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

• ClinicalTrials.gov Identifier: NCT02343120
• Recruitment Status: Completed
• First Posted: January 21, 2015
• Results First Posted: April 27, 2022
• Last Update Posted: April 28, 2022
• Sponsor: BeiGene
• Information provided by (Responsible Party): BeiGene

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
B-cell Malignancies	Drug: Zanubrutinib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 385 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 4, 2014
• Actual Primary Completion Date: March 31, 2021
• Actual Study Completion Date: March 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Zanubrutinib; Participants 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	Drug: Zanubrutinib; Oral administration by capsule; Other Names: BGB-3111; Brukinsa

Outcome Measures

Primary Outcome Measures :

1. Part 1 and Part 2: Number of Participants With Adverse Events [ Time Frame: Up to approximately 6 years and 7 months ]
   Number of participants with adverse events and serious adverse events, including clinically relevant physical examinations and laboratory measurements
2. Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib [ Time Frame: Month 9 ]
   RP2D for zanubrutinib was the maximum tolerated dose (MTD) or less, which was determined by testing increasing doses up to 320 mg QD

Secondary Outcome Measures :

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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Week 2 Day 1 pre-dose and 24 hours ]
5. Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib [ Time Frame: 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 [ Time Frame: Week 2 Day 1 pre-dose and 24 hours ]
7. Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Up to 6 years and 7 months ]
    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).
11. Part 1 and Part 2: Complete Response Rate (CRR) [ Time Frame: Up to 6 years and 7 months ]
    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).
12. Part 1 and Part 2: Partial Response (PR) or Better [ Time Frame: Up to 6 years and 7 months ]
    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).
13. Part 1 and Part 2: Progression-free Survival (PFS) [ Time Frame: Up to 6 years and 7 months ]
    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).
14. Part 1 and Part 2: Overall Survival (OS) [ Time Frame: Up to 6 years and 7 months ]
    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).
15. Part 1 and Part 2: Duration of Response (DOR) [ Time Frame: Up to 6 years and 7 months ]
    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).
16. Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy [ Time Frame: Week 1 Day 1 (W1D1) predose, W1D1 4 hours, W1D2 24 hours, W1D3 predose, and W2D1 predose ]
    Number of participants with greater than 75% BTK occupancy of zanubrutinib in peripheral blood mononuclear cells (PBMCs)

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Aged ≥ 18 years, voluntarily consented to the study.
2. WHO classification defined B-lymphoid malignancy, with the exception of Burkitt lymphoma/leukemia, plasma cell myeloma, acute lymphoblastic leukemia, lymphoblastic lymphoma, and plasmablastic lymphoma.
3. Requirement for treatment in the opinion of the investigator.
4. Disease which has relapsed, or is refractory, following at least one line of therapy, with no therapy of higher priority available.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. 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.
7. 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).
8. 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).
9. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN.
10. 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.
11. Male participants must not donate sperm from initial study drug administration, until 90 days after drug discontinuation.

Exclusion Criteria:

1. Current central nervous system (CNS) involvement by disease
2. Current histologically transformed disease.
3. Prior Bruton's tyrosine kinase (BTK) inhibitor treatment.
4. Allogeneic stem cell transplantation within 6 months, or has active graft-versus-host disease (GVHD) requiring ongoing immunosuppression.
5. 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.
6. Not recovered from toxicity of any prior chemotherapy to grade ≤ 1.
7. 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.
8. Uncontrolled systemic infection requiring parenteral anti-microbial therapy.
9. Major surgery in the past 4 weeks.
10. Known HIV, or active hepatitis B or hepatitis C infection (detected positive by PCR).
11. Cardiovascular disease resulting in New York Heart Association function status of ≥ 3.
12. 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.
13. Inability to comply with study procedures.
14. On medications which are cytochrome P450 (CYP) 3A inhibitors.

Contacts and Locations

Locations

United States, Arizona

Banner MD Anderson Cancer Centre

Gilbert, Arizona, United States, 85234

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55901

United States, Texas

M.D. Anderson Cancer Center

Houston, Texas, United States, 77030

Australia, New South Wales

Concord Repatriation General Hospital

Concord, New South Wales, Australia

St George Hospital

Sydney, New South Wales, Australia

Westmead Hospital

Westmead, New South Wales, Australia

Australia, Queensland

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Australia, Tasmania

Royal Hobart Hospital

Hobart, Tasmania, Australia

Australia, Victoria

Monash Health

Clayton, Victoria, Australia

Austin Health

Heidelberg, Victoria, Australia

St Vincent's Hospital

Melbourne, Victoria, Australia

Peter MacCallum Cancer Centre, East Melbourne

Parkville, Victoria, Australia, 3050

Melbourne Health

Parkville, Victoria, Australia

Australia, Western Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Italy

Policlinico S.Orsola Malpighi, AOU di Bologna

Bologna, Italy

Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda

Milano, Italy

Korea, Republic of

Dong-A University Medical Centre

Busan, Korea, Republic of

Inje University Busan Paik Hospital

Busan, Korea, Republic of

National Cancer Center

Goyang-si, Korea, Republic of

Samsung Medical Center

Seoul, Korea, Republic of

New Zealand

North Shore Hospital

Auckland, New Zealand

United Kingdom

Derriford Hospital

Plymouth, Devon, United Kingdom

Sponsors and Collaborators

BeiGene

Investigators

• Study Director: Study Director; BeiGene

  Study Documents (Full-Text)

Documents provided by BeiGene:

Study Protocol  [PDF] September 25, 2018

Statistical Analysis Plan  [PDF] October 19, 2018

More Information

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.

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. Erratum In: Blood. 2021 Feb 25;137(8):1131.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT02343120
• Other Study ID Numbers: BGB-3111-AU-003; 2016-003364-39 ( EudraCT Number )
• First Posted: January 21, 2015
• Results First Posted: April 27, 2022
• Last Update Posted: April 28, 2022
• Last Verified: April 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms; Zanubrutinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents