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A Study Comparing BGB-3111 and Ibrutinib in Participants With Waldenström's Macroglobulinemia (WM) (ASPEN)

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ClinicalTrials.gov Identifier: NCT03053440
Recruitment Status : Completed
First Posted : February 15, 2017
Results First Posted : June 9, 2023
Last Update Posted : June 9, 2023
Sponsor:
Information provided by (Responsible Party):
BeiGene

Study Description
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Brief Summary:
This study evaluated the safety, efficacy and clinical benefit of BGB-3111 (zanubrutinib) vs ibrutinib in participants with MYD88 Mutation Waldenström's Macroglobulinemia.

Condition or disease Intervention/treatment Phase
Waldenström's Macroglobulinemia Drug: BGB-3111 Drug: Ibrutinib Phase 3

Detailed Description:
This open-label, randomized study compared the efficacy and safety of the Bruton's Tyrosine Kinase (BTK) inhibitors BGB-3111 and ibrutinib in participants with Waldenström's Macroglobulinemia who require therapy. Participants had baseline bone marrow samples assayed for sequencing of the MYD88 gene. 201 participants with the MYD88 mutation were enrolled and randomized to receive 160 mg BGB-3111 orally twice per day (PO BID) (treatment Arm A) or to receive 420mg ibrutinib orally once per day (PO QD) (treatment Arm B) until disease progression or unacceptable toxicity.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 201 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the Efficacy and Safety of the Bruton's Tyrosine Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects With Waldenström's Macroglobulinemia (WM)
Actual Study Start Date : January 25, 2017
Actual Primary Completion Date : June 21, 2022
Actual Study Completion Date : June 21, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A : Ibrutinib
Participants with the MYD88 mutation received Ibrutinib
 Drug: Ibrutinib
420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
Other Name: IMBRUVICA
Active Comparator: Arm B: Zanubrutinib
Participants with the MYD88 mutation received zanubrutinib
 Drug: BGB-3111
160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
Other Names:
  • Zanubrutinib
  • Brukinsa


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Participants Achieving Either a Complete Response (CR) or Very Good Partial Response (VGPR) Using an Adaptation of the Response Criteria Updated at the Sixth International Workshop on WM as Assessed by an Independent Review Committee (IRC) [ Time Frame: Up to approximately 2 years and 7 months ]
    Percentage of participants with CR, defined as normal serum immunoglobulin M (IgM) levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values.


Secondary Outcome Measures :
  1. Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC [ Time Frame: Up to approximately 2 years and 7 months ]
    MRR defined as the percentage of participants achieving a best response of response of CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) defined as ≥50% reduction of serum IgM from baseline.

  2. Duration of Response (DOR) as Assessed by IRC [ Time Frame: Up to approximately 2 years and 7 months ]
    DOR defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first. CR is defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, is defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) is defined as ≥50% reduction of serum IgM from baseline.

  3. DOR as Assessed by IRC: Event -Free Rate [ Time Frame: 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months) ]
    Estimated percentage of participants who were event-free based on Kaplan-Meier method.

  4. Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator [ Time Frame: Up to approximately 5 years and 5 months ]
    Percentage of participants with CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at Baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values.

  5. DOR as Assessed by the Investigator [ Time Frame: Up to approximately 5 years and 5 months ]
    DOR is defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first

  6. DOR as Assessed by the Investigator: Event-Free Rate [ Time Frame: 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months) ]
    Estimated percentage of participants who were event-free based on Kaplan-Meier method.

  7. Progression Free Survival (PFS) as Assessed by the IRC [ Time Frame: Up to approximately 2 years and 7 months ]
    PFS as assessed by the IRC, defined as time from randomization to the first documentation of progression (per modified International Workshop on Waldenström macroglobulinemia [IWWM criteria]) or death, whichever occurs first

  8. PFS as Assessed by IRC: Event-Free Rate [ Time Frame: 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months) ]
    Estimated percentage of participants who were event-free based on Kaplan-Meier method

  9. PFS as Assessed by the Investigator [ Time Frame: Up to approximately 5 years and 5 months ]
    PFS as assessed by the Investigator, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first.

  10. PFS as Assessed by the Investigator: Event-Free Rate [ Time Frame: 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months) ]
    Percentage of participants who were event-free based on Kaplan-Meier method.

  11. Percentage of Participants With Resolution of All Treatment-precipitating Symptoms [ Time Frame: Up to approximately 5 years and 5 months ]
  12. Percentage of Participants With an Anti-Lymphoma Effect [ Time Frame: Up to approximately 5 years and 5 months ]
    Anti-Lymphoma Effect is defined as any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by CT scan, at any time during the course of study treatment.

  13. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 5 years and 5 months ]

Eligibility Criteria
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Information from the National Library of Medicine

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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

Key Inclusion Criteria:

  • Clinical and definitive histologic diagnosis of WM
  • Measurable disease, requiring treatment
  • Participants with no prior therapy for WM, must be considered inappropriate candidates for treatment with a standard chemoimmunotherapy regimen
  • Age ≥ 18 years old
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Adequate bone marrow function
  • Adequate renal and hepatic function
  • Electrocardiogram/multigated acquisition scan (ECHO/MUGA) demonstrating left ventricular ejection fraction (LVEF)≥ the lower limit of institutional normal
  • Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 3 months after transplant, and after allogeneic transplant if they are at least 6 months post-transplant.
  • Females of childbearing potential must agree to use highly effective forms of birth control throughout the course of the study and at least up to 90 days after last dose of study drug. Males must have undergone sterilization- vasectomy, or utilize a barrier method
  • Life expectancy of > 4 months

Key Exclusion Criteria:

  • Prior exposure to a BTK inhibitor
  • Evidence of disease transformation at the time of study entry
  • Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy given with antineoplastic intent, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapy within 4 weeks of the start of study drug
  • Major surgery within 4 weeks of study treatment
  • Toxicity of ≥ Grade 2 from prior anticancer therapy
  • 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 with curative intent
  • Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease within 6 months of screening
  • QTcF prolongation (defined as a QTcF > 480 msec)
  • Active, clinically significant Electrocardiogram (ECG) abnormalities
  • Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
  • Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy
  • Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C
  • Pregnant or lactating women
  • Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator's opinion, could compromise the subject's safety
  • Any medications which are strong or moderate cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers

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): NCT03053440


Locations
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Sponsors and Collaborators
BeiGene
Investigators
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Study Director: Study Director BeiGene
  Study Documents (Full-Text)

Documents provided by BeiGene:
Study Protocol  [PDF] September 2, 2019
Statistical Analysis Plan  [PDF] October 21, 2019

More Information
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Publications of Results:

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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT03053440    
Other Study ID Numbers: BGB-3111-302
2016-002980-33 ( EudraCT Number )
First Posted: February 15, 2017    Key Record Dates
Results First Posted: June 9, 2023
Last Update Posted: June 9, 2023
Last Verified: May 2023
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
Additional relevant MeSH terms:
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Waldenstrom Macroglobulinemia
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
 Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Zanubrutinib
Ibrutinib
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents