BTK Inhibitor BGB-3111 in Chinese Participants With Diffuse Large B-Cell Lymphoma (Non-GCB) and Indolent Lymphoma (FL and MZL)

Study Overview
=================
Brief Summary
-----------------
This was a multicenter, open-label, phase 2 study to evaluate efficacy, safety, and tolerability of BGB-3111 (zanubrutinib) 160 milligrams (mg) twice daily (BID) in combination with rituximab in Chinese participants with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (non-GCB [non-germinal center B-cell-like] subtype) and R/R indolent lymphoma (follicular lymphoma [FL] and marginal zone lymphoma [MZL]).

Official Title
-----------------
A Phase 2 Study to Assess the Safety, Tolerability, and Activity of BGB-3111 in Combination With Rituximab in Chinese Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (Non-GCB Subtype) and Relapsed/Refractory Indolent Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma)

Conditions
-----------------
Marginal Zone Lymphoma, Follicular Lymphoma, Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Zanubrutinib
* Drug: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: ≥ Age 18 years at time of signing of informed consent. Measurable disease by computed tomography (CT) or positron emission tomography/CT or magnetic resonance imaging, defined as ≥1 nodal lesion that was >1.5 centimeters (cm) in the longest diameter, or ≥1 extra-nodal lesion (for example, hepatic nodules) that was >1 cm in the longest diameter. Availability of archival or fresh tumor tissue sample from an evaluable core or excisional biopsy. Participants meet the following criteria: Cohort 1: R/R non-GCB DLBCL i. Histologically confirmed non-GCB DLBCL per Hans criteria with non-transformed disease; additional methodologies for confirming non-GCB DLBCL may have been considered in consultation with the medical monitor. ii. Relapsed disease (disease progression after most recent therapy for DLBCL occurring more than 6 months after the completion of last therapy) or refractory disease (failure to achieve complete response [CR] or partial response [PR] to therapy for non-GCB DLBCL or disease progression within 6 months after completion of the most recent therapy for non-GCB DLBCL). iii. Must have received at least one standard anthracycline ± rituximab-based treatment (for example, rituximab plus cyclophosphamide, doxorubicin [or epirubicin, hydroxydaunorubicin, or similar], vincristine, and prednisone) or cyclophosphamide, vincristine, and prednisone +/- rituximab for DLBCL. Cohort 2: R/R FL or R/R MZL i. Histologically confirmed CD20+ FL (Grade 1, 2, or 3a) or MZL. ii. Relapsed disease (disease progression after most recent therapy for FL or MZL occurring more than 6 months after the completion of last therapy) or refractory disease (failure to achieve complete response (CR) or partial response (PR) to most recent therapy for FL or MZL, or disease progression within 6 months after completion of the most recent therapy for FL or MZL). Laboratory parameters as specified below: Hematologic: Platelet count ≥75 x 10^9/liter (L) independent of growth factor or transfusion within 7 days of study entry; absolute neutrophil count (ANC) ≥1 x 10^9/L independent of growth factor within 7 days of study entry, hemoglobin >8 grams/deciliter within 7 days of study entry. Hepatic: Total bilirubin ≤ 2x upper limit of normal (ULN) unless documented Gilbert's syndrome; aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine transaminase/serum glutamic-pyruvic transaminase ≤3x ULN. Renal: Creatinine clearance ≥30 milliliters/minute (as estimated by the Cockcroft-Gault equation based on ideal body weight or as measured by nuclear medicine scan or 24-hour urine collection). International normalized ratio and activated partial thromboplastin time ≤1.5x ULN. Participants with anti-phospholipid syndrome, acquired von Willebrand disease, factor inhibitors or on vitamin K antagonist may have been enrolled after discussion with the Medical Monitor. Left ventricular ejection fraction ≥50%. Life expectancy ≥6 months. Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Female participants of childbearing potential must have practiced highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥90 days after the last dose of zanubrutinib, or 12 months after the last dose of rituximab, whichever is longer. Male participants were eligible if vasectomized or if they agreed to the use of barrier contraception in combination with other methods above during the study treatment period and for ≥90 days after the last dose of zanubrutinib. Able to provide written informed consent and could understand and comply with the requirements of the study. Key Exclusion Criteria: Known central nervous system lymphoma or leukemia. Histological confirmed gastric mucosa-associated lymphoid tissue type MZL. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. Clinically significant cardiovascular disease. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug. Severe or debilitating pulmonary disease. Hypersensitivity reaction to zanubrutinib or rituximab or any of the other ingredients of the study drugs. Prior Bruton tyrosine kinase inhibitor treatment. Required ongoing treatment with a strong cytochrome P450 protein inhibitor or inducer. Vaccination with a live vaccine within 28 days of the first dose of study drug. Hematopoietic stem cell transplantation within 6 months of first dose of study drug. Receipt of the following treatment prior to first dose of study drug: Corticosteroids at doses >20 mg/day prednisone equivalent or steroids given with anti-neoplastic intent within 7 days prior to first dose of study drug. Chemotherapy or radiotherapy within 4 weeks. Monoclonal antibody within 4 weeks. Investigational therapy within 4 weeks. Chinese patent medicine with anti-neoplastic intent within 4 weeks. Not recovered from toxicity of any prior anti-cancer therapy to ≤Grade 1, except for alopecia, ANC, hemoglobin (Hgb), and platelets. For ANC, Hgb and platelets, see inclusion criterion #5. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, history of bariatric surgery, or partial or complete bowel obstruction. Major surgery within 4 weeks prior to first dose of study treatment. Active fungal, bacterial and/or viral infection requiring systemic therapy. Known infection with human immunodeficiency virus, or serologic status reflecting active hepatitis B or C infection as follows: Presence of hepatitis B surface antigen (HBsAg) or anti-hepatitis B core antibody (anti-HBc). Participants with presence of anti-HBc, but absence of HBsAg, were eligible if hepatitis B virus (HBV) DNA was <500 international units (IU)/mL, anti-viral therapy started before the first dose of study treatment, and if they were willing to undergo monthly monitoring for HBV reactivation. Presence of hepatitis C virus (HCV) antibody. Participants with presence of HCV antibody were eligible if HCV RNA was undetectable (<15 IU/mL). Pregnant or lactating women. Underlying medical conditions that, in the investigator's opinion, would have rendered the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events. Concurrent participation in another therapeutic clinical trial. Note: Other protocol defined Inclusion/Exclusion criteria may have applied.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R/R Non-GCB DLBCL<br>Participants with non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. | Drug: Zanubrutinib<br>* Administered zanubrutinib 160 mg orally (PO) BID continuously<br>* Other names: BGB-3111;Drug: Rituximab<br>* Administered rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.<br>|
| Experimental: R/R FL or MZL<br>Participants with R/R FL or MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. | Drug: Zanubrutinib<br>* Administered zanubrutinib 160 mg orally (PO) BID continuously<br>* Other names: BGB-3111;Drug: Rituximab<br>* Administered rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) As Measured By The Investigator | The percentage of participants whose best overall response met partial response (PR) or complete response (CR) criteria among all participants. The 95% confidence interval (CI) was calculated with the Clopper-Pearson method. | Up to approximately 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration Of Response (DOR) As Determined By Investigator | The DOR was defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method. | Up to approximately 2.5 years | 
| DOR: Event-free Rate | The DOR was defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. The event-free rate was estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula. | Up to approximately 2.5 years | 
| Progression-free Survival (PFS) As Determined By Investigator | The PFS was defined as time from first dose of study treatment until first documentation of progression, assessed per the Lugano Classification, or death, whichever occurred first. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method. | Up to approximately 2.5 years | 
| PFS: Event-free Rate | The PFS was defined as time from first dose of study treatment until first documentation of progression, assessed per the Lugano Classification, or death, whichever occurred first. The event-free rate was estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula. | Up to approximately 2.5 years | 
| Overall Survival (OS) | The OS was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley. | Up to approximately 2.5 years | 
| OS: Survival Rate | The OS was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Survival rates were estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula. | Up to approximately 2.5 years | 
| Time To Response (TTR) As Determined By The Investigator | The TTR was defined as the time from the date of the first dose of study treatment to the date of the first qualifying response (partial response or better). | Up to approximately 2.5 years | 
| Median TTR | The TTR was defined as the time from the date of the first dose of study treatment to the date of the first qualifying response (partial response or better). | Up to approximately 2.5 years | 
| Complete Response Rate As Determined By The Investigator | The percentage of participants whose best overall response met complete response or complete metabolic response criteria among all participants are reported. The 95% CI was calculated with Clopper-Pearson method. | Up to approximately 2.5 years | 
| Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) And Serious TEAEs | A treatment-emergent adverse event was defined as an adverse event with an onset or worsening (if present pretreatment) starting on or after the first dose of study drug up to 30 days after discontinuation of zanubrutinib or 90 days after discontinuation of rituximab, whichever occurred later; or initiation of new anticancer therapy if it occurred prior to the other 2 dates. Worsening of a treatment-emergent adverse event to Grade 5 beyond Day 30 after the last dose of zanubrutinib or Day 90 after the last dose rituximab was also considered a treatment-emergent adverse event if the event occurred prior to initiation of new anticancer therapy. | Up to approximately 2.5 years |