Clinical trial NCT03206918: Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia
Relapsed or Refractory Small Lymphocytic Lymphoma
Keywords: Bruton's tyrosine kinase
Chronic lymphocytic leukemia
Relapsed/refractory
Zanubrutinib
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-07-02
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response Rate (ORR) by Independent Review Committee (IRC)
timeFrame: Up to 1 year and 4 months
Secondary outcomes:
measure: Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free
timeFrame: 6, 12, 24, and 36 months
measure: Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free
timeFrame: 6, 12, 24, and 36 months
measure: Time to Response (TTR)
timeFrame: Up to 3.5 years
measure: Overall Response Rate as Determined by the Investigator
timeFrame: up to 3.5 years
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: Up to 3.5 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University Peoples Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology
state: Hubei
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
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
Study officials:
affiliation: BeiGene
name: Study Director
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.