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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Refractory Lymphoma; DLBCL; MYD88 Gene Mutation; Relapse; CD79A Gene Mutation; CD79B Gene Mutation
• Intervention / Treatment: Drug: Ibrutinib Combined With Rituximab

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: yuankai Shi, M.D.; Phone Number: 86 010-87788293; Email: syuankaipumc@126.com
• Study Contact Backup: Name: Yan Qin, M.D.; Phone Number: 86 13601282738; Email: qinyan66@vip.sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Investigators: Principal Investigator: Yuankai Shi, M.D., Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): July 1, 2025

Study Registration Dates

• First Submitted: August 3, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 6, 2021

Study Record Updates

• Last Update Posted (Actual): August 6, 2021
• Last Update Submitted That Met QC Criteria: August 3, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Rituximab; Ibrutinib; R/R DLBCL; MYD88 Gene Mutation; CD79A/B Gene Mutation
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Recurrence; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: NCC2613

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No