Phase III Randomized Trial of High-Dose Chemotherapy with Autologous Stem Cell Transplantation versus R-MP in Elderly Patients with Primary CNS Lymphoma

The primary objective of this randomized phase III trial is to demonstrate the superiority of intensified chemotherapy followed by consolidating high-dose chemotherapy and **autologous stem-cell transplantation** (HCT-ASCT) over conventional chemotherapy with R-MP followed by maintenance in elderly patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The primary endpoint is progression-free survival (PFS), which is clinically relevant as it measures the length of time during and after treatment that a patient lives with the disease without it getting worse. This is particularly important given the poor prognosis associated with PCNSL in this patient population.

Secondary objectives include comparing the following between both treatment arms: quality of life, remission after induction treatment, remission after maintenance treatment (arm A) or consolidation treatment (arm B), event-free survival, overall survival, and treatment-related morbidities such as neurotoxicity and adverse events. These secondary endpoints provide a comprehensive evaluation of the treatment's impact on patient outcomes and safety, offering insights into the overall efficacy and tolerability of the treatment regimens.

The clinical trial involves participants diagnosed with **primary diffuse large B-cell lymphoma of the central nervous system** (PCNSL), a rare condition affecting only the central nervous system. The study population includes both male and female subjects, primarily aged 60 years or older, with a focus on those over 70 years or between 65-70 years if not eligible for more intensive treatment. Participants are immunocompetent individuals with newly diagnosed PCNSL, and the disease is exclusively located in the CNS. The trial includes a vulnerable population, as indicated by the inclusion of elderly patients with poor prognoses. The selection criteria require a histological or cytological diagnosis of B-cell lymphoma, with at least one measurable lesion and an ECOG Performance Status of 2 or less. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial aims to assess the efficacy of intensified chemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation compared to conventional chemotherapy in terms of progression-free survival and other secondary outcomes.

The clinical trial is a **randomized**, **phase III** study designed to evaluate the efficacy of intensified chemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation (HCT-ASCT) compared to conventional chemotherapy with R-MP in elderly patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). The primary objective is to assess progression-free survival, while secondary objectives include comparisons of quality of life, remission rates, event-free survival, overall survival, and treatment-related morbidities between the two treatment arms. The trial is expected to conclude by March 31, 2031, with recruitment having commenced on March 31, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and performance status. Following randomization, participants will receive either the intensified chemotherapy regimen or the conventional R-MP regimen. 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 or upon early termination. The expected duration of participant involvement varies depending on the treatment arm, with the maximum treatment period for individual drugs ranging from 2 to 30 days.

Participants may be withdrawn from the study early if they experience disease progression, unacceptable toxicity, or withdrawal of consent. The trial employs a **double-blind** design to ensure unbiased assessment of outcomes. The inclusion criteria specify that participants must be immunocompetent, have a histologically or cytologically confirmed diagnosis of B-cell lymphoma, and have disease confined to the central nervous system. The study aims to provide valuable insights into the optimal treatment strategy for this patient population, which typically has a poor prognosis.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Procarbazine** is provided in a hard capsule form and is administered orally. The dosage is calculated based on body surface area, with a maximum daily dose of 60 mg/m² and a total maximum dose of 1800 mg/m² over a treatment period of up to 30 days. This medication is of chemical origin.

**Methotrexate Disodium** is administered as a solution for injection or infusion. The dosage is also based on body surface area, with a maximum daily dose of 3.5 g/m² and a total maximum dose of 24.5 g/m² over a 7-day treatment period. This medication is of chemical origin and is delivered via infusion.

**Busulfan** is provided as a concentrate for solution for infusion and is administered intravenously. The dosage is calculated per body weight, with a maximum daily dose of 3.2 mg/kg and a total maximum dose of 6.4 mg/kg over a 2-day treatment period. This medication is of chemical origin.

**Thiotepa** is available as a powder for concentrate for solution for infusion and is administered intravenously. The dosage is based on body weight, with a maximum daily dose of 5 mg/kg and a total maximum dose of 10 mg/kg over a 2-day treatment period. This medication is of chemical origin.

**Cytarabine** is administered as a solution for infusion, with the dosage based on body surface area. The maximum daily dose is 4 g/m², and the total maximum dose is 16 g/m² over a 4-day treatment period. This medication is of chemical origin and is delivered intravenously.

**Rituximab** is provided as a concentrate for solution for infusion and is administered intravenously. The dosage is based on body surface area, with a maximum daily dose of 375 mg/m² and a total maximum dose of 2625 mg/m² over a 7-day treatment period. This medication is of biological/biotechnological origin.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The trial aims to evaluate the efficacy and safety of these experimental medications in the treatment of elderly patients with newly diagnosed primary central nervous system lymphoma (PCNSL).

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. This endpoint is designed to evaluate the time during and after treatment in which a patient's disease does not worsen. Secondary efficacy endpoints include overall survival (OS), event-free survival (EFS), remission rates during and after induction treatment, and remission after maintenance treatment. Additionally, quality of life (QoL) will be assessed using the EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires. These assessments will be conducted during the screening period, at the second randomization and premature end-of-treatment visit, and subsequently every 12 months during follow-up.