Nivolumab and Combination Chemotherapy in Treating Participants With Diffuse Large B-Cell Lymphoma

This phase I/II trial studies the side effects and best dose of nivolumab and how well it works when giving together with combination chemotherapy in treating participants with diffuse large B-cell lymphoma. Monoclonal antibodies, such as nivolumab, interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, 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. Giving nivolumab and combination chemotherapy may work better in treating participants with diffuse large B-cell lymphoma.

PRIMARY OBJECTIVES:

I. To identify the maximum tolerated dose (MTD) for the combination treatment of nivolumab and rituximab, cyclophosphamide, doxorubicin hydrochloride (doxorubicin), vincristine sulfate (vincristine), and prednisone (R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL). (Phase I) II. To assess the impact of nivolumab + R-CHOP on response by looking at complete response (CR) rates. (Phase II)

SECONDARY OBJECTIVES:

I. To look at preliminary efficacy as measured by overall response rate for combination nivolumab + R-CHOP.

II. To assess the impact of nivolumab + R-CHOP on survival outcomes, specifically progression-free survival (PFS), overall survival (OS) and event-free-survival (EFS).

III. To assess toxicity and tolerability of patients treated with nivolumab + R-CHOP.

IV. To assess quality of life in patients treated with nivolumab + R-CHOP.

EXPLORATORY OBJECTIVES:

I. To explore the impact of the PD-1:PD-L1 regulatory axis and targeting this axis on the immune microenvironment.

II. To identify the process of cachexia as a potential mechanism of resistance to anti-PD-1 therapy.

OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study.

Participants receive nivolumab intravenously (IV) over 30 minutes on day 1. Participants also receive rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone orally (PO) on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed for up to 18 months.

Eligibility Criteria:
Inclusion Criteria:

* Patient must have a confirmed diagnosis of:

  * De novo DLBCL including the clinical subtypes of primary mediastinal, - cell/histiocyte-rich large B-cell lymphoma and intravascular DLBCL OR
  * De novo transformed DLBCL from follicular lymphoma (FL) OR
  * Any high grade CD20+ B-cell lymphoma per World Health Organization (WHO) 2016 OR
  * CD20+ aggressive B-cell lymphoma unclassifiable.
* Patient must be deemed an appropriate candidate for R-CHOP therapy.
* Patients must be naive to prior therapy for the study diagnosis.
* Patient must have advanced stage III/IV early stage disease where provider determines single modality therapy with chemo-immunotherapy is most appropriate (i.e radiation deferred).
* Patient must have measurable disease (defined as \>= 1.5 cm in diameter) with correlated fludeoxyglucose F-18 (FDG)-avidity on positron emission tomography (PET) scan with Deauville score of 4 or 5 at time of diagnosis.
* Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =\< 2.
* Absolute neutrophil count (ANC) \>= 1000/mm\^3, independent of growth factor support or \>= 500/mm\^3 in cases of ongoing bone marrow involvement (in either case, these must be independent of transfusion support) documented =\< 28 days prior to registration.
* Platelets \>= 100,000/mm\^3, or \>= 50,000 in cases of ongoing bone marrow involvement (In either case, these must be independent of transfusion support) documented =\< 28 days prior to registration.
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) documented =\< 28 days prior to registration.
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) /alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SPGT\]) =\< 3 x ULN documented =\< 28 days prior to registration.
* Creatinine clearance \>= 25 mL/min documented =\< 28 days prior to registration.
* Females of child-bearing potential (FOCBP) and men who are sexually active with FOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment and the designated post-treatment period.

  * NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    * Has not undergone a hysterectomy or bilateral oophorectomy.
    * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months).
* Females of childbearing potential (FOCBP) must have a negative urine or serum pregnancy test within 7 days prior to registration on study.
* Patients must have the ability to understand and willingness to sign a written informed consent prior to registration on study.

Exclusion Criteria:

* Patients who have received prior therapy intended to treat the study diagnosis are not eligible.
* Patients who have received prior anti-PD-1/L1 therapy for any indication are not eligible.
* Patients who require urgent cytoreductive therapy (e.g. surgery or radiation) are not eligible.
* Subjects with known immunodeficiency, known autoimmune disease, or concurrent use of immunomodulatory agents are not eligible.
* Patients who have a condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications =\< 14 days prior to registration are not eligible.

  * NOTE: Inhaled steroids and adrenal replacement steroid doses \>10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
* Patients with known central nervous system (CNS) involvement are not eligible.
* Patients with an active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy are not eligible.

  * NOTE: Exceptions to this are as follows: localized non-melanotic skin cancer and any cancer that in the judgment of the investigator has been treated with curative intent and will not interfere with the study treatment plan and response assessment. Prostate and breast cancer patients undergoing hormone therapy with no currently active disease are eligible.
* Patients with known human immunodeficiency virus (HIV) are not eligible.
* Patients with clinically active hepatitis A, B, or C infections are not eligible.

  * NOTE: Patients with a history of hepatitis may be eligible if they have a normal titer. Such cases should be approved by the study principal investigator (PI).
* Patients who have any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator?s opinion, could compromise the subject?s safety or put the study outcomes at risk are not eligible.
* Pregnant or nursing females are not eligible.
* Patients with uncontrolled intercurrent illness including, but not limited to, any of the following are not eligible:

  * Ongoing or active systemic infection.
  * Symptomatic congestive heart failure.
  * Myocardial infarction within 6 months prior to registration.
  * Unstable angina pectoris.
  * Uncontrolled or symptomatic cardiac arrhythmias.
  * Any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional classification.
  * Psychiatric illness/social situations that would limit compliance with study requirements.