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A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies

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ClinicalTrials.gov Identifier: NCT05006716
Recruitment Status : Recruiting
First Posted : August 16, 2021
Last Update Posted : April 3, 2024
Sponsor:
Information provided by (Responsible Party):
BeiGene

Study Description
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Brief Summary:
Study consists of two main parts to explore BGB-16673 recommended dosing, a Phase 1 monotherapy dose finding comprised of monotherapy dose escalation and monotherapy safety expansion of selected doses, and a Phase 2 (expansion cohorts)

Condition or disease Intervention/treatment Phase
B-cell Malignancy Marginal Zone Lymphoma Follicular Lymphoma Non-Hodgkin Lymphoma Waldenström Macroglobulinemia Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Mantle Cell Lymphoma Diffuse Large B Cell Lymphoma Drug: BGB-16673 Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 466 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Open-Label, Dose-Escalation and -Expansion Study of the Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 in Patients With B-Cell Malignancies
Actual Study Start Date : September 13, 2021
Estimated Primary Completion Date : September 30, 2024
Estimated Study Completion Date : September 30, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1a (Monotherapy Dose Escalation)
Dose escalation in selected R/R B-Cell malignancies to inform safety, tolerability and MTD.
 Drug: BGB-16673
Orally administered
Experimental: Part 1b (Monotherapy Safety Expansion)
Additional participants with selected R/R B-Cell malignancies will be enrolled at selected doses to help inform the selection of the recommended phase two dose (RP2D).
 Drug: BGB-16673
Orally administered
Experimental: Part 1c (Additional Monotherapy Safety Expansion)
After RP2D is determined, additional safety data will be collected to confirm RP2D for participants with selected B-cell malignancies not being evaluated in Part 2
 Drug: BGB-16673
Orally administered
Experimental: Part 2 (Monotherapy Expansion)
The totality of the data from Part 1a, Part 1b, and Part 1c will be used to further evaluate the safety and efficacy of BGB-16673 at the recommended dose(s) for Phase 2 expansion in specific histologies.
 Drug: BGB-16673
Orally administered


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) with adverse events leading to discontinuation, and Adverse Events (AEs) graded according NCI-CTCAE V5. [ Time Frame: approximately 3 years ]
    TEAE is defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of the first dose of the study drug and up to 30 days after the last dose of study treatment or the initiation of a new anticancer therapy, whichever is earlier

  2. Recommended Phase 2 Dose (RP2D) of BGB-16673 [ Time Frame: approximately 3 years ]
    RP2D is the recommended dose for further evaluation in Part 2, determined based on the totality of the available clinical safety, clinical efficacy, pharmacokinetics (PK), and pharmacodynamic data in Part 1.

  3. Maximum Tolerated Dose (MTD) of BGB-16673 [ Time Frame: approximately 3 years ]
    determined by the sponsor based on the Safety Monitoring Committee's recommendation considering the totality of the available clinical safety, clinical efficacy, pharmacokinetics (PK), and pharmacodynamic data

  4. Phase 2: Overall response rate (ORR) [ Time Frame: approximately 3 years ]
    Cohort specific ORRs based on best overall response of partial response (PR) or better as assessed by Independent Review Committee (IRC) for prticipants in cohorts 1 and 2; by investigator for other cohorts.


Secondary Outcome Measures :
  1. Single Dose Maximum observed plasma concentration (Cmax) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  2. Single Dose Minimum observed plasma concentration (Cmin) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  3. Single Dose Time to reach Cmax (tmax) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  4. Single Dose Time to reach half of Cmax (T1/2) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  5. Single Dose Area under the plasma concentration-time curve (AUC) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  6. Single Dose apparent total clearance of drug from plasma after oral administration (CL/F) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  7. Single Dose apparent volume of distribution (Vz/F) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  8. Single Dose accumulation ratios of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  9. Steady State Maximum observed plasma concentration (Cmax) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  10. Steady State minimum observed plasma concentration (Cmin) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  11. Steady State Time to reach Cmax (tmax) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  12. Steady State Time to reach half of Cmax (T1/2) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  13. Steady State Area under the plasma concentration-time curve (AUC) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  14. Steady State apparent total clearance of drug from plasma after oral administration (CL/F) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  15. Steady State apparent volume of distribution (Vz/F) of BGB-16673 [ Time Frame: Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  16. Bruton's tyrosine kinase (BTK) protein degradation in peripheral blood after BGB-16673 monotherapy [ Time Frame: Day 1 pre-dose and 8 hours post-dose (approximately 2 years) ]
    Collected for both Part 1 and Part 2

  17. Phase 1: Overall response rate (ORR) [ Time Frame: approximately 3 years ]
    defined as the proportion of participants whose best overall response is better than stable disease.

  18. Phase 1: Number of Waldenström Macroglobulinemia (WM) Participants with major response rate (MRR) [ Time Frame: approximately 3 years ]
    MRR is defined as the proportion of participants whose best overall response (BOR) is partial response (PR) or better (PR, very good partial response (VGPR), or complete response (CR)).

  19. Phase 2: Duration of Response (DOR) [ Time Frame: approximately 3 years ]
    DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first as assessed by the investigator and the IRC.

  20. Phase 2: Time to Response (TTR) [ Time Frame: approximately 3 years ]
    TTR is defined as the time from study treatment start to date of the earliest qualifying response (partial response or better), as assessed by IRC and the investigator

  21. Phase 2: Progression- Free Survival (PFS) [ Time Frame: approximately 3 years ]
    PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by IRC and the investigator

  22. Phase 2: Overall Survival (OS) [ Time Frame: approximately 3 years ]
    OS is defined as the time from first study drug administration to the date of death due to any cause

  23. Phase 2 (Cohort 1): Best Overall Response (BOR) of partial response with lymphocytosis or better [ Time Frame: approximately 3 years ]
    Best overall response is defined as the best response recorded from the first dose of the study drug until the data cutoff date or initiation of a new anticancer treatment, whichever occurs first. As determined by IRC and investigators.

  24. Phase 2 (Cohort 3): BOR of minor response or better [ Time Frame: approximately 3 years ]
  25. Phase 2 (Cohort 1): Participant-reported outcomes (PRO) via Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionarre [ Time Frame: approximately 3 years ]

    FACT-Leu is a PRO questionnaire that is developed to measure disease-specific symptoms and/or treatment-related concerns in participants with leukemia (Cela et al. 2012). It has been linguistically validated in over 50 languages, and frequently to measure HRQoL in chronic lymphocytic leukemia (CLL) participants.

    The questionnaire is comprised of 44 questions and 5 subscales including Physical Well-being (7 items), Social / Family Well-being (7 items), Emotional Well-being (6 items), Functional Wellbeing (7 items), and 17 single items under Additional Concerns).


  26. Phase 2 (Cohort 2): Participant-reported outcomes (PRO) via National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Cancer Symptom Index - 18 (NFLymSI-18) [ Time Frame: approximately 3 years ]
    The NFlymSI-18 is a participant-reported outcome questionnaire that is developed to measure disease-specific symptoms and/or treatment-related concerns in participants with advanced lymphoma


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

Inclusion Criteria :

  1. Confirmed diagnosis (per World Health Organization (WHO) guidelines, unless otherwise noted) of one of the following: Marginal Zone Lymphoma (MZL) , Follicular Lymphoma (FL), R/R Mantle Cell Lymphoma (MCL), R/R chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), Diffuse large B-cell lymphoma (DLBCL), or >2 treatments per the Richter's transformation to DLBCL.
  2. Participants who have previously received a covalently-binding Bruton´s tyrosine kinase (BTK) inhibitor (BTKi) in any line of therapy must have received treatment with the BTK inhibitor for ≥ 8 weeks (unless reason for discontinuation is intolerance).
  3. For dose-finding and dose-expansion, participants who had previously received a covalently-binding BTK inhibitor as monotherapy or in combination with other anticancer agents are eligible for the study if they meet any of the following criteria: discontinued the previous BTK inhibitor due to disease progression, experienced disease progression after completing treatment with a BTK inhibitor or discontinued the BTK inhibitor due to toxicity or intolerance.
  4. Measurable disease by radiographic assessment or serum IgM level (WM only)
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
  6. Participants enrolling in the dose finding phase of the study may be previously treated with a BTKi or may be naïve to BTKi therapy depending on the diagnosis and country of enrollment; participants with MCL enrolling in the expansion cohorts (Phase 2) must have been treated with a BTKi in a prior line of therapy; CLL/SLL participants, in addition to being treated with a BTKi in a prior line of therapy, must also have received a Bcl-2 inhibitor in a prior line of therapy as well (Phase 2).

Exclusion Criteria:

  1. Prior malignancy (other than the disease under study) within the past 2 years, except in situ malignancies that have been curatively resected, localized breast cancer treated with curative intent with no evidence of breast active disease for more than 3 years and receiving adjuvant hormonal therapy, localized Gleason score ≤ 6 prostate cancer undergoing observation or treatment with androgen depravation, or any other cancer treated with curative intent, not on adjuvant treatment, and in the opinion of the investigator is unlikely to recur.
  2. Requires ongoing systemic treatment for any other malignancy
  3. Requires ongoing systemic (defined as ≥ 10 mg/day of prednisone or equivalent) corticosteroid treatment.
  4. Current or history of central nervous system involvement including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging, cytology, or biopsy) by B-cell malignancy, regardless of whether participants had received treatment for central nervous system disease
  5. Known active plasma cell neoplasm, prolymphocytic leukemia, T-cell lymphoma, Burkitt lymphoma, acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, Castleman disease, post-transplant lymphoproliferative disorders, hairy cell leukemia, germinal center B-cell (GCB), DLBCL, EBV+ DLBCL NOS, primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL - leg type, DLBCL associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, primary effusion lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, high-grade B-cell lymphoma - NOS, B-cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, or history of or currently suspected transformation of an indolent lymphoma to an aggressive histology (except for participants with Richter Transformation to DLBCL are eligible for Part 1a, 1c, or Phase 2 and participants with history of follicular lymphoma transforming to non-GCB DLBCL who are eligible for Part 1a, 1c, or Phase 2).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05006716


Contacts
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Contact: BeiGene 1.877.828.5568 clinicaltrials@beigene.com
Contact: Study Director, MD

Locations
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Sponsors and Collaborators
BeiGene
More Information
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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT05006716    
Other Study ID Numbers: BGB-16673-101
2022-502157-33-00 ( Other Identifier: EU CT Number )
First Posted: August 16, 2021    Key Record Dates
Last Update Posted: April 3, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Neoplasms
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Leukemia, Lymphoid
 Leukemia
Hematologic Diseases
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hemorrhagic Disorders