A Study to Investigate Efficacy and Safety of BCL2 Inhibitor Sonrotoclax as Monotherapy and in Combination With Zanubrutinib in Adults With Waldenström Macroglobulinemia

Phase 2

Recruiting

• Conditions: Waldenstrom's Macroglobulinemia Refractory; Waldenstrom's Macroglobulinemia Recurrent; Waldenstrom Macroglobulinemia
• Interventions: Drug: Sonrotoclax; Drug: Zanubrutinib

• Registration Number: NCT05952037
• Lead Sponsor: BeiGene

Brief Summary

This study will evaluate the safety and efficacy of the BCL2 inhibitor sonrotoclax (BGB-11417) in participants with relapsed/refractory Waldenström's Macroglobulinemia (R/R WM) and in combination with zanubrutinib in adult participants with previously untreated WM.

Detailed Description

This study will test whether sonrotoclax (BGB-11417) can be used to improve outcomes in participants with Waldenström's Macroglobulinemia (WM) both when used alone in those who have not responded well to conventional treatments and when used in combination with zanubrutinib in those who have not yet received treatment. The main goals of the study are to determine how many participants no longer have evidence of cancer or have some improvement in the signs and symptoms of cancer after treatment, and to determine what adverse events, or side effects, participants might experience.

BCL2 is a key protein involved in cell death, and abnormal levels of BCL2 are associated with many cancers. Blocking the action of BCL2 proteins is a promising approach with potential therapeutic benefits in participants with different types of cancers, including WM. This study will enroll approximately 105 participants. All participants will receive sonrotoclax orally as a tablet.

The study will take place at multiple centers worldwide. The overall time to participate in this study is approximately 5 years.

Study Timeline

• Study First Submitted: 2023-07-11
• Study First Submitted QC: 2023-07-18
• Study First Posted: 2023-07-19
• Study Start: 2023-09-28
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-03
• Last Update Posted: 2025-07-08
• Primary Completion: 2026-12
• Study Completion: 2028-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 105

Inclusion Criteria

• Clinical and definitive histologic diagnosis of WM.
• Meeting ≥ 1 criterion for treatment according to consensus panel criteria from the 2nd International Workshop on Waldenström's Macroglobulinemia (IWWM).
• For Cohorts 1-3, refractory or relapsed disease at study entry unless participants had intolerance to the most recent therapy. Refractory disease is defined as not attaining at least a major response, or progressing while on or within 6 months of completing therapy. Relapsed disease is defined as attaining at least a major response to therapy and meeting the criteria for disease progression beyond 6 months after completing therapy.
• For Cohort 4, patients must not have received prior therapy for WM (except for plasmapheresis).
• Adequate organ function.

Exclusion Criteria

• Central nervous system (CNS) involvement by WM.
• Transformation to aggressive lymphoma, such as diffuse large B-cell lymphoma.
• History of other malignancies ≤ 2 years before study entry.
• Uncontrolled active systemic infection or recent infection requiring parenteral antimicrobial therapy that was completed ≤ 14 days before the first dose of the study drug.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	Sonrotoclax	Participants with R/R disease to both Bruton tyrosine kinase (BTK) inhibitor and anti-CD20 antibody-based systemic therapy containing chemotherapy or proteasome inhibitor will receive sonrotoclax at a standard dose, given orally once daily.
Cohort 2	Sonrotoclax	Participants with R/R disease to anti-CD20 antibody-based systemic therapy containing chemotherapy or proteasome inhibitor and were intolerant to BTK inhibitor will receive sonrotoclax at a standard dose, given orally once daily.
Cohort 3	Sonrotoclax	Participants with R/R disease to a BTK inhibitor treatment and are unsuitable for chemoimmunotherapy will receive sonrotoclax at a standard dose, given orally once daily.
Cohort 4	Sonrotoclax	Participants with previously untreated WM will receive sonrotoclax and zanubrutinib combination therapy for a fixed duration.
Cohort 4	Zanubrutinib	Participants with previously untreated WM will receive sonrotoclax and zanubrutinib combination therapy for a fixed duration.

Primary Outcome Measures

Name	Time	Method
Cohort 1: Major Response Rate (MRR)	Up to approximately 4 years	MRR is defined as the percentage of participants achieving partial response (PR) or better, as assessed by the Independent Review Committee (IRC) per the 11th International Workshop on Waldenström Macroglobulinemia (IWWM-11) WM response criteria.

Secondary Outcome Measures

Name	Time	Method
All Cohorts: Time to major response as assessed by the investigator	Up to approximately 5 years	Time to major response is defined as the time from start of study treatment to the first documentation of major response.
Cohorts 1, 2, and 3: Overall Survival (OS)	Up to approximately 5 years	OS is defined as the time from first study drug administration to the date of death due to any cause.
Cohort 4: Time to next treatment	Up to approximately 5 years	Defined as the time from the start of treatment to the start of first subsequent therapy for WM.
All Cohorts: DoMR as assessed by the Investigator	Up to approximately 5 years	DoMR is defined as the time from first determination of major response until first documentation of progression or death, whichever occurs first.
Cohorts 1, 2, and 3: Complete Response (CR) + Very Good Partial Response (VGPR) as assessed by the IRC	Up to approximately 5 years	CR + VGPR is defined as the percentage of participants who achieve CR or VGPR.
All Cohorts: CR + VGPR as assessed by the Investigator	Up to approximately 5 years	CR + VGPR is defined as the percentage of participants who achieve CR or VGPR.
Cohorts 1, 2, and 3: Overall Response Rate (ORR) as assessed by the IRC	Up to approximately 5 years	ORR is defined as the percentage of participants with minor response (MR) or better.
All cohorts: ORR as assessed by the investigator	Up to approximately 5 years	ORR is defined as the percentage of participants with MR or better.
Cohorts 1, 2, and 3: Duration of Response (DOR) as assessed by the IRC	Up to approximately 5 years	DOR is defined as the time from first determination of response until first documentation of progression or death, whichever occurs first.
All Cohorts: DOR as assessed by the investigator	Up to approximately 5 years	DOR is defined as the time from first determination of response until first documentation of progression or death, whichever occurs first.
Cohorts 1, 2, and 3: Progression-Free Survival (PFS)	Up to approximately 5 years	PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by the IRC and by the investigator.
Cohorts 1, 2, and 3: Time to major response as assessed by the IRC	Up to approximately 5 years	Time to major response is defined as the time from start of study treatment to the first documentation of major response.
Number of participants reporting adverse events	Up to approximately 5 years	Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory abnormalities, physical examination results, and vital signs.
Cohorts 2 and 3: MRR as assessed by the IRC	Up to approximately 5 years	MRR is defined as the percentage of participants achieving PR or better.
All Cohorts: MRR as assessed by the Investigator	Up to approximately 5 years	MRR is defined as the percentage of participants achieving PR or better.
Cohorts 1, 2, and 3: Duration of Major Response (DoMR) as assessed by the IRC	Up to approximately 5 years	DoMR is defined as the time from first determination of major response until first documentation of progression or death, whichever occurs first.
All Cohorts: Change from Baseline in Health-Related Quality of Life (HRQoL): NFLymSI-18 Disease-related Symptoms-Physical and Treatment-Related Side Effects Subscales	Baseline and approximately months 7, 13, 19, and 25	HRQoL based on participant-reported outcomes using National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Cancer Symptom Index - 18 Item (NFLymSI-18) Version 4. The questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and is divided into a total score.

Trial Locations

Locations (72)

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

Medstar Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

University of Miami; 🇺🇸 Miami, Florida, United States

Northwestern Medicine Cancer Center; 🇺🇸 Warrenville, Illinois, United States

Mission Cancer and Blood; 🇺🇸 Waukee, Iowa, United States

University of Maryland Greenebaum Comprehensive Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic Rochester; 🇺🇸 Rochester, Minnesota, United States

Hattiesburg Hematology and Oncology Clinic; 🇺🇸 Hattiesburg, Mississippi, United States

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