Clinical trial NCT03145064: Study of BTK Inhibitor Zanubrutinib in Participants With Relapsed/Refractory Non-GCB Type Diffuse Large B Cell Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Relapsed/refractory non-GCB type
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-05-09
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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+
2. Men and women ≥ 18 years of age.
3. Eastern Cooperative Oncology Group performance status of 0-2.
4. Measurable disease was defined as at least 1 lymph node \> 1.5 centimeters in longest diameter and measurable in 2 perpendicular dimensions.
5. All participants must have provided fresh tumor biopsy or recent tumor tissue samples (within 2 years of study entry \[informed consent form signed\]).
6. Received at least one prior therapy for DLBCL that included anthracycline-based chemotherapy.
7. Participant not eligible for or refused intensive chemotherapy and hematopoietic stem cell transplant.
8. Documented failure to achieve at least partial response with, or documented disease progression after response to, the most recent treatment regimen.
9. Neutrophils ≥ 1 x 10\^9/liter (L) independent of growth factor support within 7 days of study entry.
10. Platelets ≥ 75 x 10\^9/L, independent of growth factor support or transfusion within 7 days of study entry.
11. Creatinine clearance of ≥ 30 milliliters/minute (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate).
12. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN).
13. Bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome), then up to 5 x ULN allowed.
14. Independent of erythropoietin support or transfusion within 7 days of first dose of study drug.
15. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN.
16. 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).
17. 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.
18. Life expectancy of \> 3 months.
19. 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.

Primary outcomes:
measure: Overall Response Rate
timeFrame: Up to approximately 23 months
Secondary outcomes:
measure: Progression-free Survival
timeFrame: Up to 3 years and 2 months
measure: Duration Of Response
timeFrame: Up to 3 years and 2 months
measure: Time To Response
timeFrame: Up to 3 years and 2 months
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the time of informed consent to 30 days after the last dose of study drug (approximately Up to 3 years and 2 months)
Other outcomes:
measure: Overall Survival
timeFrame: Up to 3 years and 2 months
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University Branch Shizi
state: Jiangsu
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Shanghai
country: China
facility: Rui Jin Hospital Shanghai Jiao Tong University School of Medicine
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Tianjin
country: China
facility: Institute of Hematology and Hospital of Blood Disease
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
Study officials:
affiliation: BeiGene
name: Study Director
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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