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Marginal Zone LymphomaPhase 2MALIBUNCT03697512

MALIBU Trial - Combination of Ibrutinib and Rituximab in Untreated Marginal Zone Lymphomas

A Phase 2 study testing Ibrutinib and Rituximab in people with Marginal Zone Lymphoma and Nodal Marginal Zone Lymphoma, run by International Extranodal Lymphoma Study Group (IELSG) at 36 sites in 5 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

Single-arm, phase II clinical trial of patients with Extranodal Marginal Zone Lymphoma (EMZL). It is planned to recruit 130 patients. Additional patients with Splenic Marginal Zone Lymphoma (SMZL), up to 30, and Nodal Marginal Zone Lymphoma (NMZL), up to 15, will be included in the trial in order to preliminary… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ibrutinib and Rituximab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
175 participants
Where
36 sitesin 5 countries
Study dates
27 Sep 2019to 15 Jun 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

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 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Chemotherapy and immunotherapy-naïve, symptomatic and in need of treatment patients, with histologically proven CD20-positive MZL, not eligible for local therapy, including:
  • EMZL (MALT Lymphoma) patients with MALT- IPI score 1-2 in need of systemic therapy.
  • Either de novo or relapsed following local therapy (including surgery, radiotherapy and antibiotics for H. pylori-positive gastric lymphoma) arisen at any extranodal site with MALT-international prognostic index (IPI) score 1-2 at the time of study entry.
  • 1.1.The following patients with gastric MALT Lymphoma can be entered:
  • H. pylori-negative cases, either de novo (non pretreated) or at relapse following local therapy (i.e., surgery, radiotherapy or antibiotics).
  • H. pylori-positive cases at diagnosis, who either first line antibiotics or further local treatment (surgery or radiotherapy), including patients with:
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  • clinical (endoscopic) and histological evidence of disease progression at any time post H. pylori eradication;
  • clinical (endoscopic) and histological relapse (without H. pylori re-infection), after a remission patients;
  • persistent (stable) lymphoma at ≥ 1 year post H. pylori eradication. 1.2. Similar consideration may be applied to patients with ocular adnexal lymphoma treated with antibiotics.
  • SMZL patients in need of therapy. Either de novo or relapsed following local therapy [including surgery and antiviral therapy for Hepatitis C virus (HCV)]. Patient must have a symptomatic disease requiring treatment and be not eligible for splenectomy or not willing to undergo splenectomy.
  • 2.1. Patients with SMZL can be entered if any of the following criteria is present:
  • bulky progressive or painful splenomegaly;
  • enlarged lymph nodes or involvement of extranodal sites with or without cytopenias , i.e. involvement of ≥3 nodal sites, each with a diameter of ≥3 cm. Any nodal tumor mass with a diameter of ≥7 cm (GELG criteria, as adopted in follicular lymphoma);
  • one of the following symptomatic/progressive cytopenias:
  • Hgb < 10 g/dL;
  • ANC < 1000/μL:
  • PLT< 80 000/μL whatever the reason (autoimmune or hypersplenism or bone marrow infiltration).
  • 2.2. Splenectomised patients with rapidly raising lymphocyte counts, lymphadenopathy or involvement of extranodal sites can be entered.
  • 2.3. SMZL with concomitant HCV infection who have not responded to or are relapsed after antiviral therapy can be entered.
  • NMZL patients in need of therapy Either, de novo presenting with disseminated disease or relapsed after local radiotherapy or following antiviral therapy for HCV. Localized nodal MZL is not eligible.
  • Measurable or evaluable disease.
  • Ann Arbor II-IV. Stage I disease may be eligible only if not candidate to local therapy (surgery or radiotherapy).
  • Age ≥ 18.
  • Life expectancy of at least 1 year.
  • ECOG Performance status 0-2.
  • Adequate bone marrow, kidney and liver function
  • For women of childbearing potential only: negative serum pregnancy test done within 7 days prior to study drugs administration or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to the first study drugs administration.
  • Fertile male or female patients of childbearing potential and their partners must use higly effective contraception methods during the study and for at least 12 months after the last dose of subcutaneous rituximab. In case hormonal methods of birth control is used a barrier method must be added.
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • Any type of lymphoma other than MZL (including MZL with histologic transformation to high-grade lymphoma).
  • Localized (stage IE and IIE) MALT lymphoma, for example gastric, ocular and cutaneous lymphoma, that may benefit from local therapy only (surgery or radiotherapy).
  • Known CNS involvement of MZL.
  • Any previous systemic treatment with immunotherapy or chemotherapy or with BTK inhibitors.
  • Major surgery within 4 weeks prior to registration.
  • History of stroke or intracranial bleeding within 6 months.
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  • Known bleeding diathesis (eg, von Willebrand's disease) or hemophilia.
  • Concurrent use of warfarin of other vitamin K antagonists.
  • Concurrent use of strong cytochrome P450 (CYP)3A4/5 inhibitors (see http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).
  • Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
  • International normalized ratio (INR) or prothrombin time (PT) ≥1.5 ULN. Partial thromboplastin time (PTT) or activated PTT (aPTT) ≥1.5 ULN unless due to lupus anticoagulant.
  • Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
  • Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions to the compound of ibrutinib and/or rituximab themselves or to the excipients in their formulation).
  • Positive test results for chronic HBV infection (defined as positive HBsAg serology).
  • Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing and taking specific antiviral prophylaxis, according to local policy. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination are eligible.
  • Positive test results for hepatitis C. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
  • HIV infection or immunodeficiency.
  • Active, severe infections
  • Pregnancy or breastfeeding.
  • Clinically significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
  • Any serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Prior history of malignancies other than MZL within 3 years,with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
  • Current enrolment or participation in another therapeutic clinical trial within 28 days prior to treatment start

Trial locations and contacts

36 sites in 5 countries.

36 sites in 5 countries

Italy16 sites

  • Azienda Ospedaliera Universitaria Ospedali Riuniti - Università Politecnica delle Marche

    Ancona, 60100

  • Giovanni Paolo II/I.R.C.C.S. Istituto Tumori

    Bari, 70124

  • A.O. Spedali Civili di Brescia

    Brescia, 25123

  • Ospedale Oncologico Businco

    Cagliari, 09121

  • Ospedale San Raffaele

    Milan, MI, 20132

  • Fondazione IRCCS - Cà Granda - Ospedale Maggiore Policlinico

    Milan, 20122

  • Fondazione IRCCS - Istituto Nazionale dei Tumori

    Milan, 20133

  • AAST Grande Ospedale Metropolitano Niguarda

    Milan, 20162

  • Fondazione IRCCS - Policlinico San Matteo

    Pavia, 27100

  • Ospedale degli Infermi

    Ponderano, BI, 13875

  • U.O. Ematologia AUSL Ravenna

    Ravenna, 48121

  • Azienda Ospedaliera Arcispedale Santa Maria Nuova IRCCS

    Reggio Emilia, 42123

  • Università degli Studi di Roma La Sapienza

    Roma, 00185

  • A.O.U. Città della Salute e della Scienza di Torino Ospedale Molinette

    Torino, TO, 10126

  • Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI)

    Trieste

  • Ospedale di Circolo e Fondazione Macchi di Varese

    Varese, 21100

Other trials in Italy

France13 sites

  • Institut Bergonié

    Bordeaux, 33076

  • IHBN - CHU Côte de Nacre

    Caen, 14033

  • CHU d'Estaing

    Clermont-Ferrand, Cedex 1, 63003

  • CHU Dijon Bourgogne - Hôpital François Mitterand

    Dijon, 21000

  • CHU de Grenoble - Hôpital Albert MICHALLON

    La Tronche, 38700

  • CHU de Montpellier

    Montpellier, Cedex 05, 34295

  • Saint Louis Hospital

    Paris, 75010

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, 69495

  • CHU de Rennes Pontchaillou

    Rennes, Cedex 9, 35033

  • CHRU de Strasbourg

    Strasbourg, 67091

  • IUCT Oncopole Toulouse

    Toulouse, 31100

  • CHU de Tours - Hôpital Bretonneau

    Tours, Cedex 01, 37004

  • CHU de Nancy - Hôpital Brabois

    Vandœuvre-lès-Nancy, 54500

Other trials in France

Switzerland5 sites

  • Kantonalspital Baden

    Baden, 5404

  • Istituto Oncologico della Svizzera Italiana (IOSI)

    Bellinzona, Canton Ticino, 6500

  • Inselspital Bern

    Bern, 3010

  • Hôpitaux Universitaires de Genève

    Geneva, 1211

  • Universitätsspital Zürich

    Zurich, 8091

Other trials in Switzerland

Belgium1 site

  • CHU UCL Namur / site Godinne

    Yvoir, B5530

Other trials in Belgium

Portugal1 site

  • Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.

    Lisbon, 1099-023

Other trials in Portugal

About this study

Official title: MALIBU Trial - Phase II Study of Combination Ibrutinib and Rituximab in Untreated Marginal Zone Lymphomas

Single-arm, phase II clinical trial of patients with Extranodal Marginal Zone Lymphoma (EMZL). It is planned to recruit 130 patients.

Additional patients with Splenic Marginal Zone Lymphoma (SMZL), up to 30, and Nodal Marginal Zone Lymphoma (NMZL), up to 15, will be included in the trial in order to preliminary explore the clinical activity and safety of the combination treatment proposed.

The study primary endpoints will be analysed on the EMZL population. Outcome of patients with SMZL and NMZL will be analysed and reported separately

Read the detailed description

Marginal zone lymphomas (MZL) represent a group of indolent B-cell lymphomas that arises from marginal zone B-cells in extranodal tissues, such as spleen and mucosa associated lymphoid tissues, and more rarely also in nodal tissues. MZL comprises 5 to 17% of all non-Hodgkin lymphomas (NHL) in adults. The 2016 World Health Organization (WHO) recognized three separate subtypes of MZL according to their primary localization, namely the:

  1. extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphoma
  2. splenic MZL (SMZL)
  3. nodal MZL (NMZL). These three subtypes are distinct disease entities that are classified together because they all seem to originate from post germinal centre marginal zone B-cells.

MALIBU trial is a prospective multicenter trial combining rituximab and ibrutinib in front-line for patients with MZL, including EMZL, SMZL and NMZL Aim of the study is to assess the safety and efficacy of the combination of rituximab and ibrutinib in EMZL patients and to explore its activity in SMZL and NMZL as exploratory subset.

Being tested
Ibrutinib, Rituximab
Medical subject headings
Lymphoma, B-Cell, Marginal Zone

What participants receive

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

  • IbrutinibDrug

    capsules for oral intake in a dosage of 560 mg (four capsules) daily

  • RituximabDrug

    Concentrate solution for infusion - intravenous use; Solution for injection - subcutaneous use.

Study groups in NCT03697512
Study groupRoleWhat they receive
Ibrutinib and RituximabExperimentalInduction PART A, from Day 1 to Day 56. Patients will be treated with: * Ibrutinib 560 mg/day continuously up to Day 56; * Rituximab 375 mg/m2 intravenously at Day 1, and then subcutaneous (1400 mg, flat dose) at Day 8, 15 and 22 of cycle 1. Induction PART B, from Day 57 to Day 196. Patients will be treated with: * Ibrutinib 560 mg/day continuously up to Day 196; * Rituximab subcutaneous (1400 mg, flat dose) at Day 1 every 28 days for 4 cycles. Maintenance PART C, from Day 197 to Day 730. Patients will be treated with: - Ibrutinib 560 mg/day continuously up to Day 730.
Receives: Drug: Ibrutinib; Drug: Rituximab

What is being measured

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

  1. Complete Response Rate at 12 months

    The proportion of patients with complete response after 12 months from treatment start

    Measured: 12 months after treatment start

  2. Progression Free Survival at 5 years

    The proportion of patients without disease progression after 5 years from treatment start

    Measured: 5 years from treatment start

Secondary outcomes (4)

  1. Number of treatment-Emerging Adverse Events

    Analysis of incidence, severity and relationship of adverse events graded according to NCI Common Toxicity Criteria, version 4.0

    Measured: From the time of informed consent signature until 28 days after treatment discontinuation or until resolution of all treatment-related AEs, whichever occurs later

  2. Complete Response Rate at 24 months

    The proportion of patients with complete response after 24 months from treatment start

    Measured: 24 months from treatment start

  3. Overall Response Rate at 12 and 24 months

    The proportion of responding patients (partial and complete responses) assessed at 12 and 24 months after treatment start

    Measured: 12 and 24 months after treatment start

  4. Overall survival

    The time from the date of treatment start to the date of death from any cause

    Measured: From the date of treatment start to the date of death due to any cause until 5 years from treatment discontinuation

Timeline

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

  1. First posted5 Oct 2018
  2. Study start27 Sep 2019
  3. Primary completion15 Jun 2027 (estimated)
  4. Study completion15 Jun 2027 (estimated)

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
175 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03697512
Sponsor's protocol ID
IELSG47
Other IDs
2018-002364-44, 2018
Acronym
MALIBU
Status last verified
Apr 2026
First submitted
28 Sep 2018
Last updated
8 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Sharp J, Shana'ah AY, Voorhees TJ, Bond DA, Sawalha Y, Sigmund A, Hanel W, Sehgal L, Alinari L, Baiocchi R, Maddocks K, Jones D, Christian B, Epperla N. Resistance Mechanism for Zanubrutinib in Marginal Zone Lymphoma. J Natl Compr Canc Netw. 2025 Jun 23;23(7):e257045. doi: 10.6004/jnccn.2025.7045.

    PubMed 40550489

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ibrutinib and Rituximab in people with Marginal Zone Lymphoma and Nodal Marginal Zone Lymphoma, run by International Extranodal Lymphoma Study Group (IELSG) at 36 sites in 5 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 29 inclusion and 23 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: under way, not looking for participants, as of the sponsor's last update on 8 Apr 2026. 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, France, Switzerland, Belgium, Portugal. 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?

This study is still under way. Results are not available in the source record yet.

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?

Complete Response Rate at 12 months (time frame: 12 months after treatment start). The study lists 2 primary outcomes in all. 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 NCT03697512, 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 Apr 2026.

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