Adjusted High-dose Chemotherapy With Autologous Stem Cell Transplant vs. Conventional Immunochemotherapy in Elderly PCNSL Patients

NCT06830421 | Recruiting Phase 3 DMC

• 3 other identifiers: P0030772020-001181-10DRKS00024085
• Study Type: interventional
• Target: 340
• Locations: 1 country
• Sites: 35

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.

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

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS) between the 2 arms

  PFS is defined as the time from randomization to disease progression or death of any cause, with censoring at the last date the patient was seen alive and free of disease progression

  up to 6 years

Secondary Outcomes (7)

• Overall survival (OS) between the 2 arms

  up to 6 years

• Event free survival (EFS) between the 2 arms

  up to 6 years

• Remission status after 2 cycles of rituximab-methotrexate-procarbazine (R-MP) (arm A)/2 cycles of R-MTX/cytarabine (AraC)

  at RA I: after 8 weeks (Arm A), after 6 weeks (Arm B)

• Remission status after 3 cycles of R-MP (arm A)/consolidating HCT-ASCT (arm B)

  at RA II: after 12 weeks

• Remission status after completion of maintenance treatment (arm A)/6 months follow-up (arm B)

  6 months after RA II

Other Outcomes (4)

• Safety: Toxicity

  from date of informed consent form (ICF) signature until 30 days after end of treatment

• Safety: Neurotoxicity

  from date of informed consent form (ICF) signature up to 6 years

• Unplanned hospital admissions

  from date of informed consent form (ICF) signature until 30 days after ASCT or 30 days after last administration of investigational medicinal products (IMP)

Study Arms (2)

Arm A

ACTIVE COMPARATOR

Patients will receive 3 cycles (28 days cycle) of R-MP (Rituximab 375 mg/m² i.v. d0,14; MTX 3.5 g/m² i.v. d1,15; Procarbazine 60 mg/m²/d p.o. d2-11) followed by maintenance therapy with Procarbazine 100 mg absolute/d p.o. d1-5 for additional 6 cycles (28 days cycle).

Drug: R-MP and Procarbazine maintenance

Arm B

EXPERIMENTAL

Patients will receive 2 cycles (21 days cycle) of R-MTX/AraC (Rituximab 375 mg/m² i.v. d0,4; MTX 3.5 g/m² i.v. d1; AraC 2x2 g/m² i.v. d2+d3) followed by consolidating HCT-ASCT with Rituximab 375 mg/m² d-8, Busulfan 3.2 mg/kg/d i.v. d-7 and d-6 and Thiotepa 5 mg/kg/d i.v. d-5 and d-4.

Drug: R-MTX/AraC (MARTA) induction followed by consolidating HCT-ASCT

Interventions

R-MP and Procarbazine maintenance DRUG

Firstline systemic treatment with conventinal immunochemotherapy (3 cycles of Rituximab-MTX-Procarbazine) followed by Procarbazine maintenance

Arm A

R-MTX/AraC (MARTA) induction followed by consolidating HCT-ASCT DRUG

Firstline systemic treatment with age-adjusted MTX based induction (2 cycles of Rituximab-Methotrexate-Cytarabin) followed by consolidating aged-adapted high-dose chemotherapy and autologous stem cell transplantation

Arm B

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Immunocompetent patients with newly-diagnosed primary DLBCL of the central nervous system.
• Age \> 70 years or age 65-70 years if not eligible for more intensive treatment (e.g. OptiMATe trial).
• Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist.
• Diagnostic sample obtained by stereotactic or surgical biopsy, cerebrospinal fluid (CSF) cytology examination or vitrectomy.
• Disease exclusively located in the CNS.
• At least 1 measurable lesion.
• Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) ≤ 2. ECOG PS \> 2 accepted if due to PCNSL symptoms.
• Patients possibly eligible for HCT-ASCT as judged by the treating physician.
• 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:
• 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.
• No evidence of disease progression after pre-phase treatment.

You may not qualify if:

• Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation.
• Systemic lymphoma manifestation (outside the CNS).
• Primary vitreoretinal lymphoma or primary leptomeningeal lymphoma without manifestation in the brain parenchyma or spinal cord.
• 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.
• Previous systemic Non-Hodgkin lymphoma at any time.
• Inadequate renal function (creatinine 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 administration of study medication within the last thirty 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 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 and who are unable to understand the nature, significance and consequences of the study and without designated legal representative.

Sponsors & Collaborators

• University Hospital Freiburg: lead
• German Federal Ministry of Education and Research: collaborator
• University Hospital Tuebingen: collaborator
• Heinrich-Heine University, Duesseldorf: collaborator
• Klinikum Stuttgart: collaborator
• University of Kaiserslautern: collaborator
• University Hospital Munich: collaborator
• University Hospital Regensburg: collaborator

Study Sites (35)

University Hospital Freiburg, Department Medicine I, Hematology, oncology and stem cell transplantation

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

RECRUITING

Klinikum Stuttgart, Clinic of Hematology, Oncology and Palliative Care, Stuttgart Cancer Center / Tumor Center Eva Mayr-Stihl

Stuttgart, Baden-Wurttemberg, 70174, Germany

RECRUITING

University Hospital Aachen

Aachen, Germany

RECRUITING

University Hospital Augsburg

Augsburg, Germany

RECRUITING

Helios Klinikum Berlin-Buch

Berlin, Germany

NOT YET RECRUITING

University Hospital Berlin

Berlin, Germany

RECRUITING

Evangelisches Klinikum Bethel

Bielefeld, Germany

NOT YET RECRUITING

Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH

Bochum, Germany

RECRUITING

Städtisches Klinikum Braunschweig gGmbH

Braunschweig, Germany

RECRUITING

Klinikum Bremen-Mitte gGmbH

Bremen, Germany

RECRUITING

Klinikum Chemnitz gGmbH

Chemnitz, Germany

NOT YET RECRUITING

Universitätsklinikum Köln

Cologne, Germany

NOT YET RECRUITING

Carl Gustav Carus Universitätsklinikum Dresden

Dresden, Germany

RECRUITING

Universitätsklinikum Düsseldorf

Düsseldorf, Germany

NOT YET RECRUITING

Universitätsklinikum Erlangen

Erlangen, Germany

RECRUITING

Universitätsklinikum Essen

Essen, Germany

NOT YET RECRUITING

Klinikum der Johann-Wolfgang-Goethe-Universität

Frankfurt, Germany

RECRUITING

Universitätsmedizin Göttingen Georg-August-Universität

Göttingen, Germany

NOT YET RECRUITING

Universitätsklinikum Halle (Saale)

Halle, Germany

NOT YET RECRUITING

Universitätsklinikum des Saarlandes Homburg

Homburg, Germany

RECRUITING

Städtisches Klinikum Karlsruhe

Karlsruhe, Germany

RECRUITING

Universitätsklinkum Schleswig-Holstein, Campus Kiel

Kiel, Germany

RECRUITING

Gemeinschaftsklinikum Mittelrhein gGmbH - Koblenz Ev. Stift St. Martin

Koblenz, Germany

RECRUITING

Universitätsklinikum Leipzig

Leipzig, Germany

NOT YET RECRUITING

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Lübeck, Germany

RECRUITING

Klinikum rechts der Isar TU München

München, Germany

NOT YET RECRUITING

Universitätsklinikum Münster

Münster, Germany

RECRUITING

Universitätsklinik der Paracelsus Medizinischen Privatuniversität

Nuremberg, Germany

NOT YET RECRUITING

Pius-Hospital Oldenburg

Oldenburg, Germany

RECRUITING

Klinikum Oldenburg gGmbh

Oldenburg in Holstein, Germany

NOT YET RECRUITING

Universitätsklinikum Regensburg

Regensburg, Germany

RECRUITING

Universitätsmedizin Rostock

Rostock, Germany

NOT YET RECRUITING

Universtitätsklinikum Tübingen

Tübingen, Germany

NOT YET RECRUITING

Universitätsklinikum Ulm

Ulm, Germany

RECRUITING

Schwarzwald-Baar-Klinikum Villingen-Schwenningen

Villingen-Schwenningen, Germany

RECRUITING

Related Publications (15)

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  PMID: 38301670 BACKGROUND

• Mendez JS, Ostrom QT, Gittleman H, Kruchko C, DeAngelis LM, Barnholtz-Sloan JS, Grommes C. The elderly left behind-changes in survival trends of primary central nervous system lymphoma over the past 4 decades. Neuro Oncol. 2018 Apr 9;20(5):687-694. doi: 10.1093/neuonc/nox187.

  PMID: 29036697 BACKGROUND

• Houillier C, Soussain C, Ghesquieres H, Soubeyran P, Chinot O, Taillandier L, Lamy T, Choquet S, Ahle G, Damaj G, Agape P, Molucon-Chabrot C, Amiel A, Delwail V, Fabbro M, Jardin F, Chauchet A, Moles-Moreau MP, Morschhauser F, Casasnovas O, Gressin R, Fornecker LM, Abraham J, Marolleau JP, Tempescul A, Campello C, Colin P, Tamburini J, Laribi K, Serrier C, Haioun C, Chebrek S, Schmitt A, Blonski M, Houot R, Boyle E, Bay JO, Oberic L, Tabouret E, Waultier A, Martin-Duverneuil N, Touitou V, Cassoux N, Kas A, Mokhtari K, Charlotte F, Alentorn A, Feuvret L, Le Garff-Tavernier M, Costopoulos M, Mathon B, Peyre M, Delgadillo D, Douzane H, Genet D, Aidaoui B, Hoang-Xuan K, Gyan E. Management and outcome of primary CNS lymphoma in the modern era: An LOC network study. Neurology. 2020 Mar 10;94(10):e1027-e1039. doi: 10.1212/WNL.0000000000008900. Epub 2020 Jan 6.

  PMID: 31907289 BACKGROUND

• Schorb E, Fox CP, Kasenda B, Linton K, Martinez-Calle N, Calimeri T, Ninkovic S, Eyre TA, Cummin T, Smith J, Yallop D, De Marco B, Krampera M, Trefz S, Orsucci L, Fabbri A, Illerhaus G, Cwynarski K, Ferreri AJM. Induction therapy with the MATRix regimen in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system - an international study of feasibility and efficacy in routine clinical practice. Br J Haematol. 2020 Jun;189(5):879-887. doi: 10.1111/bjh.16451. Epub 2020 Jan 29.

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• Olivier G, Clavert A, Lacotte-Thierry L, Gardembas M, Escoffre-Barbe M, Brion A, Cumin I, Legouffe E, Solal-Celigny P, Chabin M, Ingrand P, Colombat P, Delwail V. A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial. Am J Hematol. 2014 Nov;89(11):1024-9. doi: 10.1002/ajh.23812. Epub 2014 Aug 27.

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• Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosee PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Ruda R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gorlov JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group (IELSG). Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. doi: 10.1016/S2352-3026(16)00036-3. Epub 2016 Apr 6.

  PMID: 27132696 BACKGROUND

• Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosee P, Binder M, Fabbri A, Torri V, Minacapelli E, Falautano M, Ilariucci F, Ambrosetti A, Roth A, Hemmaway C, Johnson P, Linton KM, Pukrop T, Sonderskov Gorlov J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabras G, Angrilli F, Ponzoni M, Deckert M, Politi LS, Finke J, Reni M, Cavalli F, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group (IELSG). Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017 Nov;4(11):e510-e523. doi: 10.1016/S2352-3026(17)30174-6. Epub 2017 Oct 17.

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• Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Mohle R, Low S, Binder M, Atta J, Keller U, Wolf HH, Krause SW, Hess G, Naumann R, Sasse S, Hirt C, Lamprecht M, Martens U, Morgner A, Panse J, Frickhofen N, Roth A, Hader C, Deckert M, Fricker H, Ihorst G, Finke J, Illerhaus G. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017 Apr;31(4):846-852. doi: 10.1038/leu.2016.334. Epub 2016 Nov 15.

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• Schorb E, Kasenda B, Ihorst G, Scherer F, Wendler J, Isbell L, Fricker H, Finke J, Illerhaus G. High-dose chemotherapy and autologous stem cell transplant in elderly patients with primary CNS lymphoma: a pilot study. Blood Adv. 2020 Jul 28;4(14):3378-3381. doi: 10.1182/bloodadvances.2020002064.

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• Schorb E, Finke J, Ihorst G, Kasenda B, Fricker H, Illerhaus G. Age-adjusted high-dose chemotherapy and autologous stem cell transplant in elderly and fit primary CNS lymphoma patients. BMC Cancer. 2019 Mar 29;19(1):287. doi: 10.1186/s12885-019-5473-z.

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• Schorb E, Isbell LK, Illerhaus G, Ihorst G, Meerpohl JJ, Grummich K, Nagavci B, Schmucker C. Treatment Regimens for Immunocompetent Elderly Patients with Primary Central Nervous System Lymphoma: A Scoping Review. Cancers (Basel). 2021 Aug 24;13(17):4268. doi: 10.3390/cancers13174268.

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Central Study Contacts

Elisabeth Schorb, MD

CONTACT

+49 761 270-35360; elisabeth.schorb@uniklinik-freiburg.de

Gerald Illerhaus, MD

CONTACT

+49 711 278-30400; g.illerhaus@klinikum-stuttgart.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: June 5, 2023
• First Posted: February 17, 2025
• Study Start: August 9, 2023
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): August 31, 2031
• Last Updated: February 17, 2025

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: year 2023 and after completion of study
• Access Criteria: Isbell LK et al. 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 - the randomized phase III PRIMA-CNS trial. BMC Cancer. 2023 Aug 18;23(1):767. doi: 10.1186/s12885-023-11193-7. PMID: 37596517; PMCID: PMC10436648.

Locations

DE (35)