A Phase 3 Study of Zanubrutinib (BGB-3111) Compared with Bendamustine plus Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BeOne Medicines AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 May 2018 → ongoing

Decision date (initial)

2024-06-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BeiGene, Ltd.

External identifiers

EU CT number

2023-509976-40-00

EudraCT number

2017-001551-31

ClinicalTrials.gov

NCT03336333

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

To compare efficacy between treatment groups in Cohort 1, as measured by progression-free survival determined by independent central review

Secondary objectives 9

1. Compare efficacy between Arms A and B, measured by: - Overall response rate (ORR), - Duration of Response (DOR), - Overall survival (OS), - Progression-free survival (PFS), - Patient-reported outcomes
2. Compare efficacy between Arms A and B in pooled Cohort 1/1a patients from Chinese sites, measured by: - PFS, ORR, DOR
3. To evaluate efficacy in Cohort 2 (patients with del17p) for Arm C, measured by: - ORR, PFS, DOR
4. To evaluate efficacy in Cohort 3 for Arm D, measured by: - ORR, PFS, DOR, Assess undetectable minimal residual disease at 10^-4 sensitivity at various timepoints
5. Compare safety between the treatment groups in Cohort 1
6. Compare safety between the treatment groups in pooled Cohort 1/1a patients from Chinese sites
7. Summarize safety in Cohort 2 (Arm C), Cohort 3 (Arm D)
8. Evaluate zanubrutinib pharmacokinetics in Arms A and C
9. Evaluate pharmacokinetics of zanubrutinib and venetoclax (Arm D)

Conditions and MedDRA coding

Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Patients must be unsuitable for treatment with FCR defined as: ≥ 65 years of age at the time of informed consent, OR 18 - 64 years of age and have one or more of the following factors: a. Cumulative Illness Rating Scale (CIRS) score > 6. A CIRS is not required, it may be used to meet this inclusion requirement. b. Creatinine clearance < 70 mL/min c. History of previous serious infection or multiple infections in the past 2 years NOTE: For Arm D only: -Patients without del17p: must meet one of the above criteria for unsuitability for FCR. -Patients with del17p/TP53 variant: central laboratory confirmation of del17p-positive CLL/SLL will fulfill the requirement for unsuitability for FCR. For patients with a central FISH test result other than del17ppositive CLL/SLL, a local laboratory test result documenting pathogenicTP53 variant may meet this requirement (refer to Appendix 18 of PA5).
2. Confirmed diagnosis of CD20-positive CLL or SLL that meets the CLL criteria (Hallek et al, 2008)
3. Measurable disease by CT/MRI. Measurable disease is defined as ≥ 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters
4. CLL/SLL requiring treatment
5. ECOG performance status of 0, 1, or 2
6. Life expectancy ≥ 6 months
7. Adequate bone marrow function
8. Patient must have adequate organ function
9. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib, ≥ 30 days after the last dose of venetoclax,3 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer
10. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or 3 months after the last dose of bendamustine whichever is longer
11. Ability to provide written informed consent and can understand and comply with the requirements of the study
12. Must have FISH results from the study-specified central laboratory confirming the presence or absence of del17p.a. For Arm D only: Patients must have a central laboratory FISH test for del17p performed. A patient with a result other than "with del17p" may be eligible for enrollment into the del17p-positive subset only if the patient has a pathogenic TP53 variant previously documented per local laboratory test meeting the criteria specified in Appendix 18.

Exclusion criteria 22

1. Previous systemic treatment for CLL/SLL
2. Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids must be fully tapered off/stopped at least 5 days before day of first study drug
3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
4. Clinically significant cardiovascular disease
5. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer
6. History of severe bleeding disorder
7. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
8. Severe or debilitating pulmonary disease
9. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
10. Active fungal, bacterial and/or viral infection requiring systemic therapy
11. Known central nervous system involvement by leukemia or lymphoma
12. Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs
13. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection
14. Major surgery within 4 weeks of the first dose of study drug
15. Pregnant or lactating women
16. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
17. Ongoing alcohol or drug addiction
18. Hypersensitivity to zanubrutinib, bendamustine, rituximab or venetoclax (as applicable) or any of the other ingredients of the applicable study drugs
19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
20. Concurrent participation in another therapeutic clinical study
21. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura)
22. Arm D only: requires ongoing treatment with warfarin or warfarin derivatives

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is PFS in Cohort 1 (patients without del17p) determined by central review using the iwCLL guidelines with modification for treatment-related lymphocytosis in patients with CLL and the Revised Criteria for Response for Malignant Lymphoma in patients with SLL, and defined as the time from randomization to disease progression or death

Secondary endpoints 17

1. ORR in Cohort 1 defined as the proportion of patients who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by independent central review and by investigator assessment
2. OS in Cohort 1 defined as the time from randomization to the date of death due to any reason
3. Duration of response in Cohort 1 determined by central review and by investigator assessment using the iwCLL criteria with modification for treatment-related lymphocytosis (in patients with CLL) and the Lugano Classification for NHL (in patients with SLL), and defined as the time from the date that criteria for response are first met to disease progression or death
4. PFS in Cohort 1 determined by investigator assessment
5. PROs in Cohort 1 measured by the European Quality of Life 5 Dimensions 5 Levels Health Questionnaire (EQ-5D-5L) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
6. PFS in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment
7. ORR in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment
8. Duration of response in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment
9. ORR in Cohort 2 (patients with del17p), Arm C, determined by independent central review and investigator review
10. PFS in Cohort 2 (Arm C), determined by independent central review and investigator review
11. Duration of response in Cohort 2 (Arm C), determined by independent central review and investigator review
12. ORR in Cohort 3, Arm D, determined by investigator review
13. PFS in Cohort 3 (Arm D), determined by investigator review
14. Duration of response in Cohort 3 (Arm D), determined by investigator review
15. Cohort 3 (Arm D) only: undetectable MRD4 rate
16. Safety parameters, including AEs, SAEs, clinical laboratory tests, physical examination, and vital signs
17. Pharmacokinetic parameters of zanubrutinib such as apparent clearance of the drug from plasma (CL/F) and AUC from time 0 to 12 hours postdose (AUC0-12) for Arms A, C, and D

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BeOne Medicines AG

Sponsor organisation

BeOne Medicines AG

Address

Aeschengraben 27

City

Basel

Postcode

4051

Country

Switzerland

Scientific contact point

Organisation

BeOne Medicines AG

Contact name

BeOne Medical Officer

Public contact point

Organisation

BeOne Medicines AG

Contact name

BeOne Medical Officer

Third parties 13

Locations

8 EU/EEA countries · 58 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 95 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications