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

This phase III trial compares the effect of adding immunotherapy (brentuximab vedotin and
nivolumab) to standard treatment (chemotherapy with or without radiation) to the standard
treatment alone in improving survival in patients with stage I and II classical 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. A monoclonal antibody is a type of
protein that can bind to certain targets in the body, such as molecules that cause the
body to make an immune response (antigens). Immunotherapy with monoclonal antibodies,
such as nivolumab, may help the body's immune system attack the cancer, and may interfere
with the ability of tumor cells to grow and spread. Chemotherapy drugs such as
doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, dacarbazine, and
procarbazine hydrochloride 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. Cyclophosphamide is in a class of medications called alkylating agents. It
works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. It
may also lower the body's immune response. Etoposide is in a class of medications known
as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and
DNA repair and may kill cancer cells. Vincristine is in a class of medications called
vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill
them. Prednisone is in a class of medications called corticosteroids. It is used to
reduce inflammation and lower the body's immune response to help lessen the side effects
of chemotherapy drugs. Radiation therapy uses high energy x-rays to kill tumor cells and
shrink tumors. Adding immunotherapy to the standard treatment of chemotherapy with or
without radiation may increase survival and/or fewer short-term or long-term side effects
in patients with classical Hodgkin lymphoma compared to the standard treatment alone.

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) with known or suspected mediastinal disease must
have an upright posteroanterior (PA) chest X-ray (CXR) for assessment of bulky
mediastinal disease.

- Note: Pediatric patients who have received both a CT chest and upright PA CXR
may meet the definition of bulk through either modality.

- 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 28 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 28 days prior to enrollment)
OR a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within 28 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 28 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 28 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 28 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 28 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 28 days prior to enrollment) or
ejection fraction of >= 50% by radionuclide angiogram, ECHO, MUGA, or cardiac
imaging scan (within 28 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 28 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

- Short term use of corticosteroids for premedication or treatment of an allergy
or hypersensitivity is considered an acceptable use of corticosteroids.

- 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 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