New Combination of Chemoimmunotherapy for Systemic B-cell Lymphoma With Central Nervous System Involvement

NCT02329080 | Completed Phase 2 Results

• 1 other identifier: IELSG42
• Study Type: interventional
• Target: 79
• Locations: 4 countries
• Sites: 36

Brief Summary

This is an open, non comparative, multicentre phase II trial, to evaluate the efficacy and feasibility of a new sequential combination of HD-MTX-AraC-based chemoimmunotherapy, followed by R-ICE regimen, and by high-dose chemotherapy supported by ASCT.

Conditions

Diffuse Large B-cell Lymphoma

Outcome Measures

Primary Outcomes (1)

• 1 Year Progression Free Survival (PFS)

  Percentage of patients free from progression after 1 year from study entry

  From study entry until 1 year after

Secondary Outcomes (2)

• 2 Years Progression Free Survival (PFS)

  From study entry until 2 years after

• 2 Years Overall Survival (OS)

  From trial entry until 2 years after

Study Arms (1)

MATRIX - R-ICE - Conditioning and ASCT

EXPERIMENTAL

MATRIX (courses 1,2,3): Rituximab 375 mg/m2 d0/Methotrexate 3.5 g/m2 d1/Cytarabine 2 g/m2 d2 \& d3/Thiotepa 30 mg/m2 d4/Liposomial Cytarabine 50 mg\* d5 R-ICE (courses 4,5,6):Rituximab 375 mg/m2 d1/Etoposide 100 mg/m2 d1,d2, d3/Ifosfamide 5 g/m2 d2/Carboplatin 5 AUC d2/Liposomial Cytarabine 50 mg\* d4 \*If liposomal cytarabine is not available, standard intrathecal chemotherapy with methotrexate 10 mg + cytarabine 40 mg + hydrocortisone 50 mg can be administered. Oral steroids are suggested for 2-3 days after intrathecal liposomial cytarabine delivery to prevent chemical or aseptic meningitis/ arachnoiditis. Conditioning and ASCT: BCNU (carmustine)\*\* 400 mg/m2 d-6/Thiotepa 5 mg/kg d-5 \& d-4 ASCT: 5 x 106 CD34+cells/kg d0 \*\*In case of BCNU unavailability, the recommended conditioning regimen (Phase IV) is: Thiotepa 5 mg/kg d-6 \& d-5/Busulfan 3.2 mg/kg d-4,d -3,d-2/Clonazepam 2 mg/d d-4,d -3,d-2 ASCT: 5 x 106 CD34+cells/kg d0

Drug: Methotrexate; Drug: Rituximab; Drug: Cytarabine; Drug: Thiotepa; Drug: liposomial cytarabine; Drug: Etoposide; Drug: Ifosfamide; Drug: Carmustine; Radiation: whole brain radiotherapy

Interventions

Methotrexate DRUG

methotrexate 3.5 g/m2 on day 1 courses 1, 2,3 of MATRIX regimen

MATRIX - R-ICE - Conditioning and ASCT

Rituximab DRUG

Rituximab 375 mg/m2 as conventional IV infusion on day 0 courses 1, 2,3 (MATRIX regimen) and on day 1 courses 4,5,6 (R-ICE)

MATRIX - R-ICE - Conditioning and ASCT

Cytarabine DRUG

Cytarabine 2 g/m2 every 12 hours, in 3-hr infusion on days 2,3 courses 1, 2,3 (MATRIX regimen)

MATRIX - R-ICE - Conditioning and ASCT

Thiotepa DRUG

Thiotepa 30 mg/m2 in 30 minutes infusion on day 4 courses 1, 2,3 (MATRIX regimen) and 5 mg/kg in 250 ml of saline sol. in 2-hrs infusion every 12 hours on day -5 and -4 of conditioning and ASCT

MATRIX - R-ICE - Conditioning and ASCT

liposomial cytarabine DRUG

Intrathecal liposomial cytarabine 50 mg on day 5 courses 1, 2,3 (MATRIX regimen) and on day 4 courses 4,5,6 (R-ICE)

MATRIX - R-ICE - Conditioning and ASCT

Etoposide DRUG

Etoposide 100 mg/m2/d in 500 mL saline sol. in 30 minutes on day 1-2-3 courses 4,5,6 (R-ICE)

MATRIX - R-ICE - Conditioning and ASCT

Ifosfamide DRUG

Ifosfamide 5 g/m2 in 1.000 mL saline sol. in 24-hour infusion on day 2 courses 4,5,6 (R-ICE)

MATRIX - R-ICE - Conditioning and ASCT

Carmustine DRUG

BCNU (carmustine) 400 mg/m2 in 500 mL glucose 5% sol. in 1-hr infusion on day-6 of conditioning and ASCT

MATRIX - R-ICE - Conditioning and ASCT

whole brain radiotherapy RADIATION

whole-brain irradiation 36 Gy + tumor- bed boost 10 Gy in patients with residual disease in the parenchymal brain/cerebellum.

MATRIX - R-ICE - Conditioning and ASCT

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed diagnosis of diffuse large B-cell lymphoma
• CNS involvement (brain, meninges, cranial nerves, eyes and/or spinal cord) at diagnosis (concomitant to extra-CNS disease) or relapse after conventional chemo(-immuno)therapy
• Diagnosis of CNS involvement either by brain biopsy or CSF cytology examination. Neuroimaging alone is acceptable when stereotactic biopsy is formally contraindicated or when the disease has been previously histologically documented in other areas and the CNS localization is concomitant with a diffuse progression of systemic disease.
• No previous treatment with high-dose methotrexate-based chemotherapy and/or brain irradiation. One-two courses of R-CHOP combination as upfront therapy are admitted in patients with large amount and/or extensive extra-CNS disease that could condition prognosis in an early phase of treatment. Local investigator decides if initial R-CHOP is needed based on patient's conditions
• Age 18-70 years
• ECOG performance status 0-3
• Adequate bone marrow (Platelets count ≥100.000/mm3, hemoglobin ≥9 g/dL, neutrophils count≥1.500/mm3), renal (creatinine clearance ≥60 mL/min), cardiac (LVEF ≥50%), and hepatic function (total serum bilirubine ≤3 mg/dL, AST/ALT and GGT ≤2.5 per upper normal limit value), unless the abnormality is due to lymphoma infiltration
• Absence of HIV infection and of detectable HCV-RNA and/or HBsAg and/or HBV-DNA
• No concurrent malignancies. Previous malignancies are accepted if surgically cured or if there was no evidence of disease in the last 3 years at a regular follow-up
• Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Female patients must be non-pregnant and non-lactating. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation
• No treatment with other experimental drugs within the 6 weeks previous to enrolment

You may not qualify if:

• Other lymphoma categories other than diffuse large B-cell lymphoma. In particular, patients with primary mediastinal lymphoma, intravascular large B-cell lymphoma or leg-type large B-cell lymphoma are excluded.
• Patients with positive flow cytometry examination of the CSF, but negative results in CSF conventional cytology, and without any other evidence of CNS disease.
• Patients with exclusive CNS disease at presentation (primary CNS lymphoma) are excluded
• Previous treatment with support of autologous or allogeneic stem cells/bone marrow transplantation.
• Symptomatic coronary artery disease, cardiac arrhythmias not well controlled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease)
• Any other serious medical condition which could impair the ability of the patient to participate in the trial.

Sponsors & Collaborators

• International Extranodal Lymphoma Study Group (IELSG): lead

Study Sites (36)

Facultni nemocnice

Brno, Czechia

Location

FNKV (Facultni Nemocnice Kralovske Vinohrady)

Prague, Czechia

Location

Vseobecna facultni nemocnice v Praze

Prague, Czechia

Location

Spedali Civili

Brescia, Italy

Location

UO Ematologia e CTMO, PO Businco

Cagliari, Italy

Location

IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Italy

Location

UO Ematoliga Ospedale dell'Angelo

Mestre, Italy

Location

San Raffaele H Scientific Institute

Milan, Italy

Location

Istituto Nazionale Tumori

Milan, Italy

Location

Ospedale Maggiore Policlinico

Milan, Italy

Location

AOU Policlinico di Modena

Modena, Italy

Location

SCDU Ematologia

Novara, Italy

Location

Ematologia ed Immunologia Clinica - AO di Padova

Padua, Italy

Location

UO Oncoematologia Ospedale Tortora

Pagani, Italy

Location

Villa Sofia - Cervello

Palermo, Italy

Location

Ematologia AOU

Parma, Italy

Location

Ematologia Ospedale S.Maria delle Croci

Ravenna, Italy

Location

A.O. Bianchi-Melacrino-Morelli, Divisione di Ematologia

Reggio Calabria, Italy

Location

Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio Emilia

Reggio Emilia, Italy

Location

Ematologia Università La Sapienza

Roma, Italy

Location

IRCCS Istituto Regina Elena (IFO)

Roma, Italy

Location

Policlinico Universitario Campus Bio-Medico

Rome, Italy

Location

IRCCS Casa Sollievo Della Sofferenza

San Giovanni Rotondo, Italy

Location

AOU Senese

Siena, Italy

Location

AO S.Maria di Terni

Terni, Italy

Location

SC Ematologia AO Città della Salute e della Scienza

Torino, Italy

Location

UO Ematologia Ospedale Panico

Tricase, Italy

Location

AOU Santa Maria della Misericordia

Udine, Italy

Location

UOC Ematologia Policlinico Rossi

Verona, Italy

Location

Ematologia Ospedale S. Bortolo

Vicenza, Italy

Location

Erasmus MC

Rotterdam, Netherlands

Location

Beatson Cancer Center

Glasgow, United Kingdom

Location

Liverpool Aintree

Liverpool, United Kingdom

Location

UCLH University College London Hospitals NHS foundation trust

London, United Kingdom

Location

The Christie Hospital

Manchester, United Kingdom

Location

Southampton General Hospital

Southampton, United Kingdom

Location

Related Publications (1)

• Ferreri AJM, Doorduijn JK, Re A, Cabras MG, Smith J, Ilariucci F, Luppi M, Calimeri T, Cattaneo C, Khwaja J, Botto B, Cellini C, Nassi L, Linton K, McKay P, Olivieri J, Patti C, Re F, Fanni A, Singh V, Bromberg JEC, Cozens K, Gastaldi E, Bernardi M, Cascavilla N, Davies A, Fox CP, Frezzato M, Osborne W, Liberati AM, Novak U, Zambello R, Zucca E, Cwynarski K; International Extranodal Lymphoma Study Group (IELSG). MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematol. 2021 Feb;8(2):e110-e121. doi: 10.1016/S2352-3026(20)30366-5.

  PMID: 33513372 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

Methotrexate; Rituximab; Cytarabine; Thiotepa; Etoposide; Ifosfamide; Carmustine

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Phosphoramides; Organophosphorus Compounds; Organic Chemicals; Triethylenephosphoramide; Aziridines; Azirines; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Oxazines; 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

  IELSG

  STUDY CHAIR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: December 22, 2014
• First Posted: December 31, 2014
• Study Start: December 1, 2014
• Primary Completion: August 1, 2019
• Study Completion: March 22, 2024
• Last Updated: July 8, 2025
• Results First Posted: July 8, 2025

Record last verified: 2025-07

Locations

NL (1); CZ (3); GB (5); IT (27)