Odronextamab + CAR-T Cell Therapy for Diffuse Large B-Cell Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Davis

Must not be taking: Antiretrovirals, Corticosteroids

Disqualifiers: CNS lymphoma, Active infection, Recent surgery, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 32

Duration: Up to 2 years

34 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like systemic corticosteroids above a specific dose and some experimental drugs are not allowed. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the treatment Odronextamab + CAR-T Cell Therapy for Diffuse Large B-Cell Lymphoma?

Research shows that Odronextamab, a type of antibody treatment, has helped some patients with diffuse large B-cell lymphoma who did not respond to previous CAR-T cell therapy, achieving complete responses lasting over two years. Additionally, studies suggest that combining Odronextamab with other treatments can enhance its effectiveness in fighting this type of cancer. ^{1 2 3 4 5}

What safety data exists for Odronextamab + CAR-T Cell Therapy in humans?

CAR-T cell therapy, often combined with other treatments, has been studied for safety in patients with diffuse large B-cell lymphoma and other similar conditions. Common side effects include cytokine release syndrome (a reaction that can cause fever and low blood pressure) and neurotoxicity (affecting the nervous system), but these are generally manageable with proper medical care. Studies have shown that these therapies can be safe when administered by trained professionals. ^{6 7 8 9 10}

How is the drug odronextamab unique for treating diffuse large B-cell lymphoma?

Odronextamab is unique because it is a bispecific antibody that targets both CD20 on B cells and CD3 on T cells, helping the immune system attack cancer cells. It has shown promising results in patients who did not respond to previous CAR T-cell therapy, offering a new option for those with difficult-to-treat lymphoma. ^{1 2 3 4 11}

What is the purpose of this trial?

This phase II trial tests how well odronextamab works before and after standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapy in treating patients with diffuse large B-cell lymphoma (DLBCL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR-T cell therapy is the SOC treatment most patients receive when other treatments have failed. CAR-T cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Odronextamab is a monoclonal antibody that is called bispecific, as it individually targets 2 cell proteins, CD20 and CD3. Proteins are part of each cell in the body, which work together like little machines for the cell to function. CD20 is a protein that is found on the surface of both normal B-cells and B-cells that make up certain cancers, like DLBCL. CD3 is a protein that is found on the surface of T cells. T-cells and normal B-cells are types of white blood cells in the body and are a part of the immune system that fights infections. Odronextamab is designed to help T-cells find and kill the B-cells including the cancer cells in DLBCL. Giving odronextamab before and after CAR T-cell therapy may improve response in patients with relapsed or refractory DLBCL.

Research Team

Joseph M Tuscano

Principal Investigator

University of California, Davis

Eligibility Criteria

This trial is for patients with a type of blood cancer called diffuse large B-cell lymphoma (DLBCL) that has either returned after treatment or hasn't responded to previous therapies. It's specifically for those who are candidates for CAR T-cell therapy, which is often used when other treatments don't work.

Inclusion Criteria

Life expectancy ≥ 3 months

Leukocytes ≥ 2,500/µL

Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

Exclusion Criteria

Pregnancy or lactation

Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she/they were to participate in the study or confounds the ability to interpret data from the study as determined by the study principal investigator (PI) or enrolling physician

I have not had major surgery in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive odronextamab intravenously on specified days of each cycle, with cycles repeating every 21 days initially and then every 28 days for up to 2 years

Up to 2 years

Multiple visits per cycle (in-person)

CAR T-cell Therapy

Participants receive standard of care CAR T-cell therapy if disease assessment shows less than a complete response after cycle 4 or progressive disease after cycle 5

1 cycle

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 years

Follow-up at 30 days then every 4 months

Treatment Details

Interventions

• Chimeric Antigen Receptor T-Cell Therapy
• Odronextamab

Trial Overview The study tests odronextamab, a dual-targeting antibody, given before and after standard CAR T-cell therapy in DLBCL patients. The goal is to see if this approach can boost the immune system's ability to fight cancer by helping T-cells identify and destroy B-cells involved in the disease.

Participant Groups

Group I: Treatment (odronextamab, CAR T-cell therapy) Experimental Treatment 2 Interventions

Patients receive odronextamab IV over 1-4 hours on days 1, 2, 8, 9, 15, and 16 of cycle 1, on days 1, 8, and 15 of cycles 2-4 then on days 1 and 15 of subsequent cycles until achievement of durable CR. Cycles repeat every 21 days in the absence of durable CR, disease progression, or unacceptable toxicity. Patients with durable CR for ≥ 9 months may then receive odronextamab IV over 1-4 hours on day 1 of each subsequent cycle. These cycles repeat every 28 days for up to a total of 2 years in the absence of disease progression or unacceptable toxicity. Patients receive SOC CAR T-cell therapy if disease assessment shows less than a CR after cycle 4, or after cycle 5 if disease assessment shows PD any time after cycle 5.

Who Is Running the Clinical Trial?

University of California, Davis

Lead Sponsor

Trials

958

Recruited

4,816,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Odronextamab, a bispecific antibody targeting CD20 and CD3, has shown promising results in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, achieving durable complete responses in two patients for over 2 years after treatment.

The treatment was well-tolerated, with no severe cytokine release syndrome or neurological adverse events reported, indicating a manageable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete responses to odronextamab in two patients with diffuse large B-cell lymphoma refractory to chimeric antigen receptor T-cell therapy. Weinstock, M., Elavalakanar, P., Bright, S., et al.[2023]

Odronextamab, a bispecific antibody targeting CD20 and CD3, shows early promise in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL), but many patients still do not achieve complete responses.

The addition of REGN5837, which engages CD28 on T cells, significantly enhances the antitumor activity of odronextamab in preclinical models, suggesting a potential chemotherapy-free treatment strategy for DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models. Wei, J., Montalvo-Ortiz, W., Yu, L., et al.[2022]

Odronextamab, a bispecific antibody targeting CD20 and CD3, has shown adequate safety and tolerability in an ongoing first-in-human study for patients with relapsed/refractory B-cell non-Hodgkin lymphoma, indicating its potential as a therapeutic option.

Preclinical studies demonstrated that effective concentrations of odronextamab for inhibiting tumor growth in mouse models can inform dose escalation strategies for clinical trials, suggesting a translational approach to optimize dosing in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational findings for odronextamab: From preclinical research to a first-in-human study in patients with CD20+ B-cell malignancies. Zhu, M., Olson, K., Kirshner, JR., et al.[2022]

CAR T-cell therapy is an important treatment option for patients with refractory or relapsed diffuse large B-cell lymphoma, providing a targeted approach to combat this aggressive cancer.

The review discusses the criteria for selecting patients for CAR T-cell therapy and emphasizes the importance of bridging therapy and timing to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview. Mohty, M., Dulery, R., Gauthier, J., et al.[2023]

In a study involving 11 patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the combination of CD19 CAR-T cells and the anti-PD-1 antibody nivolumab was found to be safe, with no dose-limiting toxicities and manageable side effects like cytokine release syndrome in a minority of patients.

The treatment showed promising efficacy, achieving an objective response rate of 81.81% and a complete response rate of 45.45%, indicating strong anti-lymphoma activity that warrants further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma. Cao, Y., Lu, W., Sun, R., et al.[2020]

In a study involving 9 patients with refractory/relapsed B cell lymphoma, a novel anti-CD19 CAR T cell therapy showed a high overall response rate of 77.8%, with 55.6% achieving complete remission.

The treatment demonstrated a favorable safety profile, with only 11.1% of patients experiencing severe cytokine release syndrome and neurotoxicity, while some patients maintained complete remission for over 20 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. Liu, X., Zhang, Y., Li, K., et al.[2021]

Chimeric antigen receptor (CAR)-T cell therapy, specifically targeting CD19, has shown promising results in treating non-Hodgkin lymphomas (NHLs) resistant to standard therapies, leading to FDA and EMA approvals for tisagenlecleucel and axicabtagene ciloleucel.

While CAR-T cell therapy can cause significant adverse events like cytokine release syndrome and neurological toxicity, these effects are manageable with proper medical support, highlighting the importance of trained teams in administering this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. Hopfinger, G., Jäger, U., Worel, N.[2020]

The novel CD19-PD-1/CD28 chimeric antigen receptor (CAR) T-cell therapy showed improved T-cell proliferation and effectiveness in killing PD-L1+ B-cell lymphoma cells, demonstrating enhanced efficacy compared to standard CD19 CAR T cells.

In a phase Ib study involving 17 adult patients with refractory or relapsed B-cell lymphoma, 58.8% of patients achieved an objective response, with 41.2% reaching complete remission, and the treatment was well-tolerated with no severe side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma. Liu, H., Lei, W., Zhang, C., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Complete responses to odronextamab in two patients with diffuse large B-cell lymphoma refractory to chimeric antigen receptor T-cell therapy. [2023]

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

CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models. [2022]

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

Outcomes of relapsed/refractory diffuse large B-cell lymphoma and influence of chimaeric antigen receptor T trial eligibility criteria in second line-A population-based study of 736 patients. [2022]

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

Translational findings for odronextamab: From preclinical research to a first-in-human study in patients with CD20+ B-cell malignancies. [2022]

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

CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview. [2023]

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

Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy of programmed cell death 1 inhibitor maintenance therapy after combined treatment with programmed cell death 1 inhibitors and anti-CD19-chimeric antigen receptor T cells in patients with relapsed/refractory diffuse large B-cell lymphoma and high tumor burden. [2023]

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

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. [2021]

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

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. [2020]

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

Radiation Priming Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma With High Tumor Burden. [2021]

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

CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma. [2022]