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
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 20
- 主要终点
- Objective Response Rate(ORR)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Ibrutinib Combined With Rituximab
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.
干预措施: Ibrutinib Combined With Rituximab (Drug)
结局指标
主要结局
Objective Response Rate(ORR)
时间窗: 24 months after the last patient's enrollment
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.
次要结局
- Adverse events(24 months after the last patient's enrollment)
- Progression Free Survival (PFS)(at 6 month and 1 year)
- Overall Survival (OS)(at 6 month and 1 year)
- Event Free Survival (EFS)(at 6 month and 1 year)
- Assessment of the correlation between MYD88 and/or CD79A/B or other gene abnormality and efficacy.(24 months after the last patient's enrollment)
研究者
Shi Yuankai
chief physician
Chinese Academy of Medical Sciences