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

Relapse Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04994626
• Other study ID #: NCC2613
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: October 1, 2021
• Est. completion date: July 1, 2025

Study information

• Verified date: August 2021
• Source: Chinese Academy of Medical Sciences
• Contact: Yuankai Shi, M.D.
• Phone: 86 010-87788293
• Email: syuankaipumc[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: July 1, 2025
• Est. primary completion date: April 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Participants must be able to understand and be willing to sign a written informed consent document;

2. Men and woman who are at least 18 years of age on the day of consenting to the study;

3. According to the WHO 2016 classification criteria, pathologically confirmed CD20+diffuse large B-cell lymphoma;

4. Patients with MYD88 and CD79A/B mutations or CD79B alone;

5. Relapse or progression after treatment with at least two prior therapies;

6. 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;

7. Eastern Cooperative Oncology Group (ECOG) performance status =< 2

8. Blood routine examination meets the following criteria:

Neutrophil count = 1.0 x 109 / L; Platelet = 75 x 109 / L; Hemoglobin = 10.0 g / dL;

9. 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;

10. Must agree to effective contraception

Exclusion Criteria:

1. Transformed diffuse large B-cell lymphoma;

2. HBV DNA positive or HCV RNA positive;

3. Patient is known to have an uncontrolled active systemic infection;

4. Left ventricular ejection fraction < 40%;

5. Previous autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, dry syndrome, ankylosing spondylitis, etc;

6. Immunosuppressive drugs are being or have been used in the past;

7. Known hypersensitivity to the study drug or any of its excipients;

8. There are other active malignant tumors that may interfere with this study requiring treatment;

9. Known history of human immunodeficiency virus (HIV) infection;

10. Previous autologous stem cell transplantation or allogeneic hematopoietic stem cell transplantation;

11. The investigator judges that the patient has other inappropriate circumstances.

Related Conditions & MeSH terms

• CD79A Gene Mutation
• CD79B Gene Mutation
• DLBCL
• Lymphoma, Large B-Cell, Diffuse
• MYD88 Gene Mutation
• Refractory Lymphoma
• Relapse

Intervention

Drug:
• Ibrutinib Combined With Rituximab
Drug: ibrutinib ibrutinib 560mg administered orally once daily. Other Name: Imbruvica Drug: rituximab rituximab 375mg/m² administered intravenously (IV)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Chinese Academy of Medical Sciences

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Progression Free Survival (PFS)	From the date into this study to disease progression or death	at 6 month and 1 year
Secondary	Overall Survival (OS)	From the date into this study to death	at 6 month and 1 year
Secondary	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
Secondary	Adverse events	AEs will be evaluated using the NCI CTCAE v4.0.	24 months after the last patient's enrollment
Secondary	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