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.
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
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
Sequential
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bleomycin Sulfate
Biological/VaccineGiven IV
Brentuximab Vedotin
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT and/or PET-CT
Cyclophosphamide
DrugGiven IV
Dacarbazine
DrugGiven IV
Doxorubicin Hydrochloride
DrugGiven IV
Etoposide
DrugGiven IV
Etoposide Phosphate
DrugGiven IV
Fludeoxyglucose F-18
Other interventionUndergo FDG-PET
Involved-site Radiation Therapy
RadiationUndergo ISRT
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI and/or PET-MRI
Nivolumab
Biological/VaccineGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo FDG-PET, PET, PET-CT, and/or PET-MRI
Prednisolone
DrugGiven PO
Prednisone
DrugGiven PO
Procarbazine Hydrochloride
DrugGiven PO
Questionnaire Administration
Other interventionAncillary studies
Vinblastine Sulfate
DrugGiven IV
Vincristine Sulfate
DrugGiven IV
8
Treatment groupsSee each treatment group below.
Progression-free survival (PFS) in rapid early responder (RER) patients
Will compare the PFS of RER patients randomized to immunotherapy (IO) therapy (brentuximab vedotin-nivolumab) against those randomized to standard therapy. PFS curves will be estimated separately by arm using Kaplan Meier methodology, and the test will be a 1-sided log-rank test between the (pooled) IO and standard arms, stratified according to the stratification factors at randomization and including all eligible and evaluable randomized patients.
PFS in slow-early responder (SER) patients
Will compare PFS among SER patients randomized to IO therapy and involved-site radiation therapy against arms containing standard therapy. PFS curves will be estimated separately by arm using Kaplan Meier methodology, and the test will be a 1-sided log-rank test between the (pooled) IO and standard arms, stratified according to the stratification factors at randomization and including all eligible and evaluable randomized patients.
Overall survival (OS) in RER patients
The non-inferiority of IO therapy to standard therapy will be tested in the randomized and eligible RER cohort using a confidence interval approach performed 12 years after the last patient not lost to follow-up has reached more than 12 years of follow-up (patients are followed up to 13 years).
OS in SER patients
Will be compared between a standard chemotherapy approach and an IO therapy approach among the SER patients.
OS for entire patient population
Will be based on a confidence interval approach conducted after the last patient not lost to follow-up has been followed for at least 12 years from randomization. Twelve-year OS and its corresponding 90% confidence interval will be estimated with the Kaplan-Meier method for each study arm within the entire randomized and evaluable trial population.
PFS for favorable risk patients
Will be estimated in patients with favorable features at diagnosis. PFS and a corresponding confidence interval will be estimated using the Kaplan-Meier approach. PFS will also be compared between the (pooled) IO therapy and standard therapy arms using stratified log-rank tests within each cohort.
PFS comparison between treatment arms for each age group
Will be compared between a standard chemotherapy approach and an IO therapy approach within different age groups (ages 5-11 years, 12-21 years, 22-39 years, 40-60 years) using log-rank tests. Cox regression models will be constructed to evaluate the treatment effects for different age groups while considering the impact of other potentially prognostic variables including baseline demographics and clinical risk factors. PFS and corresponding confidence intervals for each age group will be estimated with the Kaplan-Meier method, overall and by treatment arms. In additional models, age may be evaluated as a continuous variable with potentially non-linear effects on PFS.
Concordance and discordance of 5-point score (PS) visual PET assessments
The concordance and discordance of 5-PS visual PET assessment from rapid central review and local institutional review will be evaluated at each of the timepoints. Will collect and retrospectively review local vs. central review concordance rates. For discordant cases, will document the differences in treatments if only local review or only central review were performed
Association between FDG PET parameters obtained by automated measurements and PFS
The association between FDG PET parameters obtained by automated measurements using convolutional neural networks and PFS will be evaluated in this aim. The PET parameters of interest are total MTV and TLG, tumor standardized uptake value change. PET parameters will be obtained based on artificial intelligence (AI) based measurements. The effect of these PET measurements will be evaluated by Cox regression models.
Agreement between AI derived FDG-PET measurement extraction and physician-based manual quantitative PET measurement
Will compare AI derived automated quantitative FDG-PET measurement extraction and physician-based manual quantitative PET measurement with Spearman rank correlation coefficients for each extracted PET metric.
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