Clinical trial NCT06830421: Adjusted High-dose Chemotherapy With Autologous Stem Cell Transplant vs. Conventional Immunochemotherapy in Elderly PCNSL Patients
Official title: Age-adjusted High-dose Chemotherapy Followed by Autologous Stem Cell Transplantation or Conventional Chemotherapy With R-MP as First-line Treatment in Elderly Primary CNS Lymphoma Patients - a Randomized Phase III Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Primary Central Nervous System Lymphoma
Keywords: Primary central nervous system lymphoma
HD-chemotherapy followed by autologous stem cell transplantation
Age-adjusted HCT-ASCT
First-line treatment in elderly PCNSL patients
HD-MTX induction
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
name: University Hospital Tuebingen
name: Heinrich-Heine University, Duesseldorf
name: Klinikum Stuttgart
name: University of Kaiserslautern
name: University Hospital Munich
name: University Hospital Regensburg
First posted: 2025-02-17
Enrollment: 340
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized, controlled, open-label, multicenter phase III trial with 2 parallel arms investigating a more intensive, shorter treatment with 2 cycles of MARTA (rituximab, HD-MTX, AraC) followed by HCT with rituximab, busulfan and thiotepa followed by ASCT compared to standard therapy comprising 3 cycles of R-MP followed by procarbazine maintenance for 6 months.
Primary purpose: TREATMENT

Brief summary: Most patients being diagnosed with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) are 60 years or older. Elderly patients with PCNSL have a poor prognosis and there is a great medical need to improve outcome for this vulnerable population. In Germany and many international centres, there are currently two widely used strategies to treat elderly PCNSL patients who are eligible for high-dose methotrexate (HD-MTX) treatment, which have not yet been compared head-to-head. The R-MP regimen has been established by the Cooperative PCNSL Study Group as a "conventional" immunochemotherapy standard treatment for elderly patients with newly diagnosed disease and consists of Rituximab, HD-MTX and Procarbazine followed by maintenance therapy with Procarbazine. In contrast, another recently established protocol also includes HD-MTX-based induction therapy, but followed by consolidating high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT). This is an overall more intensive, but substantially shorter treatment approach, feasible for elderly patients being considered eligible for a more intensive treatment. The PRIMA-CNS trial aims to compare these two treatment approaches with respect to survival, response rates and toxicity.

Detailed description: Primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is a rare lymphoma affecting only the central nervous system compartment. PCNSL patients are typically 60 years or older and have poor prognoses. However, there are alternative treatment approaches to consider with the potential to improve medical outcomes for this patient population. The current standard of care in Germany and many international centres for patients 65 and older is treatment with R-MP, comprising rituximab, high-dose methotrexate (HD-MTX) and procarbazine followed by maintenance therapy with procarbazine. An alternative approach comprised of a shorter induction treatment with rituximab, HD-MTX and cytarabine (MARTA) followed by age-adjusted high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) was recently shown to be feasible and effective in elderly PCNSL patients considered eligible for high-dose chemotherapy requiring autologous stem cell transplantation. Nevertheless, data evaluating this short duration treatment approach remains scarce, and randomized trials have not yet been published. The objective of the PRIMA-CNS trial is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with R-MP followed by maintenance with procarbazine in elderly patients with newly diagnosed PCNSL; not only regarding survival and remission after treatment but also regarding standards like quality of life (QOL) and treatment related morbidities. Results of this randomized trial will either change the standard of care to an intense and shorter treatment approach or re-define R-MP as a proven treatment standard. In addition, a geriatric assessement is implemented in this trial with the goal to better define transplant eligibility. If this trial shows the superiority of HCT-ASCT, the investigators will establish an improved treatment standard with increased chances for long-term remission and cure and reduced frequency and length of chemotherapy treatment. Considering the poor prognosis of this patient population, this randomized phase III trial is of great clinical importance to provide patients, the patients' families and care takers with optimal treatment.

Eligibility criteria: Inclusion Criteria:

1. Immunocompetent patients with newly-diagnosed primary DLBCL of the central nervous system.
2. Age \> 70 years or age 65-70 years if not eligible for more intensive treatment (e.g. OptiMATe trial).
3. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist.
4. Diagnostic sample obtained by stereotactic or surgical biopsy, cerebrospinal fluid (CSF) cytology examination or vitrectomy.
5. Disease exclusively located in the CNS.
6. At least 1 measurable lesion.
7. Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) ≤ 2. ECOG PS \> 2 accepted if due to PCNSL symptoms.
8. Patients possibly eligible for HCT-ASCT as judged by the treating physician.
9. 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.

Additional randomization criteria:

1. Patients eligible for HCT-ASCT defined by the EBL score (at most one of the 3 following conditions may apply: ECOG PS \> 1, Barthel Index of activities of daily living (ADL) \< 20 and Lachs geriatric screening \> 3), improvement of PS after pre-phase treatment or clinical judgement by the treating physician after discussion with the study expert team.
2. No evidence of disease progression after pre-phase treatment.

Exclusion Criteria:

1. Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation.
2. Systemic lymphoma manifestation (outside the CNS).
3. Primary vitreoretinal lymphoma or primary leptomeningeal lymphoma without manifestation in the brain parenchyma or spinal cord.
4. Previous or concurrent malignancies with the exception of surgically cured carcinoma in situ or other kinds of cancer without evidence of disease for at least 5 years.
5. Previous systemic Non-Hodgkin lymphoma at any time.
6. Inadequate renal function (creatinine clearance \<60 ml/min).
7. Inadequate bone marrow, cardiac, pulmonary or hepatic function according to investigator´s decision.
8. Active hepatitis B or C disease.
9. Concurrent treatment with other experimental drugs or participation in an interventional clinical trial with administration of study medication within the last thirty days before the start of this study.
10. Third space fluid accumulation \>500 ml.
11. Hypersensitivity to study treatment or any component of the formulation.
12. Taking any medications likely to cause interactions with the study medication.
13. Known or persistent abuse of medication, drugs or alcohol.
14. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic.
15. Patients without legal capacity and who are unable to understand the nature, significance and consequences of the study and without designated legal representative.
16. Previous participation in this trial.
17. Persons who are in a relationship of dependency/employment to the sponsor and/ or investigator.
18. Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
19. Fertile patients refusing to use safe contraceptive methods during the study.

Primary outcomes:
measure: Progression free survival (PFS) between the 2 arms
timeFrame: up to 6 years
Secondary outcomes:
measure: Overall survival (OS) between the 2 arms
timeFrame: up to 6 years
measure: Event free survival (EFS) between the 2 arms
timeFrame: up to 6 years
measure: Remission status after 2 cycles of rituximab-methotrexate-procarbazine (R-MP) (arm A)/2 cycles of R-MTX/cytarabine (AraC)
timeFrame: at RA I: after 8 weeks (Arm A), after 6 weeks (Arm B)
measure: Remission status after 3 cycles of R-MP (arm A)/consolidating HCT-ASCT (arm B)
timeFrame: at RA II: after 12 weeks
measure: Remission status after completion of maintenance treatment (arm A)/6 months follow-up (arm B)
timeFrame: 6 months after RA II
measure: Quality of life (EORTC QLQ-C30)
timeFrame: from date of informed consent form (ICF) signature up to 6 years
measure: Quality of Life (EORTC-QLQ BN 20)
timeFrame: from date of informed consent form (ICF) signature up to 6 years
Other outcomes:
measure: Safety: Toxicity
timeFrame: from date of informed consent form (ICF) signature until 30 days after end of treatment
measure: Safety: Neurotoxicity
timeFrame: from date of informed consent form (ICF) signature up to 6 years
measure: Unplanned hospital admissions
timeFrame: from date of informed consent form (ICF) signature until 30 days after ASCT or 30 days after last administration of investigational medicinal products (IMP)
measure: Length of hospital stays
timeFrame: from date of informed consent form (ICF) signature until 30 days after ASCT or day 30 after last administration of IMP
Locations:
city: Freiburg
country: Germany
facility: University Hospital Freiburg, Department Medicine I, Hematology, oncology and stem cell transplantation
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart, Clinic of Hematology, Oncology and Palliative Care, Stuttgart Cancer Center / Tumor Center Eva Mayr-Stihl
state: Baden-Wuerttemberg
city: Aachen
country: Germany
facility: University Hospital Aachen
city: Augsburg
country: Germany
facility: University Hospital Augsburg
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Berlin
country: Germany
facility: University Hospital Berlin
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel
city: Bochum
country: Germany
facility: Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbH
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte gGmbH
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Dresden
country: Germany
facility: Carl Gustav Carus Universitätsklinikum Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der Johann-Wolfgang-Goethe-Universität
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen Georg-August-Universität
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes Homburg
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Kiel
country: Germany
facility: Universitätsklinkum Schleswig-Holstein, Campus Kiel
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein gGmbH - Koblenz Ev. Stift St. Martin
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Luebeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Lübeck
city: München
country: Germany
facility: Klinikum rechts der Isar TU München
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Universitätsklinik der Paracelsus Medizinischen Privatuniversität
city: Oldenburg In Holstein
country: Germany
facility: Klinikum Oldenburg gGmbh
city: Oldenburg
country: Germany
facility: Pius-Hospital Oldenburg
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
city: Tübingen
country: Germany
facility: Universtitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar-Klinikum Villingen-Schwenningen
Study officials:
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