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Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
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.
Study details:
PRIMARY OBJECTIVE:. I. To determine if nivolumab + chemo-immunotherapy results in a superior long term progression-free survival (PFS) (events defined as disease progression confirmed by central review or death) when compared with chemo-immunotherapy alone in patients with newly diagnosed primary mediastinal B-cell lymphoma.
SECONDARY OBJECTIVES:. I. To compare the rates of "efficacy-related event-free survival (EFS)" (eEFS) (events defined as progression, change in therapy due to finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, or death) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL.
II. To compare the rates of "therapy-related EFS" (tEFS) (events defined as relapse/progression, change in therapy for any reason, biopsy + disease after 6 cycles of therapy, secondary malignancy \[SMN\] or death) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL. III.
To compare the rates of overall survival (OS) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL. IV. To establish the rate of a positive positron emission tomography (PET)-computed tomography (CT) (defined as Deauville score 4 or 5) at the completion of 6 cycles of nivolumab + rituximab (R)- cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/dose-adjusted (DA)-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)-R and R-CHOP/DA-EPOCH-R in patients with newly diagnosed PMBCL and evaluate the prognostic significance of such a finding.
EXPLORATORY OBJECTIVES:. I. To bank radiology images for further studies.
II. To bank specimens for future correlative studies. III.
Characterize the immune profile of patients treated with nivolumab + chemo-immunotherapy to identify markers predictive of response. IV. Define the rate of complete response at the completion of initial planned therapy.
OUTLINE: Patients are randomly assigned to backbone therapy or backbone therapy + nivolumab within each of 6 strata. The strata are determined by physician's choice of backbone (DA-EPOCH-R versus \[vs. \] R-CHOP vs.
R-CHOP + RT) and whether or not the patient had 1 prior cycle of therapy. ARM A (DA-EPOCH-R): Patients receive prednisone or prednisolone orally (PO) once daily (QD) on days 1-5 and rituximab intravenously (IV) or rituximab and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 or 5. Patients also receive etoposide phosphate, doxorubicin hydrochloride, and vincristine sulfate IV over 96 hours on days 1-4 and cyclophosphamide IV over 30-60 minutes on day 5.
Beginning 24-72 hours after completing cyclophosphamide, patients receive filgrastim or pegylated filgrastim SC daily until absolute neutrophil count (ANC) is \>= 500/uL after the expected nadir. 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 echocardiography (ECHO) during screening and as clinically indicated and alumbar puncture (LP) for cerebral spinal fluid (CSF) collection optionally during screening.
Patients also undergo computed tomography (CT) or positron emission tomography (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.
ARM B (DA-EPOCH-R + NIVOLUMAB): Patients receive treatment as in Arm A. Patients also receive nivolumab IV over 30 minutes on day 1. 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.
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. ARM D (R-CHOP + NIVOLUMAB): Patients receive treatment as in Arm C. Patients also receive nivolumab IV over 30 minutes on day 1.
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. ARM E (R-CHOP + RADIOTHERAPY): 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. ARM F (R-CHOP + RADIOTHERAPY + NIVOLUMAB): 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. After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and annually thereafter.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 2 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2021-10-05
Primary completion: 2027-09-30
Study completion finish: 2027-09-30
Study type
TREATMENT
Phase
PHASE3
Trial ID
NCT04759586
Intervention or treatment
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
Conditions
- • Primary Mediastinal Large B-Cell Lymphoma
Find a site
Closest Location:
The Children's Hospital at Westmead
Research sites nearby
Select from list below to view details:
The Children's Hospital at Westmead
Westmead, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Royal Children's Hospital
Parkville, Victoria, Australia
Perth Children's Hospital
Perth, Western Australia, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Participant Group/Arm | Intervention/Treatment |
---|---|
ACTIVE_COMPARATOR: Arm A (DA-EPOCH-R)
| PROCEDURE: Biospecimen Collection
|
EXPERIMENTAL: Arm B (DA-EPOCH-R, nivolumab)
| PROCEDURE: Biospecimen Collection
|
ACTIVE_COMPARATOR: Arm C (R-CHOP)
| PROCEDURE: Biospecimen Collection
|
EXPERIMENTAL: Arm D (R-CHOP, nivolumab)
| PROCEDURE: Biospecimen Collection
|
ACTIVE_COMPARATOR: Arm E (R-CHOP, radiation therapy)
| PROCEDURE: Biospecimen Collection
|
EXPERIMENTAL: Arm F (R-CHOP, nivolumab, radiation therapy)
| PROCEDURE: Biospecimen Collection
|
What is the study measuring?
Primary outcome
Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
---|---|---|
Progression-free survival (PFS) | 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. | From enrollment on the study to first occurrence of relapse/progression or death, assessed up to 7 years |
Secondary outcome
Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
---|---|---|
Efficacy-related event-free survival | 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. | Up to 7 years |
Therapy-related event-free survival | 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. | Up to 7 years |
Overall survival | 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. | Up to 7 years |
Proportion of positive positron emission tomography (PET) scans | 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. | Up to 6 cycle (1 cycle = 21 days) |
Frequently Asked Questions
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