Ibrutinib Combined With Rituximab for Treatment of Relapsed Refractory MYD88 and CD79A/B (or CD79B Alone) DLBCL Who Have Received at Least Two Prior Therapies

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of Ibrutinib Combined With Rituximab in Relapsed Refractory MYD88 and CD79A/B (or CD79B Alone) DLBCL Who Have Received at Least Two Prior Therapies.

Detailed Description
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Recent studies have found that about 30% of DLBCL have mutations in MYD88 and/or CD79A/B genes. MYD88 and CD79A/B protein molecules belong to two signal transduction pathways, which regulate B cell proliferation. Both MYD88 and CD79A/B gene mutations can abnormally activate BTK located downstream of MYD88 and CD79A/B, leading to over activation and proliferation of B cells. Ibrutinib is the first generation of oral BTKi, which may theoretically inhibit the tumorigenesis of DLBCL with abnormal BTK activation caused by mutations in MYD88 and CD79A/B genes. A phase II clinical study of ibrutinib monotherapy in the treatment of relapsed and refractory DLBCL showed that the effective rate of ibutinib for single CD79B mutation was 55.5% (5/9 cases), and that for both CD79B and MYD88 mutations was 80% (4/5 cases). About 40   50% of primary central nervous system large B cell lymphoma (PCNSL) have CD79B and MYD88 mutations. A small sample study found that the overall response rate (ORR) for the treatment of relapsed and refractory PCNSL with ibrutinib was 77% (10/13). An expanded sample study of 44 cases of PCNSL treated with ibrutinib found that the ORR is 52% and progression-free survival (PFS) is 4.8 months. These results suggest that ibrutinib may be more effective in DLBCL with MYD88 and CD79A/B or CD79B mutations. The relationship between mutations in MYD88 and CD79B and therapeutic sensitivity of ibrutinib can not be simply categorized, because abnormalities in other genes of B cell signaling pathway, such as CARD11, TNFAIP3, CXCR4, JAK1 and PIM1, may also affect the efficacy of ibrutinib. Therefore, it is necessary to comprehensively analyze the gene abnormalities of other B cell related signaling pathways, such as downstream signal of Bruton kinase, CXCR, JAK-STAT, and NFKB, to find out the most effective group of DLBCL patients treated with ibrutinib. This phase II, single-arm, open-label, multi-center clinical trial will evaluate the efficacy and safety of ibrutinib combined with rituximab in treating relapsed refractory MYD88 and CD79A/B (or CD79B alone) DLBCL who have received at least two prior therapies. The study will also explore the relationship between MYD88 and/or CD79A/B and efficacy, and detect the gene abnormality by Next Generation Sequencing (NGS) and evaluate the relationship between other gene abnormality and efficacy.

Official Title
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Phase II, Multi-Center Study to Evaluate the Efficacy and Safety of Ibrutinib Combined With Rituximab for Treatment of Relapsed Refractory MYD88 and CD79A/B (or CD79B Alone) DLBCL Who Have Received at Least Two Prior Therapies

Conditions
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Relapse, DLBCL, MYD88 Gene Mutation, CD79A Gene Mutation, CD79B Gene Mutation, Refractory Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib Combined With Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be able to understand and be willing to sign a written informed consent document; Men and woman who are at least 18 years of age on the day of consenting to the study; According to the WHO 2016 classification criteria, pathologically confirmed CD20+diffuse large B-cell lymphoma; Patients with MYD88 and CD79A/B mutations or CD79B alone; Relapse or progression after treatment with at least two prior therapies; There is at least one measurable lesion, defined as a two-path measurable, intraductal lesion short neck >1.5cm, extranodal lesion short diameter >1.0cm; Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Blood routine examination meets the following criteria: Neutrophil count ≥ 1.0 x 109 / L; Platelet ≥ 75 x 109 / L; Hemoglobin ≥ 10.0 g / dL; The main organ function meets the following criteria: Aspartate aminotransferase and alanine aminotransferase ≤ 2.0 times the upper limit of normal value; Bilirubin ≤ 2.0 mg / dL; Creatinine clearance rate ≥ 60 mL / min; Must agree to effective contraception Exclusion Criteria: Transformed diffuse large B-cell lymphoma; HBV DNA positive or HCV RNA positive; Patient is known to have an uncontrolled active systemic infection; Left ventricular ejection fraction < 40%; Previous autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, dry syndrome, ankylosing spondylitis, etc; Immunosuppressive drugs are being or have been used in the past; Known hypersensitivity to the study drug or any of its excipients; There are other active malignant tumors that may interfere with this study requiring treatment; Known history of human immunodeficiency virus (HIV) infection; Previous autologous stem cell transplantation or allogeneic hematopoietic stem cell transplantation; The investigator judges that the patient has other inappropriate circumstances.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 Combined With Rituximab<br>Induction therapy: Ibrutinib 560mg administered oral once a day of each 21-day cycle for 6 cycles. Rituximab 375mg/m² administered intravenously (IV) on Day 1 of each 21-day cycle for 6 cycles. Maintenance therapy: Ibrutinib 560mg administered oral once a day of each 56-day cycle for 6 cycles. Rituximab 375mg/m² administered intravenously (IV) on Day 1 of each 56-day cycle for 6 cycles. | Drug: Ibrutinib Combined With Rituximab<br>* Drug: ibrutinib ibrutinib 560mg administered orally once daily. Other Name: Imbruvica Drug: rituximab rituximab 375mg/m² administered intravenously (IV)<br>* Other names: Imbruvica Combined With Rituximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate(ORR) | The ORR includes complete response and partial response. The treatment response assessments are as follows: Evaluation of treatment response are performed every 2 cycles followed the International Lymphoma Collaborative Group guidelines. | 24 months after the last patient's enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | From the date into this study to disease progression or death | at 6 month and 1 year | 
| Overall Survival (OS) | From the date into this study to death | at 6 month and 1 year | 
| Event Free Survival (EFS) | From the date into this study to disease progression, relapse from CR as assessed by the investigator, completion of study treatment followed by subsequent systemic anti-lymphoma therapy, or death from any cause, whichever occurred first. | at 6 month and 1 year | 
| Adverse events | AEs will be evaluated using the NCI CTCAE v4.0. | 24 months after the last patient's enrollment | 
| Assessment of the correlation between MYD88 and/or CD79A/B or other gene abnormality and efficacy. | To explore the relationship between MYD88 and/or CD79A/B and efficacy and to detect the gene abnormality by Next Generation Sequencing (NGS) and evaluate the relationship between other gene abnormality and efficacy. | 24 months after the last patient's enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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R/R DLBCL, MYD88 Gene Mutation, CD79A/B Gene Mutation, Ibrutinib, Rituximab