A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the progression-free survival (PFS) of a standard chemotherapy approach versus an immunotherapy (IO) approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage classic Hodgkin lymphoma (cHL) who have a rapid early response (RER) as determined by position emission tomography post cycle 2 (PET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. II. To compare the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) plus involved site radiation therapy (ISRT) in patients with newly diagnosed early stage cHL who have a slow early response (SER) as determined by PET2 after 2 cycles of ABVD chemotherapy. SECONDARY OBJECTIVES: I. To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients who have a RER as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. II. To evaluate the overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients who have a SER as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. III. To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients. IV. To evaluate in patients with newly diagnosed early stage cHL the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in the overall cohort, in the favorable risk cohort, and in the unfavorable risk cohort. V. To evaluate the event-free survival (EFS) at 12 years of patients undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab). VI. To compare the physician-reported treatment-related adverse event (AE) rates between a standard chemotherapy approach and an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL. VII. To compare patient-reported adverse events using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), stratified by age groups, therapeutic arms, and receipt of radiation therapy (RT) over time. VIII. To evaluate changes in patient-reported fatigue, cognitive functioning, and health-related quality of life (HRQoL), e.g., emotional, physical, and role functioning, by treatment arm, using validated adult and pediatric measurement systems. IX. To evaluate self-reported late morbidities (e.g., cardiovascular, pulmonary and endocrine) over time for children, adolescents and adults undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab) with and without RT using measures from the St. Jude Lifetime Cohort Study (SJLIFE). X. To evaluate fludeoxyglucose F-18 (FDG)-position emission tomography (PET) measurements of metabolic tumor burden (MTV and total lesion glycolysis [TLG]) at PET at baseline (PET1) as a predictive marker of PFS. XI. To evaluate the associations between race/ethnicity and key outcomes including early response to therapy, PFS and OS. EXPLORATORY OBJECTIVES: I. To evaluate the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL across different age groups (ages 5-11 years, 12-21 years, 22-39 years, 40-60 years). II. To bank specimens for future correlative studies. III. To assess concordance and discordance of rapid central review and local institutional review of FDG PET 5-point score (5-PS; previously referred to as Deauville score) at baseline PET1, interim PET2 and end of systemic therapy PET-end of systemic therapy (EST) SER. IV. To assess the association between PFS and the quantitative FDG-PET/computed tomography (CT) parameters (PET MTV, TLG, delta-standardized uptake value [SUV] and PET SUV-based quantitative surrogates [qPET] of visual qualitative 5-PS) on measurements by automated measurements using convolutional neural networks (CNNs) through artificial-intelligence (AI) machine learning in the entire population. V. To assess the agreement between quantitative FDG-PET/CT parameters obtained using AI and those based on measurements by a trained imaging physician. VI. To compare patient-reported adverse events (via pediatric [Ped]-PRO-CTCAE and PRO-CTCAE) to provider adverse event reporting. VII. To evaluate the association between self-reported race/ethnicity and social determinants of health. VIII. To evaluate the associations between race/ethnicity and post-progression/post-relapse overall survival. IX. To evaluate the completion rates of PRO and health-related quality of life (HRQoL) contact forms at 1 year off treatment for the first 450 eligible patients. X. To collect contact information from participants for future re-contact. OUTLINE: Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive 2 cycles of ABVD regimen (doxorubicin hydrochloride intravenously [IV], bleomycin sulfate IV, vinblastine sulfate IV, and dacarbazine IV) on days 1 and 15 of each treatment cycle. Each treatment cycle lasts 28 days. Patients then undergo early response assessment and are randomized to 1 of 8 arms. ARM A (RER, FAVORABLE): Patients receive ABVD IV for an additional 2 cycles on study. Each cycle lasts 28 days and ABVD is administered on days 1 and 15 of each cycle. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo blood sample collection on trial. ARM B (RER, FAVORABLE): Patients receive brentuximab vedotin IV and nivolumab IV once during each treatment cycle. Each cycle lasts 21 days. Treatment continues for 4 cycles. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM C (SER, FAVORABLE): Patients receive eBEACOPP regimen (doxorubicin hydrochloride IV on day 1, cyclophosphamide IV on day 1, etoposide or etoposide phosphate IV on days 1-3, prednisone or prednisolone orally [PO] daily for the first 14 days of each treatment cycle, procarbazine hydrochloride PO on days 1-7, bleomycin sulfate IV on day 8, and vincristine sulfate IV) on day 8 of each treatment cycle. Treatment continues for 2 cycles. Each cycle lasts 21 days. Subsequently, patients undergo ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM D (SER, FAVORABLE): Patients receive brentuximab vedotin IV and nivolumab IV as in arm B followed by ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM E (RER, UNFAVORABLE): Patients receive AVD regimen (doxorubicin hydrochloride IV, vinblastine IV, and dacarbazine IV) on days 1 and 15 of each treatment cycle. Each cycle lasts 28 days. Treatment continues for 4 cycles. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM F (RER, UNFAVORABLE): Patients receive treatment as in arm B. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM G (SER, UNFAVORABLE): Patients receive treatment and imaging, and may undergo blood sample collection as in arm C. ARM H (SER, UNFAVORABLE): Patients receive treatment and imaging, and may undergo blood sample collection as in arm D. After completion of study treatment, patients are followed up every 3 months for the first year, then every 6 months for the second and third year, then annually until 12 years from date of registration.

Official Title
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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

Conditions
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Lugano Classification Limited Stage Hodgkin Lymphoma AJCC v8

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Biological: Bleomycin Sulfate
* Drug: Brentuximab Vedotin
* Procedure: Computed Tomography
* Drug: Cyclophosphamide
* Drug: Dacarbazine
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Drug: Etoposide Phosphate
* Other: Fludeoxyglucose F-18
* Radiation: Involved-site Radiation Therapy
* Procedure: Magnetic Resonance Imaging
* Biological: Nivolumab
* Procedure: Positron Emission Tomography
* Drug: Prednisolone
* Drug: Prednisone
* Drug: Procarbazine Hydrochloride
* Other: Questionnaire Administration
* Drug: Vinblastine Sulfate
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (ABVD)<br>Patients receive ABVD IV for an additional 2 cycles on study. Each cycle lasts 28 days and ABVD is administered on days 1 and 15 of each cycle. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo blood sample collection on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;|
| Experimental: Arm B (ABVD, brentuximab vedotin, nivolumab)<br>Patients receive brentuximab vedotin IV and nivolumab IV once during each treatment cycle. Each cycle lasts 21 days. Treatment continues for 4 cycles. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Drug: Brentuximab Vedotin<br>* Given IV<br>* Other names: SGN-35;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;|
| Experimental: Arm C (ABVD, eBEACOPP, ISRT)<br>Patients receive eBEACOPP regimen (doxorubicin hydrochloride IV on day 1, cyclophosphamide IV on day 1, etoposide or etoposide phosphate IV on days 1-3, prednisone or prednisolone orally [PO] daily for the first 14 days of each treatment cycle, procarbazine hydrochloride PO on days 1-7, bleomycin sulfate IV on day 8, and vincristine sulfate IV) on day 8 of each treatment cycle. Treatment continues for 2 cycles. Each cycle lasts 21 days. Subsequently, patients undergo ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Radiation: Involved-site Radiation Therapy<br>* Undergo ISRT<br>* Other names: ISRT;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Drug: Prednisolone<br>* Given PO<br>* Other names: Sterane;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Drug: Procarbazine Hydrochloride<br>* Given PO<br>* Other names: Ro 4-6467/1;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm D (ABVD, brentuximab vedotin, nivolumab, ISRT)<br>Patients receive brentuximab vedotin IV and nivolumab IV as in arm B followed by ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Drug: Brentuximab Vedotin<br>* Given IV<br>* Other names: SGN-35;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Radiation: Involved-site Radiation Therapy<br>* Undergo ISRT<br>* Other names: ISRT;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;|
| Experimental: Arm E (ABVD, AVD)<br>Patients receive AVD regimen (doxorubicin hydrochloride IV, vinblastine IV, and dacarbazine IV) on days 1 and 15 of each treatment cycle. Each cycle lasts 28 days. Treatment continues for 4 cycles. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;|
| Experimental: Arm F (ABVD, brentuximab vedotin, nivolumab)<br>Patients receive treatment as in arm B. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Drug: Brentuximab Vedotin<br>* Given IV<br>* Other names: SGN-35;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;|
| Experimental: Arm G (ABVD, eBEACOPP, ISRT)<br>Patients receive treatment and imaging, and may undergo blood sample collection as in arm C. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Radiation: Involved-site Radiation Therapy<br>* Undergo ISRT<br>* Other names: ISRT;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Drug: Prednisolone<br>* Given PO<br>* Other names: Sterane;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Drug: Procarbazine Hydrochloride<br>* Given PO<br>* Other names: Ro 4-6467/1;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm H (ABVD, brentuximab vedotin, nivolumab, ISRT)<br>Patients receive treatment and imaging, and may undergo blood sample collection as in arm D. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Biological: Bleomycin Sulfate<br>* Given IV<br>* Other names: Oil Bleo;Drug: Brentuximab Vedotin<br>* Given IV<br>* Other names: SGN-35;Procedure: Computed Tomography<br>* Undergo CT and/or PET-CT<br>* Other names: tomography;Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Fludeoxyglucose F-18<br>* Undergo FDG-PET<br>* Other names: Fluorodeoxyglucose F18;Radiation: Involved-site Radiation Therapy<br>* Undergo ISRT<br>* Other names: ISRT;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI and/or PET-MRI<br>* Other names: Structural MRI;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo FDG-PET, PET, PET-CT, and/or PET-MRI<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vinblastine Sulfate<br>* Given IV<br>* Other names: VINCALEUKOBLASTINE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) in rapid early responder (RER) patients | Will compare PFS of the immunotherapy (IO) therapy to that of the standard therapy in RER patients. PFS curves will be estimated using Kaplan Meier approach. Primary analyses will be based on 1-sided log-rank test comparisons of PFS curves between the 2 randomized arms per intention-to-treat principle. | Time from randomization to the first event (disease progression, relapse or death), assessed up to 3 years after the randomization of the last patient or when reaching 230 events, whichever comes first | 
| PFS in slow-early responder (SER) patients | Will compare PFS of the IO therapy and involved site radiation therapy (ISRT) to that of the standard therapy and ISRT in SER patients. PFS curves will be estimated using Kaplan Meier approach. Primary analyses will be based on 1-sided log-rank test comparisons of PFS curves between the 2 randomized arms per intention-to-treat principle. | Time from randomization to the first event (disease progression, relapse or death), assessed up to 3 years after the randomization of the last patient or when reaching 116 events, whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) in RER patients | Will compare OS in IO therapy to standard therapy in RER patients. OS will be determined by positron emission tomography (PET)/computed tomography (CT) and compared using a 1-sided log-rank test. The analysis will be conducted based on confidence interval (CI) approach at 12 years after the last enrollment. The 12-year OS and corresponding confidence interval will be estimated with Kaplan-Meier method for each study arm. | Time of randomization to death, assessed up to 12 years after the last enrollment | 
| OS in SER patients | Will compare OS in IO therapy and ISRT to standard therapy and ISRT in SER patients. OS will be determined by PET/CT and compared using a 1-sided log-rank test. The analysis will be conducted based on CI approach at 12 years after the last enrollment. The 12-year OS and corresponding confidence interval will be estimated with Kaplan-Meier method for each study arm. | Time of randomization to death, assessed up to 12 years after the last enrollment | 
| OS for entire patient population | Comparison will be conducted using 1-sided log-rank tests. The 12-year OS and corresponding CI will be estimated with Kaplan-Meier method. | At 12 years after the last enrollment | 
| PFS for favorable risk patients | 3-year PFS and corresponding confidence interval will be estimated using the Kaplan-Meier approach. Meanwhile, the 3-year PFS will also be compared between the IO therapy and the standard therapy cohorts with the log-rank test. | Time from randomization to the first event (disease progression, relapse or death), assessed up to 3 years | 
| PFS for unfavorable risk patients | 3-year PFS and corresponding confidence interval will be estimated using the Kaplan-Meier approach. Meanwhile, the 3-year PFS will also be compared between the IO therapy and the standard therapy cohorts with the log-rank test. | Time from randomization to the first event (disease progression, relapse or death), assessed up to 3 years from last enrollment | 
| PFS for entire population | 3-year PFS and corresponding confidence interval will be estimated using the Kaplan-Meier approach. Meanwhile, the 3-year PFS will also be compared between the IO therapy and the standard therapy cohorts with the log-rank test. | Time from randomization to the first event (disease progression, relapse or death), assessed up to 3 years from last enrollment | 
| Event-free survival (EFS) | 12-year EFS and corresponding confidence interval will be estimated with Kaplan-Meier approach for patients with and without radiation therapy (RT) under each treatment arm (standard chemotherapy and IO therapy). Meanwhile the EFS curves will be compared between patients with and without RT for each of the treatment arm with log-rank test. | Time from randomization to the first event (disease progression, relapse, subsequent malignant neoplasms, or death), assessed up to 12 years from last enrollment | 
| Incidence of adverse events (AEs) | Will use the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer guidelines to capture immune-related adverse events. Physician-reported treatment related adverse events will be reported for all grades using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Comparison of toxicities with grades greater or equal to 3 will be conducted between the arms using Fisher's exact test. The maximum grade for each toxicity will be recorded for each patient. The averages and confidence intervals for these toxicity frequencies will be provided. Comparison of AEs will also be conducted for physician-reported treatment-related adverse events between RT and non-RT patients. | Assessed up to 12 years from last enrollment | 
| Patient reported outcomes (PROs) | PROs will be assessed using the PRO-CTCAE for patients 17 and older. The pediatric (Ped)-PRO-CTCAE will be used for patients aged 7-17 and the PRO-CTCAE will be used for those 18 and older. the scores for each attribute together with frequency, severity and/or interference will be presented descriptively using summary statistics at each assessment time. Additionally, the worst severity and/or interference over the entire course will be summarized. The changes among main time points will be calculated. Regression models based on longitudinal measurements can be constructed by considering the following covariates besides age groups: baseline demographics, clinical risk factors, and study arms. Comparisons of PRO CTCAE will also be conducted between RT and non-RT patients. | Assessed up to 12 years from last enrollment | 
| Patient-reported fatigue | Will be measured by validated short forms from the Patient Reported Outcomes Measurement Information System initiative. Domain scores will be converted to T-scores with an established standard deviation of 10 points with an average score normalized to 50 within the healthy adult population. The minimal clinically important difference (MCID) in these PRO measures has been accepted to be 2-3 points of the standard deviation ([SD] = 10) of the measure. To account for the dual primary PRO outcomes of fatigue, will consider Bonferroni correction family-wise p-value for overall difference evaluation. Primary interests will be differences in T-scores between immunotherapy and chemotherapy arms at 1-year post completion of therapy. | At baseline, during chemotherapy (cycle 2, day 1), at completion of therapy (time 0 of follow up) and at 1 and 4 years post completion of therapy | 
| Patient-reported cognitive deficits | Will be measured by validated short form, Quality of Life in Neurological Disorders initiatives. Domain scores will be converted to T-scores with an established standard deviation of 10 points with an average score normalized to 50 within the healthy adult population. The MCID in these PRO measures has been accepted to be 2-3 points of the standard deviation (SD = 10) of the measure. To account for the dual primary PRO outcomes of cognitive deficits, will consider Bonferroni correction family-wise p-value for overall difference evaluation. Primary interests will be differences in T-scores between immunotherapy and chemotherapy arms at 1-year post completion of therapy. | At baseline, during chemotherapy (cycle 2, day 1), at completion of therapy (time 0 of follow up) and at 1 and 4 years post completion of therapy | 
| Patient-reported health-related quality of life |  | At baseline, during chemotherapy (cycle 2, day 1), at completion of therapy (time 0 of follow up) and at 1 and 4 years post completion of therapy | 
| Incidence of self-reported late morbidities | Will be collected by using validated measures from the St. Jude Life Cohort. The cumulative incidence of late-morbidities (e.g., cardiovascular, pulmonary and endocrine) will be compared between the standard chemotherapy and the IO therapy and among different age groups (7-14; 15-40 and 41-60) with K-sample method. The frequencies of selected organ toxicities will be compared between two treatment arms, among the three age groups and between RT and non-RT with chi-square tests. | Assessed up to 12 years from last enrollment | 
| Effect of metabolic tumor burden (MTV) on PFS | MTV will be measured at baseline using fludeoxyglucose F-18 (FDG)-PET. The Kaplan-Meier curves of PFS will be compared between the two levels with log-rank tests. | At baseline prior to initiation of therapy | 
| Effect of total lesion glycolysis (TLG) on PFS | TLG will be measured at baseline using FDG-PET. The Kaplan-Meier curves of PFS will be compared between the two levels with log-rank tests. | At baseline prior to initiation of therapy | 
| Contribution of social determinants of health (SDOH) to initial response to therapy by race/ethnicity |  | Assessed post cycle 2 | 
| Contribution of SDOH to PFS by race/ethnicity | Kaplan-Meier (K-M) curves of PFS will be generated by racial/ethnic groups. The p values for the K-M curve comparison will be provided via log-rank test. Life tables will provide the PFS over the follow-up years. Associations between race/ethnicity and survival outcomes (PFS) will be evaluated with univariable and multivariable Cox proportional hazard models by considering other covariates such as baseline clinical conditions, toxicities and up-front therapy (conventional versus IO). Backward selection will be used to select those factors with p-value < 0.2, which will be included in final multivariable models. | Assessed up to 12 years after last enrollment | 
| Contribution of SDOH to OS by race/ethnicity | Kaplan-Meier curves of OS will be generated by racial/ethnic groups. The p values for the K-M curve comparison will be provided via log-rank test. Life tables will provide the OS over the follow-up years. Associations between race/ethnicity and survival outcomes (OS) will be evaluated with univariable and multivariable Cox proportional hazard models by considering other covariates such as baseline clinical conditions, SDOH, toxicities and up-front therapy (conventional versus IO). Backward selection will be used to select those factors with p-value < 0.2, which will be included in final multivariable models. | Assessed up to 12 years after last enrollment |