BGB-11417 for Waldenström's Macroglobulinemia

Recruiting at74 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: BeiGene

Disqualifiers: CNS involvement, Aggressive lymphoma, Recent malignancies, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug BGB-11417, Sonrotoclax, for treating Waldenström's Macroglobulinemia?

Research on a similar drug, venetoclax, shows it can help patients with Waldenström's Macroglobulinemia, as some patients experienced partial improvement. This suggests that BGB-11417, which may work in a similar way, could also be effective. ^{1 2 3 4 5}

Is BGB-11417 (Sonrotoclax) generally safe for humans?

While specific safety data for BGB-11417 (Sonrotoclax) is not available, similar drugs like venetoclax, which also target BCL-2, have been studied. Venetoclax is generally well tolerated, with common side effects including nausea, diarrhea, and blood-related issues like anemia and neutropenia (low white blood cell count). ^{1 4 6 7 8}

How is the drug BGB-11417 (Sonrotoclax) different from other treatments for Waldenström's Macroglobulinemia?

BGB-11417 (Sonrotoclax) is unique because it may offer a novel mechanism of action compared to the standard treatment, which typically involves an anti-CD20 antibody like rituximab combined with other agents. While the standard treatment targets B-cells, BGB-11417 might work differently, potentially providing an alternative for patients who do not respond to existing therapies. ^{9 10 11 12 13}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for people with Waldenström's Macroglobulinemia who have tried other treatments that didn't work or stopped working. They should not have had any other cancers in the last two years, no brain involvement from their disease, and no recent serious infections.

Inclusion Criteria

My disease did not improve or got worse with the last treatment, or I couldn't tolerate it.

My organs are working well.

I have been diagnosed with Waldenstrom macroglobulinemia.

Exclusion Criteria

I haven't had a severe infection or needed IV antibiotics in the last 2 weeks.

My lymphoma has changed into a more aggressive form.

I have not had any other cancers in the last 2 years.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sonrotoclax as monotherapy or in combination with zanubrutinib, depending on their cohort

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• BGB-11417 (BCL2 Inhibitor)

Trial Overview The study tests BGB-11417, a drug designed to block a protein called BCL2 that helps cancer cells survive. Participants are grouped into three cohorts to assess how well the drug works and its safety in those with relapsed/refractory Waldenström's Macroglobulinemia.

Participant Groups

Group I: Cohort 4 Experimental Treatment 2 Interventions

Participants with previously untreated WM will receive sonrotoclax and zanubrutinib combination therapy for a fixed duration.

Group II: Cohort 3 Experimental Treatment 1 Intervention

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.

Group III: Cohort 2 Experimental Treatment 1 Intervention

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.

Group IV: Cohort 1 Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a study of 106 patients with relapsed/refractory non-Hodgkin lymphoma, venetoclax showed a median progression-free survival of 5.4 months and a median duration of response of 14.9 months, indicating its effectiveness as a treatment.

The safety profile of venetoclax was manageable, with infrequent hematologic adverse events and common nonhematologic effects like nausea and diarrhea, which decreased after the first year of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study. Davids, MS., Roberts, AW., Kenkre, VP., et al.[2023]

In a phase 2 trial involving 45 patients with relapsed or refractory chronic lymphocytic leukaemia, 76% achieved undetectable minimal residual disease (uMRD) after a triple therapy regimen of obinutuzumab, acalabrutinib, and venetoclax, indicating promising efficacy.

Despite the high rate of uMRD, the trial did not meet the predefined activity threshold, suggesting that further research is needed to evaluate the benefits of this triple therapy compared to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. Cramer, P., Fürstenau, M., Robrecht, S., et al.[2022]

In a study of 45 pediatric patients with B-cell non-Hodgkin's lymphoma, both the CCCG-97 and BFM-90 chemotherapy protocols resulted in high complete response rates (88.9%), with the CCCG-97 group achieving a slightly higher rate of 95.2%.

The 5-year event-free survival rates were comparable between the two protocols, with 76.2% for CCCG-97 and 75.0% for BFM-90, indicating that both treatment strategies are effective and have manageable toxicity, primarily myelosuppression and mucositis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of the efficacy of CCCG-97 and BFM-90 protocols in the treatment for children with mature B-cell non-Hodgkin's lymphoma]. Meng, JH., Gao, YJ., Lu, FJ., et al.[2018]

Venetoclax, an oral BCL-2 inhibitor, shows promising efficacy for treating patients with t(11;14) plasma cell disorders, both alone and in combination with other therapies.

Despite its effectiveness, the BELLINI trial indicated an increased mortality risk primarily in patients without the t(11;14) genetic marker, highlighting the need for careful patient selection in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How do we manage t(11;14) plasma cell disorders with venetoclax? Chakraborty, R., Bhutani, D., Lentzsch, S.[2022]

In a review of ten patients with relapsed/refractory multiple myeloma (RRMM) treated with venetoclax, the overall response rate was 78%, indicating its potential efficacy, especially in patients with the t(11;14) genetic alteration.

While venetoclax treatment showed promising results, it was associated with hematologic toxicities requiring transfusions and gastrointestinal side effects, highlighting the need for monitoring and management of these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data on safety and efficacy of venetoclax-based regimens in relapsed/refractory t(11;14) multiple myeloma. Basali, D., Chakraborty, R., Rybicki, L., et al.[2022]

In a phase I trial involving 106 patients with various subtypes of non-Hodgkin lymphoma, venetoclax, a BCL-2 inhibitor, was found to be generally well tolerated, with a 44% overall response rate across different lymphoma types.

The study identified 1,200 mg as the recommended dose for future studies in follicular lymphoma and diffuse large B-cell lymphoma, while 800 mg was effective for mantle cell lymphoma, indicating varying efficacy based on lymphoma subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. Davids, MS., Roberts, AW., Seymour, JF., et al.[2018]

A 71-year-old patient with Waldenström's macroglobulinemia, who was resistant to standard treatments, showed rapid clinical improvement when treated with idelalisib, suggesting its potential efficacy in this context.

This case highlights idelalisib as a viable treatment option for patients with Waldenström's macroglobulinemia who cannot receive ibrutinib due to complications like renal failure or other health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idelalisib in a patient with refractory Waldenström's macroglobulinemia complicated by anuric renal failure: a case report. D'Aveni-Piney, M., Divoux, M., Busby-Venner, H., et al.[2019]

Waldenstrom macroglobulinemia (WM) primarily affects older males, with common symptoms including fatigue, weight loss, splenomegaly, and lymphadenopathy, based on a study of 15 patients followed for an average of 82 months.

While WM is currently incurable, treatments such as chemotherapy, bortezomib, and thalidomide have been shown to improve therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical analysis of 15 patients with Waldenstrom macroglobulinemia]. Hu, Y., Chen, SL., Zhong, YP., et al.[2015]

Waldenstrom's macroglobulinemia (WM) is characterized by the production of monoclonal immunoglobulin M (IgM) and requires standardized diagnostic criteria, including the presence of IgM monoclonal protein and lymphoplasmacytic cells in the marrow or lymph nodes.

The establishment of uniform response criteria for WM is crucial for accurately assessing treatment responses, remission durations, and survival outcomes in clinical trials, similar to criteria used for other blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uniform response criteria in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Weber, D., Treon, SP., Emmanouilides, C., et al.[2007]

In a study of 91 patients with Waldenström's macroglobulinemia, 19 exhibited various ocular impairments, including serious conditions like central retinal vein occlusion and macular detachments, highlighting the potential sight-threatening nature of these manifestations.

Treatment involving plasmapheresis followed by chemotherapy, with or without rituximab, led to significant improvements in eye health for 15 patients, demonstrating the efficacy of recent therapeutic advances in managing ocular symptoms associated with WM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Spectrum of Ocular Manifestations in Patients with Waldenström's Macroglobulinemia. Dammacco, R., Lisch, W., Kivelä, TT., et al.[2022]

A 73-year-old male with Waldenstrom's Macroglobulinemia exhibited a serous macular detachment, which was analyzed using fluorescein and indocyanine green angiography before and after chemotherapy, revealing important details about the condition.

The study suggests that the serous detachment may be linked to various factors, including toxic changes in the retinal pigment epithelium and abnormal pressure dynamics between the optic disc and surrounding spaces, highlighting the complexity of the disease's effects on the retina.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Serous detection of the neuroretina in Waldenström disease. A case report]. Feigl, B., Sill, H., Haas, A.[2015]

References

1. United States pubmed.ncbi.nlm.nih.gov

Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Comparison of the efficacy of CCCG-97 and BFM-90 protocols in the treatment for children with mature B-cell non-Hodgkin's lymphoma]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

How do we manage t(11;14) plasma cell disorders with venetoclax? [2022]

5. England pubmed.ncbi.nlm.nih.gov

Real-world data on safety and efficacy of venetoclax-based regimens in relapsed/refractory t(11;14) multiple myeloma. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Idelalisib in a patient with refractory Waldenström's macroglobulinemia complicated by anuric renal failure: a case report. [2019]

10. China pubmed.ncbi.nlm.nih.gov

[Clinical analysis of 15 patients with Waldenstrom macroglobulinemia]. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Uniform response criteria in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. [2007]

12. England pubmed.ncbi.nlm.nih.gov

The Spectrum of Ocular Manifestations in Patients with Waldenström's Macroglobulinemia. [2022]

13. Germany pubmed.ncbi.nlm.nih.gov

[Serous detection of the neuroretina in Waldenström disease. A case report]. [2015]