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

• ClinicalTrials.gov Identifier: NCT03053440
• Recruitment Status: Active, not recruiting
• First Posted: February 15, 2017
• Last Update Posted: July 19, 2019
• Sponsor: BeiGene
• Information provided by (Responsible Party): BeiGene

Study Description

Brief Summary:

This study is to evaluate the safety, efficacy and clinical benefit of BGB-3111 (Zanubrutinib) vs ibrutinib in subjects 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 subjects with Waldenström's Macroglobulinemia who require therapy. Subjects will have baseline bone marrow samples assayed for sequencing of the MYD88 gene. Approximately 188 subjects 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. Subjects 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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 210 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

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (Experimental Arm-BGB-3111); Approximately 94 subjects 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 subjects 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 subjects 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

Primary Outcome Measures :

1. 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 ]

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 subjects 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

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

Criteria

Inclusion Criteria:

• Clinical and definitive histologic diagnosis of WM
• Measurable disease, requiring treatment
• Patients 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

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

Contacts and Locations

  Show 80 Study Locations

Sponsors and Collaborators

BeiGene

More Information

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT03053440 History of Changes
• Other Study ID Numbers: BGB-3111-302; 2016-002980-33 ( EudraCT Number )
• First Posted: February 15, 2017
• Last Update Posted: July 19, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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