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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.

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.

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.

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.

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.

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.

Patients receive treatment and imaging, and may undergo blood sample collection as in arm C.

Patients receive treatment and imaging, and may undergo blood sample collection as in arm D.

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Undergo FDG-PET, PET, PET-CT, and/or PET-MRI

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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.

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.

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

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

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Will be compared between a standard chemotherapy approach and an IO therapy approach stratified by different age groups (ages 5-11 years, 12-21 years, 22-39 years, 40-60 years) with log-rank test. Cox regression model will be constructed to evaluate the treatment effects for different age groups by considering all other significant including baseline demographics and clinical risk factors. The 3-year PFS and corresponding confidence interval for each age group and each treatment arm will be provided with Kaplan-Meier method.

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 versus central review concordance rates. For discordant cases, will document the differences in treatments if only local review or only central review were performed

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.

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.

Will be collected by PRO-CTCAE and Ped-PRO-CTCAE. The patient reported adverse events will be compared to provider reported adverse events. The descriptive statistics will be reported, and frequencies will be compared with chi-square tests.

Will be evaluated by chi-square tests. Will also calculate the area deprivation index (derived from patient-reported address and zip code to census block-group data for patients treated in the United States, and the Canadian Index of Multiple Deprivation for patients treated in Canada) and investigate its association with race/ethnicity and SDOH.

The K-M curves will be presented together with p-values via log-rank tests across the different race/ethnicity groups for each treatment arm. Cox proportional hazard models to evaluate the relationship between race/ethnicity and post-relapse OS will be constructed.

Will be evaluated for the first 450 eligible participants.

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.

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.

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.

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.

Comparison will be conducted using 1-sided log-rank tests. The 12-year OS and corresponding CI will be estimated with Kaplan-Meier method.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for lugano classification limited stage hodgkin lymphoma ajcc v8