Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
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.
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 randomized to 1 of 6 arms.

 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 in the absence of disease progression or unacceptable toxicity.

 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 in
 the absence of disease progression or unacceptable toxicity.

 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 in the absence of disease progression or
 unacceptable toxicity.

 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 in
 the absence of disease progression or unacceptable toxicity.

 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.

 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.

 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.
Inclusion Criteria:

 -  Age >= 2 years

 -  Patient must have histologically confirmed primary mediastinal B-cell lymphoma (PMBCL)
 as defined by World Health Organization (WHO) criteria

 -  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

 -  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

 -  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 permitted if chemotherapy can still be
 delivered with standard dose reductions

 -  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

 Exclusion Criteria:

 -  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, or a pediatric
 mature B-cell non-Hodgkin lymphoma (B-NHL) induction therapy (such as ANHL1131)
 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

 -  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

 -  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