Clinical trial NCT04994626: 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
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: DLBCL
MYD88 Gene Mutation
CD79A Gene Mutation
CD79B Gene Mutation
Relapse
Refractory Lymphoma
Keywords: R/R DLBCL
MYD88 Gene Mutation
CD79A/B Gene Mutation
Ibrutinib
Rituximab
Lead sponsor: ChineseAMS
Sponsor class: UNKNOWN
First posted: 2021-08-06
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Objective Response Rate(ORR)
timeFrame: 24 months after the last patient's enrollment
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: at 6 month and 1 year
measure: Overall Survival (OS)
timeFrame: at 6 month and 1 year
measure: Event Free Survival (EFS)
timeFrame: at 6 month and 1 year
measure: Adverse events
timeFrame: 24 months after the last patient's enrollment
measure: Assessment of the correlation between MYD88 and/or CD79A/B or other gene abnormality and efficacy.
timeFrame: 24 months after the last patient's enrollment
Other outcomes:
Locations:
Study officials:
affiliation: Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College
name: Yuankai Shi, M.D.
role: PRINCIPAL_INVESTIGATOR
References: