Phase III Randomized Open-Label Trial of Tisagenlecleucel Versus Standard of Care in Adults with Relapsed/Refractory Follicular B-cell Non-Hodgkin Lymphoma

The primary objective of this study is to demonstrate the superiority of the **tisagenlecleucel** treatment strategy over standard of care (SOC) therapy in terms of progression-free survival (PFS) in adult patients with relapsed or refractory follicular lymphoma. This is determined by a blinded independent review committee (BIRC) based on the Lugano response criteria. The clinical relevance of this objective lies in potentially offering a more effective treatment option for patients who have not responded to at least two prior lines of systemic therapy, thereby improving their prognosis and quality of life.

Secondary objectives include:

• Evaluating the **tisagenlecleucel** treatment strategy and SOC therapy with respect to complete response rate (CRR) by BIRC.
• Assessing overall response rate (ORR) by BIRC, overall survival (OS), and time to next anti-lymphoma treatment (TTNT).
• Evaluating the duration of response on **tisagenlecleucel** treatment strategy and SOC therapy.
• Characterizing the incidence and prevalence of **tisagenlecleucel** immunogenicity (humoral and cellular) and its impact on cellular kinetics, efficacy, and safety in participants receiving **tisagenlecleucel** therapy in arm A.
• Evaluating the safety of the **tisagenlecleucel** treatment strategy and SOC therapy.
• Characterizing the in vivo cellular kinetics of **tisagenlecleucel** transduced cells into target tissues summarized by clinical response in participants receiving **tisagenlecleucel** therapy in arm A.
• Assessing the presence of replication competent lentivirus (RCL) in participants receiving **tisagenlecleucel** in arm A.

The clinical trial involves a total of **50 participants** diagnosed with **follicular B-cell non-Hodgkin lymphoma** grade 1-3A, who have experienced relapse or refractory conditions following at least two prior lines of systemic therapy. The study population includes both male and female adults aged 18 years and older, with a focus on individuals who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening. Participants were selected based on their confirmed histological diagnosis of follicular lymphoma and their disease activity as determined by PET and CT scans. The trial includes individuals with adequate hematologic, renal, hepatic, and pulmonary function, and those eligible for leukapheresis and treatment with the selected standard of care regimen. The study does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment strategy across a diverse group of patients.

The clinical trial is designed as a **randomized**, open-label, multi-center phase III study aimed at comparing the efficacy of **tisagenlecleucel** to standard of care in adult participants with relapsed or refractory follicular lymphoma. The primary objective is to demonstrate the superiority of the tisagenlecleucel treatment strategy over standard therapy with respect to progression-free survival, as determined by a blinded independent review committee based on the Lugano response criteria. The trial is expected to commence recruitment on December 20, 2023, and conclude by February 20, 2031, with an estimated duration of participant involvement varying based on individual treatment response and protocol adherence.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of follicular lymphoma, and previous treatment history. Following randomization, participants will receive either the investigational product or standard care, with regular follow-up visits scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur upon completion of the treatment period or earlier if specific conditions necessitate withdrawal, such as disease progression, unacceptable toxicity, or withdrawal of consent.

The trial will include several key endpoints, with the primary endpoint being progression-free survival. Secondary endpoints will assess best overall response, overall survival, time to next treatment, and immunogenicity, among others. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it in their best interest. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **PREDNISOLONE** is provided in tablet form and is administered orally. The maximum daily dose is 40 mg/m², with a total dose not exceeding 40 mg/m² over a treatment period of up to 24 weeks. This medication is classified as a glucocorticoid.

**LENALIDOMIDE** is administered as hard capsules taken orally, with a maximum daily dose of 20 mg and a total dose of 20 mg over a 48-week period. It is categorized as an anticancer immunomodulatory agent.

**TOCILIZUMAB** is provided as a concentrate for solution for infusion and is administered intravenously. The maximum daily dose is 24 mg/kg, with a total dose of 32 mg/kg over a 2-week period. This product has been re-labeled for clinical trial use.

**BENDAMUSTINE HYDROCHLORIDE** is administered intravenously as a powder for concentrate for solution for infusion. The maximum daily and total dose is 90 mg/m², with a treatment period of 2 weeks. It is classified as an anticancer alkylating agent.

**FLUDARABINE PHOSPHATE** is provided as a powder for solution for injection or infusion, administered intravenously. The maximum daily dose is 25 mg/m², with a total dose of 75 mg/m² over a 3-week period. It is categorized as an anticancer antimetabolite.

**PREDNISONE** is administered orally in tablet form, with a maximum daily dose of 40 mg/m² and a total dose of 40 mg/m² over a 24-week period. It is classified as a glucocorticoid and has been re-labeled for clinical trial use.

**VINCRISTINE SULFATE** is provided as a solution for injection, administered intravenously. The maximum daily and total dose is 1.4 mg/m², with a treatment period of 24 weeks. It is classified as an anticancer vinca alkaloid agent.

**CYCLOPHOSPHAMIDE MONOHYDRATE** is administered intravenously as a powder for solution for injection. The maximum daily dose is 750 mg/m², with a total dose of 750 mg/m² over a 24-week period. It is classified as an anticancer alkylating agent and has been re-labeled for clinical trial use.

**TISAGENLECLEUCEL** is provided as a dispersion for infusion, administered via intravenous infusion. The maximum daily and total dose is 600,000,000 dosage forms, with a treatment period of 1 week. This product is an orphan drug and has been re-labeled for clinical trial use.

**DOXORUBICIN HYDROCHLORIDE** is administered intravenously as a solution for injection. The maximum daily and total dose is 50 mg/m², with a treatment period of 24 weeks. It is classified as an anticancer anthracycline and has been re-labeled for clinical trial use.

**RITUXIMAB** is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily and total dose is 375 mg/m², with a treatment period of 24 weeks. It is a human monoclonal antibody directed against CD-20 and has been re-labeled for clinical trial use.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of these treatments in adult participants with relapsed or refractory follicular lymphoma.

Efficacy in this clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as determined by a blinded independent review committee (BIRC) using the Lugano response criteria. PFS is defined as the time from randomization to the occurrence of either progressive disease or death from any cause. Secondary efficacy endpoints include the **Best Overall Response (BOR)**, which is the best disease response observed from randomization until the start of new anticancer therapy, and the **Complete Response Rate (CRR)**, which is the proportion of participants achieving a BOR of complete response. Additionally, the **Overall Response Rate (ORR)**, which includes both complete and partial responses, and **Overall Survival (OS)**, defined as the time from randomization to death from any cause, will be evaluated. Other secondary endpoints include the **Time to Next Treatment (TTNT)**, the duration from randomization until the start of new anticancer therapy or death, and the time from the first documented BIRC response of complete or partial response to the first documented progression or death.

Further assessments will include the summary and levels of pre-existing and treatment-induced immunogenicity, both cellular and humoral, of **tisagenlecleucel**. Cellular kinetic parameters, concentration, and time profiles by immunogenicity category will be analyzed. The type, frequency, and severity of serious and non-serious adverse events, laboratory abnormalities, and discontinuations due to adverse events will also be documented. Additionally, the trial will summarize qPCR-detected Chimeric Antigen Receptor (CAR) transgene levels in peripheral blood and bone marrow, with cellular kinetic parameters from peripheral blood transgene levels analyzed by clinical response status. These efficacy parameters will be measured and collected at various timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on participants with relapsed or refractory follicular lymphoma.