Phase III Randomized Trial of De-escalated MATRix Induction Therapy in Newly Diagnosed Primary CNS Lymphoma: Methotrexate, Cytarabine, Thiotepa, and Rituximab

The primary objective of this study is to demonstrate the superiority of a **de-escalated induction treatment** strategy followed by autologous stem cell transplantation compared to the standard MATRix protocol in terms of event-free survival (EFS) in patients with newly diagnosed primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system. This objective is clinically relevant as it aims to improve the prognosis of a rare and aggressive form of lymphoma, which currently has a poor median survival rate in untreated individuals.

Secondary objectives include comparing overall survival, progression-free survival, remission rate prior to and after consolidation, complication rate, neurocognitive impairment, and quality of life between both treatment arms. These secondary objectives are crucial for evaluating the broader impact of the treatment strategies on patient outcomes and quality of life, providing a comprehensive assessment of the therapeutic approaches.

The clinical trial involves a total of **40 participants** diagnosed with primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system, a rare disorder affecting the cerebral parenchyma, leptomeninges, eyes, or spinal cord. The study population includes both male and female patients, aged 18 to 65 years, and those aged 66 to 70 years with a Karnofsky Performance Status Scale of 50% or higher. Participants are immunocompetent individuals with a histologically or cytologically confirmed diagnosis of high-grade B-cell lymphoma, with the disease exclusively located in the central nervous system. The trial population was selected based on specific inclusion criteria, ensuring that all participants have at least one measurable lesion and have not received prior treatment, although previous surgery or ongoing steroid treatment is permitted. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to understand the nature of the trial and comply with its procedures, except in cases where legal competence is affected by the condition. The trial includes a vulnerable population, highlighting the need for careful ethical considerations in the study design and execution.

The clinical trial is designed to evaluate the efficacy of a de-escalated induction treatment strategy followed by autologous stem cell transplantation in patients with newly diagnosed **primary diffuse large B-cell lymphoma** of the central nervous system (PCNSL). This is a randomized, phase III trial comparing the de-escalated treatment to the standard MATRix protocol. The trial employs a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from August 2021 to August 2030, with participant involvement expected to last up to 12 months, depending on individual treatment response and follow-up requirements.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis, and disease location. Following randomization, participants will receive treatment according to their assigned group. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment protocol and necessary follow-up assessments. The primary endpoint is event-free survival, defined as the time from randomization to premature end of treatment due to any reason, lymphoma progression, or death. Secondary endpoints include overall survival, progression-free survival, and quality of life assessments.

Participant involvement may be terminated early if there is evidence of disease progression, unacceptable toxicity, or withdrawal of consent. The trial aims to provide valuable insights into optimizing treatment strategies for PCNSL, potentially improving patient outcomes and quality of life. The study drugs, including **rituximab**, **methotrexate disodium**, **thiotepa**, **carmustine**, **busulfan**, and **cytarabine**, will be administered intravenously, with dosing and treatment periods tailored to each drug's specific protocol. The trial's rigorous design and comprehensive monitoring plan ensure the collection of high-quality data to support the study's objectives.

**Rituximab** is administered as a **concentrate for solution for infusion**. The active substance, rituximab, is delivered intravenously. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over a treatment period of up to 12 weeks. This medication is not formulated for pediatric use and is of chemical origin.

**Methotrexate Disodium** is provided as a **solution for injection/infusion**. The active substance, methotrexate disodium, is administered via infusion. The maximum daily dose is 3.5 g/m², with a total maximum dose of 42 g/m² over a 12-week period. This formulation is not intended for pediatric patients and is chemically derived.

**Thiotepa** is available as a **powder for concentrate for solution for injection/infusion**. The active substance, thiotepa, is administered intravenously. The maximum daily dose is 30 mg/m², with a total maximum dose of 360 mg/m² over a 12-week treatment period. This product is not designed for pediatric use and originates from chemical synthesis.

**Carmustine** is supplied as a **powder and solvent for solution for infusion**. The active substance, carmustine, is delivered intravenously. The maximum daily and total dose is 400 mg/m², administered over a single treatment period. This medication is not suitable for pediatric patients and is of chemical origin.

**Busulfan** is administered as a **concentrate for solution for infusion**. The active substance, busulfan, is given intravenously. The maximum daily dose is 3.2 mg/kg, with a total maximum dose of 6.4 mg/kg over a 2-week period. This formulation is not intended for pediatric use and is chemically synthesized.

**Cytarabine** is provided as a **solution for infusion**. The active substance, cytarabine, is administered intravenously. The maximum daily dose is 8 g/m², with a total maximum dose of 96 g/m² over a 12-week treatment period. This product is not formulated for pediatric patients and is of chemical origin.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **event-free survival (EFS)**, defined as the time from randomization to the premature end of treatment due to any reason, lymphoma progression, or death, whichever occurs first. Secondary endpoints include overall survival (OS), progression-free survival (PFS), remission prior to consolidation therapy (RA II), remission after consolidation 30 days post-autologous stem cell transplantation (ASCT) (RA III), the proportion of patients reaching consolidation, and quality of life (QoL). QoL will be measured using the EORTC QLQ-C30 and EORTC QLQ-BN20 instruments during the screening period, at the end of treatment (30 days after ASCT), and every 12 months during follow-up.