Phase 3 Study of Axicabtagene Ciloleucel Versus Standard Therapy in Relapsed/Refractory Follicular Lymphoma

The primary objective of this Phase 3 randomized, open-label, multicenter study is to determine if **axicabtagene ciloleucel** is superior to standard of care therapy (SOCT) in subjects with relapsed/refractory **Follicular Lymphoma**. This is measured by progression-free survival (PFS) as assessed by a blinded independent radiologic review committee. The clinical relevance of this objective lies in potentially improving the management and outcomes for patients with this challenging condition, offering a more effective treatment option compared to existing therapies.

Secondary objectives include further characterizing the efficacy and safety profile of axicabtagene ciloleucel compared to SOCT, as well as evaluating patient-reported outcomes. These objectives aim to provide a comprehensive understanding of the treatment's impact on patient quality of life and its overall therapeutic value.

The clinical trial involves a total of **75 participants** diagnosed with **relapsed/refractory follicular lymphoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a histologically-confirmed diagnosis of follicular lymphoma (Grade 1, 2, or 3a) and relapsed/refractory disease after first-line chemoimmunotherapy, with high-risk disease characterized by relapse or progression within 24 months of the initial treatment, or after two or more prior systemic lines of therapy. All participants must have at least one measurable lesion per the Lugano Classification and demonstrate adequate renal, hepatic, pulmonary, and cardiac function. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **Phase 3 randomized, open-label, multicenter study** designed to evaluate the efficacy of **axicabtagene ciloleucel** compared to standard of care therapy in subjects with relapsed/refractory follicular lymphoma. The primary objective is to determine if axicabtagene ciloleucel is superior in terms of progression-free survival, as assessed by a blinded independent radiologic review committee. The trial is expected to conclude by October 31, 2030, with recruitment having commenced on March 9, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically-confirmed follicular lymphoma and adequate organ function. Following randomization, participants will receive either the investigational product or standard therapy. The trial includes multiple follow-up visits to monitor efficacy and safety outcomes, with assessments conducted per the International Working Group Lugano Classification. The end-of-study visit will conclude the participant's involvement, which may last up to 336 days, depending on the treatment arm and response.

Participants may be withdrawn from the study early due to reasons such as disease progression, unacceptable toxicity, or withdrawal of consent. The trial will measure primary and secondary endpoints, including overall survival, complete response rate, and incidence of adverse events. The study will also assess quality of life changes using validated questionnaires. The trial's design ensures rigorous evaluation of the investigational product's efficacy and safety, contributing valuable data to the treatment landscape for relapsed/refractory follicular lymphoma.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **YESCARTA**, a dispersion for infusion containing **axicabtagene ciloleucel**, a structurally diverse substance used in cell therapy. This medication is administered intravenously with a maximum dose of 2 x 10^8 cells, and the treatment period is limited to a single administration. The product is modified by the addition of a full clinical trial label, and it is designated as an orphan drug.

**Prednisolone 5 mg Soluble Tablets** are used as a comparator treatment. This medication is formulated as an oral solution and is administered orally. The maximum daily dose is 40 mg/m², with a total maximum dose of 1200 mg/m² over a treatment period of 126 days. The active substance, **prednisolone**, is of chemical origin.

**Vincristine Sulfate 1 mg/ml Solution for Injection or Infusion** is another comparator treatment. It is administered intravenously, with a maximum daily dose of 2 mg and a total maximum dose of 12 mg over 126 days. The active substance, **vincristine sulfate**, is chemically derived.

**MabThera 500 mg concentrate for solution for infusion** contains **rituximab**, a protein-based monoclonal antibody. It is administered intravenously, with a maximum daily dose of 375 mg/m² and a total maximum dose of 2625 mg/m² over 336 days.

**Doxorubicin Teva 2 mg/ml Concentrate for Solution for Infusion** is administered intravenously, with a maximum daily dose of 50 mg/m² and a total maximum dose of 300 mg/m² over 126 days. The active substance, **doxorubicin hydrochloride**, is of chemical origin.

**Endoxana Injection 1000 mg Powder for Solution for Injection** contains **cyclophosphamide** and is administered intravenously. The maximum daily dose is 750 mg/m², with a total maximum dose of 4500 mg/m² over 126 days. The active substance is chemically derived.

**Revlimid 20 mg hard capsules** contain **lenalidomide** and are administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 5040 mg over 336 days. The active substance is of chemical origin.

**Bendamustine 100mg Powder for Concentrate for Solution for Infusion** is administered intravenously, with a maximum daily dose of 90 mg/m² and a total maximum dose of 1080 mg/m² over 168 days. The active substance, **bendamustine hydrochloride**, is chemically derived.

The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, which is defined as the time from randomization to disease progression or death due to any cause. This will be determined according to the International Working Group Lugano Classification and assessed by a blinded independent radiologic review committee. Secondary efficacy endpoints include overall survival (OS), complete response (CR) rate, overall response rate (ORR), duration of response (DOR), duration of complete response, event-free survival (EFS), and time to next treatment (TTNT). These will also be evaluated per the Lugano Classification by the blinded central assessment.

Additional secondary endpoints involve the incidence of adverse events and clinically significant changes in safety laboratory values, as well as the detection of replication-competent retrovirus (RCR) in blood over time. Patient-reported outcomes will be measured using changes from baseline in the Global Health Status Quality of Life scale, the physical functioning domain of the EORTC QLQ-C30, the Low Grade Non-Hodgkin Lymphoma-20 (NHL-LG20), and the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) including the visual analogue scale (VAS). These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive evaluation of the treatment's efficacy.