Nivolumab + Chemo-Immunotherapy for Large B-Cell Lymphoma

Not currently recruiting at 261 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Heart disease, Infection, Autoimmune, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 10

Duration: 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding nivolumab, an immunotherapy drug, to standard chemo-immunotherapy treatments can enhance the body's ability to fight large B-cell lymphoma, a type of cancer. Researchers aim to determine if nivolumab can boost the immune system's effectiveness in attacking cancer cells compared to chemo-immunotherapy alone. Suitable candidates for this trial include those with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). Participants will receive a combination of chemotherapy drugs and rituximab (another immunotherapy), with or without nivolumab, and some may also undergo radiation therapy. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants an opportunity to contribute to the development of a promising treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on systemic treatment for an active autoimmune disease, you may not be eligible to participate. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nivolumab, whether used alone or with other treatments, is generally well-tolerated by patients. For instance, studies found that combining nivolumab with brentuximab vedotin was safe over three years, with no new safety issues. When used with radiation therapy, nivolumab proved effective and safe for patients with certain types of lymphoma. However, some studies reported that about 62% of patients experienced severe side effects, with only 24% directly linked to the treatment. This indicates that while nivolumab is generally safe, significant side effects can occur, though not all are caused by the drug itself. Overall, these studies suggest that nivolumab is generally safe for treating certain types of lymphoma, but awareness of possible side effects is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for large B-cell lymphoma because they integrate nivolumab, an immunotherapy drug that boosts the immune system's ability to fight cancer cells. Unlike the standard R-CHOP regimen, which includes a combination of chemotherapy drugs and rituximab, these investigational treatments incorporate nivolumab to potentially enhance effectiveness. Furthermore, certain arms of the study add radiation therapy after chemotherapy to target residual cancer cells more precisely. This combination approach aims to improve outcomes by leveraging both the body's immune response and targeted treatment strategies against lymphoma.

What evidence suggests that this trial's treatments could be effective for large B-cell lymphoma?

Research has shown that nivolumab, one of the treatments in this trial, might work well for certain types of lymphoma when combined with other treatments. Studies have found that nivolumab can help the immune system fight cancer cells, leading to lasting improvements in some patients with hard-to-treat lymphoma. Some patients treated with nivolumab have even experienced long-term remissions. In this trial, some participants will receive nivolumab combined with radiation therapy, which has shown potential in treating refractory primary mediastinal B-cell lymphoma (PMBCL), even when other treatments have failed. Overall, these findings suggest that nivolumab, especially when used with other therapies, could be a valuable option for treating PMBCL. ^{1 2 6 7 8}

Who Is on the Research Team?

Lisa G Roth

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for people with newly diagnosed primary mediastinal B-cell lymphoma. Eligible participants include children over 2 years old and adults with good kidney function, no severe liver issues unrelated to lymphoma, and a stable heart condition. HIV-positive patients can join if they have an undetectable viral load. Pregnant women, breastfeeding mothers, those with active autoimmune diseases or infections, and individuals who've had certain recent cancer treatments are excluded.

Inclusion Criteria

All patients and/or their parents or legal guardians must sign a written informed consent

I am between 2 and 6 years old with a creatinine level at or below 0.8 mg/dL.

I am between 13 and 16 years old with a creatinine level below the gender-specific limit.

Exclusion Criteria

I started a specific cancer treatment less than 3 weeks ago.

I had cancer treated with chemo or chest radiation but have been in remission for 3 years.

I am not breastfeeding, or I agree not to breastfeed during and for 6 months after the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive chemo-immunotherapy with or without nivolumab for up to 6 cycles, each cycle lasting 21 days

18 weeks

6 visits (in-person)

Radiation

Participants in certain arms undergo radiation therapy over 25 fractions within 6-8 weeks after chemotherapy

6-8 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 7 years

Every 3 months for year 1, every 6 months for years 2-3, annually thereafter

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Etoposide Phosphate
• Nivolumab
• Radiation Therapy
• Rituximab

Trial Overview

The study tests nivolumab combined with chemo-immunotherapy against chemo-immunotherapy alone in treating primary mediastinal B-cell lymphoma. Nivolumab is an immunotherapy drug that may help the immune system fight cancer by stopping cancer cells from growing.

How Is the Trial Designed?

Group I: Arm F (R-CHOP, nivolumab, radiation therapy) Experimental Treatment 15 Interventions

Patients receive treatment as in Arm D. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study.

Group II: Arm D (R-CHOP, nivolumab) Experimental Treatment 15 Interventions

Patients receive treatment as in Arm C. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study.

Group III: Arm B (DA-EPOCH-R, nivolumab) Experimental Treatment 18 Interventions

Patients receive treatment as in Arm A. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO and LP for CSF collection during screening. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study.

Group IV: Arm C (R-CHOP) Active Control 14 Interventions

Patients receive prednisone or prednisolone PO QD on days 1-5 and rituximab IV or rituximab and hyaluronidase human SC over 5 minutes on day 1 or 5. Patients also receive cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV over 1-15 minutes or up to 60 minutes, and vincristine sulfate IV over 1 or up to 60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study.

Group V: Arm A (DA-EPOCH-R) Active Control 17 Interventions

See Detailed Description

Group VI: Arm E (R-CHOP, radiation therapy) Active Control 15 Interventions

Patients receive treatment as in Arm C. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 33 patients with aggressive non-Hodgkin's lymphoma, the combination of Rituxan (rituximab) and CHOP chemotherapy resulted in a high overall response rate of 94%, with 61% achieving a complete response.

The treatment was well-tolerated, with common side effects like fever and chills, and did not hinder the completion of the full six-course regimen, indicating both safety and efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. Vose, JM., Link, BK., Grossbard, ML., et al.[2022]

In a study of 130 non-Hodgkin's lymphoma patients undergoing RCHOP chemotherapy, 28% developed asymptomatic cardiotoxicity, highlighting the risk of heart damage even when patients do not show symptoms.

Myocardial work parameters, particularly global work efficiency (GWE) and global constructive work (GCW), were identified as strong predictors of left ventricular ejection fraction (LVEF) decline, suggesting they should be monitored to detect early signs of cardiotoxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myocardial work-A new tool for early detection of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy induced-cardiotoxicity in hematological patients. Mihalcea, D., Memis, H., Balinisteanu, A., et al.[2023]

In a study of 115 patients with Waldeyer's ring diffuse large B-cell lymphoma, those treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) showed significantly better progression-free survival (PFS) and overall survival (OS) compared to those receiving standard R-CHOP treatment, with 2-year PFS rates of 90.1% versus 80.5%.

The DA-EPOCH-R treatment was associated with fewer deaths (2 out of 42 patients) compared to R-CHOP (9 out of 42 patients) during a median follow-up of 45 months, while both treatments had similar clinical responses and treatment-related toxicities, indicating that DA-EPOCH-R is a safer and more effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution. Liang, Y., Liu, X., Yang, J., et al.[2023]

The combination of rituximab with CHOP chemotherapy significantly improves response rates, event-free survival, and overall survival in elderly patients (over 60 years) with diffuse large B-cell lymphomas compared to CHOP alone.

The addition of rituximab does not increase the number or severity of toxic events compared to CHOP alone, indicating it is a safe and effective treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of diffuse large B-cell lymphomas. Coiffier, B.[2018]

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard treatment for relapsed diffuse large B-cell lymphoma, but the addition of rituximab has improved outcomes after first-line treatment and relapses.

The CORAL trial found no significant difference in response rates between two salvage regimens (R-ICE and R-DHAP), and identified that factors like early relapse and certain genetic markers significantly affect survival, indicating that over 70% of patients may not benefit from standard salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Gisselbrecht, C.[2022]

In a pooled analysis of 150 patients with HIV-associated aggressive B-cell non-Hodgkin lymphoma, those treated with R-EPOCH showed significantly better event-free survival (EFS) and overall survival (OS) compared to those receiving R-CHOP, particularly in patients with a CD4 count ≥100/μL.

Patients with CD4 counts <50/μL experienced a much higher rate of treatment-related deaths (37% vs 6%), indicating that lower immune function increases the risk of lethal toxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Barta, SK., Lee, JY., Kaplan, LD., et al.[2022]

The R-VNCOP-B regimen, which includes rituximab and several other chemotherapy agents, showed high efficacy and manageable toxicity in treating an elderly patient with high-grade B-cell lymphoma, leading to rapid improvement and long-lasting complete remission.

This case study suggests that R-VNCOP-B could be a promising first-line treatment option for elderly patients with aggressive non-Hodgkin lymphoma, especially those who may not tolerate more intensive regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable response after VNCOP-B and rituximab in an elderly patient with high-grade B-cell lymphoma. Cencini, E., Fabbri, A., Schiattone, L., et al.[2019]

In a study of 195 patients with relapsed/refractory aggressive B-cell lymphomas, the overall response rate to second-line platinum-based immunochemotherapy was 44%, with a median progression-free survival (PFS) of 3 months and overall survival (OS) of 8 months.

Patients who experienced early treatment failure (relapse within 12 months of first-line therapy) had significantly worse outcomes, with a median PFS of only 2.8 months and OS of 6 months, suggesting a need for alternative treatment strategies in this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure. Ayers, EC., Li, S., Medeiros, LJ., et al.[2020]

In a study of 40 patients with low-grade or follicular B-cell non-Hodgkin's lymphoma, the combination of Rituxan (Rituximab) and CHOP chemotherapy resulted in a high overall response rate of 95%, with 55% achieving complete remission.

The combination therapy showed promising safety, with common side effects being manageable, and it also indicated potential for clearing minimal residual disease, as evidenced by the conversion of the bcl-2 translocation from positive to negative in several patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. Czuczman, MS., Grillo-López, AJ., White, CA., 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]

The combination of rituximab with CHOP chemotherapy significantly improves response rates, event-free survival, and overall survival in elderly patients (over 60 years) with diffuse large B-cell lymphomas compared to CHOP alone.

The addition of rituximab does not increase the number or severity of toxic events compared to CHOP alone, indicating it is a safe and effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of diffuse large B-cell lymphomas. Coiffier, B.[2022]

In a study of 20 patients with untreated poor prognosis diffuse large B-cell lymphoma (DLBCL), the two-weekly dose-adjusted EPOCH-like chemotherapy (DA-EDOCH14-R) showed a promising three-year progression-free survival (PFS) rate of 95%, compared to 74% in a previous trial with a three-weekly regimen.

The treatment was well-tolerated with manageable toxicity and no therapy-related deaths, highlighting its safety, especially for patients with a high-risk prognosis (age-adjusted International Prognostic Index of 3), where PFS reached 100% compared to just 30% in the previous trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. García-Suárez, J., Flores, E., Callejas, M., et al.[2015]

In a study of 163 patients with relapsed or refractory diffuse large B-cell lymphoma treated with R-ESHAP, those who had not been previously exposed to rituximab (R- group) showed significantly better progression-free survival (57% vs. 17% at 3 years) and overall survival (67% vs. 38% at 3 years) compared to those who had prior rituximab treatment (R+ group).

Prior exposure to rituximab was identified as an independent adverse prognostic factor, indicating that patients with primary refractory disease had very low response rates (8% complete remission) when treated with R-ESHAP, highlighting the need for alternative treatment strategies for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Martín, A., Conde, E., Arnan, M., et al.[2015]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6528729/

Nivolumab for Relapsed/Refractory Diffuse Large B-Cell ...

All three patients with complete remission—3% of the auto-HCT–failed cohort—had durable response (11 or more, 14 or more, and 17 months).

2.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40706069/

Nivolumab in Combination with R-CHOP for Treatment ...

The observed therapy-related adverse events were not significantly different from previous reports each nivolumab and R-CHOP, respectively.

3.

ashpublications.org

ashpublications.org/bloodadvances/article/7/18/5272/496496/Nivolumab-combined-with-brentuximab-vedotin-for-R

Nivolumab combined with brentuximab vedotin for R/R ...

Nivolumab + BV showed durable safety and efficacy as salvage in patients with R/R PMBL after 3-year follow-up, with no new safety signals.

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S2949820125000840

Outcomes in relapsed/refractory diffuse large B-cell ...

The median OS for patients with primary refractory DLBCL was only 4.7 months, whereas it was 8.7 months for patients with disease refractory to second-line ...

5.

astctjournal.org

astctjournal.org/article/S2666-6367(24)00692-4/fulltext

Addition of Nivolumab Tailored by Expansion of CAR-T ...

We conclude that the addition of nivolumab based on CAR-T cell expansion in patients with SD/PD-LBCL is safe and yields promising early response ...

6.

packageinserts.bms.com

packageinserts.bms.com/pi/pi_opdivo.pdf

OPDIVO U.S. Prescribing Information

HIGHLIGHTS OF PRESCRIBING INFORMATION. These highlights do not include all the information needed to use OPDIVO safely and effectively. See full prescribing ...

7.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.19.01492

Efficacy and Safety From the Phase II CheckMate 436 Study

In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.

8.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0006497123110639

A Phase Ib Study to Evaluate the Safety and Efficacy of ...

This study demonstrates promising efficacy of frontline combination nivolumab-R-CHOP for high-risk DLBCL including pts with intermediate/high risk IPI, tLL, ...