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

• 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: BeiGene
• Information provided by (Responsible Party): BeiGene

Tracking Information

• First Submitted Date: February 7, 2017
• First Posted Date: February 15, 2017
• Results First Submitted Date: March 29, 2023
• Results First Posted Date: June 9, 2023
• Last Update Posted Date: June 9, 2023
• Actual Study Start Date: January 25, 2017
• Actual Primary Completion Date: June 21, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 29, 2023)

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.

• Original Primary Outcome Measures (submitted: February 12, 2017): Proportion of subjects 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 ]

Current Secondary Outcome Measures (submitted: May 17, 2023)

• 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.
• 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.
• 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.
• 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.
• 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
• 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.
• 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
• 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
• 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.
• 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.
• Percentage of Participants With Resolution of All Treatment-precipitating Symptoms [ Time Frame: Up to approximately 5 years and 5 months ]
• 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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 5 years and 5 months ]

Original Secondary Outcome Measures (submitted: February 12, 2017)

• Efficacy measured by major response rate (MRR) in Cohort 1 [ Time Frame: Up to 5 years ]
  MRR defined as the proportion of subjects achieving a best response of response of CR, VGPR, or partial response (PR)
• 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
• 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
• 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 ]
• Anti-lymphoma effect in Cohort 1, as measured by any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or hepatosplenomegaly [ Time Frame: Up to 5 years ]
• Safety measured by the incidence, timing, and severity of treatment-emergent AEs in Cohort 1 [ Time Frame: Up to 5 years ]
• The incidence of AEs of Special Interest in Cohort 1 [ Time Frame: Up to 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Comparing BGB-3111 and Ibrutinib in Participants With Waldenström's Macroglobulinemia (WM)
• 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)
• 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.
• 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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Waldenström's Macroglobulinemia

Intervention

• 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
• Drug: Ibrutinib
  420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
  Other Name: IMBRUVICA

Study Arms

• Experimental: Arm A : Ibrutinib
  Participants with the MYD88 mutation received Ibrutinib
  Intervention: Drug: Ibrutinib
• Active Comparator: Arm B: Zanubrutinib
  Participants with the MYD88 mutation received zanubrutinib
  Intervention: Drug: BGB-3111

• Publications *: Tam CS, LeBlond V, Novotny W, Owen RG, Tedeschi A, Atwal S, Cohen A, Huang J, Buske C. A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia. Future Oncol. 2018 Sep;14(22):2229-2237. doi: 10.2217/fon-2018-0163. Epub 2018 Jun 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 29, 2023): 201
• Original Estimated Enrollment (submitted: February 12, 2017): 167
• Actual Study Completion Date: June 21, 2022
• Actual Primary Completion Date: June 21, 2022 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Czechia, France, Germany, Greece, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT03053440
• Other Study ID Numbers: BGB-3111-302; 2016-002980-33 ( 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

• Plan to Share IPD: Yes

• Current Responsible Party: BeiGene
• Original Responsible Party: Same as current
• Current Study Sponsor: BeiGene
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; BeiGene

• PRS Account: BeiGene
• Verification Date: May 2023