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

  • STATUS
    Recruiting
  • End date
    Jun 15, 2027
  • participants needed
    175
  • sponsor
    International Extranodal Lymphoma Study Group (IELSG)
Updated on 16 June 2021
remission
rituximab
antiviral
cytopenia
marginal zone lymphoma
lymphadenopathy
gastric malt lymphoma
splenic marginal zone lymphoma

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

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.

Details
Condition MALT Lymphoma, Splenic Marginal Zone Lymphoma, Marginal Zone Lymphoma, monocytoid b-cell lymphoma
Treatment Rituximab, Ibrutinib
Clinical Study IdentifierNCT03697512
SponsorInternational Extranodal Lymphoma Study Group (IELSG)
Last Modified on16 June 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Chemotherapy and immunotherapy-nave, 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
-2 at the time of study entry
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
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
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/L
PLT< 80 000/L whatever the reason (autoimmune or hypersplenism or bone marrow infiltration)
2. Splenectomised patients with rapidly raising lymphocyte counts
lymphadenopathy or involvement of extranodal sites can be entered
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

Exclusion Criteria

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
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
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