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

NCT ID: NCT04994626

Last Updated: 2021-08-06

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-01
• Study Completion Date: 2025-07-01

Brief 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.

Detailed 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.

Conditions

DLBCL; MYD88 Gene Mutation; CD79A Gene Mutation; CD79B Gene Mutation; Relapse; Refractory Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ibrutinib Combined With Rituximab

Intervention Type: DRUG

Drug: ibrutinib ibrutinib 560mg administered orally once daily. Other Name: Imbruvica

Drug: rituximab rituximab 375mg/m² administered intravenously (IV)

Interventions

Ibrutinib Combined With Rituximab

Drug: ibrutinib ibrutinib 560mg administered orally once daily. Other Name: Imbruvica

Drug: rituximab rituximab 375mg/m² administered intravenously (IV)

Intervention Type: DRUG

Other Intervention Names

Imbruvica Combined With Rituximab

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chinese Academy of Medical Sciences

OTHER

Sponsor Role: lead

Responsible Party

Shi Yuankai

chief physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yuankai Shi, M.D.

Role: PRINCIPAL_INVESTIGATOR

Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Central Contacts

Yuankai Shi, M.D.

Role: CONTACT

syuankaipumc@126.com

86 010-87788293

Yan Qin, M.D.

Role: CONTACT

qinyan66@vip.sina.com

86 13601282738

Other Identifiers

NCC2613

Identifier Type: -

Identifier Source: org_study_id