Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Study of Ibrutinib and Rituximab in Treatment-naïve Follicular Lymphoma Patients

The primary objective of this study is to evaluate whether the addition of **ibrutinib** to **rituximab** will result in prolongation of progression-free survival (PFS) when compared with rituximab alone in treatment-naïve subjects with **follicular lymphoma**. Prolongation of PFS is clinically relevant as it may indicate a delay in disease progression, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• To evaluate whether the addition of ibrutinib to rituximab will result in improvement in investigator-assessed overall response rate (ORR) compared to rituximab alone.
• To assess whether the addition of ibrutinib will result in prolongation of overall survival (OS).
• To determine if the addition of ibrutinib will lead to a reduction in infusion-related reactions.
• To evaluate whether the addition of ibrutinib will result in prolongation of duration of response (DOR).
• To assess the safety and tolerability of ibrutinib combined with rituximab compared to rituximab alone.

The clinical trial involves a total of **215 participants** diagnosed with **Follicular Lymphoma**, specifically CD20+ Grade 1, 2, or 3a, and classified under Ann Arbor Stage II, III, or IV. The study population includes both male and female subjects, aged 70 years or older, or those aged 60-69 with one or more comorbidities. Participants were selected based on their ability to meet one or more Groupe d'Etude des Lymphomes Folliculaire (GELF) criteria, and they must have adequate hematologic, hepatic, and renal function as defined by the protocol. The trial excludes vulnerable populations and requires participants to have an ECOG performance status score of 0-2. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The selection process ensures that participants are not incarcerated and are capable of providing informed consent.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled Phase 3 study designed to evaluate the efficacy of the **Bruton's Tyrosine Kinase (BTK) inhibitor**, **Ibrutinib**, in combination with **Rituximab** compared to a placebo in combination with Rituximab in treatment-naïve subjects with **Follicular Lymphoma**. The primary objective is to assess whether the addition of Ibrutinib to Rituximab prolongs progression-free survival (PFS) compared to Rituximab alone. The trial is expected to run from July 2021 to June 2026, with a maximum treatment period of 120 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of Follicular Lymphoma, measurable disease, and adequate hematologic, hepatic, and renal function. Subjects must be 70 years or older, or 60-69 years with comorbidities, and meet specific performance status scores. Follow-up visits will be conducted to monitor the primary endpoint of PFS and secondary endpoints, including overall response rate, overall survival, and adverse events. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and safety of the treatment.

Participant involvement is expected to last up to 120 weeks, with conditions for early termination including withdrawal of consent, adverse events, or disease progression. The trial will ensure that all procedures adhere to ethical standards, with informed consent obtained from all participants. The study aims to provide valuable insights into the treatment of Follicular Lymphoma, potentially improving therapeutic strategies for this condition.

The clinical trial involves the administration of **Ibrutinib**, a Bruton’s Tyrosine Kinase (BTK) inhibitor, in the form of hard capsules for oral use. The pharmaceutical form of the medication is a hard capsule, and it is administered orally. The maximum daily dose of Ibrutinib is 560 mg, with a total maximum dose of 2044 mg over the treatment period. The treatment period is set to a maximum of 120 days. The active substance in Ibrutinib is chemically derived, and the product is manufactured by Pharmacyclics LLC. The trial aims to evaluate the efficacy of Ibrutinib in combination with Rituximab in treatment-naïve subjects with follicular lymphoma.

In addition to the experimental treatment, the study includes a comparator treatment involving a placebo in combination with Rituximab. Rituximab is a standard-of-care therapy for follicular lymphoma and is used as a control to assess the efficacy of the experimental treatment. The placebo is administered in a manner identical to the experimental medication to maintain the double-blind nature of the study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. This endpoint will evaluate the duration during which the subjects with follicular lymphoma remain free from disease progression. Secondary efficacy endpoints include the **Overall Response Rate (ORR)** as per Cheson 2014 criteria, **Overall Survival (OS)**, the rate of infusion-related reactions between treatment arms, the **Duration of Response (DOR)** as assessed by investigators, and the frequency, severity, seriousness, and relatedness of adverse events (AEs).

The trial is designed as a multicenter, randomized, double-blind, placebo-controlled Phase 3 study. The efficacy parameters will be collected and analyzed at various timepoints throughout the study, with specific methods and schedules for measurement not detailed in the provided data. The trial aims to determine whether the addition of ibrutinib to rituximab therapy results in a significant prolongation of PFS compared to rituximab alone in treatment-naïve subjects with follicular lymphoma.