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
• Last Update Posted: July 7, 2022
• Sponsor: BeiGene
• Information provided by (Responsible Party): BeiGene

Tracking Information

• First Submitted Date: February 7, 2017
• First Posted Date: February 15, 2017
• Last Update Posted Date: July 7, 2022
• 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: January 23, 2020): 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 ]
• 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: January 23, 2020)

• 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)
• 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, 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
• 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 ]
• New onset of atrial fibrillation and/or ventricular arrhythmia of any NCI-CTCAE v4.03grade [ Time Frame: Up to 5 years ]

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 is to evaluate 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 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 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
  160mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
• Drug: Ibrutinib
  420mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
  Other Name: IMBRUVICA

Study Arms

• 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]
  Intervention: Drug: BGB-3111
• 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]
  Intervention: Drug: Ibrutinib
• 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]
  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: January 23, 2020): 229
• 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
• (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.

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: Aileen Cohen, MD; BeiGene

• PRS Account: BeiGene
• Verification Date: July 2022