Odronextamab + Cemiplimab for Aggressive B-Cell Lymphoma

(CLIO-1 Trial)

Recruiting at40 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Regeneron Pharmaceuticals

Must be taking: Anti-CD20 antibody

Must not be taking: Immunosuppressive treatments

Disqualifiers: CNS lymphoma, Autoimmune disease, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This study is researching a combination of 2 experimental drugs, referred to as "study drugs", called odronextamab (also known as REGN1979) and cemiplimab (also known as REGN2810). The study is focused on patients who have relapse/refractory aggressive B-cell lymphoma. The aim of the study is to see how safe and tolerable the study drugs are, and to define the recommended dose regimen for the combination with odronextamab. This study is also looking at several other research questions, including: * What side effects may happen from taking the study drugs * How effective the study drugs are against the disease * How much study drug is in the blood at different times * Whether the body makes substances or protein called antibodies against the study drugs (that could make the drugs less effective or could lead to side effects)

Do I have to stop taking my current medications for the trial?

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

What data supports the effectiveness of the drug combination Odronextamab and Cemiplimab for treating aggressive B-cell lymphoma?

Odronextamab has shown promising results in patients with difficult-to-treat diffuse large B-cell lymphoma, with some achieving complete responses lasting over two years. Additionally, combining different immunotherapies, like Odronextamab, has been shown to enhance treatment effectiveness in similar conditions. ^{1 2 3 4 5}

What is known about the safety of Odronextamab and Cemiplimab in humans?

Odronextamab has shown promising activity in early trials for aggressive B-cell lymphoma, with no specific safety concerns mentioned in the available research. However, the combination with another antibody, REGN5837, showed no toxicity in primate studies, suggesting a potentially manageable safety profile. ^{3 6 7 8 9}

What makes the drug combination of Odronextamab and Cemiplimab unique for treating aggressive B-cell lymphoma?

The combination of Odronextamab and Cemiplimab is unique because Odronextamab is a bispecific antibody that targets both CD20 on B cells and CD3 on T cells, enhancing the immune system's ability to attack cancer cells, while Cemiplimab is an immune checkpoint inhibitor that helps the immune system recognize and fight cancer cells. This dual approach may offer a novel, chemotherapy-free option for patients who have not responded to other treatments. ^{1 3 10 11 12}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

Adults with aggressive B-cell lymphoma that's come back or hasn't responded to treatment, and no standard care options are left. They must have a life expectancy over 6 months, good organ function, measurable disease by imaging, and be able to follow the study plan. Excluded are those with certain infections (HIV/hepatitis), CNS lymphoma involvement, allergy to tetracycline antibiotics, unwillingness to use contraception, recent significant autoimmune disease needing immunosuppressants, prior specific cancer treatments including stem cell transplant or PD-1/PD-L1 inhibitors (unless beneficial), known allergies relevant here.

Inclusion Criteria

My organs are working well.

My bone marrow is working well.

I am fully active or can carry out light work.

Exclusion Criteria

I do not have an uncontrolled infection like HIV or hepatitis.

History of hypersensitivity to any compound in the tetracycline antibiotics group

You are pregnant or currently breastfeeding.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Safety assessment of odronextamab in combination with cemiplimab and selection of recommended phase 2 dose regimen(s)

8-12 weeks

Dose Expansion

Administration of the recommended phase 2 dose (RP2D) regimen of the combination treatment

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Cemiplimab (Monoclonal Antibodies)
• REGN1979 (Monoclonal Antibodies)

Trial Overview The trial is testing how safe and tolerable two experimental drugs—odronextamab (REGN1979) and cemiplimab (REGN2810)—are when combined in adults with relapsed/refractory aggressive B-cell lymphoma. It aims to find the best dose regimen for this combination therapy while also examining side effects effectiveness against the disease levels of drug in blood over time potential development of antibodies against these drugs.

Participant Groups

Group I: Dose expansion phase Experimental Treatment 2 Interventions

RP2D administration of the combination treatment.

Group II: Dose escalation phase Experimental Treatment 2 Interventions

Safety assessment of odronextamab in combination with cemiplimab and selection of recommended phase 2 dose (RP2D) regimen(s) for the combination of odronextamab and cemiplimab.

Cemiplimab is already approved in Canada, Brazil for the following indications:

Approved in Canada as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in Brazil as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

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]

In a phase 1b trial involving 36 patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the combination of obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola) showed limited efficacy, with complete response rates of 33% and 14% for follicular lymphoma patients at different doses, and only 13% for diffuse large B-cell lymphoma patients receiving rituximab-atezo-pola.

Safety concerns were significant, particularly with G-atezo-pola, where 62% of follicular lymphoma patients experienced severe adverse events, including two deaths, leading to the decision not to pursue further development of either combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma. Topp, MS., Eradat, H., Florschütz, A., 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]

A comprehensive analysis of 63 treatment regimens for relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) showed that combination therapies significantly improve overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared to monotherapy.

Specific regimens, such as rituximab combined with inotuzumab ozogamicin and R-BEAM+ASCT, demonstrated particularly high efficacy, with median overall survival times ranging from 25 to 48.2 months, highlighting the potential of these combinations in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative evaluation of therapy options for relapsed/refractory diffuse large B-cell lymphoma: A model-based meta-analysis. Li, T., Yu, J., Hou, M., et al.[2023]

In a study of 379 patients with diffuse large B-cell lymphoma (DLBCL), the treatment regimen R-ACVBP showed a significant survival advantage over R-CHOP, particularly for patients with non-germinal center B-cell-like (non-GCB) tumors, indicating that tumor classification can influence treatment outcomes.

The Hans algorithm for subclassifying tumors was found to be a significant predictor of progression-free survival and overall survival, suggesting it could be used as a biomarker to identify patients who would benefit from the more intensive R-ACVBP treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. Molina, TJ., Canioni, D., Copie-Bergman, C., et al.[2019]

The combination of rituximab and lenalidomide (R2) significantly improves treatment efficacy for recurrent non-Hodgkin lymphoma compared to rituximab alone, leading to its approval for use in previously treated patients with follicular and marginal zone lymphoma.

R2 has a manageable safety profile, with common adverse events including grade 3/4 neutropenia, skin rashes, and gastrointestinal issues, indicating that while it is effective, careful monitoring and management of side effects are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma. Cheson, BD., Morschhauser, F., Martin, P.[2021]

Lenalidomide, especially when combined with rituximab (the 'R(2)' regimen), shows enhanced efficacy in treating indolent B-cell and mantle cell lymphomas, even in patients resistant to rituximab, while maintaining a manageable safety profile.

The most common serious side effect is asymptomatic neutropenia, which can be managed through dose adjustments, and while immune-related symptoms like rash are more frequent with the R(2) regimen, they are generally low-grade and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. Ruan, J., Shah, B., Martin, P., et al.[2020]

In a phase III trial involving 36 Japanese patients with relapsed indolent non-Hodgkin lymphoma, the combination of lenalidomide and rituximab (R2) significantly improved progression-free survival (PFS) compared to rituximab plus placebo, with a hazard ratio of 0.32.

While R2 showed superior efficacy with a median PFS not reached versus 16.5 months for the placebo group, it also had a higher incidence of grade 3/4 adverse events (67% vs. 22%), mainly due to increased neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Japanese patients from the AUGMENT phase III study of lenalidomide + rituximab (R2) vs. rituximab + placebo in relapsed/refractory indolent non-Hodgkin lymphoma. Izutsu, K., Minami, Y., Fukuhara, N., et al.[2020]

Odronextamab, a bispecific antibody targeting CD20 and CD3, demonstrated a manageable safety profile with no dose-limiting toxicities observed during a phase 1 trial involving 145 heavily pretreated patients with B-cell non-Hodgkin lymphoma.

The treatment showed promising efficacy, with an overall objective response rate of 51%, and particularly high response rates in patients with follicular lymphoma (91%) and in those with diffuse large B-cell lymphoma who had not received prior CAR T therapy (53%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Bannerji, R., Arnason, JE., Advani, RH., et al.[2023]

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]

Rituximab (RTX) is a widely used monoclonal antibody for treating diffuse large B-cell lymphoma, often combined with other drugs in the R-CHOP regimen, but some patients experience suboptimal responses or resistance.

New developments in CD20-targeting monoclonal antibodies, including second- and third-generation agents like ofatumumab and obinutumumab, are being actively researched to improve treatment outcomes for B-cell non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. Cang, S., Mukhi, N., Wang, K., 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. Germany pubmed.ncbi.nlm.nih.gov

Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma. [2023]

3. 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]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Quantitative evaluation of therapy options for relapsed/refractory diffuse large B-cell lymphoma: A model-based meta-analysis. [2023]

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

Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. [2019]

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

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma. [2021]

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

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. [2020]

8. Australia pubmed.ncbi.nlm.nih.gov

Radioimmunotherapy with 131 I-rituximab for patients with relapsed or refractory follicular or mantle cell lymphoma. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

Analysis of Japanese patients from the AUGMENT phase III study of lenalidomide + rituximab (R2) vs. rituximab + placebo in relapsed/refractory indolent non-Hodgkin lymphoma. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. [2023]

11. 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]

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

Novel CD20 monoclonal antibodies for lymphoma therapy. [2022]