BMS-986458 + Rituximab for Non-Hodgkin Lymphoma

Recruiting at 26 trial locations

Overseen By First line of the email MUST contain the NCT# and Site#

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bristol-Myers Squibb

Must not be taking: Cereblon-modulating, CAR-T

Disqualifiers: ECOG ≥ 2, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

273 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called BMS-986458 to see if it is safe and effective for patients whose non-Hodgkin Lymphoma has come back or didn't respond to other treatments. The study will look at how well the drug works alone and with other cancer-fighting drugs.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that you cannot have had certain treatments like CAR-T or radiotherapy recently. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug BMS-986458 + Rituximab for Non-Hodgkin Lymphoma?

Research suggests that combining rituximab with treatments targeting BCL-2, a protein similar to BCL6, can enhance the effectiveness against lymphoma, as seen in studies with antisense oligonucleotides. This indicates potential for improved outcomes when combining rituximab with BMS-986458, which targets BCL6. ^{1 2 3 4 5}

What safety data exists for BMS-986458 and Rituximab in humans?

Rituximab has been widely used in treating various blood cancers and is generally considered safe, though it can have side effects like infusion reactions (allergic reactions during the drug administration) and infections. There is no specific safety data available for BMS-986458 in humans from the provided research articles. ^{3 6 7 8 9}

What makes the drug BMS-986458 combined with Rituximab unique for treating non-Hodgkin lymphoma?

BMS-986458 is a novel treatment that targets BCL6, a protein involved in the growth of certain cancer cells, and when combined with Rituximab, it offers a new approach for treating non-Hodgkin lymphoma by potentially enhancing the effectiveness of existing therapies. ^{4 10 11 12 13}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for people with Non-Hodgkin Lymphoma who have tried at least two prior treatments. They must have a type of lymphoma that shows up on certain body scans and agree to follow a pregnancy prevention plan.

Inclusion Criteria

I have had at least 2 treatments for my lymphoma, including chemotherapy with rituximab.

I have follicular lymphoma, not type 3b, and have had at least 2 prior treatments.

Participants must accept and follow pregnancy prevention plan.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BMS-986458 as a single agent or in combination with anti-lymphoma agents

12 weeks

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BMS-986458
• Rituximab

Trial Overview The study tests BMS-986458, both alone and combined with other anti-lymphoma drugs like Rituximab, to see how safe it is and if it works against relapsed/refractory non-Hodgkin Lymphoma.

Participant Groups

Group I: Part B2 Experimental Treatment 2 Interventions

Combination Treatment

Group II: Part B1 Experimental Treatment 1 Intervention

Single Agent

Group III: Part A2 Experimental Treatment 2 Interventions

Combination Treatment

Group IV: Part A1 Experimental Treatment 1 Intervention

Single Agent

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

BCL6 gene rearrangement was found in 19.5% of patients with diffuse large B-cell lymphoma and was linked to a non-germinal center B-cell immunophenotype, indicating a specific genetic profile associated with this cancer.

In patients treated with R-CHOP, there was a trend towards poorer overall survival for those with BCL6 rearrangement, suggesting that rituximab may change the impact of this genetic abnormality on patient outcomes, although further research is needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlations between BCL6 rearrangement and outcome in patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. Shustik, J., Han, G., Farinha, P., et al.[2021]

In patients with diffuse large B-cell lymphoma (DLBCL) who are Bcl-6 negative, the addition of rituximab (R) to standard CHOP chemotherapy significantly improves failure-free survival (76% vs. 9%) and overall survival (79% vs. 17%).

For Bcl-6 positive patients, there was no significant difference in treatment outcomes between R-CHOP and CHOP alone, indicating that the benefit of rituximab may be limited to those without Bcl-6 expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correlative study. Winter, JN., Weller, EA., Horning, SJ., et al.[2021]

Patients with diffuse large B-cell lymphomas that have genetic alterations in MYC, BCL2, and/or BCL6 tend to have poorer outcomes with standard RCHOP chemotherapy, leading to the suggestion of more intense treatment regimens.

There is currently insufficient evidence to recommend consolidative stem cell transplants for these patients, highlighting the need for collaborative clinical trials to determine the best treatment strategies for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6: Double hit and triple hit lymphomas and double expressing lymphoma. Rosenthal, A., Younes, A.[2018]

The LYM-2034 phase 2 trial involved 164 patients with non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), comparing the efficacy of two treatment regimens: R-CHOP and VR-CAP.

The study highlights the heterogeneity of DLBCL, suggesting that different subtypes may require tailored treatment approaches, as evidenced by the comparison of traditional chemotherapy (R-CHOP) with the addition of bortezomib (VR-CAP).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subtype-specific therapy for DLBCL: are we there yet? Khan, N., Fisher, RI.[2021]

Combining rituximab, a monoclonal antibody, with antisense oligonucleotides (AS-ODNs) that down-regulate the antiapoptotic protein BCL-2 significantly enhances apoptosis in B-cell lymphoma cells and improves therapeutic outcomes, as shown in vitro with DoHH2 cells and in vivo in mouse models.

This combination therapy not only prolongs survival in mice with human lymphoma but also shows potential for curative effects with higher and repeated doses, suggesting a promising avenue for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts. Smith, MR., Jin, F., Joshi, I.[2020]

In a phase 2 trial involving 23 elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the combination of oral lenalidomide and rituximab resulted in an overall response rate of 35%, with 8 patients achieving a complete response after maintenance therapy.

The treatment was generally safe, with manageable adverse effects primarily including neutropenia and thrombocytopenia, indicating that this regimen could be a viable option for elderly patients who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Zinzani, PL., Pellegrini, C., Gandolfi, L., et al.[2020]

BCL6 is a key oncogene in various cancers, particularly B-cell lymphomas, and its inhibition can effectively kill lymphoma cells by blocking the recruitment of corepressor complexes that repress target genes.

BCL6 inhibitors have shown promise not only in diffuse large B-cell lymphomas but also in other cancers like leukemia and breast cancer, and their combination with other treatments has resulted in enhanced therapeutic effects, suggesting a strong potential for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target. Cardenas, MG., Oswald, E., Yu, W., et al.[2021]

In a study of 567 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with rituximab-CHOP (RCHOP), bone marrow (BM) involvement was found in 8.5% of cases and significantly worsened overall survival (OS) and event-free survival (EFS) rates.

Patients without BM involvement had a five-year OS of 76.3% and EFS of 67.5%, while those with BM involvement had much lower rates of 44.3% and 40.1%, respectively, indicating that BM involvement is a negative prognostic factor even with effective RCHOP therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcome of Rituximab-Based Therapy (RCHOP) in Diffuse Large B-Cell Lymphoma Patients with Bone Marrow Involvement. Kang, BW., Moon, JH., Chae, YS., et al.[2021]

Rituximab, a monoclonal antibody, has significantly improved survival rates for patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) when used in combination with chemotherapy.

In patients with chronic lymphocytic leukaemia (CLL), rituximab-based chemoimmunotherapy has led to higher complete response and progression-free survival rates, demonstrating its efficacy in both untreated and relapsed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Hagemeister, F.[2021]

Rituximab combined with Bruton tyrosine kinase inhibitors (BTKis) shows potential efficacy in treating elderly patients with diffuse large B-cell lymphoma (DLBCL), based on a case study of two patients.

The treatment involved an initial two courses of the R-miniCHOP chemotherapy regimen followed by the combination therapy, suggesting a new strategy for managing DLBCL in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports. Zhang, CJ., Zhao, ML.[2023]

In a phase 1 study involving 20 patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL), bortezomib could be safely added to the standard R-CHOP chemotherapy regimen at a dose of 1.3 mg/m2, with acceptable levels of toxicity.

The treatment showed promising efficacy, with a 95% complete response rate among evaluable patients and a 4-year overall survival rate of 75%, indicating that this combination could be a viable option for patients with these types of lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma. Furman, RR., Martin, P., Ruan, J., et al.[2022]

Rituximab is the first monoclonal antibody approved for treating B-cell lymphomas, showing significant effectiveness in conditions like follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.

The combination of rituximab with standard chemotherapy agents (cyclophosphamide, doxorubicin, vincristine, and prednisone) has achieved the highest efficacy reported for treating diffuse large B-cell lymphoma and follicular lymphoma, while maintaining low toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. Traullé, C., Coiffier, BB.[2015]

In a study of 824 young patients with good-prognosis diffuse large-B-cell lymphoma, adding rituximab to CHOP-like chemotherapy significantly improved 3-year event-free survival (79% vs 59%) and overall survival (93% vs 84%).

The study identified two prognostic subgroups based on treatment response and disease characteristics, allowing for a more tailored therapeutic approach without increasing the frequency of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Pfreundschuh, M., Trümper, L., Osterborg, A., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Correlations between BCL6 rearrangement and outcome in patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. [2021]

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

Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correlative study. [2021]

3. England pubmed.ncbi.nlm.nih.gov

High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6: Double hit and triple hit lymphomas and double expressing lymphoma. [2018]

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

Subtype-specific therapy for DLBCL: are we there yet? [2021]

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

Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts. [2020]

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

Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. [2020]

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

The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target. [2021]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Clinical Outcome of Rituximab-Based Therapy (RCHOP) in Diffuse Large B-Cell Lymphoma Patients with Bone Marrow Involvement. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Rituximab for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. [2021]

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

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports. [2023]

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

Phase 1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma. [2022]

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

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. [2015]

13. England pubmed.ncbi.nlm.nih.gov

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. [2022]