OptiMATe: De-escalated Induction Treatment in Primary CNS Lymphoma

Study Overview
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Brief Summary
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This phase III study investigates if a de-escalated induction treatment in newly diagnosed primary CNS lymphoma is superior to the standard MATRix protocol in terms of event free survival.

Detailed Description
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This phase III study investigates if a de-escalated induction treatment in newly diagnosed primary CNS lymphoma is superior to the standard MATRix protocol in terms of event free survival. Two arms are compared, in the experimental treatment group, participants receive one course of R/HD-MTX, followed by two courses of MATRix and autologous stem cell transplantation. In the control treatment, participants receive four coourses of MATRix followed by autologous stem cell transplantation.

Official Title
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Optimizing MATRix as Remission Induction in PCNSL: De-escalated Induction Treatment in Newly Diagnosed Primary CNS Lymphoma - a Randomized Phase III Trial

Conditions
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Primary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: Experimental Treatment: one course Rituximab/HD-Methotrexate, two courses of MATRix
* Drug: Control intervention: four courses of MATRix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Immunocompetent patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). Male or female patients aged 18-65 years irrespective of ECOG or 66-70 years with ECOG Performance Status ≤2. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist. Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy. Disease exclusively located in the CNS. At least one measurable lesion. Previously untreated patients (previous or ongoing steroid treatment admitted) Negative pregnancy test Written informed consent obtained according to international guidelines and local laws by patient or authorized legal representative in case patient is temporarily legally not competent due to his or her disease. Ability to understand the nature of the trial and the trial related procedures and to comply with them. Exclusion Criteria: Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation. Systemic lymphoma manifestation (outside the CNS). Primary vitreoretinal lymphoma without manifestation in the brain parenchyma or spinal cord Previous or concurrent malignancies with the exception of surgically cured carcinoma in situ of the cervix, carcinoma of the skin or other kinds of cancer without evidence of disease for at least 5 years. Previous Non-Hodgkin lymphoma at any time. Inadequate renal function (clearance < 60 ml/min). Inadequate bone marrow, cardiac, pulmonary or hepatic function according to investigator´s decision Active hepatitis B or C disease. Concurrent treatment with other experimental drugs or participation in an interventional clinical trial with study medication being administered within the last 30 days before the start of this study. Third space fluid accumulation > 500 ml. Hypersensitivity to study treatment or any component of the formulation. Taking any medications that are likely to cause interactions with the study medication Known or persistent abuse of medication, drugs or alcohol. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic Patients without legal capacity who are unable to understand the nature, significance and consequences of the trial and without designated legal representative. Previous participation in this trial. Persons who are in a relationship of dependency/employment with the sponsor and/or the investigator. Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Current or planned pregnancy, nursing period For fertile patients: Failure to use one of the following safe methods of contraception: intra-uterine device or hormonal contraception in combination with a mechanical method of contraception.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control treatment (Arm A)<br>Patients receive four courses of MATRix (Rituximab 2 x 375 mg/m2, HD-Methotrexate 3.5 g/m2, HD-Cytarabine 2 x 2 g/m2, Thiotepa 30 mg/m2; i.v.) as induction treatment. Response assessment with gadolinium-enhanced brain MRI (centrally reviewed) takes place after course two and four. Patient with at least PR proceed to 3rd course of MATRix after first response assessment and to HCT-ASCT (BCNU 400 mg/m2, Thiotepa 4 x 5 mg/kg; i.v.) after second response assessment. Collection of autologous stem cells is planed after the second course of MATRix. | Drug: Control intervention: four courses of MATRix<br>* Patients receive four courses of MATRix as induction treatment.<br>|
| Experimental: Experimental treatment (Arm B)<br>As induction treatment, patients receive one course of Rituximab/HD-Methotrexate (Rituximab 375 mg/m2, HD-Methotrexate 3.5 g/m2; i.v.). In the absence of clinical signs of progression, patients proceed to two courses of MATRix (Rituximab 2 x 375 mg/m2, HD-Methotrexate 3.5 g/m2, HD-Cytarabine 2 x 2 g/m2, Thiotepa 30 mg/m2; i.v.) followed by a response assessment with gadolinium-enhanced brain MRI (centrally reviewed). Patients with at least PR will proceed to HCT-ASCT (BCNU 400 mg/m2, thiotepa 4 x 5 mg/kg; i.v.). Collection of autologous stem cells is planed after the first course of MATRix | Drug: Experimental Treatment: one course Rituximab/HD-Methotrexate, two courses of MATRix<br>* De-escalated induction treatment with R/HD-MTX and two courses of MATRix<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | time from randomization to premature end of treatment due to any reason, lymphoma progression or death, whichever occurs first | up to 24 months after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | time from randomization to death of any course | up to 24 months after end of treatment | 
| Progression free survival (PFS) | time from randomization until disease progression, relapse or death from any cause | up to 24 months after end of treatment | 
| Remission rate prior to consolidation therapy | Remission prior to consolidation therapy will be determined at RA II and will be divided in CR, uCR, PR, CD, PD according to IPCG criteria | assesed at RA II (Arm B: day 18-20 of cycle 2, each cycle is 21 days. Arm A: day 18-20 of cycle 4, each cycle is 21 days) | 
| Remission rate after consolidation therapy | Remission after consolidation therapy will be determined on day 30 after ASCT and will be divided in CR, uCR, PR, SD, PD according to IPCG criteria | 30 days after ASCT | 
| rate of patients reaching consolidation therapy | defined as obtaining at least the first dose of consolidation therapy, will be determined after the response assessment II (following 4 cycles of MATRix in the control arm and following 1 cycle of R/HD-MTX and 2 cycles of MATRix in the experimental arm) | determined up to 4 weeks after response assessment II | 
| Quality of life (QOL), EORTC QLQ-C30, | EORTC (European Organization for research and cancer treatment) QLQ-C30, measured during screening, at response assessment II, and with beginning of RA III every 12 months until end of follow-up | up to 24 months after end of treatment | 
| Quality of life (QOL), QLQ-BN20 | EORTC (European Organization for research and cancer treatment) QLQ-BN20; measured during screening, at response assessment II, and with beginning of RA III every 12 months until end of follow-up | up to 24 months after end of treatment |