Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma
Purpose
This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. 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. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.
Conditions
- Recurrent Classic Hodgkin Lymphoma
- Refractory Classic Hodgkin Lymphoma
Eligibility
- Eligible Ages
- Over 12 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
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
Study Design
- Phase
- Phase 1/Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Phase I Arm I (brentuximab vedotin, ipilimumab) |
Patients receive brentuximab vedotin IV over 30 minutes on day 1 of cycles 1-16 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4, 8, 12, and 16. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study. |
|
|
Experimental Phase I Arm II (brentuximab vedotin, nivolumab) |
Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-46. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study. |
|
|
Experimental Phase I Arm III (brentuximab vedotin, nivolumab, ipilimumab) |
Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-46, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study. |
|
|
Experimental Phase II Arm I (brentuximab vedotin, nivolumab) |
Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-34. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study. |
|
|
Experimental Phase II Arm II (brentuximab vedotin, nivolumab, ipilimumab) |
Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-34, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study. |
|
More Details
- Status
- Suspended
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) II. To evaluate the complete response (CR) rate for the regimens of brentuximab vedotin and nivolumab compared to brentuximab vedotin, ipilimumab, and nivolumab. (Phase II; adult cohort [aged >= 18 years]) III. To characterize the safety and toxicity of treatment combination in the pediatric population. (Phase II; pediatric cohort [aged 12-17 years]) SECONDARY OBJECTIVES: I. To evaluate complete response (CR) rate, partial response (PR) rate and overall response rate (ORR), for the combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) II. To evaluate the duration of remission (DOR) to these combinations and compare with the DOR achieved with the most recent prior systemic therapy. (Phase I) III. To evaluate the progression-free survival (PFS) and the overall survival (OS) in patients receiving the combination of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) IV. To evaluate the ORR, PR, and stable disease (SD) rate for the combinations of brentuximab vedotin and nivolumab and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II) V. To evaluate the DOR to these combinations and compare with the DOR achieved with the most recent prior systemic therapy. (Phase II) VI. To evaluate the 5 year PFS and OS in patients receiving the combinations of brentuximab vedotin and nivolumab and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II) VII. To further evaluate the safety and characterize the toxicity for the combinations of brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II) CORRELATIVE STUDY OBJECTIVES: I. To evaluate the ability of these combinations to alter tumor specific T cell immunity. (Phase I) II. To evaluate the effects of these combinations on systemic immunity. (Phase I) III. To evaluate a panel of cytokine and T cell specific biomarkers from the peripheral blood as a potential immune signature of treatment response to therapy with these combinations for patients with relapsed/refractory Hodgkin lymphoma (HL). (Phase I) IV. To evaluate using gene expression profiling (GEP) a signature of response to these novel combinations of an antibody drug conjugate with immunomodulatory therapy. (Phase I) V. To evaluate the ability of these combinations to alter tumor specific T cell immunity, and circulating T cell phenotypes, in patients as a function of treatment response at multiple timepoints during therapy. (Phase II) VI. To evaluate peripheral blood cytokine profiles in responding and resistant patients at multiple timepoints during therapy. (Phase II) VII. To evaluate using GEP a signature of response versus (vs.) resistance to these novel combinations of an antibody drug conjugate with immunomodulatory therapy. (Phase II) VIII. To evaluate the influence of human gut microbiome dysbiosis on HL lymphomagenesis and the systemic immune response. (Phase II) IMAGING CORRELATIVE STUDY OBJECTIVES: I. To evaluate atypical response patterns with currently available response evaluation criteria. (Phase II) II. To correlate response evaluated using currently available response evaluation criteria with duration of response (PFS, event free survival [EFS], failure free survival [FFS]). (Phase II) III. To evaluate response patterns in different immunotherapy treatment schemes and correlate with historical data using chemotherapy. (Phase II) IV. To correlate imaging changes in all treatment schemes quantitatively with PFS. (Phase II) EXPLORATORY OBJECTIVES: I. Evaluate outcomes (CR, PFS) between patients with/without prior transplants. (Phase II) II. Evaluate outcomes (PFS, OS) between the patients who stay on treatment and do not go to transplant in both arms (the post auto and the few others who don't want transplant) vs the patients who go off for transplant. (Phase II) III. Evaluate outcomes (CR, PFS) in pediatric population (age 12 to < 18 years of age) vs. adult population. (Phase II) OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin, ipilimumab, and nivolumab followed by a phase II study. PHASE I: Patients are assigned into 1 of 3 arms. ARM I: Patients receive brentuximab vedotin intravenously (IV) over 90 minutes on day 1 of cycles 1-16 and ipilimumab IV over 30 minutes on day 1 of cycles 1-4, 8, 12, and 16. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-46. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity. ARM III: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-46, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 arms. ARM I: Patients receive brentuximab vedotin IV over 30 minutes on day 1 of cycles 1-16 and nivolumab IV over 90 minutes on day 1 of cycles 1-34. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-34, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity. All patients also undergo computed tomography (CT) or positron emission tomography (PET) scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study. After completion of phase I study treatment, patients are followed up every 3 months for 1 year, then every 6 months for 2 years. After completion of phase II study treatment, patients are followed up for 10 years.