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.