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Diffuse Large B-cell LymphomaPhase 2NCT02329080

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

A Phase 2 study testing Methotrexate, Rituximab and Cytarabine in people with Diffuse Large B-cell Lymphoma, run by International Extranodal Lymphoma Study Group (IELSG) at 36 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Diffuse Large B-cell Lymphoma
What is being tested?
Methotrexate, Rituximab and Cytarabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
79 participants
Where
36 sitesin 4 countries
Study dates
Dec 2014to 22 Mar 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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
  • Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice. Informed consent signed by a patient's guardian is acceptable if the patient is not able to decide inclusion in the study due to cognitive impairment

Who cannot join

  • 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.

Trial locations and contacts

36 sites in 4 countries.

36 sites in 4 countries

Italy27 sites

  • Spedali Civili

    Brescia

  • UO Ematologia e CTMO, PO Businco

    Cagliari

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

    Meldola

  • UO Ematoliga Ospedale dell'Angelo

    Mestre

  • San Raffaele H Scientific Institute

    Milan

  • Istituto Nazionale Tumori

    Milan

  • Ospedale Maggiore Policlinico

    Milan

  • AOU Policlinico di Modena

    Modena

  • SCDU Ematologia

    Novara

  • Ematologia ed Immunologia Clinica - AO di Padova

    Padova

  • UO Oncoematologia Ospedale Tortora

    Pagani

  • Villa Sofia - Cervello

    Palermo

  • Ematologia AOU

    Parma

  • Ematologia Ospedale S.Maria delle Croci

    Ravenna

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

    Reggio Calabria

  • Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio Emilia

    Reggio Emilia

  • Ematologia Università La Sapienza

    Roma

  • IRCCS Istituto Regina Elena (IFO)

    Roma

  • Policlinico Universitario Campus Bio-Medico

    Rome

  • IRCCS Casa Sollievo Della Sofferenza

    San Giovanni Rotondo

  • AOU Senese

    Siena

  • AO S.Maria di Terni

    Terni

  • SC Ematologia AO Città della Salute e della Scienza

    Torino

  • UO Ematologia Ospedale Panico

    Tricase

  • AOU Santa Maria della Misericordia

    Udine

  • UOC Ematologia Policlinico Rossi

    Verona

  • Ematologia Ospedale S. Bortolo

    Vicenza

Other trials in Italy

United Kingdom5 sites

  • Beatson Cancer Center

    Glasgow

  • Liverpool Aintree

    Liverpool

  • UCLH University College London Hospitals NHS foundation trust

    London

  • The Christie Hospital

    Manchester

  • Southampton General Hospital

    Southampton

Other trials in United Kingdom

Czechia3 sites

  • Facultni nemocnice

    Brno

  • FNKV (Facultni Nemocnice Kralovske Vinohrady)

    Prague

  • Vseobecna facultni nemocnice v Praze

    Prague

Other trials in Czechia

Netherlands1 site

  • Erasmus MC

    Rotterdam

Other trials in Netherlands

About this study

Official title: An International Phase II Trial Assessing Tolerability and Efficacy of Sequential Methotrexate-Aracytin-based Combination and R-ICE Combination, Followed by HD Chemotherapy Supported by ASCT, in Patients With Systemic B-cell Lymphoma With CNS Involvement at Diagnosis or Relapse (MARIETTA Regimen)

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.

Read the detailed description

Treatment includes 6 courses of chemoimmunotherapy, the first three courses with an high dose methotrexate-based combination (MATRIX) followed by other three courses of R-ICE combination and finally a BCNU-thiotepa- containing conditioning and subsequent autologous stem cell transplantation.

MATRIX (courses 1, 2, 3):

Rituximab 375 mg/m2, Methotrexate 3.5 g/m2, Cytarabine 2 g/m2, Folinic rescue 15 mg/m2, Thiotepa 30 mg/m2, Intrathecal liposomial cytarabine 50 mg, rHuG-CSF 2,5 g/kg s.c.

R-ICE (courses 4, 5, 6):

Rituximab 375 mg/m2, Etoposide 100 mg/m2/d , Ifosfamide 5 g/m2, Intrathecal liposomial cytarabine 50 mg

Being tested
Methotrexate, Rituximab, Cytarabine, Thiotepa, liposomial cytarabine
Medical subject headings
Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MethotrexateDrug

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

  • RituximabDrug

    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)

  • CytarabineDrug

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

  • ThiotepaDrug

    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

  • liposomial cytarabineDrug

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

  • EtoposideDrug

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

  • IfosfamideDrug

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

  • CarmustineDrug

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

  • whole brain radiotherapyRadiation

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

Study groups in NCT02329080
Study groupRoleWhat they receive
MATRIX - R-ICE - Conditioning and ASCTExperimentalMATRIX (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
Receives: Drug: Methotrexate; Drug: Rituximab; Drug: Cytarabine; Drug: Thiotepa; Drug: liposomial cytarabine; Drug: Etoposide; Drug: Ifosfamide; Drug: Carmustine; Radiation: whole brain radiotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 1 Year Progression Free Survival (PFS)

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

    Measured: From study entry until 1 year after

Secondary outcomes (2)

  1. 2 Years Progression Free Survival (PFS)

    Percentage of patients free from progression after 2 years from study entry

    Measured: From study entry until 2 years after

  2. 2 Years Overall Survival (OS)

    Percentage of participants alive after 2 years from study entry

    Measured: From trial entry until 2 years after

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Dec 2014 (estimated)
  2. Study startDec 2014
  3. Primary completionAug 2019
  4. Study completion22 Mar 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
79 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02329080
Sponsor's protocol ID
IELSG42
Status last verified
Jul 2025
First submitted
22 Dec 2014
Last updated
8 Jul 2025
Data monitoring committee
No

Publications

  • 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.

    PubMed 33513372

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Methotrexate, Rituximab and Cytarabine in people with Diffuse Large B-cell Lymphoma, run by International Extranodal Lymphoma Study Group (IELSG) at 36 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in Italy, United Kingdom, Czechia, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

1 Year Progression Free Survival (PFS) (time frame: From study entry until 1 year after). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02329080, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jul 2025.

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