Evaluation of Safety and Preliminary Efficacy of CLDN6 CAR-T and CLDN6 RNA-LPX in CLDN6-Positive Relapsed or Refractory Advanced Solid Tumors

The primary objective of this clinical trial is to assess the **safety** and tolerability of claudin 6 (CLDN6) Chimeric Antigen Receptor T cell (CAR-T) therapy, with or without CLDN6 Liposomally-formulated vaccine encoding ribonucleic acid (RNA-LPX), in patients with CLDN6-positive relapsed or refractory advanced **solid tumors**. Additionally, the study aims to evaluate the comparability of CLDN6 CAR-T produced through manual and automated processes. This is clinically relevant as it addresses the potential for personalized cell therapy in treating advanced solid tumors, which are often resistant to conventional treatments.

Secondary objectives include:

• Describing the profile of soluble immune factors in CLDN6 CAR-T ± CLDN6 RNA-LPX, which could provide insights into the immune response elicited by the therapy.
• Evaluating the anti-tumor activity of CLDN6 CAR-T ± CLDN6 RNA-LPX according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), which is crucial for determining the therapy's efficacy in reducing tumor size or progression.

The clinical trial involves a total of **20 participants** diagnosed with **solid tumors**. The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on their CLDN6-positive tumor status, with at least 50% of tumor cells expressing the CLDN6 protein. The trial requires participants to have adequate hematologic, hepatic, renal, and coagulation functions at screening. Additionally, participants must have a histologically confirmed solid tumor that is metastatic or unresectable, with no available standard therapy likely to confer clinical benefit. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to attend trial visits as required by the protocol. The trial includes both men and women of childbearing potential, with specific requirements for contraception and reproductive considerations during and after the trial period.

The clinical trial is designed as a **Phase I/IIa**, first-in-human, open-label, dose escalation study with expansion cohorts. The primary objective is to evaluate the safety and preliminary efficacy of **CLDN6 CAR-T** with or without **CLDN6 RNA-LPX** in patients with **CLDN6-positive** relapsed or refractory advanced solid tumors. The trial will assess the safety and tolerability of **CLDN6 Chimeric Antigen Receptor T cell (CAR-T)** therapy, with or without the liposomally-formulated vaccine encoding ribonucleic acid (RNA-LPX), and compare the **CLDN6 CAR-T** from manual and automated processes. The trial is expected to commence recruitment on August 16, 2024, and conclude by September 1, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as **CLDN6-positive** tumor status, adequate hematologic, hepatic, renal, and coagulation function, and an Eastern Cooperative Oncology Group performance status of 0 to 1. Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception. The trial includes multiple follow-up visits to monitor safety, efficacy, and any treatment-emergent adverse events (TEAEs). The end-of-study visit will evaluate the overall response and duration of response, defined by RECIST 1.1 criteria.

Participant involvement is expected to last throughout the trial duration, with specific conditions outlined for early termination, such as the occurrence of dose-limiting toxicity (DLT) or serious TEAEs. The primary endpoints include the occurrence of TEAEs, dose reduction, and discontinuation of the investigational medicinal product due to TEAEs. Secondary endpoints focus on changes in soluble immune factors, objective response rate, and duration of response. The investigational products, **BNT211**, are administered as a dispersion for infusion via intravenous bolus use. The trial is not categorized as low intervention and involves advanced therapy medicinal products derived from autologous patient-derived CD4+ and CD8+ T cells.

The clinical trial involves the administration of several experimental medications, all under the product name **BNT211**, developed by BioNTech SE. The first experimental medication is based on the active substance **RBP030.2**, which is a nucleic acid. This medication is formulated as a **dispersion for infusion** and is administered via **intravenous bolus use**. The dosing schedule and frequency of administration are determined by the trial protocol, and participant compliance is monitored throughout the study.

Another experimental treatment in the trial is **CLDN6 RNA-LPX**, a structurally diverse substance used in cell therapy. Like the previous medication, it is also provided as a **dispersion for infusion** and administered through **intravenous bolus use**. The trial protocol specifies the dosage and administration frequency, with compliance monitoring in place to ensure adherence to the treatment regimen.

The trial also includes the administration of **CLDN6 CAR-T**, a chimeric antigen receptor T cell therapy. This treatment is derived from autologous patient-derived CD4+ and CD8+ T cells and is classified as a structurally diverse substance for cell therapy. It is delivered as a **dispersion for infusion** via **intravenous bolus use**. The dosing schedule is outlined in the trial protocol, and participant compliance is closely monitored.

Additionally, the study evaluates **CLDN6 CAR-T(A)**, another variant of the chimeric antigen receptor T cell therapy. This treatment shares the same formulation and administration route as the other medications, being a **dispersion for infusion** administered through **intravenous bolus use**. The trial protocol provides detailed instructions on dosing and administration, with mechanisms in place to monitor participant compliance.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus of the trial is to assess the safety and preliminary efficacy of these experimental treatments in patients with CLDN6-positive relapsed or refractory advanced solid tumors.

The efficacy of the investigational medicinal product BNT211 in the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints focus on safety-related parameters, including the occurrence of treatment-emergent adverse events (TEAEs) of grade 3 or higher, serious or fatal TEAEs, and the occurrence of dose-limiting toxicity (DLT) during the DLT evaluation period. Additionally, the trial will monitor the occurrence of dose reduction and discontinuation of the investigational product due to TEAEs.

Secondary endpoints will evaluate the efficacy of BNT211 by measuring changes from baseline in the levels and kinetics of soluble immune factors using a cytokine multiplex assay. The objective response rate (ORR) will be determined, defined as the proportion of patients achieving a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Furthermore, the duration of response (DOR) will be assessed, defined as the time from the first objective response (CR or PR) to the first occurrence of objective progressive disease (PD) per RECIST 1.1, recurrence, or death from any cause, whichever occurs first.