Study to Evaluate Efficacy and Safety of BGB-3111 in Participants With Relapsed or Refractory Mantle Cell Lymphoma (MCL)

• Sponsor: BeiGene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03206970
• Collaborator: (none)
• Enrollment: 86
• Locations: 14
• Arm: 1
• Actual Duration (Months): 42.3
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study was to evaluate the efficacy of zanubrutinib in participants with centrally confirmed relapsed or refractory MCL.

Condition or Disease	Intervention/Treatment	Phase
Refractory Mantle Cell Lymphoma; Relapsed Mantle Cell Lymphoma	Drug: Zanubrutinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 86 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate Efficacy and Safety of BGB-3111, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Subjects With Relapsed or Refractory Mantle Cell Lymphoma (MCL)
• Actual Study Start Date: Mar 2, 2017
• Actual Primary Completion Date: Feb 15, 2019
• Actual Study Completion Date: Sep 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zanubrutinib Zanubrutinib (160 milligrams) administered orally twice daily	Drug: Zanubrutinib; Administered as specified in the treatment arm.; Other Names: BGB-3111

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) As Assessed By Independent Review Committee [Up to 1 year and 11 months]

   The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR). The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR.

Secondary Outcome Measures

1. Progression-free Survival [Up to 3 years and 6 months]

   Progression-free survival was defined as the time from the starting date of zanubrutinib to the date of first documentation of disease progression or death, whichever occurred first. Participants who did not have disease progression were censored at their last valid tumor assessment. A six-month progression-free survival rate was defined as no disease progression after treated with zanubrutinib for over six months (under control). The 95% confidence interval (CI) lower bound was 33.1 months while the upper bound could not be estimated.

2. Time To Response [Up to 3 years and 6 months]

   Time to response was defined as the time from treatment initiation to the first documentation of response.

3. Duration Of Response [Up to 3 years and 6 months]

   The duration of response was defined as the time from the date that the response criteria are first met to the date that Progressive Disease was objectively documented or death (whichever occurs first). Participants who did not have disease progression were censored at their last valid assessment.

4. ORR As Assessed By The Investigator [Up to 3 years and 6 months]

   The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a BOR of CR or PR. The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR. For this outcome measure, only investigator-assessed data are analyzed and reported because of the high rate of concordance between the Independent Review Committee and investigator assessments for the primary outcome measure of ORR.

5. Number Of Participants Experiencing Treatment -Emergent Adverse Events (AEs) [From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months)]

   An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. A treatment-emergent adverse event (TEAE) is defined as an AE 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 comes first.

6. Number Of Participants Experiencing AEs Leading To Treatment Discontinuation [From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months)]

   An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to the study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Diagnostic report had to include evidence for morphological and cyclin D1 or t (11; 14).

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

3. Measurable disease by computed tomography/magnetic resonance imaging.

4. Received prior regimens for MCL.

5. Documented failure to achieve any response, (stable disease or progressive disease during treatment) or documented progressive disease after response to the most recent treatment regimen.

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

7. Total bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome).

8. Life expectancy of > 4 months.

Key Exclusion Criteria:

1. Current or history of central nervous system lymphoma.

2. Prior exposure to a BTK inhibitor before enrollment.

3. Prior corticosteroids with anti-neoplastic intent within 7 days.

4. Major surgery within 4 weeks of screening.

5. Toxicity must have recovered from prior chemotherapy.

6. History of other active malignancies within 2 years of study entry.

7. Currently clinically significant active cardiovascular disease.

8. QT interval corrected with Fridericia's formula > 450 microseconds or other significant electrocardiogram abnormalities.

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

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beijing Cancer Hospital	Beijing	Beijing	China	100142
2	Peking Union Medical College Hospital	Beijing	Beijing	China
3	Fujian Medical University Union Hospital	Fuzhou	Fujian	China
4	Nanfang Hospital of Southern Medical University	Guangzhou	Guangdong	China
5	Henan Cancer Province	Zhengzhou	Henan	China
6	Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology	Wuhan	Hubei	China
7	Jiangsu Province Hospital	Nanjing	Jiangsu	China
8	The First Affiliated Hospital of Jinlin University	Chang chun	Jilin	China
9	Fudan University Cancer Center	Shanghai	Shanghai	China
10	West China Hospital, Sichuan University	Chengdu	Sichuan	China
11	Blood Diseases Hospital, Chinese Academy of Medical Sciences	Tianjin	Tianjin	China
12	Tianjin Cancer Hospital	Tianjin	Tianjin	China
13	The First Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China
14	Zhejiang Cancer Hospital	Hangzhou	Zhejiang	China

Sponsors and Collaborators

• BeiGene

Investigators

• Principal Investigator: Study Director, BeiGene

Study Documents (Full-Text)

• Study Protocol - Sep 6, 2018
• Statistical Analysis Plan - Apr 2, 2018

More Information

Publications

None provided.

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT03206970
• Other Study ID Numbers: BGB-3111-206; CTR20160888
• First Posted: Jul 2, 2017
• Last Update Posted: Nov 5, 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
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Zanubrutinib

Study Results

Participant Flow

Recruitment Details	This study was conducted at 14 study centers in China; 13 study centers enrolled participants. Once the primary and secondary objectives were met and the analysis was complete, sponsor ended the study on 08 September 2020 and transferred all participants remaining on treatment to long term extension study.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 milligrams [mg]) administered orally twice daily (BID) until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Period Title: Overall Study
STARTED	86
Received at Least 1 Dose of Study Drug	86
COMPLETED	0
NOT COMPLETED	86

Baseline Characteristics

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until Zanubrutinib (160 milligrams [mg]) administered orally twice daily (BID) until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Overall Participants	86
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.0 (8.18)
Age, Customized (Count of Participants)
< 65 years	64 74.4%
≥ 65 years	22 25.6%
Sex: Female, Male (Count of Participants)
Female	19 22.1%
Male	67 77.9%
Race/Ethnicity, Customized (Count of Participants)
Chinese	86 100%
Region of Enrollment (participants) [Number]
China	86 100%
Mantle Cell Lymphoma (MCL) Disease Stage at Study Entry (Count of Participants)
MCL Stage I	1 1.2%
MCL Stage II	7 8.1%
MCL Stage III	14 16.3%
MCL Stage IV	64 74.4%
Disease Status (Count of Participants)
Relapsed Disease	41 47.7%
Refractory Disease	45 52.3%
Eastern Cooperative Oncology Group Performance Status (Count of Participants)
Grade 0	60 69.8%
Grade 1	22 25.6%
Grade 2	4 4.7%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) As Assessed By Independent Review Committee
Description	The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR). The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR.
Time Frame	Up to 1 year and 11 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	86
Count of Participants [Participants]	72 83.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zanubrutinib
	Comments	A binomial exact test was performed to test against the null hypothesis H0: ORR=0.40 using the significant level of 0.025 (1-sided)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Binomial Exact Test
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson
	Estimated Value	83.7
	Confidence Interval	(2-Sided) 95%; 74.2 to 90.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival was defined as the time from the starting date of zanubrutinib to the date of first documentation of disease progression or death, whichever occurred first. Participants who did not have disease progression were censored at their last valid tumor assessment. A six-month progression-free survival rate was defined as no disease progression after treated with zanubrutinib for over six months (under control). The 95% confidence interval (CI) lower bound was 33.1 months while the upper bound could not be estimated.
Time Frame	Up to 3 years and 6 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	86
Median (95% Confidence Interval) [months]	33.0

3. Secondary Outcome

Title	Time To Response
Description	Time to response was defined as the time from treatment initiation to the first documentation of response.
Time Frame	Up to 3 years and 6 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	72
Mean (Standard Deviation) [months]	2.72 (0.105)

4. Secondary Outcome

Title	Duration Of Response
Description	The duration of response was defined as the time from the date that the response criteria are first met to the date that Progressive Disease was objectively documented or death (whichever occurs first). Participants who did not have disease progression were censored at their last valid assessment.
Time Frame	Up to 3 years and 6 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	86
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	ORR As Assessed By The Investigator
Description	The ORR was assessed in accordance with the 2014 modification of the International Working Group on non-Hodgkin Lymphoma Criteria. The ORR was defined as the percentage of participants achieving a BOR of CR or PR. The BOR was defined as the best response recorded from the start of zanubrutinib until data cut or start of new antineoplastic treatment. Participants with no post-baseline response assessment (due to any reason) were considered non-responders for BOR. For this outcome measure, only investigator-assessed data are analyzed and reported because of the high rate of concordance between the Independent Review Committee and investigator assessments for the primary outcome measure of ORR.
Time Frame	Up to 3 years and 6 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	86
Count of Participants [Participants]	72 83.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zanubrutinib
	Comments	A binomial exact test was performed to test against the null hypothesis H0: ORR=0.40 using the significant level of 0.025 (1-sided)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Binomial Exact Test
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson
	Estimated Value	83.7
	Confidence Interval	(2-Sided) 95%; 74.2 to 90.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number Of Participants Experiencing Treatment -Emergent Adverse Events (AEs)
Description	An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. A treatment-emergent adverse event (TEAE) is defined as an AE 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 comes first.
Time Frame	From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	86
Count of Participants [Participants]	83 96.5%

7. Secondary Outcome

Title	Number Of Participants Experiencing AEs Leading To Treatment Discontinuation
Description	An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to the study drug or not. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	From the initiation of study drug until 30 days after the last dose (Up to 3 years and 6 months)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any dose of study drug.

Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow up, or study termination by sponsor, which comes first.
Measure Participants	86
Count of Participants [Participants]	8 9.3%

Adverse Events

Time Frame	Day 1 through 3 years and 6 months
Adverse Event Reporting Description	Safety Analysis Set
Arm/Group Title	Zanubrutinib
Arm/Group Description	Zanubrutinib (160 mg) administered BID for over 3 years.
All Cause Mortality
	Zanubrutinib
	Affected / at Risk (%)	# Events
Total	7/86 (8.1%)
Serious Adverse Events
	Zanubrutinib
	Affected / at Risk (%)	# Events
Total	25/86 (29.1%)
Blood and lymphatic system disorders
Anaemia	1/86 (1.2%)
Bone marrow necrosis	1/86 (1.2%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/86 (1.2%)
Upper gastrointestinal haemorrhage	2/86 (2.3%)
General disorders
Death	2/86 (2.3%)
Infections and infestations
Bronchitis	1/86 (1.2%)
Infection	1/86 (1.2%)
Pneumonia	10/86 (11.6%)
Pneumonia fungal	1/86 (1.2%)
Pneumonia klebsiella	1/86 (1.2%)
Upper respiratory tract infection	1/86 (1.2%)
Urinary tract infection	1/86 (1.2%)
Injury, poisoning and procedural complications
Humerus fracture	1/86 (1.2%)
Road traffic accident	1/86 (1.2%)
Investigations
Neutrophil count decreased	1/86 (1.2%)
Platelet count decreased	2/86 (2.3%)
Nervous system disorders
Cerebral haemorrhage	1/86 (1.2%)
Cerebral ischaemia	1/86 (1.2%)
Transient ischaemic attack	1/86 (1.2%)
Renal and urinary disorders
Ureterolithiasis	1/86 (1.2%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	1/86 (1.2%)
Other (Not Including Serious) Adverse Events
	Zanubrutinib
	Affected / at Risk (%)	# Events
Total	82/86 (95.3%)
Blood and lymphatic system disorders
Anaemia	14/86 (16.3%)
Leukopenia	7/86 (8.1%)
Neutropenia	7/86 (8.1%)
Thrombocytopenia	8/86 (9.3%)
Gastrointestinal disorders
Abdominal pain	3/86 (3.5%)
Constipation	6/86 (7%)
Diarrhoea	14/86 (16.3%)
Toothache	6/86 (7%)
Upper gastrointestinal haemorrhage	3/86 (3.5%)
General disorders
Oedema peripheral	4/86 (4.7%)
Peripheral swelling	3/86 (3.5%)
Pyrexia	7/86 (8.1%)
Chest discomfort	3/86 (3.5%)
Infections and infestations
Asymptomatic bacteriuria	4/86 (4.7%)
Folliculitis	3/86 (3.5%)
Otitis media	4/86 (4.7%)
Pharyngitis	4/86 (4.7%)
Upper respiratory tract infection	33/86 (38.4%)
Urinary tract infection	10/86 (11.6%)
Viral upper respiratory tract infection	5/86 (5.8%)
Pneumonia	7/86 (8.1%)
Nasopharyngitis	5/86 (5.8%)
Investigations
Alanine aminotransferase increased	16/86 (18.6%)
Aspartate aminotransferase increased	9/86 (10.5%)
Blood bilirubin increased	4/86 (4.7%)
Blood creatinine increased	8/86 (9.3%)
Blood immunoglobulin G decreased	4/86 (4.7%)
Blood urine present	11/86 (12.8%)
Lymphocyte count decreased	5/86 (5.8%)
Neutrophil count decreased	39/86 (45.3%)
Platelet count decreased	28/86 (32.6%)
Weight decreased	4/86 (4.7%)
Weight increased	7/86 (8.1%)
White blood cell count decreased	29/86 (33.7%)
Metabolism and nutrition disorders
Hyperglycaemia	12/86 (14%)
Hyperuricaemia	12/86 (14%)
Hypoalbuminaemia	4/86 (4.7%)
Hypokalaemia	15/86 (17.4%)
Decreased appetite	3/86 (3.5%)
Hyperlipidaemia	3/86 (3.5%)
Musculoskeletal and connective tissue disorders
Pain in extremity	3/86 (3.5%)
Nervous system disorders
Headache	4/86 (4.7%)
Psychiatric disorders
Insomnia	5/86 (5.8%)
Renal and urinary disorders
Haematuria	6/86 (7%)
Respiratory, thoracic and mediastinal disorders
Cough	10/86 (11.6%)
Epistaxis	3/86 (3.5%)
Skin and subcutaneous tissue disorders
Haemorrhage subcutaneous	3/86 (3.5%)
Rash	31/86 (36%)
Vascular disorders
Hypertension	13/86 (15.1%)

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.