Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
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| ClinicalTrials.gov Identifier: NCT04759586 |
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Recruitment Status :
Recruiting
First Posted : February 18, 2021
Last Update Posted : November 28, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
- Study Details
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Primary Mediastinal Large B-Cell Lymphoma | Procedure: Biospecimen Collection Procedure: Bone Marrow Aspiration Procedure: Bone Marrow Biopsy Procedure: Computed Tomography Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Procedure: Echocardiography Drug: Etoposide Phosphate Biological: Filgrastim Procedure: Lumbar Puncture Biological: Nivolumab Biological: Pegfilgrastim Procedure: Positron Emission Tomography Drug: Prednisolone Drug: Prednisone Radiation: Radiation Therapy Biological: Rituximab Biological: Rituximab and Hyaluronidase Human Drug: Vincristine Sulfate | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 244 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Phase 3 Trial of Nivolumab (NSC# 748726) in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma |
| Actual Study Start Date : | October 5, 2021 |
| Estimated Primary Completion Date : | December 31, 2028 |
| Estimated Study Completion Date : | December 31, 2028 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Lymphoma
Drug Information
available for:
Nivolumab
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Arm A (DA-EPOCH-R)
See Detailed Description
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Procedure: Biospecimen Collection
Undergo blood and CSF sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow biopsy and aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy and aspiration
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Drug: Etoposide Phosphate Given IV
Other Name: Etopophos Biological: Filgrastim Given SC
Other Names:
Procedure: Lumbar Puncture Undergo LP
Other Names:
Biological: Pegfilgrastim Given SC
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Prednisolone Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Biological: Rituximab and Hyaluronidase Human Given SC
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm B (DA-EPOCH-R, nivolumab)
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.
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Procedure: Biospecimen Collection
Undergo blood and CSF sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow biopsy and aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy and aspiration
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Drug: Etoposide Phosphate Given IV
Other Name: Etopophos Biological: Filgrastim Given SC
Other Names:
Procedure: Lumbar Puncture Undergo LP
Other Names:
Biological: Nivolumab Given IV
Other Names:
Biological: Pegfilgrastim Given SC
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Prednisolone Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Biological: Rituximab and Hyaluronidase Human Given SC
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Active Comparator: Arm C (R-CHOP)
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.
|
Procedure: Biospecimen Collection
Undergo blood and CSF sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow biopsy and aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy and aspiration
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Lumbar Puncture Undergo LP
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Prednisolone Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Biological: Rituximab and Hyaluronidase Human Given SC
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm D (R-CHOP, nivolumab)
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.
|
Procedure: Biospecimen Collection
Undergo blood and CSF sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow biopsy and aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy and aspiration
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Lumbar Puncture Undergo LP
Other Names:
Biological: Nivolumab Given IV
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Prednisolone Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Biological: Rituximab and Hyaluronidase Human Given SC
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Active Comparator: Arm E (R-CHOP, radiation therapy)
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.
|
Procedure: Biospecimen Collection
Undergo blood and CSF sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow biopsy and aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy and aspiration
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Lumbar Puncture Undergo LP
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Prednisolone Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Biological: Rituximab Given IV
Other Names:
Biological: Rituximab and Hyaluronidase Human Given SC
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm F (R-CHOP, nivolumab, radiation therapy)
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.
|
Procedure: Biospecimen Collection
Undergo blood and CSF sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow biopsy and aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy and aspiration
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Lumbar Puncture Undergo LP
Other Names:
Biological: Nivolumab Given IV
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Prednisolone Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Biological: Rituximab Given IV
Other Names:
Biological: Rituximab and Hyaluronidase Human Given SC
Other Names:
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Primary Outcome Measures :
- Progression-free survival (PFS) [ Time Frame: From enrollment on the study to first occurrence of relapse/progression or death, assessed up to 7 years ]The primary analysis will be a one-sided Log-rank test stratified by choice of backbone and radiation therapy and whether the patient had a cycle of therapy prior to enrolling.
Secondary Outcome Measures :
- Efficacy-related event-free survival [ Time Frame: Up to 7 years ]Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as progression, change in therapy due to a finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, and death.
- Therapy-related event-free survival [ Time Frame: Up to 7 years ]Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as progression, change in therapy due to a finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, and death.
- Overall survival [ Time Frame: Up to 7 years ]Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as only death.
- Proportion of positive positron emission tomography (PET) scans [ Time Frame: Up to 6 cycle (1 cycle = 21 days) ]Will be analyzed descriptively with a point estimate and Clopper-Pearson 95% confidence interval in the trial overall and in each treatment arm separately. The prognostic significance of positive PET after 6 cycles of therapy will be evaluated using a Cox proportional hazards regression on PFS with PET result (positive versus [vs.] negative), choice of backbone (rituximab [R]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] + radiation therapy [RT] regardless of end-of-therapy imaging vs. R-CHOP without RT unless biopsy positive at end-of-therapy vs. dose-adjusted [DA]-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin [EPOCH]-R without RT unless biopsy positive at end of therapy), and assignment to nivolumab (yes vs. no) as covariates.
Other Outcome Measures:
- Immune profile of patients treated with nivolumab + chemo-immunotherapy [ Time Frame: Up to 7 years ]Analysis will be by paired t-test (for pre- vs. post-treatment measurements) or two-sample equal-variance t-test (for comparisons of nivolumab vs. non-nivolumab or responders [complete response/partial response] vs. non-responders [stable disease/progressive disease]).
- Complete response rate [ Time Frame: At the completion of initial planned therapy ]Will be described using point estimates and Clopper-Pearson 95% confidence intervals for the complete response rate overall and in each treatment arm separately.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 2 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Age >= 2 years
- Patient must have histologically confirmed primary mediastinal B-cell lymphoma (PMBCL) as defined by World Health Organization (WHO) criteria
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Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or ECOG performance status of 3 if poor performance is related to lymphoma
- Children's Oncology Group (COG) Institutions: Use Karnofsky for patients >= 17 and < 18 years of age and Lansky for patients < 17 years of age
- Adults (age 18 or older): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
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Pediatric Patients (age < 18 years): The following must have been obtained within 14 days prior to registration:
- Measured or calculated (based on institutional standard) creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2, or
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Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a serum creatinine based on age/gender as follows:
- Age : 2 to < 6 year; Maximum serum creatinine (mg/dL): 0.8 (male; 0.8 (female)
- Age : 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female)
- Age : 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
- Age : 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
- Age : >= 16 years to < 18 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
- Patients with abnormal liver function will be eligible to enroll if the lab abnormality is thought to be due to the lymphoma or Gilbert's syndrome
- Age >= 18 years: Ejection fraction of >= 50% by echocardiogram
- Age < 18 years: Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- All patients and/or their parents or legal guardians must sign a written informed consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:
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Administration of prior anti-cancer therapy except as outlined below:
- A short course (=< 2 weeks) of corticosteroids for the relief of lymphoma-related symptoms
- A single course of COP (cyclophosphamide, vincristine, and prednisone)
- One cycle of chemo-immunotherapy including R-CHOP, DA-EPOCH-R, a pediatric mature B-cell non-Hodgkin lymphoma (B-NHL) induction therapy (such as ANHL1131), or intrathecal chemotherapy that has not started more than 21 days prior to enrollment
- Active ischemic heart disease or heart failure
- Active uncontrolled infection
- Central nervous system (CNS) involvement of lymphoma
- Previous cancer that required systemic chemotherapy and/or thoracic radiation. Other cancers will be permitted if in remission x 3 years
- Active autoimmune disease that has required systemic treatment (such as disease modifying agents, corticosteroids, or immunosuppressive agents) in the past 2 years. Replacement therapy such as thyroxine, insulin or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment
- In patients < 18 years of age hepatitis B serologies consistent with past or current infections
- Patients with severe hepatic impairment (Child-Pugh class C or serum total bilirubin > 5.0 mg/dL) unless thought to be due to lymphoma or Gilbert's syndrome
- Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
- Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study participation
- Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last dose of rituximab
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04759586
Locations
Show 207 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Lisa G Roth | Children's Oncology Group |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT04759586 |
| Other Study ID Numbers: |
NCI-2021-01071 NCI-2021-01071 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) ANHL1931 ( Other Identifier: Children's Oncology Group ) ANHL1931 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) |
| First Posted: | February 18, 2021 Key Record Dates |
| Last Update Posted: | November 28, 2023 |
| Last Verified: | October 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Lymphoma Lymphoma, B-Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Prednisone Prednisolone Methylprednisolone Acetate Methylprednisolone Methylprednisolone Hemisuccinate Prednisolone acetate |
Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate Cortisone Cyclophosphamide Rituximab Doxorubicin Liposomal doxorubicin Nivolumab Etoposide Vincristine Etoposide phosphate Antineoplastic Agents, Immunological Antibodies |