Phase II Evaluation of Loncastuximab Tesirine Consolidation Post-Immunochemotherapy in BTKi-Treated or Intolerant Relapsed/Refractory Mantle Cell Lymphoma

The primary objective of this study is to assess the **efficacy** of consolidation therapy with **loncastuximab tesirine** following a short course of salvage immunochemotherapy, specifically two courses of Rituximab-Bendamustine-Cytarabine (R-BAC), in patients with relapsed or refractory **Mantle Cell Lymphoma** (MCL) who have been treated with Bruton Tyrosine Kinase inhibitors (BTKi) or are intolerant to BTKi. This is clinically relevant as it aims to improve treatment outcomes in a challenging patient population with limited therapeutic options.

Secondary objectives include:

• Evaluating the safety profile of loncastuximab tesirine consolidation, which is crucial for understanding the risk-benefit ratio of this therapeutic approach.
• Assessing the rate of Minimal Residual Disease (MRD) negativity after loncastuximab tesirine consolidation, which is an important marker for long-term remission and potential cure in MCL patients.

The clinical trial focuses on participants diagnosed with **mantle cell lymphoma**, specifically those who have relapsed or are refractory after treatment with Bruton Tyrosine Kinase inhibitors or are intolerant to such treatments. The study population includes both male and female subjects aged between 18 and 84 years. Participants are required to have a histologically documented diagnosis of mantle cell lymphoma, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, unless related to the lymphoma. The trial includes individuals with a life expectancy of at least three months and those who can adhere to the study schedule. Participants must have measurable nodal or extranodal disease, and those with bone marrow involvement are eligible. The trial allows for individuals who have previously been treated with anti-CD19 agents, including CAR-T therapy, and those eligible for stem cell transplantation. The sponsor has not provided the total number of participants involved in the study. The trial population selection considers the ability to comply with protocol requirements and the use of effective contraception for women of childbearing potential and their male partners. The study does not exclude vulnerable populations, indicating inclusivity in the selection process.

The clinical trial is designed to evaluate the efficacy of **loncastuximab tesirine** as a consolidation therapy following a short course of immunochemotherapy in patients with relapsed or refractory **mantle cell lymphoma** (MCL) who have been treated with Bruton Tyrosine Kinase inhibitors (BTKi) or are intolerant to them. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to last until March 2029, with recruitment having started in March 2022. Participants will be involved in the study for a maximum treatment period of 12 months, with the possibility of early termination if they experience severe adverse events or disease progression.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented MCL, specific laboratory values, and performance status. Following the screening, participants will undergo two courses of Rituximab-Bendamustine-Cytarabine (R-BAC) as salvage immunochemotherapy. Subsequent visits will include the administration of loncastuximab tesirine and regular follow-up assessments to monitor efficacy and safety. The end-of-study visit will occur after the completion of the consolidation therapy or upon early termination.

Primary endpoints include 12-month progression-free survival (PFS), while secondary endpoints encompass overall survival (OS), conversion rates from partial to complete response, overall response rate (ORR), duration of response (DOR), event-free survival (EFS), and minimal residual disease (MRD) negativity rate. Adverse events will be recorded and classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE). Participants are required to adhere to the study visit schedule and protocol requirements, with conditions such as severe toxicity or patient preference potentially leading to early withdrawal from the trial.

The clinical trial involves the administration of **CYTARABINE**, a pyrimidine analogue, as part of the treatment regimen. **Cytarabine** is provided in an intravenous pharmaceutical form, with a maximum daily dose of 500 mg/m² and a total maximum dose of 3000 mg/m² over a treatment period of up to 8 weeks. The administration is conducted intravenously, ensuring precise delivery of the medication. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**LONCASTUXIMAB TESIRINE**, an antibody-drug conjugate, is utilized as the primary experimental medication in this study. It is administered intravenously with a maximum daily dose of 150 µg/kg and a total maximum dose of 450 µg/kg over a 12-week treatment period. The pharmaceutical form is consistent with the other medications in the trial, and participant compliance is closely monitored to ensure accurate dosing and administration.

**RITUXIMAB**, a monoclonal antibody, is included in the treatment protocol. It is administered intravenously with a maximum daily dose of 375 mg/m² and a total maximum dose of 750 mg/m² over an 8-week period. The administration schedule is designed to optimize therapeutic outcomes while minimizing potential adverse effects. Compliance is monitored through scheduled assessments and documentation of dosing adherence.

**BENDAMUSTINE HYDROCHLORIDE**, an alkylating agent, is also part of the treatment regimen. It is administered intravenously with a maximum daily dose of 70 mg/m² and a total maximum dose of 280 mg/m² over an 8-week period. The pharmaceutical form and administration route are consistent with the other medications in the trial, ensuring uniformity in treatment delivery. Participant compliance is tracked through regular monitoring and documentation of dosing schedules.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the 12-month **Progression-Free Survival (PFS)**, which is defined as the time from the date of enrollment to the first documentation of recurrence, progression, or death from any cause. This will be evaluated on an Intention to Treat (ITT) basis, with responding patients and those lost to follow-up being censored at their last assessment date.

Secondary endpoints include **Overall Survival (OS)**, which measures the time from the start of treatment until death from any cause, with similar censoring for patients lost to follow-up. The rate of conversion from partial response to complete response (PR to CR) and from stable disease (SD) to PR/CR will be assessed by comparing responses before and after treatment with loncastuximab tesirine. The **Overall Response Rate (ORR)**, including CR, PR, and SD rates, will be defined according to the Lugano 2014 criteria, with the best overall response determined between the start of therapy and the last restaging. Patients without response assessment will be considered non-responders.

Additional secondary endpoints include the **Duration of Response (DOR)**, defined as the time from the first documentation of tumor response to disease progression or death, and **Event-Free Survival (EFS)**, which is the time from the start of treatment to disease progression, death, or discontinuation of treatment for any reason. The **MRD negativity rate** will be evaluated after induction treatment, at the end of consolidation, and 6 and 12 months post-consolidation. The rate of adverse events, particularly any grade III or higher toxicities, will be recorded and classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE).