Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab with Chemoradiation and Olaparib in Limited-Stage Small Cell Lung Cancer

The primary objective of this study is to compare **progression-free survival** (PFS) and **overall survival** (OS) in participants with newly diagnosed, treatment-naïve limited-stage small cell lung cancer (LS-SCLC). These endpoints are clinically relevant as they provide insights into the efficacy of the treatment regimens in delaying disease progression and improving survival outcomes.

Secondary objectives include:

• Evaluating the safety and tolerability of concurrent chemoradiation therapy (CCT) with pembrolizumab followed by pembrolizumab plus olaparib compared to CCT alone.
• Assessing the safety and tolerability of CCT with pembrolizumab followed by pembrolizumab compared to CCT alone.
• Comparing the objective response rate (ORR) and duration of response (DOR) between different treatment groups as assessed by BICR per RECIST 1.1.
• Evaluating changes in global health status/quality of life (QoL) and time to true deterioration (TTD) in QoL between treatment groups.
• Assessing the effect of programmed cell death ligand 1 (PD-L1) expression levels on OR, DOR, PFS, and OS.

The clinical trial involves a total of **594 participants** diagnosed with **Limited Stage-Small Cell Lung Cancer** (LS-SCLC) who have not received any prior anticancer therapy for their condition. The study population includes both male and female subjects, aged 18 years and older, who are not pregnant and adhere to contraceptive guidance if of childbearing potential. Participants are required to have adequate organ function and an **Eastern Cooperative Oncology Group (ECOG) Performance score** of 0 or 1, indicating a good general health status. The trial population was selected based on specific criteria, including the absence of metastatic disease and the ability to be safely treated with definitive radiation doses. Lifestyle considerations such as abstaining from breastfeeding and sperm donation during the study period are also noted. The trial does not include individuals with mixed tumor histology or those who have previously undergone treatment for LS-SCLC. Participants must have a life expectancy of at least six months and provide a pre-treatment tumor tissue sample. The study aims to compare progression-free survival and overall survival among the participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 3 study. It aims to evaluate the efficacy and safety of **pembrolizumab** in combination with concurrent chemoradiation therapy, followed by pembrolizumab with or without **olaparib**, compared to concurrent chemoradiation therapy alone in participants with newly diagnosed, treatment-naïve limited-stage small cell lung cancer (LS-SCLC). The trial is expected to run from December 2020 to February 2028, with the primary objectives being to compare progression-free survival (PFS) and overall survival (OS) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed small cell lung cancer, adequate organ function, and no prior anticancer therapy. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes, including PFS and OS. The expected length of participant involvement is up to 66 weeks, depending on the treatment arm and individual response to therapy.

Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will also monitor secondary endpoints such as the number of participants experiencing adverse events, objective response rates, and changes in quality of life measures. The study will ensure that all participants adhere to contraceptive guidance and other safety protocols throughout the trial duration.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Etoposide** is utilized in this study as a chemical agent. It is administered in the form of a pharmaceutical formulation identified as PHF675. The dosage is calculated based on body surface area, with a maximum daily dose of 100 mg/m² and a total maximum dose of 1200 mg/m² over a treatment period of 12 weeks. The route of administration is via **intravenous infusion**.

**Pembrolizumab**, marketed as KEYTRUDA, is another experimental medication used in this trial. It is provided as a 25 mg/mL concentrate for solution for infusion. The maximum daily dose is 400 mg, with a total maximum dose of 4400 mg over a 66-week period. This biological agent is also administered through intravenous infusion.

**Carboplatin** is included as a chemical agent in the trial, with a pharmaceutical form designated as PHF00230MIG. The maximum daily dose is 750 mg, and the total maximum dose is 3000 mg over a 12-week period. Administration is conducted via intravenous infusion.

**Cisplatin** is another chemical agent used, with a pharmaceutical form also identified as PHF00230MIG. The dosing is based on body surface area, with a maximum daily dose of 75 mg/m² and a total maximum dose of 300 mg/m² over a 12-week period. It is administered through intravenous infusion.

**Olaparib** is administered in the form of a film-coated tablet. The maximum daily dose is 600 mg, with a total maximum dose of 219,000 mg over a 12-month period. The route of administration is oral. This chemical agent is used as a test product in the trial.

Non-experimental treatments include **placebos** for both Olaparib and Pembrolizumab. The Olaparib matching placebo is provided in tablet form, while the Pembrolizumab placebo is administered as a saline solution. These placebos are used to maintain the double-blind nature of the study.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The study aims to evaluate the efficacy and safety of these treatments in participants with newly diagnosed treatment-naïve limited-stage small cell lung cancer (LS-SCLC).

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-free Survival (PFS)** and **Overall Survival (OS)**. PFS is defined as the time from randomization to progression or death due to any cause, whichever occurs first, and OS is the time from randomization to death due to any cause. These endpoints will be evaluated according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR).

Secondary endpoints include the number of participants experiencing adverse events (AEs), the number of participants discontinuing study treatment due to AEs, and Objective Response (OR), which includes complete response (CR) or partial response (PR). The Duration of Response (DOR) will also be measured, defined as the time from the earliest date of first documented evidence of confirmed CR or PR until the earliest date of disease progression or death from any cause. Additionally, changes from baseline in various quality of life measures will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13).

These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, including baseline and subsequent cycles. The tools and instruments involved in these assessments include validated scales such as the EORTC QLQ-C30 and QLQ-LC13, which measure aspects like global health status, cough, chest pain, dyspnea, and physical functioning. The trial aims to provide comprehensive data on the efficacy of the treatment regimen in participants with newly diagnosed treatment-naïve limited-stage small cell lung cancer (LS-SCLC).