Evaluation of Venetoclax Addition to Rituximab, Bendamustine, and Cytarabine Regimen in High-Risk Elderly Patients with Mantle Cell Lymphoma

The primary objective of this study is to evaluate whether the addition of **venetoclax** after the standard regimen of rituximab, bendamustine, and cytarabine (R-BAC) improves progression-free survival (PFS) in high-risk elderly patients with **mantle cell lymphoma** (MCL). This is clinically relevant as improving PFS can potentially lead to better long-term outcomes and quality of life for patients with this aggressive form of lymphoma.

The clinical trial involves participants diagnosed with **Mantle Cell Lymphoma**. The study population includes both male and female subjects, with an age range of 18 years and older. Participants are required to have a measurable nodal or extranodal disease, with a longest diameter of at least 1.5 cm, and must be measurable in two perpendicular dimensions. The trial includes individuals who are previously untreated and aged 65 years or older, provided they are considered fit according to the geriatric CGA assessment. Additionally, participants aged 64 years or younger, who are not eligible for high-dose chemotherapy plus transplantation based on the physician's judgment, are also included. The trial does not involve a vulnerable population. Participants must have an ECOG performance status of 2 or less, adequate renal and liver function, and must be negative for Hepatitis B surface antigen while being positive for Hepatitis B core antibody and HBV-DNA negative, with appropriate antiviral prophylaxis administered. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants have a specific health status and meet the necessary medical and functional requirements for inclusion in the study.

The clinical trial is designed to evaluate the efficacy of adding **venetoclax** to the standard regimen of rituximab, bendamustine, and cytarabine (R-BAC) in high-risk elderly patients with **mantle cell lymphoma**. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the progression-free survival (PFS) over a two-year period from the date of enrollment. The study is expected to run from September 2018 to February 2026, with participant involvement lasting up to 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and disease characteristics. Eligible participants are those aged 65 years or older, or those aged 64 years or younger who are not candidates for high-dose chemotherapy. The screening will also ensure adequate renal and liver function and the absence of active hepatitis B infection. Following the screening, participants will be randomized to receive either the standard R-BAC regimen or R-BAC followed by venetoclax.

Study visits will occur at regular intervals to monitor treatment response, safety, and any adverse events. These visits will include assessments of molecular response, overall survival, and the duration of response. The trial will also evaluate the safety of venetoclax when used as consolidation or maintenance therapy. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will also monitor the proportion of patients achieving complete remission and those completing the expected treatment schedule. The study's primary endpoint is the two-year PFS, with secondary endpoints including overall survival, molecular response, and safety assessments.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in high-risk elderly patients with mantle cell lymphoma. **Bendamustine hydrochloride** is administered as an intravenous infusion. The pharmaceutical form is coded as PHF00230MIG, and the maximum daily dose is 70 mg/m², with a total maximum dose of 840 mg/m² over a treatment period of 6 cycles. Bendamustine acts as an alkylating agent, disrupting cancer cell DNA and inhibiting cell division.

**Cytarabine**, also administered intravenously, is provided in the same pharmaceutical form, PHF00230MIG. The maximum daily dose is 500 mg/m², with a total maximum dose of 9000 mg/m² over 6 cycles. Cytarabine is a pyrimidine analogue that interferes with DNA synthesis, thereby inhibiting the proliferation of cancer cells.

**Venetoclax** is administered orally, with a pharmaceutical form coded as PHF00082MIG. The maximum daily dose is 800 mg, with a total maximum dose of 11200 mg over a treatment period of 24 cycles. Venetoclax functions as a BCL2 inhibitor, promoting apoptosis in cancer cells by disrupting the BCL2 protein's role in cell survival.

**Rituximab** is administered intravenously, with the pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 375 mg/m², with a total maximum dose of 2250 mg/m² over 6 cycles. Rituximab is a monoclonal antibody that targets the CD20 antigen on B-cells, leading to their destruction.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment regimen. The trial aims to assess the potential benefits of adding venetoclax to the standard R-BAC regimen in terms of progression-free survival (PFS) in the specified patient population.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)** over a two-year period from the date of enrollment for high-risk patients with mantle cell lymphoma (MCL). Secondary endpoints include the proportion of molecular response, progression-free survival of all enrolled patients and specific subgroups, overall survival, duration of responses, and the proportion of complete remission before and after the administration of venetoclax in high-risk groups or low-risk groups not responding to R-BAC. Additionally, the trial will evaluate the proportion of patients completing the expected treatment schedule and the safety of venetoclax when used as consolidation or maintenance therapy following R-BAC.