Nivolumab + Chemo-Immunotherapy for Large B-Cell Lymphoma

Recruiting at 246 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

244 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Nivolumab + Chemo-Immunotherapy for Large B-Cell Lymphoma?

Research shows that adding rituximab to chemotherapy, such as in the R-CHOP regimen, improves response rates and survival in patients with diffuse large B-cell lymphoma. Additionally, rituximab combined with other chemotherapy regimens has shown high efficacy and manageable side effects in treating aggressive non-Hodgkin lymphoma. ^{1 2 3 4 5}

Is the combination of Nivolumab and chemo-immunotherapy safe for humans?

The combination of rituximab with chemotherapy drugs like cyclophosphamide and doxorubicin has been studied in various lymphomas, showing manageable toxicity and no therapy-related deaths in some trials. However, there is a risk of heart-related side effects (cardiotoxicity) with these treatments. ^{1 6 7 8 9}

What makes the drug Nivolumab + Chemo-Immunotherapy unique for treating large B-cell lymphoma?

This treatment is unique because it combines nivolumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with a chemo-immunotherapy regimen that includes rituximab, which targets B-cells, and traditional chemotherapy drugs. This combination aims to enhance the effectiveness of treatment by using both immune system activation and direct cancer cell targeting. ^{6 10 11 12 13}

What is the purpose of this trial?

This phase III trial compares the effects of nivolumab with chemo-immunotherapy versus chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Treatment for PMBCL involves chemotherapy combined with an immunotherapy called rituximab. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nivolumab with chemo-immunotherapy may help treat patients with PMBCL.

Research Team

Lisa G Roth

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 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]

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]

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 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]

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 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]

References

1. United States 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. [2022]

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

Durable response after VNCOP-B and rituximab in an elderly patient with high-grade B-cell lymphoma. [2019]

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

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

4. Italy 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. [2015]

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

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

6. United States 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. [2022]

7. England 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. [2015]

8. China 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. [2023]

9. United States 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. [2023]

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

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

11. United States 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. [2022]

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

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

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

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure. [2020]