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

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: NCT03053440
Recruitment Status : Active, not recruiting
First Posted : February 15, 2017
Last Update Posted : April 24, 2020
Sponsor:
Information provided by (Responsible Party):
BeiGene

Study Description
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Brief Summary:
This study is to evaluate 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 will compare 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 will have baseline bone marrow samples assayed for sequencing of the MYD88 gene. Approximately 188 participants with the MYD88 mutation will be enrolled onto Cohort 1 and randomized to receive 160 mg BGB-3111 PO BID (treatment Arm A) or to receive 420mg ibrutinib QD (treatment Arm B) until disease progression or unacceptable toxicity. Participants with MYD88 wild type will be enrolled to Cohort 2 and will receive 160 mg BGB-3111 PO BID (treatment Arm C) until disease progressive disease (PD) or unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination by Sponsor.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 229 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
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ibrutinib

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (Experimental Arm-BGB-3111)
Approximately 94 participants with the MYD88 mutation will be enrolled in Cohort 1 and receive BGB-3111 in treatment [Arm A]
 Drug: BGB-3111
160mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
Active Comparator: Arm B (Active Comparator-Ibrutinib)
Approximately 94 participants with the MYD88 mutation will be enrolled in Cohort 1 and receive Ibrutinib in treatment [Arm B]
 Drug: Ibrutinib
420mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
Other Name: IMBRUVICA
Experimental: Arm C (Experimental Arm-BGB-3111)
Approximately 22 participants found to have MYD88 wild type will be enrolled in Cohort 2 and receive BGB-3111 in treatment [Arm C]
 Drug: BGB-3111
160mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor


Outcome Measures
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Primary Outcome Measures :
  1. Proportion of participants achieving either a complete response (CR) or very good partial response (VGPR) in Cohort 1 using an adaptation of the response criteria updated at the Sixth IWWM as assessed by an independent review committee. [ Time Frame: Up to 3 years ]

Secondary Outcome Measures :
  1. Efficacy measured by major response rate (MRR) in Cohort 1 [ Time Frame: Up to 5 years ]
    MRR defined as the proportion of participants achieving a best response of response of CR, VGPR, or partial response (PR)

  2. Efficacy measured by duration of response (DOR) in Cohort 1 [ Time Frame: Up to 5 years ]
    DOR defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first

  3. Efficacy measured by progression-free survival (PFS) in Cohort 1 [ Time Frame: Up to 5 years ]
    PFS defined as time from randomization to the first documentation of progression or death, whichever occurs first

  4. Resolution of treatment-precipitating symptoms in Cohort 1, measured by the absence of the symptoms that triggered initiation of study treatment (per the IWWM treatment guidelines) at any point during study treatment [ Time Frame: Up to 5 years ]
  5. Anti-lymphoma effect in Cohort 1, measured by any reduction in bone marrow involvement [ Time Frame: Up to 5 years ]
    Anti-lymphoma effect in Cohort 1, measured by any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or hepatosplenomegaly and/or splenomegaly by CT scan, at any time during the course of study treatment

  6. Safety measured by the incidence, timing, and severity of treatment-emergent AEs in Cohort 1 [ Time Frame: Up to 5 years ]
  7. The incidence of AEs of Special Interest in Cohort 1 [ Time Frame: Up to 5 years ]
  8. New onset of atrial fibrillation and/or ventricular arrhythmia of any NCI-CTCAE v4.03grade [ Time Frame: Up to 5 years ]

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

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
  • (ECOG) performance status of 0-2
  • Adequate bone marrow function
  • Adequate renal and hepatic function
  • ECHO/MUGA demonstrating left ventricular ejection fraction (LVEF)≥ the lower limit of institutional normal
  • Subjects 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 > 450 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: Aileen Cohen, MD BeiGene
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
Last Update Posted: April 24, 2020
Last Verified: April 2020
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
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action