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

NCT02343120 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: BGB-3111-AU-0032016-003364-39
• Study Type: interventional
• Target: 385
• Locations: 6 countries
• Sites: 23

Brief Summary

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

Conditions

B-cell Malignancies

Outcome Measures

Primary Outcomes (2)

• 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

  Up to approximately 6 years and 7 months

• 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

  Month 9

Secondary Outcomes (16)

• 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

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

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

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

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

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

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

  Week 2 Day 1 pre-dose and 24 hours

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

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

Study Arms (1)

Zanubrutinib

EXPERIMENTAL

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

Interventions

Zanubrutinib DRUG

Oral administration by capsule

Also known as: BGB-3111, Brukinsa

Zanubrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• BeiGene: lead

Study Sites (23)

Banner MD Anderson Cancer Centre

Gilbert, Arizona, 85234, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic

Rochester, Minnesota, 55901, United States

Location

M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Concord Repatriation General Hospital

Concord, New South Wales, Australia

Location

St George Hospital

Sydney, New South Wales, Australia

Location

Westmead Hospital

Westmead, New South Wales, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, Australia

Location

Monash Health

Clayton, Victoria, Australia

Location

Austin Health

Heidelberg, Victoria, Australia

Location

St Vincent's Hospital

Melbourne, Victoria, Australia

Location

Peter MacCallum Cancer Centre, East Melbourne

Parkville, Victoria, 3050, Australia

Location

Melbourne Health

Parkville, Victoria, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Location

Policlinico S.Orsola Malpighi, AOU di Bologna

Bologna, Italy

Location

Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda

Milan, Italy

Location

North Shore Hospital

Auckland, New Zealand

Location

Dong-A University Medical Centre

Busan, South Korea

Location

Inje University Busan Paik Hospital

Busan, South Korea

Location

National Cancer Center

Goyang-si, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Derriford Hospital

Plymouth, Devon, United Kingdom

Location

Related Publications (9)

• 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.

  PMID: 31340982 BACKGROUND

• 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.

  PMID: 32698195 BACKGROUND

• 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

  BACKGROUND

• 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.

  PMID: 34915592 BACKGROUND

• 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.

  PMID: 39563886 DERIVED

• 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.

  PMID: 38502198 DERIVED

• 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.

  PMID: 35900694 DERIVED

• 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.

  PMID: 35390135 DERIVED

• 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.

  PMID: 34152395 DERIVED

MeSH Terms

Interventions

zanubrutinib

Results Point of Contact

• Title: Study Director
• Organization: BeiGene

clinicaltrials@beigene.com

1-877-828-5568

Study Officials

• Study Director

  BeiGene

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2015
• First Posted: January 21, 2015
• Study Start: September 4, 2014
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: April 28, 2022
• Results First Posted: April 27, 2022

Record last verified: 2022-04

Locations

US (4); AU (11); NZ (1); KR (4); IT (2); GB (1)