A Randomized, Double-Blind, Placebo-Controlled Study of Trilaciclib vs Placebo in Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) Receiving Topotecan Chemotherapy

The primary objective of this study is to evaluate whether **trilaciclib** administered prior to **topotecan** is non-inferior to placebo in terms of overall survival (OS) in patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC). This is clinically relevant as it aims to determine if trilaciclib can provide a survival benefit or maintain survival rates while potentially offering other therapeutic advantages.

Secondary objectives include:

• Assessing the effects of trilaciclib on anti-tumor endpoints such as progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).
• Evaluating the impact of trilaciclib on the neutrophil, red blood cell (RBC), and platelet lineages compared with placebo when administered prior to topotecan.
• Assessing the effects of trilaciclib on hospitalizations due to chemotherapy-induced myelosuppression compared with placebo.
• Evaluating the impact of trilaciclib on chemotherapy dosing compared with placebo.
• Collecting and summarizing safety and tolerability data for trilaciclib when administered prior to topotecan.

The clinical trial involves a total of **85 participants** diagnosed with **Extensive Stage Small Cell Lung Cancer** (ES-SCLC). The study population includes both male and female subjects, aged **18 years and older**, with an **ECOG performance status** of 0-2, indicating a range from fully active to ambulatory and capable of all self-care but unable to carry out any work activities. Participants were selected based on their confirmed diagnosis of ES-SCLC, progression during or after prior chemotherapy, and eligibility to receive topotecan chemotherapy. The trial population is characterized by adequate organ function and resolution of nonhematologic toxicities from previous treatments to a manageable level. Lifestyle considerations such as contraceptive use are aligned with local regulations for clinical study participants. The study includes a vulnerable population, ensuring that all participants are capable of providing informed consent. The selection criteria ensure that participants have measurable or evaluable disease as per RECIST v1.1 and known sensitivity status to first-line therapy at enrollment.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **trilaciclib** compared to placebo in patients with **extensive stage small cell lung cancer** (ES-SCLC) receiving **topotecan** chemotherapy. The primary objective is to assess whether trilaciclib administered prior to topotecan is non-inferior to placebo in terms of overall survival (OS). The trial is expected to run until May 3, 2027, with recruitment starting on October 16, 2023. Participants will be involved in the study for a maximum treatment period of 120 days.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age (≥18 years), ECOG performance status (0-2), and adequate organ function. Participants must have a confirmed diagnosis of ES-SCLC and be eligible for topotecan chemotherapy. Follow-up visits will occur regularly to monitor disease progression, treatment response, and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will also monitor secondary endpoints, including progression-free survival (PFS), objective response rate (ORR), and the occurrence of severe neutropenia. The trial will adhere to strict ethical guidelines, ensuring that all participants provide informed consent and that their safety is prioritized throughout the study duration.

The clinical trial involves the administration of several treatments, including **Topotecan**, **Trilaciclib**, and supportive care solutions such as **Sodium Chloride** and **Glucose Monohydrate**. The primary experimental medication is **Trilaciclib Dihydrochloride Dihydrate**, marketed under the code G1T28-1. This compound is administered as an **intravenous infusion** with a maximum daily dose of 240 mg/m² and a total dose of 1200 mg/m² over a treatment period of up to 120 days. The pharmaceutical form is an intravenous infusion, and the administration is conducted prior to chemotherapy sessions.

**Topotecan** is utilized in the trial in various formulations, including Topotecanum Accord, HYCAMTIN, and Topotecan Hikma. Each formulation is prepared as a **solution for infusion**. The maximum daily dose for Topotecan is 1.5 mg/m², with a total dose of 7.5 mg/m² over the treatment period. The route of administration is via **intravenous infusion**, and it is used in conjunction with Trilaciclib to assess its efficacy in patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC).

**Sodium Chloride** 0.9% Baxter is employed as a supportive care solution, provided as a **solution for infusion**. It is administered intravenously with a maximum daily volume of 250 ml and a total volume of 1250 ml over the course of the study. This solution serves as a standard-of-care therapy to maintain fluid balance and electrolyte levels during the trial.

**Glucose Monohydrate** is also included as a supportive care treatment, delivered as a **solution for infusion**. The administration is intravenous, with a maximum daily volume of 250 ml, matching the total volume for the treatment period. This solution is used to provide necessary caloric intake and support metabolic needs during the trial.

Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment protocol. The trial is designed to evaluate the non-inferiority of Trilaciclib compared to a placebo when administered prior to Topotecan in terms of overall survival in patients with ES-SCLC.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)**, which is defined as the time from randomization to death due to any cause for those who died, or time to last contact known as alive for those who survived in the study. Secondary efficacy endpoints include **Progression-Free Survival (PFS)**, defined as the time from randomization to disease progression using RECIST v1.1 or death due to any cause, whichever occurs first. Additional secondary endpoints include the **Objective Response Rate (ORR)**, duration of objective response, and various hematological parameters such as the duration and occurrence of severe neutropenia, febrile neutropenia adverse events, and occurrences of G-CSF administration.

Other secondary endpoints involve the occurrence of Grade 3 or 4 decreased hemoglobin and platelet count laboratory values, the number of RBC and platelet transfusions, and the occurrence and number of hospitalizations due to chemotherapy-induced myelosuppression. The study will also monitor all-cause dose reductions, cycle delays, and the occurrence and severity of adverse events by NCI CTCAE v5.0. The occurrence of study treatment discontinuation due to adverse events, as well as the occurrence of trilaciclib and topotecan infusion interruptions, will be recorded. The relative dose intensity of topotecan will also be evaluated.