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

Study Overview
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Brief Summary
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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

Detailed Description
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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: extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphoma splenic MZL (SMZL) 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.

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

Conditions
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Marginal Zone Lymphoma, Nodal Marginal Zone Lymphoma, Splenic Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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: 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: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib and Rituximab<br>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<br>* capsules for oral intake in a dosage of 560 mg (four capsules) daily<br>Drug: Rituximab<br>* Concentrate solution for infusion - intravenous use; Solution for injection - subcutaneous use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | The proportion of patients with complete response after 24 months from treatment start | 24 months from treatment start | 
| 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 | 12 and 24 months after treatment start | 
| Overall survival | The time from the date of treatment start to the date of death from any cause | From the date of treatment start to the date of death due to any cause until 5 years from treatment discontinuation |