Phase 3 Multicenter Randomized Open-label Study of Ifinatamab Deruxtecan Versus Physician's Choice in Relapsed Small Cell Lung Cancer

The primary objective of this Phase 3 study is to compare the **efficacy** of Ifinatamab Deruxtecan (I-DXd), an antibody-drug conjugate, with the standard of care (SoC) in patients with relapsed **Small Cell Lung Cancer (SCLC)**. This comparison will be based on objective response rate (ORR) and overall survival (OS), which are critical endpoints in assessing the therapeutic benefit and survival advantage of I-DXd over existing treatments.

Secondary objectives include:

• To further evaluate the efficacy of I-DXd compared to SoC using additional measurements.
• To assess patient-reported outcomes (PROs) when comparing the impact on health-related quality of life of I-DXd with SoC.
• To evaluate the safety and tolerability of I-DXd compared to SoC and to determine whether I-DXd triggers an immune response.
• To examine the level of B7-H3 protein in tumor tissue and understand its connection with tumor response.
• To evaluate the pharmacokinetics (PK) of I-DXd, including its absorption, distribution, and elimination from the body.

The clinical trial involves a total of **304 participants** diagnosed with **Small Cell Lung Cancer (SCLC)**. The study population includes both male and female adults aged 18 years and older, with a focus on those who have histologically or cytologically documented extensive-stage SCLC. Participants were selected based on specific criteria, including having received prior therapy with only one platinum-based line as systemic therapy for SCLC, and having at least one measurable lesion according to RECIST v1.1. The trial population is characterized by a requirement for adequate baseline tumor samples and documentation of radiological disease progression. Participants must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 and no evidence of untreated brain or leptomeningeal disease. The study includes individuals from vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, multicenter, randomized, open-label study designed to evaluate the efficacy of **Ifinatamab deruxtecan** (I-DXd), an antibody-drug conjugate, compared to the treatment of physician's choice in subjects with relapsed **Small Cell Lung Cancer (SCLC)**. The primary objective is to assess the objective response rate (ORR) and overall survival (OS) of participants. The trial is expected to commence recruitment on August 12, 2024, and conclude by May 8, 2029.

Participants will be randomly assigned to receive either I-DXd or a standard of care treatment. The study will involve a series of visits, starting with a screening visit to confirm eligibility based on criteria such as age, documented extensive-stage SCLC, and previous treatment history. Eligible participants will then proceed to the treatment phase, where they will receive the assigned intervention via **intravenous** infusion. The maximum treatment period is set at 60 days, with the dosage of I-DXd not exceeding 12 mg/kg per day.

Follow-up visits will be scheduled to monitor the participants' response to treatment and assess any adverse events. These visits will include evaluations of tumor response using RECIST v1.1 criteria, as well as assessments of health-related quality of life and the presence of antidrug antibodies. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be necessitated by factors such as disease progression, unacceptable toxicity, or withdrawal of consent.

The expected duration of participant involvement in the trial is approximately 60 days, with additional time allocated for follow-up assessments. Participants may be withdrawn from the study if they experience significant adverse effects, demonstrate disease progression, or choose to discontinue participation. The trial's design ensures rigorous monitoring and evaluation to achieve its primary and secondary endpoints, contributing valuable data to the understanding of treatment efficacy in relapsed SCLC.

The clinical trial involves the administration of **Ifinatamab deruxtecan**, an investigational **antibody-drug conjugate (ADC)**, designed for intravenous infusion. The pharmaceutical form of Ifinatamab deruxtecan is a **solution for infusion**, and it is administered at a maximum daily dose of 12 mg/kg. The treatment period is set for a maximum of 60 days. Ifinatamab deruxtecan is a protein-based therapeutic agent, specifically targeting B7-H3, and is provided by DAIICHI SANKYO, INC. The administration of this investigational drug is monitored to ensure compliance with the dosing schedule and to evaluate its efficacy in subjects with relapsed small cell lung cancer (SCLC).

In addition to the experimental treatment, the study includes the use of **Topotecan** as a comparator treatment. Topotecan is a **chemotherapy** agent available in two pharmaceutical forms: a **powder for concentrate for solution for infusion** and a **concentrate for solution for infusion**. Both forms are administered intravenously. The maximum daily dose for Topotecan is 4 mg, with a treatment period also extending up to 60 days. The administration of Topotecan involves relabeling and repackaging, although there is no change to the primary package. Compliance with the dosing regimen is monitored to ensure accurate assessment of its comparative efficacy against Ifinatamab deruxtecan in the study population.

The efficacy of the investigational drug **Ifinatamab Deruxtecan** (I-DXd) will be assessed in a Phase 3, multicenter, randomized, open-label clinical trial involving participants with relapsed Small Cell Lung Cancer (SCLC). The primary endpoints for evaluating efficacy include the **Objective Response Rate (ORR)** and **Overall Survival (OS)**. ORR is defined as the percentage of participants who achieve a confirmed complete response, indicating no detectable cancer, or a confirmed partial response, characterized by a reduction in tumor size. This assessment will be conducted by a blinded independent central review. OS is measured as the time interval from the date of randomization to the date of death from any cause.

Secondary endpoints include ORR as assessed by the investigator, progression-free survival, duration of response, disease control rate, time to response, patient-reported outcomes (PROs) related to health-related quality of life, adverse events, antidrug antibody prevalence, and the correlation of B7-H3 protein expression in tumor tissue with clinical outcomes. Pharmacokinetics (PK) will also be evaluated. The trial aims to compare the efficacy of I-DXd with the standard of care (SoC) in participants with SCLC, with the primary objective of determining whether I-DXd provides superior clinical benefits.