This phase II trial compares the impact of brentuximab vedotin and nivolumab after radiation to standard of care high dose chemotherapy (HDT)-autologous stem cell transplant (ASCT) in standard-risk patients with classic Hodgkin lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). In addition, the phase III trial will compare the effect of pembrolizumab after HDT-ASCT to standard of care HDT-ASCT alone in high-risk patients with relapsed or refractory classic Hodgkin lymphoma. Brentuximab vedotin is in a class of medications called antibody-drug conjugates. It is made of a monoclonal antibody called brentuximab that is linked to a cytotoxic agent called vedotin. Brentuximab attaches to CD30 positive lymphoma cells in a targeted way and delivers vedotin to kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. An ASCT is a procedure in which blood-forming stem cells (cells from which all blood cells develop) are removed, stored, and later given back to the same person. Giving HDT before an ASCT helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Radiation therapy (RT) uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving brentuximab vedotin and nivolumab after radiation may be safe, tolerable and more effective than standard of care HDT-ASCT in treating patients with standard risk relapsed or refractory classic Hodgkin lymphoma. In addition, giving pembrolizumab after standard of care HDT-ASCT may be safe and tolerable and more effective than HDT-ASCT alone in treating high-risk patients with relapsed or refractory classic Hodgkin lymphoma.

PRIMARY OBJECTIVES:

I. Demonstrate the non-inferiority (and possible superiority) in progression free survival (PFS) amongst patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after checkpoint inhibitor-based maintenance and localized radiation in comparison to standard of care HDT-ASCT. (Phase III Standard-Risk) II. Demonstrate the superiority of checkpoint inhibitor-based maintenance after HDT-ASCT in improving PFS among patients with R/R cHL in comparison to standard of care HDT-ASCT. (Phase II High-Risk)

SECONDARY OBJECTIVES:

I. To assess overall survival (OS) in the treatment arms in the standard risk as well as high-risk groups.

II. To assess safety and toxicity of the treatment regimens in the standard risk as well as high risk groups.

EXPLORATORY OBJECTIVES:

I. To evaluate prognostic factors (lactate dehydrogenase [LDH], erythrocyte sedimentation rate [ESR], time to relapse, B symptoms, extranodal disease, stage, bulk, treatment with a checkpoint inhibitor, response at the time of ASCT) associated with risk of progression following HDT-ASCT (Arms B and D).

II. To compare the impact of various radiation therapy modalities utilized (e.g., 3-dimensional conformal radiation therapy [3D-CRT], intensity-modulated radiation therapy [IMRT], proton therapy) and its association with dosimetric and clinical outcomes, including toxicity assessment, (grade 2+), at the end of radiation.

III. To assess PFS for patients in partial metabolic response (PMR) receiving radiation therapy, compared to those patients in complete metabolic response (CMR), for all arms of the study.

OUTLINE: Patients in the standard risk cohort are assigned to Arm S and patients in the high risk cohort are assigned to Arm H.

ARM S: Patients receive standard of care salvage therapy for up to 2-4 cycles per investigator choice. After completing salvage therapy, patients without stable disease (SD) or progressive metabolic disease (PMD) are randomized to Arm A or Arm B.

ARM A: Patients undergo photon RT with either 3DCRT, IMRT, volume modulated arc therapy (VMAT), or tomotherapy or proton RT with either passive scattering, uniform scanning, or pencil beam scanning over 15-17 fractions. Starting 4-8 weeks after completing radiation therapy, patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab for an additional 2 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive HDT and undergo ASCT per standard of care in the absence of disease progression or unacceptable toxicity. Starting within 4-8 weeks after transplant, patients with CMR may also undergo RT as in arm A over 15-17 fractions and patients with PMR may also undergo RT over 20-22 fractions per investigator. Starting 30-45 days after transplant, patients may also receive maintenance treatment with brentuximab vedotin for up to 16 cycles in the absence of disease progression or unacceptable toxicity as determined per investigator at time of randomization.

ARM H: Patients receive 2-4 cycles of standard of care salvage therapy per investigator choice. After completing salvage therapy, patients without SD or PMD are randomized to Arm C or Arm D.

ARM C: Patients receive HDT and undergo ASCT per standard of care. Starting 4-8 weeks after transplant, patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Starting within 4-8 weeks after transplant, patients with CMR may also undergo RT as in arm A over 15-17 fractions and patients with PMR may also undergo RT over 20-22 fractions per investigator. Starting 30-45 days after transplant, patients may also receive maintenance treatment with brentuximab vedotin for up to 16 cycles in the absence of disease progression or unacceptable toxicity as determined per investigator at time of randomization.

ARM D: Patients receive HDT and undergo ASCT per standard of care in the absence of disease progression or unacceptable toxicity. Starting within 4-8 weeks after transplant, patients with CMR may also undergo RT as in arm A over 15-17 fractions and patients with PMR may also undergo RT over 20-22 fractions per investigator. Starting 30-45 days after transplant, patients may also receive maintenance treatment as in arm B in the absence of disease progression or unacceptable toxicity as determined per investigator at time of randomization.

Additionally, patients may undergo blood sample collection, computed tomography (CT), and positron emission tomography (PET)/CT throughout the study.

After completion of study treatment, patients are followed every 6 months for the first 2 years then annually for up to 15 years.

Inclusion Criteria:

• STEP 0 REGISTRATION: Patient must have biopsy confirmed relapsed classical Hodgkin lymphoma

• STEP 0 REGISTRATION: Patient must be 5-75 years of age

• STEP 0 REGISTRATION: Patient must have relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after first line of chemotherapy

• STEP 0 REGISTRATION: Patients > 17 years of age must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and patients ≤ 17 years of age must have a Lansky performance status 50-100

• STEP 0 REGISTRATION: Patient must have had a PET CT or magnetic resonance imaging (MRI) (PET1) confirming relapse. The PET1 must have been completed prior to starting any salvage therapy and must be obtained within 56 days prior to Step 0 registration

  • NOTE: If patient received one cycle of salvage prior to study enrollment, PET1 confirming relapse must have been completed prior to the initiation of any salvage therapy

• STEP 0 REGISTRATION: Patient must be considered standard- or high-risk at the time of initial relapse. If a patient meets one the following criteria below, they are considered high risk:

  • Primary refractory disease to frontline therapy

  • Relapse in < 3 months after completion of frontline non-checkpoint inhibitor containing therapy

  • Relapse in < 6 months after completion of frontline checkpoint inhibitor containing therapy

  • > 4 disease sites at relapse (as defined by the German Hodgkin Study Groups [GHSG] Criteria)

  • Prior radiation that would result in overlapping fields that would exceed the RT dose to critical organs. For additional questions, contact the radiation oncology study co-chairs

  • Patients with bone marrow involvement

    • Patients who do not meet the criteria above are considered standard risk

• STEP 0 REGISTRATION: Patient must be considered eligible for high dose chemotherapy and autologous hematopoietic cell transplant

• STEP 0 REGISTRATION: Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

  • All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 0 registration to rule out pregnancy

  • A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria:

    • Has achieved menarche
    • Has not undergone a hysterectomy or bilateral oophorectomy
    • Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• STEP 0 REGISTRATION: Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study

• STEP 0 REGISTRATION: Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

• STEP 0 REGISTRATION: Absolute neutrophil count (ANC) ≥ 1,000/mm^3 (≤ 14 days prior to Step 0 registration)

• STEP 0 REGISTRATION: Platelets ≥ 100,000/mm^3 (≤ 14 days prior to Step 0 registration)

• STEP 0 REGISTRATION: Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (≤ 14 days prior to Step 0 registration)

• STEP 0 REGISTRATION: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 x institutional ULN (≤ 14 days prior to Step 0 registration)

• STEP 0 REGISTRATION: Estimated glomerular filtration rate (GFR) (eGRF) ≥ 50 mL/min/1.73 m^2 for patients > 17 years of age (≤ 14 days prior to Step 0 registration)

• STEP 0 REGISTRATION: Pediatric patients (< 17 years old) must have one of the following: (≤ 14 days prior to Step 0 registration)

  • Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m2 using the Bedside Schwartz formula (2009)

  • 24 hour urine creatinine clearance ≥ 50 mL/min/1.73 m^2

  • GFR ≥ 50 mL/min/1.73 m^2

    • Note: GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).

  • NOTE: Estimated GFR (eGFR) from cystatin C or other estimates not listed above are not acceptable for determining eligibility

• STEP 0 REGISTRATION: Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of Step 0 registration are eligible for this trial

• STEP 0 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• STEP 0 REGISTRATION: 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

• STEP 0 REGISTRATION: Patient must not have any current or prior history of central nervous system (CNS) lymphoma

• STEP 0 REGISTRATION: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• STEP 0 REGISTRATION: Patients must not have grade 2 or greater peripheral motor sensory neuropathy

• STEP 0 REGISTRATION: Patient must not have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or have current pneumonitis/interstitial lung disease

• STEP 0 REGISTRATION: Patient must not have the following symptomatic autoimmune disorders: rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, Sjögren's syndrome, or autoimmune vasculitis (e.g., Wegener's granulomatosis), or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone). Patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study

  • Replacement doses of steroids for patients with adrenal insufficiency are allowed
  • Additionally, patients must not have an autoimmune disease that is felt by the treating physician to have the potential to be exacerbated by checkpoint inhibition

• STEP 1 RANDOMIZATION: Patient must have undergone 2-4 cycles of salvage treatment as part of Step 0 of this protocol

• STEP 1 RANDOMIZATION: Patients must be considered eligible for high dose chemotherapy and autologous hematopoietic cell transplant

• STEP 1 RANDOMIZATION: Patient must have had a PET CT (PET2) following 2 cycles of on study salvage therapy and demonstrate complete metabolic response (CMR) or partial metabolic response (PMR). Patients with stable disease/no metabolic response (SD/NMR) or progressive metabolic disease (PMD) are ineligible to proceed to Step 1 randomization

• STEP 1 RANDOMIZATION: Absolute neutrophil count (ANC) ≥ 1,000/mm^3 (≤ 14 days prior to Step 1 randomization)

• STEP 1 RANDOMIZATION: Platelets ≥ 75,000/mm^3 (≤ 14 days prior to Step 1 randomization)

• STEP 1 RANDOMIZATION: Total bilirubin ≤ 2 x institutional upper limit of control (ULN) (≤ 14 days prior to Step 1 randomization)

• STEP 1 RANDOMIZATION: AST(SGOT) and ALT(SGPT) ≤ 3.0 x institutional ULN (≤ 14 days prior to Step 1 randomization)

• STEP 1 RANDOMIZATION: Pediatric patients (< 17 years old) must have one of the following: (≤ 14 days prior to Step 1 randomization)

  • Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m^2 using the Bedside Schwartz formula (2009)
  • 24 hour urine creatinine clearance ≥ 50 mL/min/1.73 m^2
  • GFR ≥ 50 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
  • NOTE: Estimated GFR (eGFR) from cystatin C or other estimates not listed above are not acceptable for determining eligibility

• STEP 1 RANDOMIZATION: Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

  • All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 randomization to rule out pregnancy
  • A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• STEP 1 RANDOMIZATION: Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Patients of childbearing potential must continue to use contraceptive measures for 5 months after the last dose of nivolumab and for 4 months after the last dose of pembrolizumab, as well as not breastfeed during these same timeframes

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