Trial for Patients With Newly Diagnosed Primary Central Nervous System (CNS) Lymphoma

March 18, 2026 updated by: International Extranodal Lymphoma Study Group (IELSG)

Randomized Phase II Trial On Primary Chemotherapy With High-Dose Methotrexate And High-Dose Cytarabine With Or Without Thiotepa, And With Or Without Rituximab, Followed By Brain Irradiation Vs. High-Dose Chemotherapy Supported By Autologous Stem Cells Transplantation For Immunocompetent Patients With Newly Diagnosed Primary CNS Lymphoma

This is a multicenter open label randomized phase II trial.

Enrolled Primary Central Nervous System Lymphoma (PCNSL) patients will be stratified according to the IELSG score and randomized to receive one of the follows as primary chemotherapy:

  • Arm A: Methotrexate (MTX) + Cytarabine (Ara-C)
  • Arm B: MTX + Ara-C + rituximab
  • Arm C: MTX + Ara-C + rituximab + thiotepa.

Chemotherapy will be administered every three weeks. The maximum number of chemotherapy induction courses will be 4. Patients in Stable Disease (SD) or better after two courses will receive two more courses of the same primary chemotherapy regimen. Stem-cells harvest will be performed in the three arms after the second course. After 4 courses response assessment will be performed.

Patients who will not achieve SD or better after the 4th course, as well as those who will experience Progressive Disease (PD) at any time and those who will not achieve a sufficient stem cell harvest, will receive Whole Brain Radiation Therapy (WBRT) 36-40 Gy +/- tumor bed boost of 9 Gy.

Patients who will achieve SD or better after the 4th course will be stratified according to objective response to primary chemotherapy and to primary chemotherapy regimen and randomly allocated to receive as consolidation therapy one of the follows:

  • Arm D: WBRT 36 Gy +/- boost 9 Gy
  • Arm E: Carmustine (BCNU) + Thiotepa + Autologous Peripheral Blood Stem Cell Transplant (APBSCT) Patients in Complete Response (CR) after WBRT or APBSCT will remain in follow-up. Patients who will not achieve a CR after WBRT will be managed according to physician's preferences. Patients who will not achieve a CR after APBSCT will be referred to WBRT.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

227

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Aarhus, Denmark
        • University Hospital
      • Copenhagen, Denmark
        • Rigshospitalet,
      • Herlev, Denmark
        • Herlev Hospital
  • Germany
      • Aachen, Germany
        • University Hospital
      • Braunschweig, Germany
        • Städtisches Klinikum
      • Bremen, Germany
        • Klinikum Bremen-Mitte
      • Chemnitz, Germany
        • Klinikum Chemnitz
      • Cologne, Germany
        • Universitätsklinikum
      • Erlangen, Germany
        • Universitätsklinikum Erlangen
      • Essen, Germany
        • "Klinik für Hämatologie Universitätsklinikum Essen"
      • Frankfurt am Main, Germany
        • Klinikum der Johann-Wolfgang- Goethe-Universität
      • Freiburg im Breisgau, Germany
        • Uniklinik Freiburg
      • Giessen, Germany
        • Klinikum der Justus-Liebig-Universität
      • Göttingen, Germany
        • Georg-August-Universität
      • Halle, Germany
        • Universitatsklinikum Halle
      • Hamburg, Germany
        • Universitätskrankenhaus Hamburg-Eppendorf
      • Heilbronn, Germany
        • SLK-Kliniken GmbH
      • Homburg/Saar, Germany
        • Universitätsklinikum des Saarlandes
      • Jena, Germany
        • Friedrich Schiller Universitaet Jena
      • Kiel, Germany
        • Universitätsklinikum und Städtisches Krankenhaus
      • Mainz, Germany
        • Johannes Gutenberg Universität Mainz
      • München, Germany
        • Technische Universität in München
      • Ulm, Germany
        • Universitatsklinikum Ulm
  • Italy
      • Alessandria, Italy
        • A.O. SS. Antonio e Biagio e Cesare Arrigo
      • Bari, Italy
        • Istituto Tumori Giovanni Paolo II
      • Bolzano, Italy
        • Ospedale Centrale di Bolzano
      • Brescia, Italy
        • Spedali Civili
      • Cagliari, Italy
        • Ospedale Businco
      • Milan, Italy
        • San Raffaele H Scientific Institute
      • Milan, Italy
        • Grande Ospedale Metropolitano Niguarda
      • Napoli, Italy
        • Istituto Nazionale Tumori, Fondazione G. Pascale
      • Nocera Inferiore, Italy
        • Ospedale Umberto I
      • Pescara, Italy
        • Ospedale Civile S.Spirito
      • Pisa, Italy
        • AOU Pisana
      • Ravenna, Italy
        • Ospedale delle Croci
      • Reggio Emilia, Italy
        • Arcispedale Santa Maria Nuova
      • Rimini, Italy
        • Ospedale degli Infermi
      • Roma, Italy
        • Istituto Nazionale dei Tumori Regina Elena
      • Roma, Italy
        • Universita Degli Studi La Sapienza
      • Rozzano, Italy
        • Humanitas
      • San Giovanni Rotondo, Italy
        • Casa Sollievo Della Sofferenza
      • Siena, Italy
        • Azienda Ospedaliera Universitaria Senese
      • Terni, Italy
        • Azienda Ospedaliera Sanitaria Santa Maria
      • Torino, Italy
        • Ospedale Maggiore S. Giovanni Battista
      • Udine, Italy
        • Azienda Sanitaria Universitaria Friuli Centrale
      • Verona, Italy
        • Policlinico G.B. Rossi
      • Vicenza, Italy
        • ULSS 8 Berica - Ospedale S. Bortolo
  • Switzerland
      • Bellinzona, Switzerland, 6500
        • IOSI - Oncology Institute of Southern Switzerland
  • United Kingdom
      • Liverpool, United Kingdom
        • University Hospital Aintree
      • London, United Kingdom
        • University College Hospital
      • Manchester, United Kingdom
        • The Christie Hospital NHS Foundation Trust
      • Nottingham, United Kingdom
        • Nottingham City Hospital
      • Romford, United Kingdom
        • Queen's Hospital
      • Southampton, United Kingdom
        • Medical Oncology Unit General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histological or cytological assessed diagnosis of non-Hodgkin's lymphoma.
  • Diagnostic sample obtained by stereotactic or surgical biopsy, Cerebrospinal Fluid (CSF) cytology examination or vitrectomy.
  • Disease exclusively localized into the central nervous system, CSF, cranial nerves or eyes.
  • At least one measurable lesion.
  • Previously untreated patients (previous or ongoing steroid therapy admitted).
  • Age 18-65 years (with ECOG Performance Status 0-3) or 66-70 (with ECOG Performance Status 0-2).
  • Adequate bone marrow, renal, cardiac, and hepatic function.
  • Sexually active patients of childbearing potential agreeing in implementing adequate contraceptive measures during study participation.
  • Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
  • Patient-signed informed consent obtained before registration.

Exclusion Criteria:

  • Patients with lymphomatous lesions outside the CNS.
  • Patients with a previous non-Hodgkin lymphoma at any time.
  • Previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the cervix, carcinoma of the skin or other cancers without evidence of disease at least from 5 years.
  • HBsAg and HCV positivity.
  • HIV infection, previous organ transplantation or other clinically evident form of immunodeficiency.
  • Concurrent treatment with other experimental drugs.
  • Concurrent Pregnancy or lactation.
  • Patients not agreeing to take adequate contraceptive measures during the study.
  • Symptomatic coronary artery disease, cardiac arrhythmias uncontrolled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: WBRT 36 Gy +/- boost 9 Gy
ARM D: WBRT with 36 Gy in the case of CR to primary chemotherapy or the same WBRT dose followed by a tumor-bed boost of 9 Gy with 1-2 cm of margin surrounding enhanced residual lesion (total tumor-bed dose 45 Gy) in patients who achieved a PR or SD after primary chemotherapy. Photons of 4-10 Mev, 180 cGy per day, 5 weekly fractions.
Radiation: radiotherapy
Photons of 4-10 Mev, 180 cGy per day, 5 weekly fractions. Whole-brain will be irradiated by two opposite lateral fields including the first two cervical vertebras and the posterior two thirds of the orbits, which must be shielded after 30 Gy (after 36 Gy in the case of evident intraocular disease at diagnosis). Tumor-bed (boost or partial-brain RT) will be irradiated by 2 to 4 isocentric treatment fields based on tumor location, with all portals treated per each RT session.
Experimental: BCNU + Thiotepa + APBSCT
Arm E BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6 Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4 Reinfusion of PBSC ≥5 x 106 CD34+ cells/kg day 0
Drug: Thiotepa
ARM C: Thiotepa 30 mg/m2 (30 min. Infusion) on day 4 every 3 weeks for a maximum of 4 courses ARM E: Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4
Drug: BCNU
BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6
Other Names:
  • Carmustine
Other: APBSCT
Autologous peripheral blood stem cell transplant (APBSCT)
Experimental: MTX + AraC
Arm A Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion) d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3
Drug: Methotrexate
Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion) on day 1, every 3 weeks for a maximum of 4 courses.
Drug: Ara-C
Cytarabine 2 g/m2 (1 hr infusion, twice a day every 12 hours), on d 2 - 3 every 3 weeks for a maximum of 4 courses
Other Names:
  • Cytarabine
Experimental: MTX + Ara-C + Rituximab
Arm B Rituximab 375 mg/m2 conventional infusion d -5 & 0 Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3
Drug: Methotrexate
Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion) on day 1, every 3 weeks for a maximum of 4 courses.
Drug: Ara-C
Cytarabine 2 g/m2 (1 hr infusion, twice a day every 12 hours), on d 2 - 3 every 3 weeks for a maximum of 4 courses
Other Names:
  • Cytarabine
Drug: Rituximab
Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles
Other Names:
  • MabThera
Experimental: MTX + Ara-C + rituximab+thiotepa
Arm C Rituximab 375 mg/m2 conventional infusion d -5 & 0 Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3 Thiotepa 30 mg/m2 30 min. Infusion d 4
Drug: Methotrexate
Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion) on day 1, every 3 weeks for a maximum of 4 courses.
Drug: Ara-C
Cytarabine 2 g/m2 (1 hr infusion, twice a day every 12 hours), on d 2 - 3 every 3 weeks for a maximum of 4 courses
Other Names:
  • Cytarabine
Drug: Rituximab
Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles
Other Names:
  • MabThera
Drug: Thiotepa
ARM C: Thiotepa 30 mg/m2 (30 min. Infusion) on day 4 every 3 weeks for a maximum of 4 courses ARM E: Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete Remission Rate After Primary Chemotherapy
Time Frame: 3 months after treatment start
Percentage of patients with complete remission after 3 month of treatment. Percentage values are rounded to whole numbers.
3 months after treatment start
2 Years Failure Free Survival (FFS) After Second Randomization
Time Frame: Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry
Percentage of patients alive and free from disease progression, relapse, need for new treatment, after 2 years from study entry. Percentage values are rounded to whole numbers.
Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
2 Years Failure Free Survival (FFS)
Time Frame: Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry
Percentage of patients alive and free from disease progression, relapse, need for new treatment, after 2 years from study entry any cause. Percentage values are rounded to whole numbers.
Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry
2 Year Overall Survival (OS)
Time Frame: From study entry until 2 years after
Percentage of patients alive after 2 years from study entry. Percentage values are rounded to whole numbers.
From study entry until 2 years after

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

International Extranodal Lymphoma Study Group (IELSG)

Investigators

  • Study Chair: Andrés JM Ferreri, MD, San Raffaele H Scientific Institute, Milan, Italy
  • Study Chair: Gerald Illerhaus, MD, University Medical Center, Freiburg, Germany
  • Principal Investigator: Emanuele Zucca, MD, IOSI, Bellinzona, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (Actual)

March 1, 2015

Study Completion (Actual)

December 19, 2024

Study Registration Dates

First Submitted

November 9, 2009

First Submitted That Met QC Criteria

November 10, 2009

First Posted (Estimated)

November 11, 2009

Study Record Updates

Last Update Posted (Actual)

March 19, 2026

Last Update Submitted That Met QC Criteria

March 18, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IELSG32
  • 2009-012432-32 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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