Phase 3 Randomized 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 (NSCLC) that has progressed following treatment with PD-1/PD-L1 inhibitors. This is measured by overall survival (OS), which is a critical endpoint in oncology trials as it directly reflects the treatment's impact on patient longevity.

Secondary objectives include:

• Assessing the efficacy of ONC-392 versus docetaxel by objective response rate (ORR) and progression-free survival (PFS), which provide additional insights into the treatment's ability to reduce tumor size and delay disease progression.
• Evaluating the safety and tolerability of ONC-392 compared to docetaxel, which is essential 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 are crucial for assessing the treatment's safety.

The clinical trial involves a total of **542 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 squamous 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 a serum LDH level not exceeding twice the upper limit of normal. The study does not include vulnerable populations, and participants must have a life expectancy of at least three months. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is a **Phase 3**, two-stage, randomized study designed to evaluate the efficacy 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. 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 employs a double-blind, controlled design to ensure unbiased results.

Participants will be involved in the study for a maximum treatment period of 52 weeks. The trial is expected to commence recruitment on September 30, 2024, and conclude by November 20, 2027. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes. Participants must have a histologically or cytologically confirmed diagnosis of metastatic squamous NSCLC, with measurable tumor lesions according to RECIST 1.1, and an ECOG score of 0 or 1. Adequate organ function and a life expectancy of at least three months are also required.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will utilize **intravenous infusion** as the route of administration for both ONC-392 and docetaxel, with ONC-392 being a humanized IgG1 monoclonal antibody against CD152, and docetaxel being a standard chemotherapy agent. The study aims to provide valuable insights into the comparative effectiveness of these treatments in a specific patient population, contributing to the optimization of therapeutic strategies for metastatic NSCLC.

The clinical trial involves the administration of **ONC-392**, a **humanised IgG1 monoclonal antibody against CD152**. This experimental medication is provided in the form of a **solution for injection**. The administration route is via **intravenous infusion**. The dosing regimen for ONC-392 is set at a maximum daily dose of 10 mg/kg, with a total maximum dose of 170 mg/kg over the course of the treatment. The treatment period is capped at 52 weeks. The medication is developed by ONCOC4 INC. and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Docetaxel**, a well-established chemotherapeutic agent. Docetaxel is administered as a **concentrate for solution for infusion**. The dosing for Docetaxel is determined by body surface area, with a maximum daily dose of 75 mg/m² and a total maximum dose of 1275 mg/m² over the treatment period. Similar to ONC-392, the treatment duration for Docetaxel is also limited to 52 weeks. The active substance, Docetaxel, is of chemical origin and is not intended for pediatric use. Compliance with the administration schedule will be closely monitored to ensure adherence to the protocol.

The efficacy of the investigational product ONC-392, a **humanised IgG1 monoclonal antibody against CD152**, will be assessed in a Phase 3, two-stage, randomized clinical trial comparing it 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 endpoint for evaluating efficacy is overall survival (OS). Secondary endpoints include objective response rate (ORR) and progression-free survival (PFS), both assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 criteria, as well as 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.

Measurements of these endpoints will be conducted at specified intervals throughout the trial, with overall survival being the primary focus. The ORR and PFS will be evaluated using validated criteria to ensure consistency and reliability in the assessment of tumor response and disease progression. The trial is designed to provide a comprehensive evaluation of the efficacy of ONC-392 compared to docetaxel, with the aim of determining the potential benefits of the investigational product in this patient population.