A Phase II, Open-label, Platform Study, to Evaluate Immunotherapy-based Combinations in Participants With Advanced Non-Small Cell Lung Cancer

The primary objective of this study is to evaluate the **objective response rate (ORR)** of immunotherapy-based combination therapy in participants with advanced non-small cell lung cancer. This is clinically relevant as ORR is a critical measure of the efficacy of cancer treatments, indicating the proportion of patients whose cancer shrinks or disappears after treatment. Additionally, the study aims to assess the safety and tolerability of these combination therapies, which is essential for determining the risk-benefit profile of the treatment regimen.

Secondary objectives include:

• Assessing the clinical activity of the immunotherapy-based combination therapy, based on investigator assessment according to RECIST v1.1, where applicable.
• Describing the pharmacokinetic (PK) profile of the investigational study treatments.
• Describing the immunogenicity of investigational biologic study treatments.

The clinical trial involves a total of **323 participants** diagnosed with **Advanced Non-Small Cell Lung Cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of Stage IV metastatic non-small cell lung cancer, as per the American Joint Committee on Cancer Version 8. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have at least one measurable target lesion according to RECIST v1.1 criteria. Adequate organ function, including hematologic counts, hepatic function, and creatinine clearance, is necessary for inclusion. The trial population also includes vulnerable groups, ensuring a comprehensive assessment of the therapy's efficacy and safety across diverse demographics. Lifestyle factors such as diet and physical activity are not specified, and the sponsor has not provided additional information regarding these aspects.

The clinical trial is designed to evaluate the efficacy and safety of immunotherapy-based combination treatments in participants with **advanced non-small cell lung cancer**. This is a Phase II, open-label, platform study. The trial employs a randomized, controlled design to ensure robust and unbiased results. The estimated duration of the trial is from December 1, 2023, to March 31, 2025, with the primary objective being to assess the objective response rate (ORR) and the safety and tolerability of the treatments. Participants will be involved in the study for a maximum treatment period of 304 weeks, depending on the specific treatment arm they are assigned to.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as histologically or cytologically documented Stage IV metastatic NSCLC, ECOG performance status of 0 to 1, and adequate organ function. Participants must also provide pretreatment tumor tissue. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints, including overall survival (OS), progression-free survival (PFS), and disease control rate (DCR).

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study duration. The investigational products, including **carboplatin**, **paclitaxel**, **pemetrexed**, **docetaxel**, **quemliclustat**, **cisplatin**, **domvanalimab**, and **zimberelimab**, will be administered intravenously, with dosing and administration schedules tailored to each treatment arm. The trial aims to provide valuable insights into the potential benefits of these combination therapies in treating advanced non-small cell lung cancer.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Carboplatin**, marketed as Carboplatine Hikma 450 mg/45 ml oplossing voor infusie, is provided as a **solution for infusion**. The maximum daily dose is 900 mg, with a total maximum dose of 3600 mg over a treatment period of 12 weeks. The administration route is **intravenous**.

**Paclitaxel**, available as Paclitaxel Ribosepharm 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung, is also a **solution for infusion**. The maximum daily dose is 200 mg/m², with a total maximum dose of 2400 mg/m² over 12 weeks. This medication is administered intravenously.

**Pemetrexed**, under the name Pemetrexed STADA 25 mg/ml Konzentrat zur Herstellung einer Infusionslösung, is provided as a **concentrate for solution for infusion**. The maximum daily dose is 500 mg/m², with a total maximum dose of 50666 mg/m² over a treatment period of 304 weeks. The administration is via the intravenous route.

**Docetaxel**, marketed as Docetaxel Hikma 160 mg/8 ml Konzentrat zur Herstellung einer Infusionslösung, is a **solution for infusion**. The maximum daily dose is 75 mg/m², with a total maximum dose of 5800 mg/m² over 58 weeks. It is administered intravenously.

**Quemliclustat** is provided as a **solution for injection**. The maximum daily dose is 300 mg, with a total maximum dose of 30400 mg over 304 weeks. The administration route is intravenous.

**Cisplatin**, available as Cisplatine Teva 1 mg/ml solution à diluer pour perfusion, is an **injection**. The maximum daily dose is 75 mg/m², with a total maximum dose of 300 mg/m² over 12 weeks. It is administered intravenously.

**Domvanalimab** is provided as a **concentrate for solution for infusion**. The maximum daily dose is 1200 mg, with a total maximum dose of 121600 mg over 304 weeks. The administration route is intravenous.

**Zimberelimab** is also a **concentrate for solution for infusion**. The maximum daily dose is 360 mg, with a total maximum dose of 36480 mg over 304 weeks. It is administered intravenously.

All medications are administered intravenously, and participant compliance is monitored throughout the study. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are used in this study. The trial aims to evaluate the efficacy and safety of these immunotherapy-based combinations in participants with advanced non-small cell lung cancer.

The efficacy of the clinical trial will be assessed using the **Objective Response Rate (ORR)** as the primary endpoint. ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) as measured by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) and assessed by the investigator. Secondary endpoints include overall survival (OS), progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), plasma or serum concentration of investigational study treatments, and estimated pharmacokinetic (PK) parameters. Additionally, the percentage of biologic treatment-emergent antidrug antibody (ADA)-positive participants and ADA-negative participants will be evaluated.

The trial will involve participants with advanced non-small cell lung cancer (NSCLC) and will assess the efficacy of immunotherapy-based combination therapy. The trial is designed as a Phase II, open-label, platform study. The schedule for measuring and collecting efficacy parameters will be aligned with the trial's protocol, ensuring that assessments are conducted at appropriate intervals to capture meaningful data on the treatment's impact on the disease. The use of RECIST v1.1 criteria ensures a standardized approach to evaluating tumor response, facilitating consistent and reliable efficacy assessments across the study population.