Randomized Phase 3 Study of ONC-392 Versus Docetaxel in Metastatic Non-Small Cell Lung Cancer Post-PD-1/PD-L1 Inhibitor Progression

The primary objective of this study is to evaluate the **efficacy** of ONC-392 compared to docetaxel in patients with metastatic non-small cell lung cancer, specifically by measuring overall survival (OS). This is clinically relevant as it directly assesses the potential of ONC-392 to improve survival outcomes in a patient population that has progressed on PD-1/PD-L1 inhibitors, a common treatment pathway for this type of cancer.

Secondary objectives include:

• Assessing the efficacy of ONC-392 versus docetaxel by objective response rate (ORR) and progression-free survival (PFS), which provides additional insights into the treatment's impact on tumor response and disease progression.
• Evaluating the safety and tolerability of ONC-392 compared to docetaxel, which is crucial for understanding the risk-benefit profile of the treatment.
• Determining the incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), immune-related adverse events (irAEs), and adverse events (AEs) leading to treatment discontinuation, which helps in identifying potential safety concerns associated with ONC-392.

The clinical trial involves a total of **465 participants** diagnosed with **Metastatic Non-Small Cell Lung Cancer**. The study population includes adults aged 18 years and older, encompassing all genders. Participants were selected based on their ability to provide informed consent and a confirmed histological or cytological diagnosis of metastatic NSCLC, with metastasis present in regional lymph nodes or distant organs. The trial population is characterized by individuals who have experienced radiographic progression following specific prior treatments, including PD-1/PD-L1 inhibitors combined with platinum-based chemotherapy. Participants are required to have at least one measurable tumor lesion according to RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function, with serum LDH levels not exceeding twice the upper limit of normal. The study does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to assess the efficacy of ONC-392 compared to docetaxel, with overall survival as the primary endpoint.

The clinical trial is a **randomized**, two-stage, **controlled** study designed to evaluate the efficacy of ONC-392 compared to **docetaxel** in patients with **metastatic non-small cell lung cancer** (NSCLC) that has progressed following treatment with PD-1/PD-L1 inhibitors. The primary objective is to assess overall survival (OS), with secondary endpoints including objective response rate (ORR), progression-free survival (PFS), and the incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), immune-related adverse events (irAEs), and adverse events (AEs) leading to treatment discontinuation. The trial is expected to last until August 2026, with recruitment starting in November 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, previous treatment history, and organ function. Following randomization, participants will receive either ONC-392 or docetaxel, with treatment cycles continuing for a maximum of 52 weeks or until disease progression or unacceptable toxicity occurs. Regular follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted by Blinded Independent Central Review (BICR) per RECIST 1.1 guidelines. The end-of-study visit will occur after the final treatment cycle or upon early termination.

Participant involvement is expected to last up to 52 weeks, contingent upon individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant disease progression, the occurrence of severe adverse events, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of two experimental medications. The first medication is **Docetaxel**, marketed under the name Docetaxel EVER Valinject 20 mg/ml. It is provided as a **solution for infusion** and is manufactured by EVER VALINJECT GMBH. The active substance, **docetaxel**, is of chemical origin. The medication is administered as a concentrate for solution for infusion, with a maximum daily dose of 75 mg/m² and a total maximum dose of 1275 mg/m² over a treatment period of up to 52 weeks. The administration route is intravenous infusion, and the dosing schedule is determined based on the patient's body surface area. Compliance with the dosing regimen is monitored throughout the study.

The second experimental medication is ONC-392, a **humanised IgG1 monoclonal antibody against CD152**, provided as a **solution for injection**. This medication is developed by ONCOC4 INC. The active substance is of protein origin, specifically classified as "Protein - Other." ONC-392 is administered via intravenous infusion, with a maximum daily dose of 10 mg/kg and a total maximum dose of 110 mg/kg over a treatment period of up to 52 weeks. The dosing schedule is based on the patient's body weight, and adherence to the treatment protocol is closely monitored to ensure participant compliance.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The primary objective of the trial is to evaluate the efficacy of ONC-392 compared to docetaxel in patients with metastatic non-small cell lung cancer that has progressed following treatment with PD-1/PD-L1 inhibitors, with overall survival as the primary endpoint.

The efficacy of the investigational products in the clinical trial will be assessed primarily through the measurement of **overall survival (OS)**. This parameter serves as the primary endpoint to evaluate the comparative effectiveness of ONC-392 versus docetaxel in patients with metastatic non-small cell lung cancer (NSCLC) that has progressed following treatment with PD-1/PD-L1 inhibitors. Secondary endpoints include the **objective response rate (ORR)** and **progression-free survival (PFS)**, both of which will be assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 criteria. Additionally, the incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), immune-related adverse events (irAEs), and adverse events leading to treatment discontinuation will be monitored.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial, with assessments aligned with the trial's schedule. The trial is structured as a Phase 3, two-stage, randomized study, and the efficacy assessments will be performed in accordance with the trial's protocol to ensure the reliability and validity of the data collected. The trial is expected to conclude by August 2026, with recruitment starting in November 2023.