Zanubrutinib Combined With Standard Chemotherapy in the Treatment for Patients With Diffuse Large B Cell Lymphoma

Study Overview
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Brief Summary
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This is a prospective single arm, multi-center, phase II clinical trial to observe the efficacy and safety of zanubrutinib combined with standard chemotherapy in the treatment for patients with diffuse large B cell lymphoma and CD79A/CD79B genetic abnormality.

Detailed Description
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Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP is world-widely used in the first-line treatment for DLBCL. There are about one second of patients suffering relapse and drug resistance. ABC-DLBCL mainly relies on the chronical activity of BCR signal, which can activate the downstream NF-kB pathway through BTK and MYD88, thereby promoting the occurrence of tumors. A study by Wyndham H Wilson et al. showed that 23% of ABC-DLBCL patients were accompanied by acquired functional mutations of the BCR component CD79A/CD79B. Zanubrutinib is a new BTK inhibitor. The goal of our trial is to assess the efficacy and safety of zanubrutinib combined with standard chemotherapy in the treatment for patients with diffuse large B cell lymphoma and CD79A/CD79B genetic abnormality.

Official Title
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A Single Arm, Multi-center, Phase II Clinical Trial of Zanubrutinib Combined With Standard Chemotherapy in the Treatment for Patients With Diffuse Large B Cell Lymphoma and CD79A/CD79B Genetic Abnormality

Conditions
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Diffuse Large B Cell Lymphoma, CD79A Gene Mutation, CD79B Gene Mutation

Intervention / Treatment
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* Drug: Rituximab
* Drug: Zanubrutinib
* Drug: Cyclophosphamide
* Drug: Epirubicin
* Drug: Vincristine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 to 70 years old (including 18 and 70) Diagnosed as diffuse large B cell lymphoma CD79A/CD79B genetic abnormality Subjects must be untreated or R/R and either a or b (a: medium to high risk/high risk: International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ b: Immunohistochemical staining of double expression (BCL2 ≥ 70% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%) Having at least one measurable lesions World health organization-Eastern Cooperative Oncology Group Performance Status (ECOG) 0-1 Life expectancy no less than 3 months enough main organ function Pregnancy test within 7 days must be negative for women of childbearing period, and appropriate measures should be taken for contraception for women in childbearing period during the study and six months after this study Agreeing to sign the written informed consents Exclusion Criteria: Diagnosed as high-grade B-cell lymphoma, including non-specified and double-strike or triple-strike Diagnosed as grey-zone lymphoma Diagnosed as primary mediastinal large B-cell lymphoma Diagnosed as CD20 negative diffuse large B-cell lymphoma Active malignant tumor need be treated at the same time Other malignant tumor history Serious surgery and trauma less than two weeks Systemic therapy for serious acute/chronic infection Congestive heart failure, uncontrolled coronary heart disease, arrhythmia and heart infarction less than 6 months Vaccination with live attenuated vaccine less than 4 weeks HIV-positive, AIDS patients and untreated active hepatitis Patients with a history of deep vein thrombosis or pulmonary embolism less than 12 months Patients with a history of mental illness Researchers determine unsuited to participate in this trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanubrutinib Combined With Standard Chemotherapy<br>A: For the first-line treatment: Rituximab, 375mg/m2, Intravenous administration on day 0, combined with regimen：CHOP (Cyclophosphamide, Epirubicin, Vincristine and Prednisone): repeated every 3 weeks, up to 6 cycles. Zanubrutinib, 160mg twice daily continuous oral administration from 2 to 6 cycles for patients with CD79A/CD79B genetic abnormality. Zanubrutinib combined with Rituximab for the 7 cycle. B: For R/R DBCLC: Rituximab, 375mg/m2, Intravenous administration on day 0, combined with regimen: GemOx(Gemcitabine, Oxaliplatin)/ DHAP(Cisplatin, Cytarabine, Dexamethasone)/ ICE(Ifosfamide, Etoposide, Carboplatin)/ GDP(Gemcitabine, Cisplatin, Dexamethasone): repeated every 3 weeks, up to 5 cycles. Zanubrutinib, 160mg twice daily continuous oral administration from 2 to 5 cycles for patients with CD79A/CD79B genetic abnormality. Maintenance treatment: Zanubrutinib, 160mg twice daily continuous oral administration for 12 months. | Drug: Rituximab<br>* 375mg/m2, Intravenous administration on day 0 of each 3-week cycle.<br>* Other names: RiTUXimab Injection;Drug: Zanubrutinib<br>* 160mg twice daily continuous oral administration.<br>* Other names: Zanubrutinib Pill;Drug: Cyclophosphamide<br>* 750mg/m2, Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease after 2 cycles treatment, disease progression after 4 cycles treatment or unacceptable toxicity develops, up to 6 cycles.<br>* Other names: Cyclophosphamide Injection;Drug: Epirubicin<br>* 70mg/m2, Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease after 2 cycles treatment, disease progression after 4 cycles treatment or unacceptable toxicity develops, up to 6 cycles.<br>* Other names: Epirubicin Injection;Drug: Vincristine<br>* 1.4mg/m2 (Max: 2mg), Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease after 2 cycles treatment, disease progression after 4 cycles treatment or unacceptable toxicity develops, up to 6 cycles.<br>* Other names: Vincristine Injection;Drug: Prednisone<br>* 100mg, oral administration on day 1 to 5 of each 3-week cycle until disease progression/stable disease after 2 cycles treatment, disease progression after 4 cycles treatment or unacceptable toxicity develops, up to 6 cycles.<br>* Other names: Prednisone Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of complete remission for 3-4 weeks after induction treatment | the total proportion of patients with complete remission (CR) for 3-4 weeks after induction treatment | from the date of the first cycle of treatment to 3-4 weeks after induction treatment of the last included patient (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| objective response rate | the total proportion of patients with complete response (CR) and partial response (PR) | every 6 weeks from the day of the first cycle of induction chemotherapy treatment and every 8 weeks from the day of the first cycle of maintenance treatment to 18 months after last patient's enrollment (each cycle is 21 days) | 
| 2-year progression-free survival | the total proportion of patients with no progression from date of the first day of treatment to the date of confirmed progressive disease or death which one occurs first | from the day of the first cycle of treatment to the date of confirmed progressive disease or death, whichever occurs first, up to 2 years after last patient's enrollment (each cycle is 21 days) | 
| 2-year overall survival | from date of first day of treatment to the date of death by any cause | from date of the first cycle of treatment to the date of death from any cause, assessed up to 2 years (each cycle is 21 days) | 
| incidence and relationship with study drugs of grade 3-4 adverse events | the incidence and relationship with study drugs of grade 3 or 4 adverse events (based on NCI CTC-AE v4.03) | from the date of the first cycle of treatment to 18 months after last patient's enrollment (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse Large B Cell Lymphoma, Zanubrutinib, CD79A/CD79B, Genetic Abnormality