Clinical trial NCT02343120: Study of the Safety and Pharmacokinetics of BGB-3111 in Subjects With B-Cell Lymphoid Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: B-cell Malignancies
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2015-01-21
Enrollment: 385
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 study evaluated the safety, tolerability, pharmacokinetic profile and efficacy of BGB-3111 in participants with B-cell lymphoid malignancies.


Eligibility 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.

Primary outcomes:
measure: Part 1 and Part 2: Number of Participants With Adverse Events
timeFrame: Up to approximately 6 years and 7 months
measure: Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib
timeFrame: Month 9
Secondary outcomes:
measure: 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
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib
timeFrame: Week 2 Day 1 pre-dose and 24 hours
measure: Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib
timeFrame: Week 2 Day 1 pre-dose and 24 hours
measure: Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F)
timeFrame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
measure: Part 1 and Part 2: Overall Response Rate (ORR)
timeFrame: Up to 6 years and 7 months
measure: Part 1 and Part 2: Complete Response Rate (CRR)
timeFrame: Up to 6 years and 7 months
measure: Part 1 and Part 2: Partial Response (PR) or Better
timeFrame: Up to 6 years and 7 months
measure: Part 1 and Part 2: Progression-free Survival (PFS)
timeFrame: Up to 6 years and 7 months
measure: Part 1 and Part 2: Overall Survival (OS)
timeFrame: Up to 6 years and 7 months
measure: Part 1 and Part 2: Duration of Response (DOR)
timeFrame: Up to 6 years and 7 months
measure: Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy
timeFrame: Week 1 Day 1 (W1D1) predose, W1D1 4 hours, W1D2 24 hours, W1D3 predose, and W2D1 predose
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Centre
state: Arizona
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St George Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Parkville
country: Australia
facility: Peter MacCallum Cancer Centre, East Melbourne
state: Victoria
city: Parkville
country: Australia
facility: Melbourne Health
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Bologna
country: Italy
facility: Policlinico S.Orsola Malpighi, AOU di Bologna
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda
city: Busan
country: Korea, Republic of
facility: Dong-A University Medical Centre
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Auckland
country: New Zealand
facility: North Shore Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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
citation: 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.
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.
citation: 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.
citation: 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.