Study of BTK Inhibitor Zanubrutinib in Participants With Relapsed/Refractory Non-GCB Type Diffuse Large B Cell Lymphoma

• Sponsor: BeiGene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03145064
• Collaborator: (none)
• Enrollment: 41
• Locations: 11
• Arm: 1
• Actual Duration (Months): 38.1
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Screening (up to 28 days); daily treatment until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow-up, or study termination from sponsor; treatment (up to 2 years), safety follow-up (30 days); survival follow-up until data cutoff for final analysis.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-cell Lymphoma	Drug: Zanubrutinib	Phase 2

Detailed Description

This is a single-arm, multicenter, open-label Phase 2 study to evaluate efficacy, safety, tolerability of BGB-3111 (zanubrutinib) in participants with relapsed/refractory non-germinal center B-cell (GCB) type diffuse large B-cell lymphoma (DLBCL).

The study will enroll approximately 40 participants treated with zanubrutinib (160 milligrams [mg]) twice daily (BID). All participants in the study were treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the study was terminated by the sponsor for final analysis. At the time of final analysis, participants who remained on treatment were considered for participation in the extension study when eligible. A treatment cycle consisted of 28 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase 2, Single Arm, Multicenter, Open-label Study of Bruton's Tyrosine Kinase (BTK) Inhibitor BGB-3111 in Subjects With Relapsed/Refractory Non-GCB Type Diffuse Large B Cell Lymphoma
• Actual Study Start Date: Jun 30, 2017
• Actual Primary Completion Date: May 24, 2019
• Actual Study Completion Date: Sep 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zanubrutinib Participants received zanubrutinib BID.	Drug: Zanubrutinib; Administered at a dose of 160 mg BID orally.; Other Names: BGB-3111 BRUKINSA

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [Up to approximately 23 months]

   Overall response rate was defined as the percentage of participants achieving either a partial response (PR) or complete response (CR) as determined by investigator according to the 2014 modification of the International Working Group (IWG) in Non-Hodgkin's lymphoma (NHL) Criteria.

Secondary Outcome Measures

1. Progression-free Survival [Up to 3 years and 2 months]

   Progression-free survival was defined as the time from first dose of zanubrutinib until first documentation of progression (by IWG on NHL criteria) or death, whichever occurred first.

2. Duration Of Response [Up to 3 years and 2 months]

   Duration of response was defined as the time from the date that the response criteria were first met to the date that progressive disease was objectively documented or death, whichever occurred first. Duration of response was summarized for responders (with a best overall response of CR or PR) only.

3. Time To Response [Up to 3 years and 2 months]

   Time to response was defined as the time from the first dose of zanubrutinib to the documentation of first response. Time to response was summarized for responders (with a best overall response of CR or PR) only.

4. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From the time of informed consent to 30 days after the last dose of study drug (approximately Up to 3 years and 2 months)]

   A treatment-emergent adverse event was defined as an adverse event that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation (Safety Follow-up Visit) or initiation of new anticancer therapy, whichever occurred first.

Other Outcome Measures

1. Overall Survival [Up to 3 years and 2 months]

   Overall survival was defined as the time from first dose of zanubrutinib until death due to any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Histologically confirmed non-germinal center DLBCL, by immunohistochemistry using the

Hans algorithm:

1. Cluster of differentiation 10 (CD10)- and B-cell lymphoma 6 protein (BCL6)-,

2. CD10-, BCL6+, but maximal unique match+

3. Men and women ≥ 18 years of age.

4. Eastern Cooperative Oncology Group performance status of 0-2.

5. Measurable disease was defined as at least 1 lymph node > 1.5 centimeters in longest diameter and measurable in 2 perpendicular dimensions.

6. All participants must have provided fresh tumor biopsy or recent tumor tissue samples (within 2 years of study entry [informed consent form signed]).

7. Received at least one prior therapy for DLBCL that included anthracycline-based chemotherapy.

8. Participant not eligible for or refused intensive chemotherapy and hematopoietic stem cell transplant.

9. Documented failure to achieve at least partial response with, or documented disease progression after response to, the most recent treatment regimen.

10. Neutrophils ≥ 1 x 10^9/liter (L) independent of growth factor support within 7 days of study entry.

11. Platelets ≥ 75 x 10^9/L, independent of growth factor support or transfusion within 7 days of study entry.

12. Creatinine clearance of ≥ 30 milliliters/minute (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate).

13. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN).

14. Bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome), then up to 5 x ULN allowed.

15. Independent of erythropoietin support or transfusion within 7 days of first dose of study drug.

16. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN.

17. Participants may be enrolled who relapsed after autologous stem cell transplant if they are at least 6 months after transplant, participants should have had no active infections (that is, fungal or viral).

18. Females of childbearing potential must have agreed to use highly effective forms of birth control throughout the course of the study and at least up to 90 days after last dose of study drug. Highly effective forms of birth control were defined as abstinence, hysterectomy, bilateral oophorectomy with no menstrual bleeding for up to 6 months, intrauterine contraception, hormonal methods such as contraceptive injection, oral contraceptive. Males must have undergone sterilization-vasectomy, or utilized a barrier method where the female partner utilized the effective forms of birth control noted above.

19. Life expectancy of > 3 months.

20. Able to provide written informed consent and could understand and comply with the requirements of the study.

Key Exclusion Criteria:

1. Current or history of central nervous system lymphoma.

2. Prior exposure to a BTK inhibitor.

3. Prior corticosteroids (at dosages equivalent to prednisone > 20 mg/day) given with anti-neoplastic intent within 7 days, prior chemotherapy, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapies or Chinese anti-cancer herbal therapies within 4 weeks of the start of study drug.

4. Major surgery within 4 weeks of screening.

5. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, absolute neutrophil count [ANC]) and platelets. For ANC and platelets, please follow inclusion criteria #9 [neutrophils] and #10 [platelets]).

6. History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other modality) with curative intent.

7. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months of screening. Left ventricular ejection fraction is lower than 50% measured by echocardiography.

8. QTcF (Fridericia's correction) > 450 milliseconds or other significant electrocardiogram abnormalities including second degree atrioventricular (AV) block Type II, or third-degree AV block.

9. 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, or partial or complete bowel obstruction.

10. Uncontrolled systemic infection or infection requiring parenteral anti-microbial therapy.

11. Known human immunodeficiency virus, or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction).

12. Pregnant or lactating women.

13. Any life-threatening illness, medical condition or organ system dysfunction, which, in the investigator's opinion, could compromise the participant's safety, or put the study at risk.

14. On medications that were strong cytochrome P450 (CYP), family 3, subfamily A (CYP3A) inhibitors or CYP3A inducers.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Peking University Cancer Hospital	Beijing	Beijing	China
2	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang	China
3	Henan Cancer Hospital	Zhengzhou	Henan	China
4	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu	China
5	The First Hospital of Jilin University	Changchun	Jilin	China
6	Fudan University Shanghai Cancer Center	Shanghai	Shanghai	China
7	Ruijin Hospital, Shanghai Jiaotong University School of Medicine	Shanghai	Shanghai	China
8	West China Hospital, Sichuan University	Chengdu	Sichuan	China
9	Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences	Tianjin	Tianjin	China
10	Tianjin Medical University Cancer Institute & Hospital	Tianjin	Tianjin	China
11	The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)	Hangzhou	Zhejiang	China

Sponsors and Collaborators

• BeiGene

Investigators

• Principal Investigator: Study Director, BeiGene

Study Documents (Full-Text)

• Study Protocol - Apr 16, 2018
• Statistical Analysis Plan - Jun 11, 2019

More Information

Publications

• Yang H, Xiang B, Song Y, Zhang H, Zhao W, Zou D, Lv F, Bai O, Liu A, Li C, Tan Z, Wang W, Gui H, Novotny W, Huang J, Li Y. Zanubrutinib monotherapy for patients with relapsed or refractory non-germinal center diffuse large B-cell lymphoma: results from a phase II, single-arm, multicenter, study. American Society of Clinical Oncology. 2020

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT03145064
• Other Study ID Numbers: BGB-3111-207; CTR20170091
• First Posted: May 9, 2017
• Last Update Posted: Nov 8, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by BeiGene: Relapsed/refractory non-GCB type
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Zanubrutinib

Study Results

Participant Flow

Recruitment Details

This study was conducted at 11 centers in China, all of which enrolled participants. The first participant was dosed on 30 June 2017. Since the primary and secondary objectives were met and the analysis was complete, the sponsor ended the study on 03 September 2020 (Last patient last visit). As of the final database lock (15 October 2020), 41 participants were enrolled and treated with zanubrutinib.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 milligrams (mg) of zanubrutinib twice daily (BID).
Period Title: Overall Study
STARTED	41
Received At Least 1 Dose of Study Drug	41
COMPLETED	0
NOT COMPLETED	41

Baseline Characteristics

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
Overall Participants	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (12.45)
Sex: Female, Male (Count of Participants)
Female	16 39%
Male	25 61%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	41 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Eastern Cooperative Oncology Group Performance Status (Count of Participants)
Grade 0	10 24.4%
Grade 1	27 65.9%
Grade 2	4 9.8%
Hepatitis B Core Antibody (Count of Participants)
Positive	13 31.7%
Negative	28 68.3%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall response rate was defined as the percentage of participants achieving either a partial response (PR) or complete response (CR) as determined by investigator according to the 2014 modification of the International Working Group (IWG) in Non-Hodgkin's lymphoma (NHL) Criteria.
Time Frame	Up to approximately 23 months

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
Measure Participants	41
Number (95% Confidence Interval) [percentage of participants]	29.3 71.5%

2. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival was defined as the time from first dose of zanubrutinib until first documentation of progression (by IWG on NHL criteria) or death, whichever occurred first.
Time Frame	Up to 3 years and 2 months

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
Measure Participants	41
Median (95% Confidence Interval) [months]	2.8

3. Secondary Outcome

Title	Duration Of Response
Description	Duration of response was defined as the time from the date that the response criteria were first met to the date that progressive disease was objectively documented or death, whichever occurred first. Duration of response was summarized for responders (with a best overall response of CR or PR) only.
Time Frame	Up to 3 years and 2 months

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
Measure Participants	12
Median (95% Confidence Interval) [months]	4.5

4. Secondary Outcome

Title	Time To Response
Description	Time to response was defined as the time from the first dose of zanubrutinib to the documentation of first response. Time to response was summarized for responders (with a best overall response of CR or PR) only.
Time Frame	Up to 3 years and 2 months

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
Measure Participants	12
Median (Full Range) [months]	2.83

5. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	A treatment-emergent adverse event was defined as an adverse event that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation (Safety Follow-up Visit) or initiation of new anticancer therapy, whichever occurred first.
Time Frame	From the time of informed consent to 30 days after the last dose of study drug (approximately Up to 3 years and 2 months)

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 milligrams (mg) of zanubrutinib twice daily (BID).
Measure Participants	41
Participants with at least1 TEAE	36 87.8%
Serious TEAE	12 29.3%
TEAE leading to treatment discontinuation	4 9.8%

6. Other Pre-specified Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from first dose of zanubrutinib until death due to any cause.
Time Frame	Up to 3 years and 2 months

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set, which included all participants who received any dose of study drug, was the analysis set used for the efficacy and safety analyses.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
Measure Participants	41
Median (95% Confidence Interval) [months]	8.4

Adverse Events

Time Frame	From the time of informed consent to 30 days after the last dose of study drug (approximately up to 3 years and 2 months).
Adverse Event Reporting Description	A treatment-emergent adverse event was defined as an adverse event that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation (Safety Follow-up Visit) or initiation of new anticancer therapy, whichever occurred first.
Arm/Group Title	Zanubrutinib
Arm/Group Description	Participants received 160 mg of zanubrutinib BID.
All Cause Mortality
	Zanubrutinib
	Affected / at Risk (%)	# Events
Total	24/41 (58.5%)
Serious Adverse Events
	Zanubrutinib
	Affected / at Risk (%)	# Events
Total	12/41 (29.3%)
Ear and labyrinth disorders
Sudden hearing loss	1/41 (2.4%)
Eye disorders
Cataract	1/41 (2.4%)
Gastrointestinal disorders
Abdominal pain	1/41 (2.4%)
Intestinal obstruction	1/41 (2.4%)
General disorders
Death	2/41 (4.9%)
Gait inability	1/41 (2.4%)
Hepatobiliary disorders
Liver injury	1/41 (2.4%)
Infections and infestations
Pneumonia	3/41 (7.3%)
Abdominal infection	1/41 (2.4%)
Herpes zoster	1/41 (2.4%)
Otitis media chronic	1/41 (2.4%)
Urinary tract infection	1/41 (2.4%)
Metabolism and nutrition disorders
Metabolic acidosis	1/41 (2.4%)
Musculoskeletal and connective tissue disorders
Back pain	1/41 (2.4%)
Other (Not Including Serious) Adverse Events
	Zanubrutinib
	Affected / at Risk (%)	# Events
Total	34/41 (82.9%)
Blood and lymphatic system disorders
Anaemia	3/41 (7.3%)
Leukopenia	3/41 (7.3%)
Lymph node pain	2/41 (4.9%)
Ear and labyrinth disorders
Tinnitus	2/41 (4.9%)
Gastrointestinal disorders
Constipation	4/41 (9.8%)
Diarrhoea	4/41 (9.8%)
General disorders
Influenza like illness	2/41 (4.9%)
Malaise	2/41 (4.9%)
Oedema peripheral	2/41 (4.9%)
Infections and infestations
Urinary tract infection	4/41 (9.8%)
Pneumonia	3/41 (7.3%)
Upper respiratory tract infection	3/41 (7.3%)
Nasopharyngitis	2/41 (4.9%)
Skin infection	2/41 (4.9%)
Investigations
Neutrophil count decreased	9/41 (22%)
Platelet count decreased	5/41 (12.2%)
Blood creatinine increased	4/41 (9.8%)
Lymphocyte count decreased	4/41 (9.8%)
White blood cell count decreased	4/41 (9.8%)
Alanine aminotransferase increased	3/41 (7.3%)
Aspartate aminotransferase increased	3/41 (7.3%)
Weight decreased	3/41 (7.3%)
Blood alkaline phosphatase increased	2/41 (4.9%)
Blood bilirubin increased	2/41 (4.9%)
Metabolism and nutrition disorders
Hypokalaemia	7/41 (17.1%)
Decreased appetite	2/41 (4.9%)
Hyperglycaemia	2/41 (4.9%)
Hypertriglyceridaemia	2/41 (4.9%)
Hyperuricaemia	2/41 (4.9%)
Hypoalbuminaemia	2/41 (4.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/41 (7.3%)
Back pain	3/41 (7.3%)
Respiratory, thoracic and mediastinal disorders
Cough	4/41 (9.8%)
Skin and subcutaneous tissue disorders
Rash	4/41 (9.8%)
Rash maculo-papular	2/41 (4.9%)
Vascular disorders
Hypertension	4/41 (9.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

BeiGene has 18 months from the end of the study at all sites to publish overall study results. After the 1st multi-site publication or the expiration of publication period, Investigators are free to publish/present the results of the study. Investigators must submit all draft publications/presentations to us for review 60 days prior to the planned publication/presentation date. BeiGene may request deletion of its confidential information & may request a further delay to protect its IP rights.