, the study also includes the administration of **JEMPERLI 500 mg concentrate for solution for infusion**, which contains the active substance **dostarlimab**. This medication is a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose for **dostarlimab** is **1000 mg**, and similar to **niraparib**, the treatment period is capped at **24 months**. The active substance **dostarlimab** is of protein origin, specifically categorized as "Protein - Other." Monitoring of participant compliance with the dosing schedule will be conducted to ensure proper administration and adherence to the treatment protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study. The trial is designed to evaluate the progression-free survival (PFS) in patients with advanced non-small cell lung cancer and/or malignant pleural mesothelioma, who are positive for PD-L1 expression and have germline or somatic mutations in the HRR genes.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. This parameter serves as the primary endpoint and will be measured to determine the time during which patients with advanced non-small cell lung cancer and/or malignant pleural mesothelioma, who are positive for PD-L1 expression and have germline or somatic mutations in the HRR genes, remain free from disease progression. Secondary endpoints include the evaluation of the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), overall survival (OS), and the safety and tolerability of the combination of Niraparib and Dostarlimab. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to provide comprehensive insights into the therapeutic impact of the treatment regimen.