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B-cell MalignanciesPhase 1/2NCT02343120

Study of the Safety and Pharmacokinetics of BGB-3111 in Subjects With B-Cell Lymphoid Malignancies

A Phase 1/2 study testing Zanubrutinib in people with B-cell Malignancies, run by BeiGene at 23 sites in 6 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This study evaluated the safety, tolerability, pharmacokinetic profile and efficacy of BGB-3111 in participants with B-cell lymphoid malignancies. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
B-cell Malignancies
What is being tested?
Zanubrutinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
385 participants
Where
23 sitesin 6 countries
Study dates
4 Sep 2014to 31 Mar 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Aged ≥ 18 years, voluntarily consented to the study.
  • WHO classification defined B-lymphoid malignancy, with the exception of Burkitt lymphoma/leukemia, plasma cell myeloma, acute lymphoblastic leukemia, lymphoblastic lymphoma, and plasmablastic lymphoma.
  • Requirement for treatment in the opinion of the investigator.
  • Disease which has relapsed, or is refractory, following at least one line of therapy, with no therapy of higher priority available.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  • Adequate hematologic function, as defined by neutrophils ≥ 1.0 x 10^9/L and platelets ≥ 50 x 10^9/L; participants with neutrophils < 1.0 x 10^9/L due to marrow infiltration are allowed to receive growth factors to bring pre-treatment neutrophils to ≥ 1.0 x 10^9/L.
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  • Adequate renal function, as defined by creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24 hour urine collection).
  • Adequate liver function, as defined by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), and bilirubin ≤ 1.5 x ULN (unless documented Gilbert's syndrome).
  • International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN.
  • Female participants of childbearing potential and non-sterile males must practice at least one of the following methods of birth control with partner(s) throughout the study and for 90 days after discontinuing study drug: total abstinence from sexual intercourse, double-barrier contraception, IUD or hormonal contraceptive initiated at least 3 months prior to first dose of study drug.
  • Male participants must not donate sperm from initial study drug administration, until 90 days after drug discontinuation.

Who cannot join

  • Current central nervous system (CNS) involvement by disease
  • Current histologically transformed disease.
  • Prior Bruton's tyrosine kinase (BTK) inhibitor treatment.
  • Allogeneic stem cell transplantation within 6 months, or has active graft-versus-host disease (GVHD) requiring ongoing immunosuppression.
  • Receipt of the following treatment prior to first dose of zanubrutinib: corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 2 weeks, monoclonal antibody within 4 weeks.
  • Not recovered from toxicity of any prior chemotherapy to grade ≤ 1.
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  • 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.
  • Uncontrolled systemic infection requiring parenteral anti-microbial therapy.
  • Major surgery in the past 4 weeks.
  • Known HIV, or active hepatitis B or hepatitis C infection (detected positive by PCR).
  • Cardiovascular disease resulting in New York Heart Association function status of ≥ 3.
  • Significant active renal, neurologic, psychiatric, hepatic or endocrinologic disease that in the investigator's opinion would adversely impact on his/her participating in the study.
  • Inability to comply with study procedures.
  • On medications which are cytochrome P450 (CYP) 3A inhibitors.

Trial locations and contacts

23 sites in 6 countries.

23 sites in 6 countries

Australia11 sites

  • Princess Alexandra Hospital

    Brisbane, Queensland

  • Monash Health

    Clayton, Victoria

  • Concord Repatriation General Hospital

    Concord, New South Wales

  • Austin Health

    Heidelberg, Victoria

  • Royal Hobart Hospital

    Hobart, Tasmania

  • St Vincent's Hospital

    Melbourne, Victoria

  • Sir Charles Gairdner Hospital

    Nedlands, Western Australia

  • Peter MacCallum Cancer Centre, East Melbourne

    Parkville, Victoria, 3050

  • Melbourne Health

    Parkville, Victoria

  • St George Hospital

    Sydney, New South Wales

  • Westmead Hospital

    Westmead, New South Wales

Other trials in Australia

United States4 sites

  • University of Michigan

    Ann Arbor, Michigan, 48109

  • Banner MD Anderson Cancer Centre

    Gilbert, Arizona, 85234

  • M.D. Anderson Cancer Center

    Houston, Texas, 77030

  • Mayo Clinic

    Rochester, Minnesota, 55901

Other trials in United States

South Korea4 sites

  • Dong-A University Medical Centre

    Busan

  • Inje University Busan Paik Hospital

    Busan

  • National Cancer Center

    Goyang-si

  • Samsung Medical Center

    Seoul

Other trials in South Korea

Italy2 sites

  • Policlinico S.Orsola Malpighi, AOU di Bologna

    Bologna

  • Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda

    Milan

Other trials in Italy

New Zealand1 site

  • North Shore Hospital

    Auckland

Other trials in New Zealand

United Kingdom1 site

  • Derriford Hospital

    Plymouth, Devon

Other trials in United Kingdom

About this study

Official title: A Phase I/II, Open-Label, Multiple-Dose, Dose Escalation and Expansion Study to Investigate the Safety and Pharmacokinetics of the BTK Inhibitor BGB-3111 in Subjects With B-Cell Lymphoid Malignancies

This study evaluated the safety, tolerability, pharmacokinetic profile and efficacy of BGB-3111 in participants with B-cell lymphoid malignancies.

Being tested
Zanubrutinib

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ZanubrutinibDrug

    Also called BGB-3111, Brukinsa

    Oral administration by capsule

Study groups in NCT02343120
Study groupRoleWhat they receive
ZanubrutinibExperimentalParticipants were administered up to 320 mg total daily dose of zanubrutinib until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Receives: Drug: Zanubrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Part 1 and Part 2: Number of Participants With Adverse Events

    Number of participants with adverse events and serious adverse events, including clinically relevant physical examinations and laboratory measurements

    Measured: Up to approximately 6 years and 7 months

  2. Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib

    RP2D for zanubrutinib was the maximum tolerated dose (MTD) or less, which was determined by testing increasing doses up to 320 mg QD

    Measured: Month 9

Secondary outcomes (16)

  1. Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  2. Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  3. Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  4. Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib

    Measured: Week 2 Day 1 pre-dose and 24 hours

  5. Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  6. Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib

    Measured: Week 2 Day 1 pre-dose and 24 hours

  7. Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  8. Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  9. Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F)

    Measured: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours

  10. Part 1 and Part 2: Overall Response Rate (ORR)

    ORR is defined as the percentage of participants with partial or complete response (CR), as assessed by the investigator. For CLL/SLL, ORR includes partial response (PR) with lymphocytosis (PR-L) or better (includes PR-L, PR, nodular PR or nPR and CR with incomplete marrow recovery or CRi) and for MW, ORR includes minor response or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).

    Measured: Up to 6 years and 7 months

  11. Part 1 and Part 2: Complete Response Rate (CRR)

    CRR is defined as the percentage of participants who achieve a complete response, as assessed by the investigator. For CLL/SLL, CRR includes CRi or better. For WM, CRR includes very good partial response (VGPR) or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).

    Measured: Up to 6 years and 7 months

  12. Part 1 and Part 2: Partial Response (PR) or Better

    PR or better is defined as the percentage of participants who achieve a partial response or better, as assessed by the investigator. For CLL/SLL, includes PR, nPR, CRi, CR and for WM includes PR, VGPR, and CR. Efficacy results are reported for the B-cell malignancy subtypes chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Waldenström macroglobulinemia (WM).

    Measured: Up to 6 years and 7 months

  13. Part 1 and Part 2: Progression-free Survival (PFS)

    PFS is defined as the time from the first dose date of study drug to the date of the earliest occurrence of progressive disease or death due to any cause, whichever occurs first. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).

    Measured: Up to 6 years and 7 months

  14. Part 1 and Part 2: Overall Survival (OS)

    OS is defined as the time from the date of the first dose to death due to any cause. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).

    Measured: Up to 6 years and 7 months

  15. Part 1 and Part 2: Duration of Response (DOR)

    DOR for responders is defined as time from the date of the earliest qualifying response to the date of progressive disease or death for any cause, whichever occurs earlier. Efficacy results are reported for responders (defined as PR or better, except CLL/SLL and WM) in each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; PR with lymphocytosis or better), Waldenstrom macroglobulinemia (WM; minor response or better), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).

    Measured: Up to 6 years and 7 months

  16. Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy

    Number of participants with greater than 75% BTK occupancy of zanubrutinib in peripheral blood mononuclear cells (PBMCs)

    Measured: Week 1 Day 1 (W1D1) predose, W1D1 4 hours, W1D2 24 hours, W1D3 predose, and W2D1 predose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jan 2015 (estimated)
  2. Study start4 Sep 2014
  3. Primary completion31 Mar 2021
  4. Study completion31 Mar 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
385 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02343120
Sponsor's protocol ID
BGB-3111-AU-003
Other IDs
2016-003364-39, 2016
Status last verified
Apr 2022
First submitted
9 Jan 2015
Last updated
28 Apr 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, Harrup R, Johnston PB, Marlton P, Munoz J, Seymour JF, Simpson D, Tedeschi A, Elstrom R, Yu Y, Tang Z, Han L, Huang J, Novotny W, Wang L, Roberts AW. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019 Sep 12;134(11):851-859. doi: 10.1182/blood.2019001160. Epub 2019 Jul 24.

    PubMed 31340982

  • Trotman J, Opat S, Gottlieb D, Simpson D, Marlton P, Cull G, Munoz J, Tedeschi A, Roberts AW, Seymour JF, Atwal SK, Yu Y, Novotny W, Holmgren E, Tan Z, Hilger JD, Huang J, Tam CS. Zanubrutinib for the treatment of patients with Waldenstrom macroglobulinemia: 3 years of follow-up. Blood. 2020 Oct 29;136(18):2027-2037. doi: 10.1182/blood.2020006449.

    PubMed 32698195

  • C.S. Tam M. Wang D. Simpson S. Opat G. Cull J. Munoz T.J. Phillips W. Kim S. Atwal R. Wei J. Huang R. Elstrom J. Trotman. UPDATED SAFETY AND EFFICACY DATA IN THE PHASE 1 TRIAL OF PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) TREATED WITH BRUTON TYROSINE KINASE (BTK) INHIBITOR ZANUBRUTINIB (BGB-3111). Hematological Oncology. 2019; 37(S2) DOI: https://doi.org/10.1002/hon.55_2630

  • Cull G, Burger JA, Opat S, Gottlieb D, Verner E, Trotman J, Marlton P, Munoz J, Johnston P, Simpson D, Stern JC, Prathikanti R, Wu K, Novotny W, Huang J, Tam CS. Zanubrutinib for treatment-naive and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study. Br J Haematol. 2022 Mar;196(5):1209-1218. doi: 10.1111/bjh.17994. Epub 2021 Dec 16.

    PubMed 34915592

  • Alfaifi A, Bahashwan S, Alsaadi M, Ageel AH, Ahmed HH, Fatima K, Malhan H, Qadri I, Almehdar H. Advancements in B-Cell Non-Hodgkin's Lymphoma: From Signaling Pathways to Targeted Therapies. Adv Hematol. 2024 Nov 12;2024:5948170. doi: 10.1155/2024/5948170. eCollection 2024.

    PubMed 39563886

  • Liu Y, Ma X, Wu X, Hou X, Jin W, Fu L, Xun X, Yu Y, Shen Z. Zanubrutinib is effective in non-germinal-center B-cell-like diffuse large B-cell lymphoma with mutated CD79B, high TCL1A expression, or over- expressed MYC/BCL-2. Leuk Lymphoma. 2024 Aug;65(8):1079-1089. doi: 10.1080/10428194.2024.2343779. Epub 2024 May 22.

    PubMed 38775302

  • Moslehi JJ, Furman RR, Tam CS, Salem JE, Flowers CR, Cohen A, Zhang M, Zhang J, Chen L, Ma H, Brown JR. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024 May 28;8(10):2478-2490. doi: 10.1182/bloodadvances.2023011641.

    PubMed 38502198

  • 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.

    PubMed 35900694

  • Phillips T, Chan H, Tam CS, Tedeschi A, Johnston P, Oh SY, Opat S, Eom HS, Allewelt H, Stern JC, Tan Z, Novotny W, Huang J, Trotman J. Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Adv. 2022 Jun 14;6(11):3472-3479. doi: 10.1182/bloodadvances.2021006083.

    PubMed 35390135

  • Tam CS, Opat S, Simpson D, Cull G, Munoz J, Phillips TJ, Kim WS, Rule S, Atwal SK, Wei R, Novotny W, Huang J, Wang M, Trotman J. Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2021 Jun 22;5(12):2577-2585. doi: 10.1182/bloodadvances.2020004074.

    PubMed 34152395

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Zanubrutinib in people with B-cell Malignancies, run by BeiGene at 23 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 23 sites in Australia, United States, South Korea, Italy, New Zealand and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part 1 and Part 2: Number of Participants With Adverse Events (time frame: Up to approximately 6 years and 7 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02343120, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2022.

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