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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Information provided by (Responsible Party):
BeiGene

Tracking Information
First Submitted Date  ICMJE January 9, 2015
First Posted Date  ICMJE January 21, 2015
Results First Submitted Date  ICMJE March 30, 2022
Results First Posted Date  ICMJE April 27, 2022
Last Update Posted Date April 28, 2022
Actual Study Start Date  ICMJE September 4, 2014
Actual Primary Completion Date March 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 30, 2022)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: January 15, 2015)
Number of participants with adverse events [ Time Frame: Screening to 28 days after last dose of study drug ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2022)
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2015)
  • Area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUClast) [ Time Frame: During first 2 weeks ]
  • Area under the plasma concentration-time curve from time 0 to infinity time (AUC∞) [ Time Frame: During first 2 weeks ]
  • Maximum plasma concentration (Cmax) [ Time Frame: During first 2 weeks ]
  • Time to reach maximum plasma concentration (tmax) [ Time Frame: During first 2 weeks ]
  • Terminal elimination half-life (t1/2) [ Time Frame: During first 2 weeks ]
  • BTK inhibition activity of BGB-3111 by measurement of free BTK [ Time Frame: During first 2 weeks ]
  • Tumor response [ Time Frame: Every 3 months from first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of the Safety and Pharmacokinetics of BGB-3111 in Subjects With B-Cell Lymphoid Malignancies
Official Title  ICMJE 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
Brief Summary This study evaluated the safety, tolerability, pharmacokinetic profile and efficacy of BGB-3111 in participants with B-cell lymphoid malignancies.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE B-cell Malignancies
Intervention  ICMJE Drug: Zanubrutinib
Oral administration by capsule
Other Names:
  • BGB-3111
  • Brukinsa
Study Arms  ICMJE 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
Intervention: Drug: Zanubrutinib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 30, 2022)
385
Original Estimated Enrollment  ICMJE
 (submitted: January 15, 2015)
75
Actual Study Completion Date  ICMJE March 31, 2021
Actual Primary Completion Date March 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Italy,   Korea, Republic of,   New Zealand,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02343120
Other Study ID Numbers  ICMJE BGB-3111-AU-003
2016-003364-39 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party BeiGene
Original Responsible Party Same as current
Current Study Sponsor  ICMJE BeiGene
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director BeiGene
PRS Account BeiGene
Verification Date April 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP