Clinical Trials /

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

NCT03697512

Description:

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 15, 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

Related Conditions:
  • Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue
  • Nodal Marginal Zone Lymphoma
  • Splenic Marginal Zone Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IELSG47
  • SECONDARY ID: 2018-002364-44
  • NCT ID: NCT03697512

Conditions

  • Marginal Zone Lymphoma
  • Nodal Marginal Zone Lymphoma
  • Splenic Marginal Zone Lymphoma

Interventions

DrugSynonymsArms
IbrutinibIbrutinib and Rituximab
RituximabIbrutinib and Rituximab

Purpose

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 15, 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

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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Ibrutinib
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

        Chemotherapy and immunotherapy-naïve, symptomatic and in need of treatment patients, with
        histologically proven CD20-positive MZL, not eligible for local therapy, including:

          1. 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:

               1. H. pylori-negative cases, either de novo (non pretreated) or at relapse following
                  local therapy (i.e., surgery, radiotherapy or antibiotics).

               2. 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.

          2. 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:

               1. bulky progressive or painful splenomegaly;

               2. enlarged lymph nodes or involvement of extranodal sites with or without
                  cytopenias;

               3. 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.

          3. 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 two forms of contraception during the study and for at least 12 months after
                  the last dose of subcutaneous rituximab.

               -  Ability to understand and the willingness to sign a written informed consent
                  document

        Exclusion Criteria:

          1. Any type of lymphoma other than MZL (including MZL with histologic transformation to
             high-grade lymphoma).

          2. Localized (stage IE and IIE) gastric, ocular and cutaneous MALT lymphoma that may
             benefit from local therapy only (surgery or radiotherapy).

          3. Known CNS involvement of MZL.

          4. Any previous systemic treatment with immunotherapy or chemotherapy or with BTK
             inhibitors.

          5. Major surgery within 4 weeks prior to registration.

          6. History of stroke or intracranial bleeding within 6 months.

          7. Known bleeding diathesis (eg, von Willebrand's disease) or hemophilia.

          8. Concurrent use of warfarin of other vitamin K antagonists.

          9. Concurrent use of strong cytochrome P450 (CYP)3A4/5 inhibitors (see
             http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).

         10. 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.

         11. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.

         12. Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions
             to the compound of ibrutinib itself or to the excipients in its formulation).

         13. Active HCV or Hepatitis B virus (HBV) infections.

         14. HIV infection or immunodeficiency.

         15. Pregnancy or breastfeeding.

         16. 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.

         17. Any serious medical or psychiatric illness likely to interfere with participation in
             this clinical study.

         18. Prior history of malignancies other than MZL within 3 years
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response Rate at 12 months
Time Frame:12 months after treatment start
Safety Issue:
Description:The proportion of patients with complete response after 12 months from treatment start

Secondary Outcome Measures

Measure:Treatment-Emerging Adverse Events
Time Frame:From the time of informed consent signature until 28 days after treatment discontinuation or until resolution of all treatment-related AEs, whichever occurs later
Safety Issue:
Description:Analysis of incidence, severity and relationship of adverse events graded according to NCI Common Toxicity Criteria, version 4.0
Measure:Complete Response Rate at 24 months
Time Frame:24 months from treatment start
Safety Issue:
Description:The proportion of patients with complete response after 24 months from treatment start
Measure:Overall Response Rate at 12 and 24 months
Time Frame:12 and 24 months after treatment start
Safety Issue:
Description:The proportion of responding patients (partial and complete responses) assessed at 12 and 24 months after treatment start
Measure:Overall survival
Time Frame:From the date of treatment start to the date of death due to any cause until 5 years from treatment discontinuation
Safety Issue:
Description:The time from the date of treatment start to the date of death from any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:International Extranodal Lymphoma Study Group (IELSG)

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