Phase II Randomized Trial of Ibrutinib, Venetoclax, and CD20 Antibody Therapy in Untreated Mantle Cell Lymphoma Patients

The primary objective of this study is to estimate the **minimum residual disease (MRD)** rate using droplet digital PCR (ddPCR) in bone marrow and/or peripheral blood at the end of induction, following 6 cycles of Ibrutinib/CD20 Ab and Ibrutinib/CD20 Ab/Venetoclax, in patients with previously untreated mantle cell lymphoma (MCL). This objective is clinically relevant as it aims to assess the effectiveness of the treatment regimen in achieving MRD negativity, which is associated with improved patient outcomes and can guide further therapeutic decisions.

Secondary objectives include:

• Evaluating MRD response in peripheral blood and bone marrow at various timepoints using techniques such as qPCR, ddPCR, and NGS.
• Assessing overall response rate and complete response rate according to the Lugano response criteria 2014.
• Determining overall survival, progression-free survival, and disease-free survival.
• Measuring response duration and the duration of MRD negativity, as well as the delay from MRD positivity to clinical relapse.
• Evaluating the tolerability and safety of Ibrutinib/CD20 Ab and Ibrutinib/CD20 Ab/Venetoclax.
• Investigating peripheral blood stem cell collection after at least 12 cycles and a washout period for Venetoclax.
• The key secondary objective is to evaluate progression-free survival at 3 years from randomization to progression or death from any cause.

The clinical trial involves a total of **24 participants** diagnosed with untreated **mantle cell lymphoma**. The study population includes both male and female subjects, aged between 18 and 79 years, who have not received prior treatment for their condition. Participants are required to have a measurable stage II-IV disease, with at least one lymph node greater than 1.5 cm, and must be deemed in need of treatment by their clinician. The general health status of participants is assessed through an **ECOG performance status** of 0 to 2, indicating they are fully active or capable of self-care. Participants must have a life expectancy of more than three months and demonstrate adequate renal and hepatic function. Lifestyle considerations include the requirement for women of childbearing potential to have a negative pregnancy test and for all participants of reproductive potential to use highly effective contraception during the study and for 18 months after the last drug administration. The trial population was selected based on these criteria, ensuring that participants are willing and able to adhere to the study visit schedule and other protocol requirements. The study does not include a vulnerable population.

The clinical trial is a **randomized**, phase II study designed to evaluate the efficacy of **ibrutinib** in combination with CD20 antibodies, and **ibrutinib** plus **venetoclax** with CD20 antibodies, in patients with untreated **mantle cell lymphoma**. The trial employs a **double-blind** methodology to ensure unbiased results. The primary objective is to estimate the minimum residual disease (MRD) rate using droplet digital PCR (ddPCR) in bone marrow and/or peripheral blood at the end of induction, following six cycles of treatment. The trial is expected to conclude by December 31, 2030, with recruitment having commenced on March 31, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and performance status. Following successful screening, participants will be randomized into one of the treatment arms. The study includes multiple follow-up visits to monitor treatment response and safety, with assessments conducted at regular intervals. The end-of-study visit will occur after the completion of the treatment cycles, where the primary endpoint of MRD negativity rate will be evaluated.

The expected duration of participant involvement is approximately 18 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study protocols. Participants must adhere to the study visit schedule and protocol requirements, including the use of effective contraception for the duration of the study and for 18 months following the last drug administration. The trial aims to increase the MRD negativity rate by 12% and progression-free survival (PFS) at three years by 10% in each treatment arm.

The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments** to evaluate their efficacy in patients with untreated mantle cell lymphoma. The primary experimental medication is **IBRUTINIB**, which is administered in the form of a capsule. The route of administration is oral, and the frequency of administration is determined by the study protocol. **IBRUTINIB** is a chemical substance and plays a central role in the trial as a test product.

Another key experimental medication is **VENETOCLAX**, provided in tablet form. Like **IBRUTINIB**, **VENETOCLAX** is administered orally. It is also a chemical substance and is used in combination with other treatments to assess its impact on the disease.

The trial also includes the use of **OBINUTUZUMAB**, which is administered as a solution for infusion. The route of administration is via intravenous infusion. **OBINUTUZUMAB** is a protein-based substance and serves as an auxiliary product in the trial, complementing the primary experimental medications.

**RITUXIMAB** is utilized in two different pharmaceutical forms within the trial. It is administered both as a solution for injection and as a solution for infusion. The injection form is delivered through standard injection routes, while the infusion form is administered intravenously. **RITUXIMAB** is a protein-based substance and functions as an auxiliary product, supporting the primary treatment regimen.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the protocol. The study aims to evaluate the minimum residual disease rate using droplet digital PCR in bone marrow and/or peripheral blood at the end of the induction phase, following six cycles of treatment with the experimental medications and auxiliary products.

The efficacy of the clinical trial titled "OASIS II - A randomized phase II trial evaluating Ibrutinib plus CD20 Ab and Ibrutinib-Venetoclax plus CD20 Ab in patients with untreated **mantle cell lymphoma**" will be assessed primarily by measuring the minimum residual disease (MRD) rate. This will be determined using droplet digital PCR (ddPCR) in bone marrow and/or peripheral blood at the end of the induction phase, which occurs after 6 cycles of treatment with Ibrutinib/CD20 Ab and Ibrutinib/CD20 Ab/Venetoclax. The primary endpoint is the MRD negativity rate at the end of induction in the informative MRD set, with an expected increase of 12% in each arm.

Secondary efficacy will be evaluated by assessing progression-free survival (PFS) at 3 years, with an anticipated increase of 10% in PFS at 3 years in each arm. The trial is designed to provide a comprehensive evaluation of the treatment's efficacy in previously untreated mantle cell lymphoma patients, utilizing advanced molecular techniques to accurately measure treatment outcomes.