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

NCT03697512 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: IELSG472018-002364-44
• Study Type: interventional
• Target: 175
• Locations: 5 countries
• Sites: 36

Brief 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 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

Conditions

Marginal Zone Lymphoma; Nodal Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma

Outcome Measures

Primary Outcomes (2)

• Complete Response Rate at 12 months

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

  12 months after treatment start

• Progression Free Survival at 5 years

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

  5 years from treatment start

Secondary Outcomes (4)

• Number of treatment-Emerging Adverse Events

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

• Complete Response Rate at 24 months

  24 months from treatment start

• Overall Response Rate at 12 and 24 months

  12 and 24 months after treatment start

• Overall survival

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

Study Arms (1)

Ibrutinib and Rituximab

EXPERIMENTAL

Induction 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.

Drug: Ibrutinib; Drug: Rituximab

Interventions

Ibrutinib DRUG

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

Ibrutinib and Rituximab

Rituximab DRUG

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

Ibrutinib and Rituximab

Eligibility Criteria

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

You may qualify if:

• 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.
• 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:
• 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.
• 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;

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• International Extranodal Lymphoma Study Group (IELSG): lead

Study Sites (36)

CHU UCL Namur / site Godinne

Yvoir, B5530, Belgium

Location

CHU de Tours - Hôpital Bretonneau

Tours, Cedex 01, 37004, France

Location

CHU de Montpellier

Montpellier, Cedex 05, 34295, France

Location

CHU d'Estaing

Clermont-Ferrand, Cedex 1, 63003, France

Location

CHU de Rennes Pontchaillou

Rennes, Cedex 9, 35033, France

Location

Institut Bergonié

Bordeaux, 33076, France

Location

IHBN - CHU Côte de Nacre

Caen, 14033, France

Location

CHU Dijon Bourgogne - Hôpital François Mitterand

Dijon, 21000, France

Location

CHU de Grenoble - Hôpital Albert MICHALLON

La Tronche, 38700, France

Location

Saint Louis Hospital

Paris, 75010, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

CHRU de Strasbourg

Strasbourg, 67091, France

Location

IUCT Oncopole Toulouse

Toulouse, 31100, France

Location

CHU de Nancy - Hôpital Brabois

Vandœuvre-lès-Nancy, 54500, France

Location

Ospedale degli Infermi

Ponderano, BI, 13875, Italy

Location

Ospedale San Raffaele

Milan, MI, 20132, Italy

Location

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

Torino, TO, 10126, Italy

Location

Azienda Ospedaliera Universitaria Ospedali Riuniti - Università Politecnica delle Marche

Ancona, 60100, Italy

Location

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

Bari, 70124, Italy

Location

A.O. Spedali Civili di Brescia

Brescia, 25123, Italy

Location

Ospedale Oncologico Businco

Cagliari, 09121, Italy

Location

Fondazione IRCCS - Cà Granda - Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Fondazione IRCCS - Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

AAST Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Fondazione IRCCS - Policlinico San Matteo

Pavia, 27100, Italy

Location

U.O. Ematologia AUSL Ravenna

Ravenna, 48121, Italy

Location

Azienda Ospedaliera Arcispedale Santa Maria Nuova IRCCS

Reggio Emilia, 42123, Italy

Location

Università degli Studi di Roma La Sapienza

Roma, 00185, Italy

Location

Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI)

Trieste, Italy

Location

Ospedale di Circolo e Fondazione Macchi di Varese

Varese, 21100, Italy

Location

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

Lisbon, 1099-023, Portugal

Location

Istituto Oncologico della Svizzera Italiana (IOSI)

Bellinzona, Canton Ticino, 6500, Switzerland

Location

Kantonalspital Baden

Baden, 5404, Switzerland

Location

Inselspital Bern

Bern, 3010, Switzerland

Location

Hôpitaux Universitaires de Genève

Geneva, 1211, Switzerland

Location

Universitätsspital Zürich

Zurich, 8091, Switzerland

Location

MeSH Terms

Conditions

Lymphoma, B-Cell, Marginal Zone

Interventions

ibrutinib; Rituximab

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)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Catherine Thieblemont, MD

  Saint-Louis Hospital, Paris, France

  STUDY CHAIR

• Annarita Conconi, MD

  Ospedale degli Infermi - Biella, Italy

  STUDY CHAIR

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: September 28, 2018
• First Posted: October 5, 2018
• Study Start: September 27, 2019
• Primary Completion (Estimated): June 15, 2027
• Study Completion (Estimated): June 15, 2027
• Last Updated: April 8, 2026

Record last verified: 2026-04

Locations

FR (13); BE (1); IT (16); PT (1); CH (5)