This phase II trial studies the effect of polatuzumab vedotin, rituximab, ifosfamide, carboplatin, and etoposide as initial salvage therapy in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Polatuzumab vedotin is a monoclonal antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79b positive cancer cells in a targeted way and delivers vedotin to kill them. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as ifosfamide, carboplatin, and etoposide, 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 chemotherapy with immunotherapy may kill more cancer cells in patients with diffuse large B-cell lymphoma.

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of polatuzumab vedotin (Pola) added to rituximab, ifosfamide, carboplatin, and etoposide (PolaR-ICE) as first salvage therapy for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). (Safety Lead-in) II. Evaluate the anti-tumor activity of PolaR-ICE as first salvage therapy for R/R DLBCL as assessed by the complete response rate after 2 cycles. (Phase 2)

SECONDARY OBJECTIVES:

I. Evaluate the overall response rate to PolaR-ICE as first salvage therapy for R/R DLBCL.

II. Evaluate the progression-free and overall survival of patients who received PolaR-ICE as first salvage therapy for R/R DLBCL followed by autologous stem cell transplantation (ASCT) and single-agent Pola consolidation after ASCT.

III. Evaluate the CR rate after Pola consolidation among those who were partial response (PR) at ASCT.

IV. Evaluate the toxicity of PolaR-ICE salvage therapy and that of Pola consolidation after ASCT.

V. Assess the rate of stem cell mobilization and collection failure in patients with R/R DLBCL who receive PolaR-ICE as first salvage therapy.

EXPLORATORY OBJECTIVES:

I. Assess the kinetics of circulating tumor deoxyribonucleic acid (DNA) after PolaR-ICE as first salvage therapy for R/R DLBCL followed by ASCT and single-agent Pola consolidation after ASCT.

II. Assess possible biomarkers of response to PolaR-ICE in patients with R/R DLBCL.

III. Examine the association between clinical outcomes (response, progression-free survival [PFS]) and pathological tumor characteristics.

IV. Examine the association between clinical outcomes (response, PFS) and circulating tumor (ct)DNA characteristics (mutation profile, kinetics of clearance).

OUTLINE:

SALVAGE THERAPY: Patients receive polatuzumab vedotin intravenously (IV) on day 1, rituximab IV on day 1, etoposide IV on days 1-3, carboplatin IV on day 2, and ifosfamide IV on day 2 or days 1-3. Treatment repeats every 21 days for up to 2-3 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response, partial response or stable disease by cycle 2 day 15 (C2D15) may receive 1 additional cycle of PolaR-ICE IV.

CONSOLIDATION THERAPY: Within 30-60 days after ASCT, patients receive polatuzumab vedotin IV on day 1. Treatment repeats every 21 days for up to 3-4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then periodically for up to 2 years.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

  • Assent, when appropriate, will be obtained per institutional guidelines

• Be willing to provide archival tissue of a biopsy that was performed after the frontline systemic therapy

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval

• Eastern Cooperative Oncology Group (ECOG) =< 2

• Histologically confirmed diagnosis of diffuse large B-cell lymphoma according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution. Subtypes of DLBCL including transformed indolent lymphomas (TIL), primary mediastinal large B-cell lymphoma (PMBCL), and aggressive B-cell lymphoma unclassified (BCL-U) are eligible

• Biopsy-proven relapsed or refractory disease after 1 line of frontline CD20-directed immunotherapy with anthracycline- or anthracenedione-based multi-agent chemotherapy. Monotherapy with rituximab or other CD20-directed immunotherapy prior to frontline chemotherapy or as maintenance therapy, and radiation therapy in a limited field or as a part of the frontline treatment plan are permitted

• Prior lymphoma therapy should be completed at least 2 weeks before start of protocol therapy

• Measurable disease by computed tomography (CT) or positron emission tomography (PET)/CT scan with one or more sites of disease >= 1.5 cm in longest dimension

• Considered eligible for high-dose chemotherapy followed by ASCT

• Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 to prior anti-cancer therapy

• Absolute neutrophil count (ANC) >= 1,000/mm^3 (without bone marrow involvement)

  • NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement

• ANC >= 750/mm^3 (with bone marrow involvement)

  • NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement

• Platelets >= 100,000/mm^3 (without bone marrow involvement)

  • NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement

• Platelets >= 75,000/mm^3 (with bone marrow involvement)

  • NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement

• Hemoglobin >= 8 g/dL (no erythropoietin and/or packed red blood cells (pRBC) transfusion allowed within 7 days prior to screening)

• Total bilirubin =< 1.5 X upper limit of normal (ULN). If hepatic involvement by lymphoma, or Gilbert's disease: =< 3 X ULN

• Aspartate aminotransferase (AST) =< 2.5 x ULN. If hepatic involvement by lymphoma: AST =< 5 x ULN

• Alanine aminotransferase (ALT) =< 2.5 x ULN. If hepatic involvement by lymphoma: ALT =< 5 x ULN

• Creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula

• If not receiving anticoagulants: international normalized ratio (INR) OR prothrombin (prothrombin time [PT]) =< 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants

• If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x ULN. If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 12 months after the last dose of polatuzumab vedotin or rituximab for women, at least 5 months following the last dose of polatuzumab vedotin or 3 months following the last dose of rituximab for men, and at least 6 months following the last dose of ifosfamide, carboplatin, or etoposide for both women and men

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Patients who are not hematopoietic stem cell transplant candidates are excluded

• Prior solid organ transplantation

• Systemic steroid therapy or any other form of immunosuppressive therapy for lymphoma symptom control must be tapered down to =< 10 mg/day prednisone or equivalent. Exceptions are:

  • Inhaled or topical steroids
  • Adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of active autoimmune disease

• Peripheral neuropathy >= grade 2 or demyelinating form of Charcot-Marie-Tooth disease

• Known active central nervous system (CNS) involvement by lymphoma, including leptomeningeal involvement

• Active infection requiring systemic therapy

• Other active malignancy requiring therapy. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to study agents

• Recent major surgery (within 4 weeks) prior to start of protocol therapy, other than for diagnosis

• Symptomatic cardiac disease (including symptomatic ventricular dysfunction, symptomatic coronary artery disease, and symptomatic arrhythmias), cerebrovascular event/stroke or myocardial infarction within the past 6 months

• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with past HBV infection (defined as negative hepatitis B surface antigen [HBsAg] and positive hepatitis B core antibody [HBcAb]) are eligible if HBV DNA is undetectable. Patients who are positive for HCV antibody are eligible if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). Testing to be done only in patients suspected of having infections or exposures

• Known active human immunodeficiency virus (HIV) infection. Subjects who have an undetectable or unquantifiable HIV viral load with CD4 >= 200 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures

• History of or current progressive multifocal leukoencephalopathy (PML)

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)