Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

Inclusion Criteria:

   - PHASE I (ARMS A, B, C, D, E, F, G, H, I, X, Y, Z)

   - Age >= 18 years

   - Patients must have pathologically confirmed relapsed or refractory classical Hodgkin
   lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including
   lymphocyte predominant (LP) HL are not permitted

   - Patients must have relapsed after first line chemotherapy; may have relapsed after
   autologous or allogeneic stem cell transplant, or have primary refractory disease; no
   upper limit for number of prior therapies; if status post allogeneic stem cell
   transplant, no active graft versus host disease

   - Patients may have received prior brentuximab vedotin, but must not have received
   brentuximab vedotin within 6 months prior to registration, and must not have relapsed
   within 6 months of receiving previous brentuximab vedotin; patients may not have
   received prior nivolumab or PD1/PDL1 axis agents; patients in the
   nivolumab/brentuximab cohorts ONLY (D, E, F, Y) may have received prior ipilimumab

   - Patients may have received other prior activating immunotherapies (i.e. checkpoint
   inhibitors), but must not have received them within 6 months prior to registration,
   and there must be no serious unresolved complication of therapy at the time of
   registration; for the purposes of this study monoclonal antibodies and antibody drug
   conjugates are not considered to be activating immunotherapies and there are no
   additional time restrictions on prior exposure to these agents (except prior
   brentuximab vedotin)

   - Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging
   Network (ACRIN) performance status between 0-2

   - Patients must have measurable disease; baseline measurements and evaluations must be
   obtained within 4 weeks of registration to the study; abnormal PET scans will not
   constitute evaluable disease unless verified by a diagnostic quality CT scan; patients
   must use the same imaging modality (CT or PET/CT) throughout the study

   - Patient must not be pregnant or breast-feeding due to risk of fetal harm by the
   chemotherapeutic agents prescribed in this protocol; all patients of childbearing
   potential must have a blood test or urine study within 2 weeks prior to registration
   to rule out pregnancy; a patient of childbearing potential is anyone, regardless of
   sexual orientation or whether they have undergone tubal ligation, who meets the
   following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
   2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has
   had menses at any time in the preceding 24 consecutive months)

   - Patient of childbearing potential and/or sexually active patients must either abstain
   from sexual intercourse for the duration of their participation in the study or agree
   to use both single barrier contraception and birth control pills or implants for at
   least one week prior to the start of the study drug and continuing for 5 months after
   the last dose of study drug (for patients of childbearing potential) and for 7 months
   after the last dose of study drug (for patients who are sexually active with anyone of
   childbearing potential); should a patient become pregnant or suspect pregnancy while
   the patient or their partner is participating in this study, the patient (or the
   participating partner) should inform the treating physician immediately

   - Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while
   breathing room air

   - Patients must have forced expiratory volume in 1 second (FEV1)/forced vital capacity
   (FVC) > 60% by pulmonary function test (PFT), unless due to large mediastinal mass
   from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted
   value; all pulmonary function tests must be obtained within one month prior to
   registration

   - Absolute neutrophil count (ANC) >= 1500/mcL (1.5 x 10^9/L) (obtained within 2 weeks
   prior to registration)

   - Platelets >= 75,000/mcL (75 x 10^9/L) (obtained within 2 weeks prior to registration)

   - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
   of normal (ULN) (obtained within 2 weeks prior to registration)

   - Bilirubin =< 2 x upper limit of normal (ULN) (unless documented Gilbert's syndrome,
   for which bilirubin =< 3 x upper limit of normal [ULN] is permitted) (obtained within
   2 weeks prior to registration)

   - Calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min (obtained
   within 2 weeks prior to registration)

   - No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in
   situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously
   disease free for >= 5 years so as not to interfere with interpretation of radiographic
   response

   - Patient must have no current or prior history of central nervous system (CNS)
   involvement

   - All prior therapy must have been completed at least 21 days prior to enrollment; no
   concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose
   of treatment of lymphoma are allowed; topical steroids are allowed

   - No history of Steven's Johnson's syndrome, toxic epidermal necrolysis (TEN)s syndrome,
   or motor neuropathy

   - Human immunodeficiency virus (HIV) positive patients are allowed on this study if they
   have a CD4 count > 400, and are on a stable antiviral regimen; patients with poorly
   controlled HIV or other chronic active viral infections will be excluded

   - Patients must not have autoimmune disorders or conditions of immunosuppression that
   require current ongoing treatment with systemic corticosteroids (or other systemic
   immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or
   continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
   history of occasional (but not continuous) use of steroid inhalers is allowed

      - Replacement doses of steroids for patients with adrenal insufficiency are
      allowed; patients who discontinue use of these classes of medication for at least
      2 weeks prior to initiation of study treatment are 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

      - Exclusion from this study also includes patients with a history of symptomatic
      autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
      [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune
      vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of
      autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other
      CNS autoimmune disease (e.g., Multiple sclerosis); patients with autoimmune
      hypothyroid disease or type I diabetes on replacement treatment are eligible

   - Patients must not have grade 2 or greater peripheral sensory neuropathy

   - Patients must not have New York Heart Association (NYHA) class III or IV heart
   failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
   electrocardiographic evidence of acute ischemia

   - Patients must not have previously existing hypersensitivity to brentuximab vedotin or
   ipilimumab

   - Patients must not have a serious medical or psychiatric illness likely to interfere
   with study participation

   - Patients must not be participating in any other clinical trial or taking any other
   experimental medications within 21 days prior to registration

   - Routine vaccinations, including seasonal influenza, should be given at least 2 weeks
   prior to study treatment; vaccines are not prohibited on study, but must be given at
   least 6 weeks after cycle 1 and not within 7 days of treatment

   - Patients registering to Arms D, E, F, G, H, I, X, Y must not currently be smoking
   tobacco or other substances and must not have smoked within the past 6 months

   - RANDOMIZED PHASE II (ARMS K AND L): Age >= 12 years

      - Pediatric patients will include any patients < 18 years of age

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must have pathologically confirmed
   relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is
   acceptable; other histologies including lymphocyte predominant (LP) HL are not
   permitted

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must have relapsed after first line
   chemotherapy; may have relapsed after autologous stem cell transplant, or have primary
   refractory disease; no upper limit for number of prior therapies; patient must not
   have received a prior allogeneic stem cell transplant (out of risk of reactivation of
   pulmonary graft versus host disease [GVHD])

   - RANDOMIZED PHASE II (ARMS K AND L): Patients may have received prior brentuximab
   vedotin, but must not have received brentuximab vedotin within 6 months prior to
   registration, and must not have relapsed within 6 months of receiving previous
   brentuximab vedotin; patients may not have received prior nivolumab or PD1/PDL1 axis
   agents; patients may not have received prior ipilimumab

   - RANDOMIZED PHASE II (ARMS K AND L): Patients may not have received other prior
   activating immunotherapies (i.e. checkpoint inhibitor therapies); for the purposes of
   this study monoclonal antibodies and antibody drug conjugates are not considered to be
   activating immunotherapies and there are no additional time restrictions on prior
   exposure to these agents (except prior brentuximab vedotin)

   - RANDOMIZED PHASE II (ARMS K AND L): Adult patient (>= 18 years of age) ECOG-ACRIN
   performance status between 0-2

      - Pediatric patients (16-17 years of age) must have a Karnofsky performance level
      >= 50%

      - Pediatric patients (12-15 years of age) must have a Lansky performance level >=
      50

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must have measurable disease; baseline
   measurements and evaluations must be obtained within 4 weeks of registration to the
   study; abnormal PET scans will not constitute evaluable disease unless verified by a
   diagnostic quality CT scan; patients must use the same imaging modality (CT or PET/CT)
   throughout the study

   - RANDOMIZED PHASE II (ARMS K AND L): Patient must not be pregnant or breast-feeding due
   to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol; all
   patients of childbearing potential must have a blood test or urine study within 2
   weeks prior to registration to rule out pregnancy; a patient of childbearing potential
   is defined as anyone, regardless of sexual orientation or 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 2) 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)

   - RANDOMIZED PHASE II (ARMS K AND L): Patient of childbearing potential and/or sexually
   active patient must either abstain from sexual intercourse for the duration of their
   participation in the study or agree to use both double barrier contraception and birth
   control pills or implants for at least one week prior to the start of the study drug
   and continuing for 5 months after the last dose of study drug (for patients of
   childbearing potential) and for 7 months after the last dose of study drug (for
   patients who are sexually active with anyone of childbearing potential); should a
   patient become pregnant or suspect pregnancy while the patient or their partner is
   participating in this study, the patient (or the participating partner) should inform
   the treating physician immediately

   - RANDOMIZED PHASE II (ARMS K AND L): Patients with impaired decision-making capacity
   are eligible with legally authorized representative

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must have no evidence of dyspnea at rest
   and a pulse oximetry > 92% while breathing room air

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must have FEV1/FVC > 60% by pulmonary
   function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide
   diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted value; all pulmonary
   function tests must be obtained within one month prior to registration

   - RANDOMIZED PHASE II (ARMS K AND L): ANC >= 1500/mcL (1.5 x 0^9/L) (obtained within 2
   weeks prior to registration)

   - RANDOMIZED PHASE II (ARMS K AND L): Platelets >= 75,000/mcL (75 x 10^9/L) (obtained
   within 2 weeks prior to registration)

   - RANDOMIZED PHASE II (ARMS K AND L): AST/ALT =< 2.5 x upper limit of normal (ULN) for
   age (obtained within 2 weeks prior to registration)

   - RANDOMIZED PHASE II (ARMS K AND L): Bilirubin =< 2 x upper limit of normal (ULN)
   (unless documented Gilbert's syndrome, for which bilirubin =< 3 x upper limit of
   normal [ULN] is permitted) (obtained within 2 weeks prior to registration)

   - RANDOMIZED PHASE II (ARMS K AND L): Adult patients (>= 18 years old) must have a
   calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min (obtained
   within 2 weeks prior to registration)

   - RANDOMIZED PHASE II (ARMS K AND L): Pediatric patients (< 18 years old) must have a
   creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
   mL/min/1.73 m^2 or serum creatinine based on age/gender as follows:

      - Age: maximum serum creatinine (mg/dL)

         - < 13 years: male (1.2), female (1.2)

         - 13 to < 16 years: male (1.5), female (1.4)

         - >= 16 years: male (1.7), female (1.4)

   - RANDOMIZED PHASE II (ARMS K AND L): No evidence of prior malignancy except adequately
   treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or
   radiation-cured malignancy continuously disease free for >= 5 years so as not to
   interfere with interpretation of radiographic response

   - RANDOMIZED PHASE II (ARMS K AND L): Patient must have no current or prior history of
   CNS involvement

   - RANDOMIZED PHASE II (ARMS K AND L): All prior therapy must have been completed at
   least 21 days prior to enrollment (6 weeks for nitrosoureas or mitomycin C); no
   concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose
   of treatment of lymphoma are allowed; topical steroids are allowed

   - RANDOMIZED PHASE II (ARMS K AND L): No history of Steven's Johnson's syndrome, TENs
   syndrome, or motor neuropathy

   - RANDOMIZED PHASE II (ARMS K AND L): HIV positive patients are eligible provided they
   meet the other protocol criteria including the following:

      - Long term survival expected were it not for the cHL

      - HIV viral loads undetectable by standard clinical HIV testing

      - Willing to adhere to effective combination antiretroviral therapy

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have autoimmune disorders, prior
   solid organ transplant, or conditions of immunosuppression that require current
   ongoing treatment with systemic corticosteroids (or other systemic
   immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or
   continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
   history of occasional (but not continuous) use of steroid inhalers is allowed;
   replacement doses of steroids for patients with adrenal insufficiency are allowed;
   patients who discontinue use of steroid medication for at least 2 weeks prior to
   initiation of therapy are 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; exclusion from this study also includes patients
   with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic
   progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome,
   autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered
   of autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other CNS
   autoimmune disease (e.g., Multiple sclerosis); patients with autoimmune hypothyroid
   disease or type I diabetes on replacement treatment are eligible

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have grade 2 or greater
   peripheral sensory neuropathy

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have NYHA class III or IV heart
   failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
   electrocardiographic evidence of acute ischemia

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have previously existing
   hypersensitivity to brentuximab vedotin or ipilimumab

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have a serious medical or
   psychiatric illness likely to interfere with study participation

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not be participating in any other
   clinical trial or taking any other experimental medications within 21 days prior to
   registration

   - RANDOMIZED PHASE II (ARMS K AND L): Routine vaccinations, including seasonal
   influenza, should be given at least 2 weeks prior to study treatment; vaccines are not
   prohibited on study, but must be given at least 6 weeks after cycle 1 and not within 7
   days of treatment

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not currently be smoking tobacco or
   other agents; vaping is not allowed

   - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have a history of or evidence of
   cardiovascular risks including any of the following:

      - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec
      at baseline

      - History of acute coronary syndromes (including myocardial infarction or unstable
      angina), coronary angioplasty, or stenting within the past 24 weeks prior to
      registration

      - History prior to registration or evidence of current >= class II congestive heart
      failure as defined by the New York Heart Association (NYHA) functional
      classification system

      - Left ventricular ejection fraction (LVEF) =< lower limit of normal on cardiac
      echocardiogram (echo) or multigated acquisition scan (MUGA)

      - Intra-cardiac defibrillator

      - History of abnormal cardiac valve morphology (>= grade 2) documented by ECHO;
      (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be
      entered on study); subjects with moderate valvular thickening should not be
      entered on study

      - History or evidence of current clinically significant uncontrolled cardiac
      arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30
      days prior to dosing are eligible

      - Treatment refractory hypertension defined as a blood pressure of systolic > 140
      mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
      therapy