Efficacy and Safety Evaluation of Rapcabtagene Autoleucel Versus Rituximab in Severe Refractory Diffuse Cutaneous Systemic Sclerosis

The primary objective of this study is to demonstrate the superiority of **rapcabtagene autoleucel** at a target dose of CAR-positive viable T cells as a single infusion compared to **rituximab**. This will be assessed by the proportion of participants achieving a Revised Composite Response Index in Systemic Sclerosis 50 (rCRISS50) response at Week 52. This objective is clinically relevant as it aims to establish a more effective treatment option for patients with severe refractory diffuse cutaneous systemic sclerosis (dcSSc), a condition characterized by significant morbidity and limited therapeutic options.

Secondary objectives include:

• To demonstrate the efficacy of rapcabtagene autoleucel versus rituximab with respect to disease progression parameters.
• To assess the overall safety and tolerability of rapcabtagene autoleucel in participants with dcSSc.

The clinical trial involves a total of **57 participants** diagnosed with **diffuse cutaneous systemic sclerosis (dcSSc)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their fulfillment of the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis, specifically the diffuse cutaneous subset. The trial includes individuals with severe, progressive systemic sclerosis, characterized by conditions such as interstitial lung disease, skin disease, or cardiac involvement. The population is considered vulnerable, and lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants have experienced disease onset within seven years prior to the screening visit, marked by symptoms like puffy hands, scleroderma, or digital ulcers.

The clinical trial is designed as a **randomized**, open-label, assessor-blinded, active-controlled, multicenter study to evaluate the efficacy and safety of **rapcabtagene autoleucel** versus **rituximab** in participants with severe refractory diffuse cutaneous systemic sclerosis (dcSSc). The trial aims to demonstrate the superiority of rapcabtagene autoleucel at a target dose of CAR-positive viable T cells as a single infusion compared to rituximab, with respect to the proportion of participants achieving a Revised Composite Response Index in Systemic Sclerosis 50 (rCRISS50) response at Week 52. The study is expected to last for three years, with an estimated recruitment start date of December 2, 2024, and an estimated end date of August 30, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis. The inclusion criteria require disease onset from the first non-Raynaud symptoms attributable to systemic sclerosis within seven years prior to the screening visit, and severe, progressive systemic sclerosis disease. The primary endpoint is the achievement of a treatment response as per the rCRISS50 definition at Week 52. Secondary endpoints include changes from baseline in FVC% predicted, mRSS, and HAQ-DI at Week 52, as well as the achievement of Week 156 progression-free survival.

Participants will be involved in the study for a maximum treatment period of 130 weeks, with follow-up visits scheduled to monitor safety and efficacy outcomes. Safety evaluations will include assessments of adverse events, laboratory parameters, vital signs, ECGs, and mortality. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or failure to adhere to the study protocol. The trial will utilize intravenous administration of the investigational products, with **tocilizumab**, **fludarabine phosphate**, and **cyclophosphamide** serving as auxiliary treatments. The study is not categorized as low intervention and is classified as a phase 2 trial.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Rapcabtagene autoleucel**, also known as YTB323, is the primary experimental treatment. It is a **dispersion for infusion** containing autologous T cells transduced with a lentiviral vector encoding a chimeric antigen receptor (CAR) directed against CD19. This cell therapy is administered via **intravenous use** as a single infusion. The maximum treatment period for rapcabtagene autoleucel is one day, and it is designed to target CAR-positive viable T cells.

**Rituximab** serves as the comparator treatment in this study. It is provided as a **concentrate for solution for infusion** and is administered intravenously. The maximum daily dose is 1000 mg, with a total maximum dose of 2000 mg over a treatment period of up to 130 days. Rituximab is classified as a biological medicinal product and is used to evaluate its efficacy against rapcabtagene autoleucel in participants with severe refractory diffuse cutaneous systemic sclerosis.

**Tocilizumab** is included as an auxiliary treatment. It is also a **concentrate for solution for infusion** and is administered intravenously. The maximum daily dose is 2400 mg, with a total maximum dose of 3200 mg over a treatment period of up to two days. Tocilizumab is utilized to support the primary and comparator treatments.

**Fludarabine phosphate** is another auxiliary treatment, provided as a **concentrate for solution for injection/infusion**. It is administered intravenously, with dosing based on body surface area in mg/m². The treatment period is up to three days. Fludarabine phosphate is classified as a chemical medicinal product.

**Cyclophosphamide** is also used as an auxiliary treatment. It is available as a **powder for solution for injection** and is administered intravenously. Similar to fludarabine phosphate, dosing is based on body surface area in mg/m², with a treatment period of up to three days. Cyclophosphamide is classified as a chemical medicinal product.

Participant compliance with the dosing schedules and administration routes is monitored throughout the trial to ensure adherence to the protocol. The study aims to assess the efficacy and safety of rapcabtagene autoleucel compared to rituximab, with additional support from auxiliary treatments, in achieving a Revised Composite Response Index in Systemic Sclerosis 50 (rCRISS50) response at Week 52.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the achievement of a treatment response as per the Revised Composite Response Index in Systemic Sclerosis 50 (**rCRISS50**) definition at Week 52. This endpoint will determine the proportion of participants who achieve a significant response to the treatment.

Secondary endpoints include several measures: change from baseline in Forced Vital Capacity percentage (FVC%) predicted at Week 52, change from baseline in the modified Rodnan Skin Score (mRSS) at Week 52, and change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 52. Additionally, the trial will assess the achievement of Week 156 progression-free survival concerning disease progression criteria, defined as meeting any of the criteria in Step 1 of rCRISS50 or all-cause mortality. Safety evaluations will also be conducted, including monitoring adverse events, laboratory parameters, vital signs, electrocardiograms (ECGs), and mortality.