Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate Safety and Efficacy of BGB-3111, a Bruton's Tyrosine Kinase (BTK) Inhibitor in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

This was a single-arm, open-label, multi-center Phase 2 study in participants with histologically documented CLL/SLL who have relapsed after or refractory to ≥ 1 prior treatment regimen(s). The study is composed of an initial screening phase, a single-arm treatment phase, and a follow-up phase.

Study Overview

• Status: Completed
• Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia; Relapsed or Refractory Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Zanubrutinib

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100730
      • Peking Union Medical College Hospital
    • Beijing, Beijing, China, 100082
      • Peking University People's Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Fujian Medical University Union Hospital
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Nanfang Hospital
  • Guangxi
    • Nanning, Guangxi, China
      • The First Affiliated Hospital of Guangxi Medical University
  • Guangzhou
    • Guangdong, Guangzhou, China
      • Guangdong Provincial People's Hospital
  • Henan
    • Zhengzhou, Henan, China, 450008
      • Henan Cancer Hospital
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital of Tongji Medical College of HUST
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Jiangsu Province Hospital
    • Suzhou, Jiangsu, China, 215006
      • The First Affiliated Hospital Of Soochow University
  • Jinlin
    • Changchun, Jinlin, China, 130021
      • The First Affilliated Hospital of Jinlin University
  • Shanghai
    • Shanghai, Shanghai, China
      • Ruijin Hospital Shanghai JiaoTong University School of Medicine
  • Shanxi
    • Xi'an, Shanxi, China
      • The First Affiliated Hospital of Xi 'an Jiaotong University
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital of Sichuan University
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Tianjin Hematonosis Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • The First Affiliated Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Confirmed diagnosis with at least one criterion for treatment according to International workshop on chronic lymphocytic leukemia (IWCLL)
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
3. Measurable disease by contrast enhanced computerized tomography / magnetic resonance imaging (CT/MRI).
4. Previously treated with a minimum of 1 prior line of standard chemotherapy-containing regimen (with completion of ≥2 treatment cycles).
5. Documented failure to achieve at least partial response (PR) or documented disease progression after response to the most recent treatment regimen. Refractory disease is defined as treatment failure (stable disease, non-response, progressive disease [PD]) or disease progression within 6 months after the most recent prior therapy (Hallek et al, 2008).
6. Neutrophils ≥ 0.75 x 109/L independent of growth factor support within 7 days of study entry
7. Platelets ≥ 50 x 109/L, independent of growth factor support or transfusion within 7 days of study entry
8. Creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD])
9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN
10. Bilirubin ≤2 x ULN (unless documented Gilbert's syndrome)
11. International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 x ULN.
12. Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 6 months after transplant.
13. Life expectancy of >4 months
14. Echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥50%; (AHA, 2016)

Key Exclusion Criteria:

1. Current or history of central nervous system (CNS) lymphoma
2. Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor
3. Prior corticosteroids given in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days.
4. Major surgery within 4 weeks of screening
5. Not recovered from toxicity of any prior anti-cancer therapy to <Grade 1 (except for alopecia, absolute neutrophil count (ANC) and 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
8. QTcF >480 msecs based on Fridericia's formula 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. Active infection including infections requiring oral or intravenous anti-microbials
11. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction [PCR]).
12. Has received allogenic hematopoietic stem cell transplantation prior to enrollment
13. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the participants's safety, or put the study at risk
14. Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer
15. Known or clinically suspected Richter's transformation at the time of study entry
16. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zanubrutinib	Drug: Zanubrutinib; Zanubrutinib 160 mg (two - 80 mg white opaque capsules) taken by mouth (PO) twice a day (BID); Other Names: BGB-3111

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) by Independent Review Committee (IRC)	ORR is defined as the number of participants who achieve a best response of CR or, CRi, Nodular Partial Response, PR, and PR with Lymphocytosis as assessed by IRC per the modified IWCLL Guidelines in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL.	Up to 1 year and 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free	PFS is defined as the time from treatment initiation to first documentation of progression by International workshop on chronic lymphocytic leukemia (IWCLL) criteria/revised criteria for response for malignant lymphoma or death, whichever is earlier.	6, 12, 24, and 36 months
Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free	DOR is defined as the time from the date that response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever occurs first	6, 12, 24, and 36 months
Time to Response (TTR)	TTR is defined as the time from treatment initiation to first signs of response	Up to 3.5 years
Overall Response Rate as Determined by the Investigator	Overall response was defined as achieving a best overall response of CR, CRi, nodular partial response (nPR), PR, or partial response with lymphocytosis (PR-L).	up to 3.5 years
Number of Participants Experiencing Adverse Events (AEs)	An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. All AEs were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version [v] 4.03 2010). A treatment emergent adverse event (TEAE) is defined as an adverse event that has 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 or initiation of new anticancer therapy, whichever occurs first.	Up to 3.5 years

Collaborators and Investigators

• Sponsor: BeiGene

Publications and helpful links

General Publications

• Xu W, Yang S, Tam CS, Seymour JF, Zhou K, Opat S, Qiu L, Sun M, Wang T, Trotman J, Pan L, Gao S, Zhou J, Zhou D, Zhu J, Song Y, Hu J, Feng R, Huang H, Su D, Shi M, Li J. Zanubrutinib Monotherapy for Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. Adv Ther. 2022 Sep;39(9):4250-4265. doi: 10.1007/s12325-022-02238-7. Epub 2022 Jul 28.
• Xu W, Yang S, Zhou K, Pan L, Li Z, Zhou J, Gao S, Zhou D, Hu J, Feng R, Huang H, Ji M, Guo H, Huang J, Novotny W, Feng S, Li J. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study. J Hematol Oncol. 2020 May 11;13(1):48. doi: 10.1186/s13045-020-00884-4.

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2017
• Primary Completion (Actual): June 15, 2018
• Study Completion (Actual): September 10, 2020

Study Registration Dates

• First Submitted: June 29, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): October 4, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Chronic lymphocytic leukemia; Zanubrutinib; Bruton's tyrosine kinase; Relapsed/refractory
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Zanubrutinib
• Other Study ID Numbers: BGB-3111-205; CTR20160890 (Registry Identifier: ChinaDrugTrials.org)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No