This phase I/Ib trial studies the side effects and best dose of parsaclisib with or without polatuzumab-vedotin (Pola) plus the standard drug therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [PaR-CHOP]) and to see how well they work compared with R-CHOP alone in treating patients with newly diagnosed, high risk diffuse large B-cell lymphoma. Parsaclisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Polatuzumab-vedotin is a monoclonal antibody, called polatuzumab, linked to a chemotherapy drug, called vedotin. Polatuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as anti-CD79b receptors, and delivers vedotin to kill them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate, 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. Anti-inflammatory drugs, such as prednisone, lower the body's immune response and are used with other drugs in the treatment of some types of cancer. It is not yet known if giving parsaclisib and R-CHOP together works better than R-CHOP alone in treating patients with high risk diffuse large B-cell lymphoma.

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of parsaclisib in combination with R-CHOP in newly diagnosed diffuse large B-cell lymphoma (DLBCL). (Phase I) II. To assess the complete metabolic response rate by positron emission tomography (PET) (PET complete response [CR]) of combining parsaclisib and R-CHOP in patients with newly diagnosed DLBCL. (Dose Expansion) III. To assess significant toxicities of parsaclisib in combination with polatuzumab vedotin (pola) and R-CHP in newly diagnosed DLBCL. (Pola Safety Lead-in)

SECONDARY OBJECTIVES:

I. To describe the toxicities associated with parsaclisib in combination with R-CHOP. (Phase I) II. To assess the objective response rate (ORR) of parsaclisib in combination with R-CHOP. (Dose Expansion) III. To assess the duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) in patients treated with parsaclisib in combination with R-CHOP. (Dose Expansion) IV. To further describe the toxicities associated with parsaclisib in combination with R-CHOP. (Dose Expansion) V. To describe the toxicities associated with parsaclisib in combination with polatuzumab vedotin and R-CHP. (Pola Safety Lead-in) VI. To assess the PET CR rate and ORR of parsaclisib in combination with polatuzumab vedotin and R-CHP. (Pola Safety Lead-in) VII. To assess the duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) in patients treated with parsaclisib in combination with polatuzumab vedotin and R-CHP. (Pola Safety Lead-in)

OUTLINE: This is a phase I, dose-escalation study of parsaclisib, and safety lead-in of pola.

ARM I (PHASE I AND DOSE EXPANSION): Patients receive parsaclisib orally (PO) once daily (QD) on days 1-10 or 1-14, rituximab intravenously (IV) or biosimilar substitute, cyclophosphamide IV over 30 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV over 15 minutes on day 1. Patients also receive prednisone PO on days 1-5 and pegfilgrastim subcutaneously (SC) or biosimilar substitute on day 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM II (PHASE I AND POLA SAFETY LEAD-IN): Patients receive parsaclisib PO once daily QD on days 1-10 or 1-14, polatuzumab vedotin IV over 90 minutes, rituximab IV or biosimilar substitute, cyclophosphamide IV over 30 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV over 15 minutes on day 1. Patients also receive prednisone PO on days 1-5 and pegfilgrastim SC or biosimilar substitute on day 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months during year 1 and every 4 months during year 2. Patients who experience disease progression before the end of year 2 are followed up every 6 months until 5 years after registration.

Inclusion Criteria:

• Age >= 18 years

• Newly diagnosed, untreated, histologically confirmed diffuse large B-cell lymphoma expressing the CD20 antigen, with ANY of the following:

  • Non-germinal center B-cell (GCB) subtype by Hans algorithm

  • Myc expression >= 40% by immunohistochemistry (IHC)

  • Bcl-2 expression >= 50% by IHC

  • Myc expression >= 40% AND Bcl-2 expression >= 50% by IHC (double expressor)

  • MYC rearrangement by fluorescence in situ hybridization (FISH)

  • Or high-grade B-cell lymphoma with MYC rearrangement AND BCL2 and/or BCL6 rearrangement (double-hit or triple-hit lymphoma) but not a candidate for more aggressive chemotherapy (such as cyclophosphamide, Oncovin [vincristine], doxorubicin, [CODOX]-methotrexate [M]- ifosfamide, Vepesid [etoposide], Ara-C [cytarabine] [IVAC])

    • NOTE: Patients with a new diagnosis of concurrent DLBCL and an indolent lymphoma (previously undiagnosed, such as follicular lymphoma or marginal zone lymphoma) are eligible. However, patients with a known prior diagnosis of indolent lymphoma with new transformation to DLBCL (i.e., transformed lymphoma) are not eligible

• Ann Arbor stages II (bulky disease, i.e., >= 5 cm, or not a candidate for combined modality treatment with R-CHOP plus radiotherapy), III, or IV

• Measurable disease (at least 1 lesion of >= 1.5 cm in one diameter) as detected by computed tomography (CT) or the CT images of PET/CT. Skins lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to registration)

• Platelet count >= 100,000/mm^3 (obtained =< 14 days prior to registration)

• Total bilirubin =< 1.5 x upper limit of normal (ULN), or if total bilirubin is > 1.5 x ULN, the direct bilirubin must be normal (obtained =< 14 days prior to registration)

• Aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with direct liver involvement by lymphoma) (obtained =< 14 days prior to registration)

• Alkaline phosphatase =< 3 x ULN, unless evidence of the direct liver involvement by lymphoma, then =< 5 x ULN (obtained =< 14 days prior to registration)

• Calculated creatinine clearance of >= 30 mL/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration)

• Negative urine pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only

  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Persons of childbearing potential must agree to use one reliable form of birth control

• Provide written informed consent

• Willingness to provide mandatory research blood specimens for banking

• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons (lactating persons are eligible provided that they agree not to breast feed while taking parsaclisib)
  • Persons of childbearing potential who are unwilling to employ adequate contraception

• Primary central nervous system (CNS) lymphoma, or parenchymal, meningeal or cerebrospinal fluid involvement with malignant lymphoma cells

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy (except for patients on effective antiretroviral therapy with undetectable viral load within 6 months)

  • NOTE: If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
  • NOTE: If history of hepatitis C virus (HCV) infection, HCV viral load must be undetectable

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Ongoing inflammatory bowel disease (such as ulcerative colitis) or other colitis requiring active treatment
  • Oxygen dependent baseline lung disease (such as interstitial lung disease or chronic obstructive pulmonary disease [COPD])
  • Or psychiatric illness/social situations that would limit compliance with study requirements

• Received or receiving any other agent which would be considered as a treatment for the lymphoma (with the exception of corticosteroid)

• Other active malignancy requiring therapy such as radiation, chemotherapy or immunotherapy. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria

  • EXCEPTIONS: Localized non-melanotic skin cancer or any cancer that in the judgment of the investigator has been treated with curative intent (e.g., disease-free survival equal or more than 5 years) and will not interfere with the study treatment plan and response assessment
  • NOTE: If there is a history of prior malignancy, they must not require therapy such as radiation, chemotherapy or immunotherapy for their cancer

• History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• >= 25% of bone marrow radiated for other diseases

• Ejection fraction of < 45% by either multigated acquisition scan (MUGA) or echocardiogram (ECHO)