MALIBU Trial - Combination of Ibrutinib and Rituximab in Untreated Marginal Zone Lymphomas
MALIBU Trial - Combination of 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
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.
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 , 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);

 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 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:

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

 2. Localized (stage IE and IIE) MALT lymphoma, for example gastric, ocular and cutaneous
 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. 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.

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

 13. 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).

 14. Positive test results for chronic HBV infection (defined as positive HBsAg serology).

 15. 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.

 16. Positive test results for hepatitis C. Patients positive for HCV antibody are eligible
 only if PCR is negative for HCV RNA.

 17. HIV infection or immunodeficiency.

 18. Active, severe infections

 19. Pregnancy or breastfeeding.

 20. 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.

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

 22. 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.

 23. Current enrolment or participation in another therapeutic clinical trial within 28
 days prior to treatment start