Phase I/II Evaluation of PTG-CARCIK-CD19 in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

The primary objective of this Phase I/II trial is to evaluate the **efficacy** and safety of CARCIK-CD19 therapy in patients with relapsed/refractory B-cell Non-Hodgkin Lymphoma and B-cell Chronic Lymphocytic Leukemia. In Phase I, the goal is to identify the recommended Phase 2 dose (RP2D) of allogeneic, HLA haploidentical familial CARCIK-CD19 cells in B-cell Non-Hodgkin Lymphoma. In Phase II, the focus is on assessing the overall response rate following CARCIK-CD19 infusion. This is clinically relevant as it aims to establish an effective and safe therapeutic dose, potentially offering a new treatment avenue for patients with these challenging hematological malignancies.

The secondary objectives include: - Characterizing the safety profile of CARCIK-CD19 therapy. - Analyzing the in vivo cellular pharmacokinetic profile of CARCIK-CD19 cells in peripheral blood and other tissues. - Describing the persistence of lymphoid chimerism in peripheral blood post-infusion. - Monitoring levels of B, T, and NK cells before and after infusion. - Evaluating efficacy in terms of best overall response rate, duration of response, disease-free survival, progression-free survival, and overall survival.

The clinical trial involves participants diagnosed with **B-Non Hodgkin Lymphoma** and **Chronic Lymphocytic Leukemia**. The study population includes both male and female subjects, encompassing a wide age range from children (1-17 years old) to adults (18 years and older). Participants are required to have a histologically-confirmed mature B-cell neoplasia, with specific eligible histologies such as indolent or aggressive forms of lymphoma, and must have relapsed after or be refractory to at least two prior lines of treatment. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less for those aged 16 and above, or a Lansky score greater than 50 for those under 16. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the necessity for participants to have no available treatment options expected to prolong survival, or to have refused such treatments. Lifestyle considerations such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the **safety** and efficacy of PTG-CARCIK-CD19, a **cell therapy** product, in patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma and B-cell Chronic Lymphocytic Leukemia. This is a Phase I/II trial, which will be conducted in a randomized, double-blind, controlled manner. The trial is expected to commence on January 29, 2024, with an estimated completion date of September 1, 2027. The primary objective of Phase I is to identify the recommended Phase 2 dose of the therapy, while Phase II aims to evaluate the overall response rate at three months post-infusion.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, disease status, and availability of a haploidentical familial donor. Following successful screening, participants will receive the investigational product via **intravenous infusion**. Subsequent follow-up visits will be scheduled to monitor the incidence of adverse events, laboratory abnormalities, and the persistence of CARCIK-CD19 cells in target tissues. The end-of-study visit will conclude the participant's involvement, assessing the overall response and any long-term effects of the treatment.

The expected length of participant involvement in the trial is approximately three years, with conditions for early termination including the occurrence of dose-limiting toxicities or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols, with adverse events graded according to the NCI-CTCAE and MedDRA standards. The study will continuously assess the persistence and kinetics of the therapy in the blood, bone marrow, and other tissues, providing comprehensive data on the treatment's impact.

The clinical trial involves the administration of **PTG-CARCIK-CD19**, an experimental medication designed for the treatment of relapsed/refractory B-cell Non-Hodgkin Lymphoma and B-cell Chronic Lymphocytic Leukemia. **PTG-CARCIK-CD19** is a **suspension for injection** and is administered via **intravenous infusion**. The active substance, **PTG-CARCIK-CD19**, is a structurally diverse substance categorized under cell therapy, specifically utilizing T-cells that have been genetically modified with a transposon to express a CD19-chimeric antigen receptor. This investigational product is not a pediatric formulation and is not classified as an orphan drug. The administration schedule and dosage are determined based on the phase of the trial, with the primary objective in Phase I being the identification of the recommended Phase 2 dose (RP2D).

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapies, placebo, or comparator treatments, depending on the specific design and requirements of the trial. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial aims to evaluate the persistence, safety, and clinical activity of the **PTG-CARCIK-CD19** infusion, with efficacy being assessed in terms of overall response rate during Phase II. The trial is conducted under the authorization of relevant regulatory bodies, ensuring adherence to ethical and safety standards.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Phase I is the determination of dose-limiting toxicity (DLT) as assessed by the investigator during the first 28 days following the infusion of **CARCIK-CD19**. For Phase II, the primary endpoint is the investigator-assessed overall response rate, which includes complete and partial remission, evaluated at month 3 post-infusion according to the 2014 Lugano criteria and iwCLL 2018 criteria for chronic lymphocytic leukemia (CLL).

Secondary endpoints include the incidence of adverse events and laboratory abnormalities, which will be continuously assessed throughout the study and reported at each scheduled visit. The description and grading of all adverse events will be based on the NCI-CTCAE and MedDRA codes. Additionally, the persistence and kinetics of **CARCIK-CD19** cells in target tissues such as blood, bone marrow, and other available tissues will be evaluated.