Phase II Evaluation of Ibrutinib and Rituximab in Treatment-Naïve CD20-Positive Marginal Zone B-Cell Lymphoma Patients Requiring Systemic Therapy
- Trial ID
- 2023-507886-25-00
- Protocol
- IELSG47
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II study is to assess the **efficacy** of the combination of rituximab and ibrutinib in patients with extranodal marginal zone lymphoma (EMZL) and to explore its activity in splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) as exploratory subsets. This is clinically relevant as it aims to determine the potential of this combination therapy in improving treatment outcomes for patients with these subtypes of marginal zone B-cell lymphoma, which are characterized by being previously untreated, symptomatic, and CD20-positive, necessitating systemic treatment.
Secondary objectives include:
- To assess the **safety** of the combination therapy.
- To evaluate further efficacy parameters.
Participants
The clinical trial involves a total of **7 participants** who are previously untreated and symptomatic patients with histologically proven CD20-positive marginal zone B-cell lymphoma (MZL) requiring systemic treatment. The study population includes both **male and female** subjects, aged **18 years and older**, with a life expectancy of at least one year and an ECOG Performance status of 0-2. Participants were selected based on their need for systemic therapy and their ineligibility for local therapy. The trial includes patients with extranodal marginal zone lymphoma (EMZL), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL), with specific criteria for each subtype. All participants must have adequate kidney and bone marrow function, and women of childbearing potential are required to have a negative pregnancy test prior to the administration of study drugs. The trial population is characterized by a vulnerable status, necessitating careful consideration of their health and treatment needs. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **ibrutinib** and **rituximab** in patients with previously untreated, symptomatic, CD20-positive marginal zone B-cell lymphoma (MZL) requiring systemic treatment. This Phase II study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to span approximately eight years, with an estimated recruitment start date in October 2019 and an anticipated end date in October 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate kidney function and a life expectancy of at least one year. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The treatment phase will involve regular follow-up visits to monitor the participants' response to the therapy and assess any adverse events. The primary endpoints include the complete response rate at 12 months and progression-free survival (PFS) at five years. Secondary endpoints focus on safety, overall response rate, and overall survival.
The expected length of participant involvement in the study is contingent upon the treatment regimen, with the maximum treatment period for **ibrutinib** being 24 months and for **rituximab** being up to 28 days, depending on the formulation. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The end-of-study visit will occur after the completion of the treatment phase, where final assessments will be conducted to evaluate the long-term outcomes of the therapy.
Treatment
The clinical trial involves the administration of **IMBRUVICA** (ibrutinib) 140 mg hard capsules, which is an experimental medication used in the study. Ibrutinib is a chemical substance provided in the form of hard capsules, with a maximum daily dose of 560 mg. The medication is administered orally, and the treatment period can extend up to 24 months. The capsules are relabeled specifically for clinical trial use. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to ibrutinib, the trial includes the administration of **MabThera** (rituximab) 500 mg concentrate for solution for infusion. Rituximab is a protein-based substance, and the pharmaceutical form is a solution for infusion. The maximum daily dose is 375 mg/m², administered intravenously. The treatment period for this formulation is limited to 1 month. The concentrate is also relabeled for clinical trial use, and participant adherence to the infusion schedule will be closely monitored.
The study further incorporates **MabThera** (rituximab) 1400 mg solution for subcutaneous injection. This formulation of rituximab is also a protein-based substance, provided as a solution for injection. The maximum daily dose is 1400 mg, with a total maximum dose of 4200 mg over a treatment period of up to 28 days. The administration route is subcutaneous, and the solution is relabeled for clinical trial use. Compliance with the injection schedule will be assessed to ensure adherence to the study protocol.
Efficacy
The efficacy of the combination of rituximab and ibrutinib in patients with marginal zone lymphomas will be assessed using specific primary and secondary endpoints. The primary endpoints include the **Complete Response (CR) rate** at 12 months and **Progression-Free Survival (PFS)** at 5 years, as evaluated by investigators according to revised response criteria for malignant lymphomas. These assessments will be conducted from the study entry to death from any cause or progression of the disease.
Secondary endpoints will focus on both acute and long-term safety, evaluated through laboratory parameters and adverse events coded with the NCI Common Toxicity Criteria, version 4.0. Additional secondary endpoints include the **Complete Response rate** at 24 months, **Overall Response Rate (ORR)** at 12 and 24 months, and **Overall Survival**. These efficacy parameters will be measured and collected at specified timepoints throughout the trial to ensure comprehensive analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- To be eligible for inclusion, each patient must fulfill all of the following 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 1-3 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: a) H. pylori-negative cases, either de novo (non pretreated) or at relapse following local therapy (i.e., surgery, radiotherapy or antibiotics). b) 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: a) bulky progressive or painful splenomegaly; b) 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) ; c) 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 (see Appendix B). 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 function
- Adequate kidney 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 during the study and for at least 12 months after the last dose of subcutaneous rituximab and 3 months after the last dose of ibrutinib.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)
- 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
- 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
- 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.
- 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
- 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).
- Active HCV or Hepatitis B virus (HBV) infections. 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
- Localized (stage IE and IIE) gastric, ocular and cutaneous MALT lymphoma that may benefit from local therapy only (surgery or radiotherapy).
- Known CNS involvement of MZL.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 03 Oct 2019 | 12 |
 France | Not Recruiting | 03 Oct 2019 | 54 |
 Italy | Not Recruiting | 03 Oct 2019 | 110 |
 Portugal | Not Recruiting | 03 Oct 2019 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MabThera 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 375 | 1 | PRD398759 |
MabThera 1400 mg solution for subcutaneous injection | Test | SOLUTION FOR SUBCUTANEOUS INJECTION | SUBCUTANEOUS USE | 1400 | 28 | PRD1182393 |
IMBRUVICA 140 mg hard capsules | Test | HARD CAPSULES | ORAL | 560 | 24 | PRD1729393 |