A Randomized Phase 3 Interim Response Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma

Inclusion Criteria

- Patients must be 5 to 60 years of age at the time of enrollment

- Patients with newly diagnosed untreated histologically confirmed classic Hodgkin

lymphoma (cHL) (nodular sclerosis, mixed cellularity, lymphocyte-rich, or

lymphocyte-depleted, or not otherwise specified [NOS]) with stage I or II disease

- Patients must have bidimensionally measurable disease (at least one lesion with

longest diameter >= 1.5 cm)

- Patients must have a whole body or limited whole body PET scan performed within 42

days prior to enrollment. PET-CT is strongly preferred. PET-MRI allowed if intravenous

contrast enhanced CT is also obtained

- Pediatric patients (age 5-17 years) must have an upright posteroanterior (PA) chest

X-ray (CXR) for assessment of bulky mediastinal disease. Adult patients must have

either a CXR or CT chest

- Patients >= 18 years must have a performance status corresponding to Zubrod scores of

0, 1 or 2

- Patients =< 17 years of age must have a Lansky performance score of >= 50

- Pediatric patients (age 5-17 years): A serum creatinine based on age/gender as follows

(within 7 days prior to enrollment):

- 2 to < 6 years (age): 0.8 mg/dL (male), 0.8 mg/dL (female)

- 6 to < 10 years (age): 1 mg/dL (male), 1 mg/dL (female)

- 10 to < 13 years (age): 1.2 mg/dL (male), 1.2 mg/dL (female)

- 13 to < 16 years (age): 1.5 mg/dL (male), 1.4 mg/dL (female)

- >= 16 years (age): 1.7 mg/dL (male), 1.4 mg/dL (female) OR a 24 hour urine

creatinine clearance >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR

a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within 7 days prior to

enrollment). 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 serum or plasma creatinine, cystatin C or other

estimates are not acceptable for determining eligibility

- For adult patients (age 18 years or older) (within 7 days prior to enrollment):

Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula or

a 24-hour urine collection. The creatinine value used in the calculation must have

been obtained within 28 days prior to registration. Estimated creatinine clearance is

based on actual body weight

- Total bilirubin =< 2 x upper limit of normal (ULN) (within 7 days prior to enrollment)

- Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing

bile duct syndrome

- Aspartate aminotransferase (AST) =< 3 x ULN (within 7 days prior to enrollment)

- Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing

bile duct syndrome

- Alanine aminotransferase (ALT) =< 3 x ULN (within 7 days prior to enrollment)

- Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing

bile duct syndrome

- Shortening fraction of >= 27% by echocardiogram (ECHO), multigated acquisition scan

(MUGA), or functional cardiac imaging scan (within 7 days prior to enrollment) or

ejection fraction of >= 50% by radionuclide angiogram, ECHO, MUGA, or cardiac imaging

scan (within 7 days prior to enrollment)

- Diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted value as

corrected for hemoglobin by pulmonary function test (PFT) (within 7 days prior to

enrollment). If unable to obtain PFTs, the criterion is: a pulse oximetry reading of >

92% on room air

- Known human immunodeficiency virus (HIV)-infected patients on effective

anti-retroviral therapy with undetectable viral load within 6 months are eligible for

this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral

load must be undetectable on suppressive therapy, if indicated. 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

Exclusion Criteria

- Patients with nodular lymphocyte predominant Hodgkin lymphoma

- Patients with a history of active interstitial pneumonitis or interstitial lung

disease

- Patients with a diagnosis of inherited or acquired immunodeficiency that is poorly

controlled or requiring active medications, such as primary immunodeficiency syndromes

or organ transplant recipients

- Patients with any known uncontrolled intercurrent illness that would jeopardize the

patient's safety such as infection, autoimmune conditions, cardiac arrhythmias, angina

pectoris, and gastrointestinal disorders affecting swallowing and/or absorption of

pills

- Patients with a condition requiring systemic treatment with either corticosteroids

(defined as equivalent to > 10 mg daily prednisone for patients >= 18 years or > 0.5

mg/kg [up to 10 mg/day] for patients < 18 years) or other immunosuppressive

medications within 14 days prior to enrollment

- Note: Replacement therapy such as thyroxine, insulin, or physiologic

corticosteroid for adrenal or pituitary insufficiency is not considered a form of

systemic treatment. Inhaled or topical steroids, and adrenal replacement doses

(=< 10 mg daily for patients >= 18 years or =< 0.5 mg/kg [up to 10 mg/day]

prednisone equivalents) are permitted in the absence of active autoimmune disease

- Note: Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but

must be discontinued by cycle 1, day 1

- Patients with peripheral neuropathy > grade 1 at the time of enrollment or patients

with known Charcot-Marie-Tooth syndrome

- Patients with a prior or concurrent malignancy whose natural history or treatment has

the potential to interfere with the safety or efficacy assessment of the

investigational regimen

- Administration of prior chemotherapy, radiation, or antibody-based treatment for cHL

- Prior solid organ transplant

- Prior allogeneic stem cell transplantation

- Live vaccine within 30 days prior to planned day 1 of protocol therapy (e.g., measles,

mumps, rubella, varicella, yellow fever, rabies, bacillus calmette guerin [BCG], oral

polio vaccine, and oral typhoid). Administration of messenger ribonucleic acid (mRNA)

vaccines are permitted

- Female patients who are pregnant since fetal toxicities and teratogenic effects have

been noted for several of the study drugs. A pregnancy test within 28 days prior to

enrollment is required for female patients of childbearing potential

- Lactating females who plan to breastfeed their infants starting with the first dose of

study therapy and for at least 6 months after the last treatment

- Sexually active patients of reproductive potential who have not agreed to use a highly

effective contraceptive method (failure rate of < 1% per year when used consistently

and correctly) for the duration of their study drug therapy. Following therapy,

patients will be advised to use contraception as per institutional practice or as

listed below for investigational agents, whichever is longer

- Men and women of childbearing potential must continue contraception for a period

of 6 months after last dose of brentuximab vedotin

- Women of child-bearing potential (WOCBP) must continue contraception for a period

of at least 5 months after the last dose of nivolumab

- All patients and/or their parents or legal guardians must sign a written informed

consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute

(NCI) requirements for human studies must be met