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

Sponsor:

Collaborators:

Information provided by (Responsible Party):

，

Tracking Information

First Submitted Date ^ICMJE

September 28, 2018

First Posted Date ^ICMJE

October 5, 2018

Last Update Posted Date

October 5, 2018

Actual Study Start Date ^ICMJE

April 15, 2019

Estimated Primary Completion Date

April 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Complete Response Rate at 12 months[ Time Frame: 12 months after treatment start ]

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

Progression Free Survival at 5 years[ Time Frame: 5 years from treatment start ]

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

Original Primary Outcome Measures ^ICMJE

Same as current

Current Secondary Outcome Measures ^ICMJE

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 ]
Analysis of incidence, severity and relationship of adverse events graded according to NCI Common Toxicity Criteria, version 4.0
Complete Response Rate at 24 months[ Time Frame: 24 months from treatment start ]
The proportion of patients with complete response after 24 months from treatment start
Overall Response Rate at 12 and 24 months[ Time Frame: 12 and 24 months after treatment start ]
The proportion of responding patients (partial and complete responses) assessed at 12 and 24 months after treatment start
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 ]
The time from the date of treatment start to the date of death from any cause

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

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

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 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.

Study Type ^ICMJE

Interventional

Study Phase

Phase 2

Study Design ^ICMJE

Allocation:
Intervention Model: Single Group Assignment
Intervention Model Description:
Masking: Interventional
Masking Description:
Primary Purpose: Treatment

Condition ^ICMJE

Intervention ^ICMJE

Drug: Ibrutinib
capsules for oral intake in a dosage of 560 mg (four capsules) daily
Drug: Rituximab
Concentrate solution for infusion - intravenous use; Solution for injection - subcutaneous use.

Study Arms

Experimental: Ibrutinib and Rituximab
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.

Recruitment Information

Recruitment Status ^ICMJE

Not yet recruiting

Estimated Enrollment ^ICMJE

160

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date

April 15, 2027

Estimated Primary Completion Date

April 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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

Sex/Gender

Sexes Eligible for Study:

All

Ages

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Listed Location Countries ^ICMJE

France|Italy|Switzerland

Removed Location Countries

Administrative Information

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

Plan to Share IPD:

Responsible Party

，

Study Sponsor ^ICMJE

International Extranodal Lymphoma Study Group (IELSG)

Collaborators ^ICMJE

Investigators ^ICMJE

Study Chair: Catherine Thieblemont, MD Saint-Louis Hospital, Paris, France
Study Chair: Annarita Conconi, MD Ospedale degli Infermi - Biella, Italy

PRS Account

Verification Date

October 2018

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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