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

NCT01011920 | Completed Phase 2 Results DMC

• 2 other identifiers: IELSG322009-012432-32
• Study Type: interventional
• Target: 227
• Locations: 5 countries
• Sites: 54

Brief Summary

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.

Conditions

Central Nervous System Lymphoma

Keywords

newly diagnosed primary central nervous system lymphoma

Outcome Measures

Primary Outcomes (2)

• Complete Remission Rate After Primary Chemotherapy

  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

  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 Outcomes (2)

• 2 Years Failure Free Survival (FFS)

  Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry

• 2 Year Overall Survival (OS)

  From study entry until 2 years after

Study Arms (5)

MTX + AraC

EXPERIMENTAL

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; Drug: Ara-C

MTX + Ara-C + Rituximab

EXPERIMENTAL

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; Drug: Ara-C; Drug: Rituximab

MTX + Ara-C + rituximab+thiotepa

EXPERIMENTAL

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; Drug: Ara-C; Drug: Rituximab; Drug: Thiotepa

WBRT 36 Gy +/- boost 9 Gy

EXPERIMENTAL

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

BCNU + Thiotepa + APBSCT

EXPERIMENTAL

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; Drug: BCNU; Other: APBSCT

Interventions

Methotrexate DRUG

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.

MTX + Ara-C + Rituximab; MTX + Ara-C + rituximab+thiotepa; MTX + AraC

Ara-C DRUG

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

Also known as: Cytarabine

MTX + Ara-C + Rituximab; MTX + Ara-C + rituximab+thiotepa; MTX + AraC

Rituximab DRUG

Rituximab 375 mg/m2 conventional infusion on day - 5 \& 0 every 3 weeks for a maximum of 4 cycles

Also known as: MabThera

MTX + Ara-C + Rituximab; MTX + Ara-C + rituximab+thiotepa

Thiotepa DRUG

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

BCNU + Thiotepa + APBSCT; MTX + Ara-C + rituximab+thiotepa

radiotherapy RADIATION

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.

WBRT 36 Gy +/- boost 9 Gy

BCNU DRUG

BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6

Also known as: Carmustine

BCNU + Thiotepa + APBSCT

APBSCT OTHER

Autologous peripheral blood stem cell transplant (APBSCT)

BCNU + Thiotepa + APBSCT

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• International Extranodal Lymphoma Study Group (IELSG): lead

Study Sites (54)

University Hospital

Aarhus, Denmark

Location

Rigshospitalet,

Copenhagen, Denmark

Location

Herlev Hospital

Herlev, Denmark

Location

University Hospital

Aachen, Germany

Location

Städtisches Klinikum

Braunschweig, Germany

Location

Klinikum Bremen-Mitte

Bremen, Germany

Location

Klinikum Chemnitz

Chemnitz, Germany

Location

Universitätsklinikum

Cologne, Germany

Location

Universitätsklinikum Erlangen

Erlangen, Germany

Location

"Klinik für Hämatologie Universitätsklinikum Essen"

Essen, Germany

Location

Klinikum der Johann-Wolfgang- Goethe-Universität

Frankfurt am Main, Germany

Location

Uniklinik Freiburg

Freiburg im Breisgau, Germany

Location

Klinikum der Justus-Liebig-Universität

Giessen, Germany

Location

Georg-August-Universität

Göttingen, Germany

Location

Universitätsklinikum Halle

Halle, Germany

Location

Universitätskrankenhaus Hamburg-Eppendorf

Hamburg, Germany

Location

SLK-Kliniken GmbH

Heilbronn, Germany

Location

Universitätsklinikum des Saarlandes

Homburg/Saar, Germany

Location

Friedrich Schiller Universitaet Jena

Jena, Germany

Location

Universitätsklinikum und Städtisches Krankenhaus

Kiel, Germany

Location

Johannes Gutenberg Universität Mainz

Mainz, Germany

Location

Technische Universität in München

München, Germany

Location

Universitätsklinikum Ulm

Ulm, Germany

Location

A.O. SS. Antonio e Biagio e Cesare Arrigo

Alessandria, Italy

Location

Istituto Tumori Giovanni Paolo II

Bari, Italy

Location

Ospedale Centrale di Bolzano

Bolzano, Italy

Location

Spedali Civili

Brescia, Italy

Location

Ospedale Businco

Cagliari, Italy

Location

San Raffaele H Scientific Institute

Milan, Italy

Location

Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Istituto Nazionale Tumori, Fondazione G. Pascale

Naples, Italy

Location

Ospedale Umberto I

Nocera Inferiore, Italy

Location

Ospedale Civile S.Spirito

Pescara, Italy

Location

AOU Pisana

Pisa, Italy

Location

Ospedale delle Croci

Ravenna, Italy

Location

Arcispedale Santa Maria Nuova

Reggio Emilia, Italy

Location

Ospedale degli Infermi

Rimini, Italy

Location

Istituto Nazionale dei Tumori Regina Elena

Roma, Italy

Location

Università degli Studi La Sapienza

Roma, Italy

Location

Humanitas

Rozzano, Italy

Location

Casa Sollievo della Sofferenza

San Giovanni Rotondo, Italy

Location

Azienda Ospedaliera Universitaria Senese

Siena, Italy

Location

Azienda Ospedaliera Sanitaria Santa Maria

Terni, Italy

Location

Ospedale Maggiore S. Giovanni Battista

Torino, Italy

Location

Azienda Sanitaria Universitaria Friuli Centrale

Udine, Italy

Location

Policlinico G.B. Rossi

Verona, Italy

Location

ULSS 8 Berica - Ospedale S. Bortolo

Vicenza, Italy

Location

IOSI - Oncology Institute of Southern Switzerland

Bellinzona, 6500, Switzerland

Location

University Hospital Aintree

Liverpool, United Kingdom

Location

University College Hospital

London, United Kingdom

Location

The Christie Hospital NHS Foundation Trust

Manchester, United Kingdom

Location

Nottingham City Hospital

Nottingham, United Kingdom

Location

Queen's Hospital

Romford, United Kingdom

Location

Medical Oncology Unit General Hospital

Southampton, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 29054815 DERIVED

• 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 DERIVED

MeSH Terms

Interventions

Methotrexate; Cytarabine; Rituximab; Thiotepa; Radiotherapy; Carmustine

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramides; Organophosphorus Compounds; Organic Chemicals; Triethylenephosphoramide; Aziridines; Azirines; Therapeutics; Nitrosourea Compounds; Urea; Amides; Nitroso Compounds

Results Point of Contact

• Title: Scientific and Medical Director
• Organization: International Extranodal Lymphoma Study Group (IELSG)

ielsg@ior.usi.ch

+41 58 666

Study Officials

• Andrés JM Ferreri, MD

  San Raffaele H Scientific Institute, Milan, Italy

  STUDY CHAIR

• Gerald Illerhaus, MD

  University Medical Center, Freiburg, Germany

  STUDY CHAIR

• Emanuele Zucca, MD

  IOSI, Bellinzona, Switzerland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2009
• First Posted: November 11, 2009
• Study Start: November 1, 2009
• Primary Completion: March 1, 2015
• Study Completion: December 19, 2024
• Last Updated: March 19, 2026
• Results First Posted: March 19, 2026

Record last verified: 2026-03

Locations

IT (24); CH (1); DK (3); DE (20); GB (6)