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

Relapsed or Refractory Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03206918
• Other study ID #: BGB-3111-205
• Secondary ID: CTR20160890
• Status: Completed
• Phase: Phase 2
• Start date: March 9, 2017
• Est. completion date: September 10, 2020

Study information

• Verified date: September 2021
• Source: BeiGene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. completion date: September 10, 2020
• Est. primary completion date: June 15, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Relapsed or Refractory Chronic Lymphocytic Leukemia
• Relapsed or Refractory Small Lymphocytic Lymphoma

Intervention

Drug:
• Zanubrutinib
Zanubrutinib 160 mg (two - 80 mg white opaque capsules) taken by mouth (PO) twice a day (BID)

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Peking University People's Hospital	Beijing	Beijing
China	The First Affilliated Hospital of Jinlin University	Changchun	Jinlin
China	West China Hospital of Sichuan University	Chengdu	Sichuan
China	Fujian Medical University Union Hospital	Fuzhou	Fujian
China	Guangdong Provincial People's Hospital	Guangdong	Guangzhou
China	Nanfang Hospital	Guangzhou	Guangdong
China	The First Affiliated Hospital	Hangzhou	Zhejiang
China	Jiangsu Province Hospital	Nanjing	Jiangsu
China	The First Affiliated Hospital of Guangxi Medical University	Nanning	Guangxi
China	Ruijin Hospital Shanghai Jiaotong University School of Medicine	Shanghai	Shanghai
China	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu
China	Tianjin Hematonosis Hospital	Tianjin	Tianjin
China	Tongji Hospital of Tongji Medical College of HUST	Wuhan	Hubei
China	The First Affiliated Hospital of Xi 'an Jiaotong University	Xi'an	Shanxi
China	Henan Cancer Hospital	Zhengzhou	Henan

Sponsors (1)

Lead Sponsor	Collaborator
BeiGene

Country where clinical trial is conducted

China, 

References & Publications (1)

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: p — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Time to Response (TTR)	TTR is defined as the time from treatment initiation to first signs of response	Up to 3.5 years
Secondary	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
Secondary	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