Pilot-trial of methotrexate, tafasitamab (Minjuvi®), lenalidomide (Revlimid®) and rituximab in patients ineligible for HCT-ASCT with primary central nervous system lymphoma (PCNSL) -MTR²

The primary objective of this study is to estimate the **efficacy** of the Methotrexate, Tafasitamab, Rituximab, and Revlimid (MTR²) regimen in patients with **Primary Central Nervous System Lymphoma (PCNSL)** who are ineligible for hematopoietic cell transplantation-autologous stem cell transplantation (HCT-ASCT). This objective is clinically relevant as it aims to develop a feasible and effective treatment regimen for PCNSL patients who cannot undergo intensive induction and consolidation therapies, potentially improving therapeutic outcomes and quality of life for this patient population.

Secondary objectives include:

• To describe the safety during therapy with 4 cycles of MTR².
• To describe the feasibility of 4 cycles of MTR².
• To describe the efficacy of 4 cycles of MTR² in terms of best overall response (BOR), progression-free survival (PFS), and overall survival (OS) rate at 1 year.
• To describe the quality of life over time.
• To describe neurocognitive impairment over time.

The clinical trial focuses on evaluating the efficacy of the Methotrexate, Tafasitamab, Rituximab, Revlimid (**MTR²**) regimen for patients diagnosed with **Primary Central Nervous System Lymphoma (PCNSL)**. The study population includes both male and female participants aged 18 to 69 years, with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 or higher, or those aged 70 years and above who are ineligible for hematopoietic cell transplantation-autologous stem cell transplantation (HCT-ASCT) as determined by the investigator. Participants must have a previously untreated, histologically or cytologically confirmed diagnosis of primary B-cell lymphoma of the central nervous system, with at least one measurable lesion. Adequate organ function is required, including kidney, hepatic, bone marrow, cardiac, and pulmonary functions. The trial does not include a vulnerable population. The total number of participants is not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not specified. Participants must provide written, signed, and dated informed consent, and adhere to contraceptive guidelines if applicable. The selection criteria ensure that the study population is representative of individuals who are unable to undergo intensive induction and consolidation therapies.

The clinical trial is designed to evaluate the efficacy and feasibility of a treatment regimen for patients with **Primary Central Nervous System Lymphoma (PCNSL)** who are ineligible for hematopoietic cell transplantation-autologous stem cell transplantation (HCT-ASCT). The trial employs a **randomized, double-blind, controlled** design and is categorized as a Phase 4 therapeutic exploratory and confirmatory trial. The estimated duration of the trial is from October 2023 to October 2026, with participant involvement expected to last up to 56 days, depending on the treatment arm and response to therapy.

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 organ function. Following successful screening, participants will be randomized to receive the investigational regimen, which includes **lenalidomide**, **tafasitamab**, **methotrexate**, and **rituximab**. The treatment will be administered in cycles, with each cycle lasting up to 56 days. Follow-up visits will occur at regular intervals to monitor efficacy and safety, including assessments of complete response rate (CRR) and adverse events. The end-of-study visit will evaluate the overall response and document any long-term effects.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoint is the complete response rate after at least two cycles of treatment, assessed by an independent review committee. Secondary endpoints include best overall response rate, progression-free survival, overall survival, and quality of life assessments. The trial aims to develop a feasible and effective regimen for PCNSL patients unable to receive intensive induction and consolidation therapies.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Lenalidomide**, marketed as Lenalidomid HEXAL, is provided in two dosage forms: 5 mg and 20 mg hard capsules. The active substance, lenalidomide, is of chemical origin and is administered orally. The maximum daily dose is 25 mg, with a total maximum dose of 1400 mg over a treatment period of 56 days. This medication is classified as a chemical origin immunomodulator.

**Tafasitamab** is another experimental medication used in this trial. It is provided as a powder for concentrate for solution for infusion. The active substance, tafasitamab, is a protein of biological origin. The administration route is via infusion, with a maximum daily dose of 12 mg/kg and a total maximum dose of 96 mg/kg over an 8-day treatment period. Tafasitamab is categorized as a biological/immunological product.

**Methotrexate**, marketed as Methotrexat medac, is provided as a 100 mg/ml solution for injection. The active substance, methotrexate, is of chemical origin and is administered via infusion. The maximum daily dose is 3.5 gm/m², with a total maximum dose of 14 gm/m² over a 4-day treatment period. Methotrexate is classified as a chemical origin product.

**Rituximab** is included in the trial as a comparator treatment. The active substance, rituximab, is a protein of biological origin. It is administered via infusion, with a maximum daily dose of 375 gm/m² and a total maximum dose of 3000 gm/m² over an 8-day treatment period. Rituximab is categorized as an immunological/biological product.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these medications in patients with primary central nervous system lymphoma who are ineligible for hematopoietic cell transplantation-autologous stem cell transplantation (HCT-ASCT).

Efficacy in this clinical trial will be assessed primarily through the **complete response rate (CRR)** after at least two cycles of treatment with the MTR² regimen, which includes Methotrexate, Tafasitamab, Rituximab, and Revlimid. This assessment will be conducted by an independent review committee (IRC) and will adhere to the criteria established by the International Primary CNS Lymphoma Collaborative Group (IPCG).

Secondary efficacy endpoints include the **best overall response rate (BORR)** after four cycles of MTR², defined as the rate of patients achieving a complete response (CR) or partial response (PR) according to at least one post-baseline tumor assessment. The **objective response rate (ORR)** at RA I and RA II will be determined by the rate of patients showing CR, CRr, or PR. **Progression-free survival (PFS)** will be calculated from the start of treatment to the date of first progression, relapse, or death, with one-year PFS rates and 90% confidence intervals estimated using the Kaplan-Meier method. **Overall survival (OS)** will be similarly calculated, with one-year OS rates and confidence intervals also estimated using the Kaplan-Meier method.

Additional assessments will include the incidence and severity of adverse events, summarized based on CTCAE grades, and the evaluation of quality of life and neurocognitive impairment over time using the EORTC QLQ-C30 and BN20 questionnaires, as well as the Montreal Cognitive Assessment (MoCA). Safety will be determined by the incidence and severity of adverse events, and feasibility will be assessed by the proportion of patients completing four cycles of MTR² and the relative dose intensity of planned and administered cycles.