Methotrexate, Tafasitamab, Lenalidomide and Rituximab in Patients With PCNSL

Study Overview
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Brief Summary
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Pilot-trial of Methotrexate, Tafasitamab (Minjuvi®), Lenalidomide (Revlimid®) and Rituximab in patients ineligible for HCT-ASCT with Primary Central Nervous System Lymphoma (PCNSL)

Detailed Description
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This is a single-arm, prospective, multicenter, single-stage phase-II trial for patients aged 18-69 years with ECOG PS ≥2 or ≥70 years with previously untreated PCNSL, who are not eligible for HCT-ASCT at investigators decision. This trial evaluates the CRR rate after at least 2 cycles of MTR2, the incidence and severity of adverse events, progression-free survival, and overall survival after one year. It is planned to enroll eligible patients with PCNSL, i.e. who receive at least 2 cycles of the combination of rituximab, MTX and the IMPs tafasitamab and lenalidomide, over a one-year period. Follow-up will be conducted for 1 year within the trial.

Official Title
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Pilot-trial of Methotrexate, Tafasitamab (Minjuvi®), Lenalidomide (Revlimid®) and Rituximab in Patients Ineligible for HCT-ASCT With Primary Central Nervous System Lymphoma (PCNSL)

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Tafasitamab
* Drug: Lenalidomide
* Drug: Rituximab
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18-69 years with ECOG PS ≥2 or ≥70 years ineligible for HCT-ASCT as per investigators discretion Previously untreated, histologically (or cytologically) confirmed diagnosis of primary B-cell lymphoma of the central nervous system (PCNSL) by local pathologist. Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy At least one measurable lesion Adequate organ function: Adequate kidney function, defined as: Serum creatinine estimated glomerular filtration rate (MDRD) ≥ 60 ml/min Adequate hepatic function, defined as: ALAT and ASAT ≤ 5 ULN Bilirubin ≤ 2.0 mg/dl (except for Meulengracht disease) Adequate bone marrow function, defined as: White blood cell (WBC) count ≥ 3000/µL or absolute neutrophil count (ANC) ≥ 1000/µL Platelets ≥ 50.000/µL Hemoglobin > 8.0 g/dl Adequate cardiac function, defined as: Cardiac ejection fraction ≥ 40% Adequate pulmonary function as per investigators discretion Written, signed, and dated informed consent must be obtained prior to participation in the study Male participants with female partners of childbearing potential are eligible to participate if they agree to contraceptive methods. Exclusion Criteria: Prior treatment for PCNSL with the exception of a pre-phase treatment comprising steroid treatment and / or single application of rituximab 375 mg/m2 and methotrexate 3.5 g/m2 Systemic lymphoma manifestation outside the CNS Diagnosis of previous Non-Hodgkin lymphoma at any time Primary vitreoretinal or leptomeningeal lymphoma without manifestation in the brain parenchyma or spinal cord HIV infection of any stage as determined by presence of anti-HIV antibodies (confirmatory test) and / or presence of RNA confirmed by PCR Previous or concurrent malignancies with the following exceptions: Surgically cured carcinoma in-situ Other kinds of cancer without evidence of disease for at least 5 years Hypersensitivity to study treatment or any component of the formulation Hepatitis B, hepatitis C or hepatitis E infection as determined by PCR Congenital or acquired immunodeficiency including previous organ transplantation Pregnant or nursing (lactating) women and women who are not confirmed to be menopausal / post-menopausal. Patient's lack of accountability and inability to appreciate the nature, meaning and consequences of the trial and to formulate his / her own wishes correspondingly Non-compliance, e.g. due to Drug dependency or substance abuse that would interfere with cooperation with requirements of the trial Refusal of blood products during treatment Any similar circumstances that appear to make protocol treatment or long-term follow-up impossible Patients who have a relationship of dependence or employer-employee relationship to the sponsor or the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: single-arm, prospective, multicenter, single-stage phase-II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: combination of Tafasitamab (Minjuvi®), Lenalidomide, Rituximab and Methotrexate<br>All patients will receive tafasitamab (Minjuvi®) 12 mg/KG body weight and rituximab 375 mg/m² on days 0 and 5, followed by methotrexate 3,5 g/m² on day 1 as an intravenous infusion. Lenalidomide will be administered orally at 20 mg/day during the first cycle and at 25 mg/day during subsequent cycles on days 4-17 of each 21-day cycle for a total number of 4 cycles. The treatment duration per patient will be 84 days. | Drug: Tafasitamab<br>* IV<br>Drug: Lenalidomide<br>* Oral<br>Drug: Rituximab<br>* IV<br>Drug: Methotrexate<br>* IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response rate (CRR) | The CRR will be determined by IRC and according to IPCG criteria. This endpoint reflects the proportion of patients who can potentially proceed to different consolidation or maintenance strategies to achieve durable responses. | At the end of cycle 2 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response rate (BORR) | is defined as the rate of patients having achieved a CR or PR according to at least one post-baseline tumor assessment | At the end of cycle 4 (each cycle is 21 days) | 
| Progression-free survival (PFS) | will be calculated for each patient as time between the start of treatment with MTR2 and the date of first progression, relapse or death or, in cases of continuing response, the date of the last documented follow-up (FU-CRF or written medical report). | After 1 year | 
| Overall survival (OS) | will be calculated for each patient as time between the start of treatment with MTR2 and the date of death or the date of the last documented follow-up (FU-CRF or written medical report). | After 1 year | 
| Incidence and severity of adverse events | Incidence and severity of adverse events, including toxic deaths during induction therapy will be summarized based on CTCAE grades | during induction therapy |