This phase II trial studies the side effects and how well brentuximab vedotin and combination chemotherapy work in treating patients with CD30-positive peripheral T-cell lymphoma. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, etoposide, and prednisone 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 brentuximab vedotin and combination chemotherapy may work better in treating patients with CD30-positive peripheral T-cell lymphoma.

PRIMARY OBJECTIVES:

I. Assess the safety and tolerability of cyclophosphamide, doxorubicin hydrochloride (doxorubicin), etoposide phosphate (etoposide), prednisone, and brentuximab vedotin (CHEP-BV), as induction therapy in patients with CD30-positive peripheral T-cell lymphoma (PTCL). (Safety lead-in) II. Assess the anti-lymphoma activity of CHEP-BV as induction treatment in patients with CD30-positive PTCL. (Phase 2)

SECONDARY OBJECTIVES:

I. Describe outcomes of CD30-positive PTCL patients who go on to receive BV consolidation therapy post CHEP-BV induction with/without autologous hematopoietic cell transplantation/radiation.

EXPLORATORY OBJECTIVES:

I. Explore the rate of minimal residual disease (MRD) negativity (as assessed by next-generation sequencing) and MRD kinetics after CHEP-BV and BV consolidation therapy in CD30-positive PTCL.

II. Explore the possible association between outcome after study treatment and CD30 expression, gene expression profiles (GEP), and genetic mutations as measured in PTCL tumor samples.

OUTLINE:

INDUCTION: Patients receive cyclophosphamide intravenously (IV) and doxorubicin IV on day 1, etoposide IV on days 1-3, and prednisone orally (PO) on days 1-5. Patients also receive brentuximab vedotin IV over approximately 30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (or for up to 5 cycles for patients who received 1 cycle of cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP]-like or brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone [CHP-BV] therapy prior to induction, per investigator's discretion) in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Between 30-60 days post-consolidative autologous stem cell therapy, post-consolidative radiation therapy, or after completing induction cycle 6 (cycle 5 for patients who qualify for receiving 5 cycles of CHEP-BV instead of 6), patients with objective response (complete response or partial response) receive brentuximab vedotin IV over approximately 30 minutes on day 1. Treatment repeats every 21 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 6 months, and 12 months.

Inclusion Criteria:

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

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies will be retrieved and submitted post-enrollment

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

• Eastern Cooperative Oncology Group (ECOG) status =< 2

• Histologically confirmed mature peripheral T-cell or natural killer (NK)-cell lymphoma per World Health Organization (WHO) classification, including:

  • Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) with international protein index (IPI) of 2 or higher (must have bulky [defined as mass >= 10 cm] stage II, or stage III-IV disease)

  • ALK-negative ALCL

    • NOTE: Per amendment dated 05-10-19, ALCL will no longer be eligible except for Canada.

  • PTCL-not otherwise specified (NOS)

  • Angioimmunoblastic T-cell lymphoma (AITL)

  • Adult T-cell lymphoma/leukemia (ATLL)

  • Enteropathy-associated T-cell lymphoma (EATL)

  • Hepatosplenic T-cell lymphoma

• CD30-positivity (e.g. at least 1%) by immunohistochemistry confirmed by hematopathology review at the participating institution

• Measurable disease of at least 1.5 cm on computed tomography (CT) or positron emission tomography (PET)-CT scan

• Absolute neutrophil count (ANC) >= 1,000/mm^3

  • Exception: unless documented bone marrow involvement by lymphoma

• Platelets >= 50,000/mm^3

  • Exception: unless documented bone marrow involvement by lymphoma

• Total serum bilirubin =< 1.5 x upper limit of normal (ULN) OR if hepatic involvement by lymphoma: =< 3 x ULN for Gilbert's disease or documented hepatic involvement by lymphoma

• Aspartate aminotransferase (AST) =< 2 x ULN OR if hepatic involvement by lymphoma: AST =< 5 x ULN

• Alanine aminotransferase (ALT) =< 2 x ULN OR if hepatic involvement by lymphoma: ALT =< 5 x ULN

• Creatinine clearance of >= 60 mL/min per the Cockcroft-Gault formula

• Left ventricular ejection fraction (LVEF) >= 45%

• 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 WOCBP 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 6 months after the last dose of protocol therapy; 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:

• Prior treatment of PTCL with systemic anti-lymphoma therapies, investigational agents, radiation

  • Exception: May have received 1 cycle of CHOP-like therapy (e.g. CHOP, CHOEP, EPOCH) or 1 cycle of CHP-BV; these participants must initiate day 1 cycle 1 of study therapy (CHEP-BV) no less than 19 days from prior CHOP-like or CHP-BV therapy; Patients who received 1 cycle of CHOP-like or 1 cycle of CHP-BV therapy prior to initiating induction with CHEP-BV are allowed to receive only 5 cycles of CHEP-BV instead of 6 cycles, per investigator's discretion

• History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has not been in remission for at least 3 years.

  • Exceptions: Non-melanoma skin cancer and in situ cervical cancer

• 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

• Central nervous system involvement by lymphoma, including leptomeningeal involvement

• History of progressive multifocal leukoencephalopathy (PML)

• Active >= grade 3 viral, bacterial, or fungal infection within 2 weeks prior to day 1 of protocol therapy

• Any known human immunodeficiency virus (HIV) infection, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

• Baseline peripheral neuropathy >= grade 2 or patients with the demyelinating form of Charcot-Marie-Tooth syndrome

• Known severe hypersensitivity to any study related agent excipient(s)

• Females only: pregnant or breastfeeding

• Any other condition that would, in the investigator's judgement, contraindicate the patient's participation in the clinical study

• 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)