NCT05675410ClinicalTrials.gov

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

RecruitingTaking participants now, according to the registry record.

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In brief

Phase 31,875 participants sought415 sites3 countries

Registered in 1 registry

ClinicalTrials.govNCT05675410Open this record at ClinicalTrials.govSynced 2 days ago

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Trial information is shown as published by the registry, in its original language.

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How this study is set up

The points below are drawn from the public registry record for this study. Each one cites the field or sentence it came from. A dash (—) means the record does not state something — not that it is missing or wrong. Many well-run studies, especially small ones, leave some of these blank.

Present: Registered before enrolment beganFirst posted 2023-01-09; recorded start 2023-05-11
Present: Has a defined primary outcomeA primary outcome measure is listed in the record
Present: The primary outcome states a time frameThe primary outcome measure records a time frame
Present: Participants are randomly assignedAllocation is recorded as randomised
Present: Has a comparison groupThe record lists a placebo or comparator arm, or more than one study arm
Not stated: Open label (no blinding)Masking is recorded as none (open label)
Not stated: An ethics committee is not stated in the registry recordThis registry's ingested record has no ethics-committee field
Not stated: Regulatory oversight (such as an IND or IDE) is not stated in the registry recordThis registry's ingested record has no regulatory-authorisation field
Not stated: A data monitoring committee is not stated in the registry recordThis registry's ingested record has no data-monitoring-committee fieldA data monitoring committee is not required for many smaller studies, and its absence here is not unusual.
Present: No cost to participants is mentioned in the recordChecked the summary, description and eligibility text; no cost-to-participant phrase found
Present: Sponsor has 1548 other studies in this databaseCounted from the lead sponsor named in the record (National Cancer Institute (NCI))
Present: Sponsor has posted results for at least one studyBased on the sponsor’s studies in this database

The record lists 1 condition.
Lead sponsor type recorded as: US National Institutes of Health.
Intervention regulatory context: investigational, within a phased regulatory pathway.

These are facts from the public registry record, not a judgement about the study. Discuss any trial with your own doctor before taking part.

What these facts mean, and what to ask · ruleset v1

Trial stature

Three independent measures of this study, described from its registry record — not a recommendation about it. A rigorous study by investigators nobody has heard of is better evidence than a weak study led by a famous one. How these are scored.

Methodological rigourSTRONG

A strong methodological design for a phase 3 study, judged from its ClinicalTrials.gov record.

How this score is built

Randomised allocation20/20
Participants are randomly allocated between arms
Blinding0/20
Open-label
Control arm15/15
Active-comparator control arm
Primary-outcome specificity10/10
Named primary outcome with a defined time frame
Endpoint type10/10
Mortality / MACE endpoint (hard clinical outcome)
Multi-centre8/8
Multi-centre: 407 sites
Data monitoring committee0/7
No data monitoring committee stated
Prospective registration5/5
Registered before the study start date
Protocol / SAP posted0/5
No protocol or SAP posted to the registry

ScaleLARGE

A large study, international in scope: 1,875 participants (target), run at 415 sites, across 3 countries.

How this score is built

Enrolment33/40
1,875 participants (target)
Site count25/25
407 sites
Country count7/15
3 countries
Planned duration10/10
Planned over about 97 months
Sponsor scale10/10
National Cancer Institute (NCI) has led 1,534 trials in our corpus

Investigator standingUNKNOWN

We have no verifiable track record for the investigator named on this trial. That is common for early-career investigators and for records held outside ClinicalTrials.gov — it is not a negative signal.

How this score is built

Investigator standing0/100
No investigator recorded in the registry for this trial

These describe the registry record only, and today we hold ClinicalTrials.gov data. Absent fields lower a score, and absence often reflects registration practice rather than study quality. A high-stature trial is not necessarily safer or a better choice for you — enrolling in a large definitive trial can mean a higher chance of receiving placebo, while a small early-phase study may be the only route to a new therapy.

Summary

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 the ABVD regimen (doxorubicin hydrochloride intravenously \[IV\] over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or magnetic resonance imaging (MRI) and are identified as RER or SER. Patients with a favorable risk status and RER are randomized to Arm A or Arm B. Patients with a favorable risk status and SER are randomized to Arm C or Arm D. Patients with an unfavorable risk status and RER are randomized to Arm E or Arm F. Patients with an unfavorable risk status and SER are randomized to Arm G or Arm H. 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 in the absence of disease progression or unacceptable toxicity. 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 B (RER, FAVORABLE): Patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes once during each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. 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 either the eBEACOPP regimen (doxorubicin hydrochloride IV over 3-15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on day 1, etoposide or etoposide phosphate IV over 2-4 hours on days 1-3, prednisone or prednisolone orally \[PO\] twice daily \[BID\] on days 1-14, procarbazine hydrochloride PO on days 1-7, bleomycin sulfate IV over at least 10 minutes on day 8, and vincristine sulfate IV on day 8 of each cycle) or the eBPDac regimen (doxorubicin hydrochloride IV 3-15 minutes on day 1, cyclophosphamide IV 30-60 minutes on day 1, etoposide or etoposide phosphate IV over 2-4 hours on days 1-3, prednisone or prednisolone PO BID on days 1-14, dacarbazine IV over 15-60 minutes on days 2 \& 3, bleomycin sulfate IV over at least 10 minutes on day 4, 5, 6, 7, or 8, vincristine sulfate IV on day 4, 5, 6, 7, or 8 of each cycle). Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. 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 over 3-15 minutes, vinblastine IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. 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.

Conditions

Lugano Classification Limited Stage Hodgkin Lymphoma AJCC v8

Eligibility

Eligibility
Sex	All
Ages	5 Years – 60 Years
Healthy volunteers	No

Eligibility as written in the registry

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/sex 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 (WOCBP) must use effective contraception during the study and for 2 months for WOCBP and 4 months for men, after last dose of brentuximab vedotin * 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

Eligibility in plain statements

This record's criteria have not been broken into separate statements yet. The registry text above is complete and is the authoritative version.

Study design

Study design
Study type	Interventional
Phase	Phase 3
Allocation	Randomised
Intervention model	SEQUENTIAL
Primary purpose	TREATMENT
Masking	NONE (0)
Enrolment	1,875 participants sought

Sponsor and collaborators

National Cancer Institute (NCI) Sponsor

Arms and interventions

Arm A (ABVD)ACTIVE_COMPARATOR
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then 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 in the absence of disease progression or unacceptable toxicity. 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 B (ABVD, brentuximab vedotin, nivolumab)EXPERIMENTAL
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes once during each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. 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 (ABVD, eBEACOPP or eBPDac, ISRT)EXPERIMENTAL
See Detailed Description.
Arm D (ABVD, brentuximab vedotin, nivolumab, ISRT)EXPERIMENTAL
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then 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 (ABVD, AVD)EXPERIMENTAL
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive AVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, vinblastine IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. 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 (ABVD, brentuximab vedotin, nivolumab)EXPERIMENTAL
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then 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 (ABVD, eBEACOPP or eBPDac, ISRT)EXPERIMENTAL
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive treatment and imaging, and may undergo blood sample collection as in arm C.
Arm H (ABVD, brentuximab vedotin, nivolumab, ISRT)EXPERIMENTAL
Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive treatment and imaging, and may undergo blood sample collection as in arm D.

Interventions

Procedure Biospecimen Collection
Undergo blood sample collection
Biological Bleomycin Sulfate
Given IV
Drug Brentuximab Vedotin
Given IV
Procedure Computed Tomography
Undergo CT and/or PET-CT
Drug Cyclophosphamide
Given IV
Drug Dacarbazine
Given IV
Drug Doxorubicin Hydrochloride
Given IV
Drug Etoposide
Given IV
Drug Etoposide Phosphate
Given IV
Other Fludeoxyglucose F-18
Undergo FDG-PET
Radiation Involved-site Radiation Therapy
Undergo ISRT
Procedure Magnetic Resonance Imaging
Undergo MRI and/or PET-MRI
Biological Nivolumab
Given IV
Procedure Positron Emission Tomography
Undergo FDG-PET, PET, PET-CT, and/or PET-MRI
Drug Prednisolone
Given PO
Drug Prednisone
Given PO
Drug Procarbazine Hydrochloride
Given PO
Other Questionnaire Administration
Ancillary studies
Drug Vinblastine Sulfate
Given IV
Drug Vincristine Sulfate
Given IV

Outcome measures

Primary outcome
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.
Time frame From the time of randomization to the earliest time of disease relapse, progression, or death due to any cause, assessed up to 3 years after the randomization of the last patient or when reaching 124 events, whichever comes first
Primary outcome
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.
Time frame From the time of randomization to the earliest time of disease relapse, progression, or death due to any cause, assessed up to 3 years after the randomization of the last patient or when reaching 71 events, whichever comes first
Secondary outcome
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).
Time frame Time from randomization to death due to any cause, assessed up to 12 years after the last enrollment
Secondary outcome
OS in SER patients
Will be compared between a standard chemotherapy approach and an IO therapy approach among the SER patients.
Time frame Time from randomization to death due to any cause, assessed up to 12 years after the last enrollment
Secondary outcome
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.
Time frame Time from randomization to death due to any cause, assessed at 12 years after the last enrollment
Secondary outcome
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.
Time frame Up to 12 years
Secondary outcome
PFS for unfavorable risk patients
Will be estimated in patients with unfavorable 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.
Time frame Up to 12 years
Secondary outcome
PFS for entire population
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.
Time frame Up to 12 years
Secondary outcome
Event-free survival (EFS)
Pooling IO treatment arms and standard treatment arms, EFS and corresponding confidence intervals will be estimated with the Kaplan-Meier approach for patients assigned versus (vs.) not assigned to receive radiaton therapy (RT), and compared using the log-rank test.
Time frame Time from randomization to the earliest of progression, relapse, second malignancy, or death due to any cause, assessed up to 12 years from last enrollment
Secondary outcome
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 AEs. Physician-reported treatment related AEs will be reported for all grades using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Rates of individual toxicities with grades greater or equal to 3 will be compared between the pooled IO and standard arms using exact binomial tests. The maximum grade for each toxicity will be recorded for each patient. The rates and confidence intervals for these toxicities will be provided. Comparison of AEs will also be conducted for physician-reported treatment-related AEs between RT and non-RT patients.
Time frame Assessed up to 12 years from last enrollment
Secondary outcome
Patient reported outcomes (PRO)-CTCAE
Targeted patient-reported AEs will be collected at each time point using the PRO-CTCAE for patients 7 years and older. For youth (7-17 years) the Pediatric PRO-CTCAE form will be used and for those 18 years and older adult the PRO-CTCAE form will be used. For information collected by each of the above forms, 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. The results will be provided for the whole population and compared between subpopulations by arms and by age groups. 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.
Time frame Assessed up to 12 years from last enrollment
Secondary outcome
Patient-reported fatigue
Will be measured by validated short forms from the Patient Reported Outcomes Measurement Information System 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 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 and cognitive deficits, we will consider Bonferroni correction of p-values. Primary interests will be differences in T-scores between IO and chemotherapy arms at 1-year post completion of therapy.
Time frame Baseline up to 1 year from end of study treatment
Secondary outcome
Patient-reported cognitive deficits
Will be measured by validated short forms from the Neuro-QoL 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 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 and cognitive deficits, we will consider Bonferroni correction of p-values. Primary interests will be differences in T-scores between IO and chemotherapy arms at 1-year post completion of therapy.
Time frame Baseline up to 1 year from end of study treatment
Secondary outcome
Patient-reported health-related quality of life
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 fatigue and cognitive deficits, we will consider Bonferroni correction of p-values. Primary interests will be differences in T-scores between IO and chemotherapy arms at 1-year post completion of therapy.
Time frame Baseline up to 1 year from end of study treatment
Secondary outcome
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.
Time frame Assessed up to 12 years from last enrollment
Secondary outcome
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.
Time frame At baseline prior to initiation of therapy
Secondary outcome
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.
Time frame At baseline prior to initiation of therapy
Secondary outcome
Contribution of social determinants of health (SDOH) to PET2 response by race and ethnicity
PET2 Response will be compared by race and ethnicity using Fisher exact tests.
Time frame After Cycle 2 of treatment (1 cycle = 28 days)
Secondary outcome
Contribution of SDOH to PFS by race and ethnicity
Kaplan-Meier (K-M) curves of PFS will be generated by racial/ethnic groups (e.g., non-Hispanic white \[NHW\], non-Hispanic black \[NHB\], Hispanic). The p values for the K-M curve comparison will be obtained from log-rank tests. Associations between race/ethnicity and PFS will be evaluated with univariable and multivariable Cox proportional hazard models by considering other covariates such as baseline clinical conditions, toxicities, SDOH, and treatment arm (standard vs. IO). Backward selection will be used to select those factors with p-value \< 0.2, which will be included in final multivariable models.
Time frame Assessed up to 12 years after last enrollment
Secondary outcome
Contribution of SDOH to OS by race and ethnicity
K-M curves of OS will be generated by racial/ethnic groups (e.g., NHW, NHB, Hispanic). The p values for the K-M curve comparison will be obtained from log-rank tests. Associations between race/ethnicity and OS will be evaluated with univariable and multivariable Cox proportional hazard models by considering other covariates such as baseline clinical conditions, toxicities, SDOH, and treatment arm (standard vs. IO). Backward selection will be used to select those factors with p-value \< 0.2, which will be included in final multivariable models.
Time frame Assessed up to 12 years after last enrollment
Other outcome
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.
Time frame Up to 12 years
Other outcome
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
Time frame At baseline, post cycle 2, and at end of systemic therapy
Other outcome
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.
Time frame At baseline, post cycle 2, and at the end of therapy
Other outcome
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.
Time frame At baseline, post cycle 2, and at the end of therapy
Other outcome
Incidence of patient reported adverse events and provider adverse event reporting
Will be collected by PRO-CTCAE and Ped-PRO-CTCAE. The patient reported AEs will be compared to provider reported AEs reported descriptively.
Time frame Assessed up to 12 years
Other outcome
Association between self-reported race/ethnicity and dimensional SDOH
Will be evaluated by Chi-square tests or Fisher exact tests for sparse data. 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.
Time frame Assessed up to 12 years
Other outcome
Post-relapse/post-progression OS by race/ethnicity and select SDOH measures
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.
Time frame Assessed up to 12 years
Other outcome
Completion rate of PRO and health-related quality of life contact forms
Will be evaluated for the first 450 eligible participants.
Time frame At 1 year off treatment

Dates

Dates
Start date	May 11, 2023 (actual)
Primary completion	April 28, 2031 (estimated)
Completion	April 28, 2031 (estimated)
First posted	January 9, 2023 (actual)
Last updated	September 18, 2026
Results posted	Not stated in the registry record
Status last verified	May 2026

Actual means the event happened. Estimated means the sponsor expects it. The two mean different things.

Locations

398 sites are recruiting

Canada

Canada
Facility	City	State or region	Status
Alberta Children's Hospital	Calgary	Alberta	Recruiting
University of Alberta Hospital	Edmonton	Alberta	Recruiting
IWK Health Centre	Halifax	Nova Scotia	Recruiting
McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Recruiting
Children's Hospital	London	Ontario	Recruiting
The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Recruiting
Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Recruiting
Children's Hospital of Eastern Ontario	Ottawa	Ontario	Recruiting
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)	Québec		Recruiting
Jim Pattison Children's Hospital	Saskatoon	Saskatchewan	Recruiting
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont	Sherbrooke	Quebec	Recruiting
Hospital for Sick Children	Toronto	Ontario	Recruiting
British Columbia Children's Hospital	Vancouver	British Columbia	Recruiting
CancerCare Manitoba	Winnipeg	Manitoba	Recruiting

Puerto Rico

Puerto Rico
Facility	City	State or region	Status
University Pediatric Hospital	San Juan		Recruiting

United States

United States
Facility	City	State or region	Status
Children's Hospital Medical Center of Akron	Akron	Ohio	Recruiting
Albany Medical Center	Albany	New York	Recruiting
University of New Mexico Cancer Center	Albuquerque	New Mexico	Suspended
Presbyterian Hospital	Albuquerque	New Mexico	Recruiting
Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	Recruiting
Providence Alaska Medical Center	Anchorage	Alaska	Recruiting
UI Health Care Mission Cancer and Blood - Ankeny Clinic	Ankeny	Iowa	Recruiting
Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan	Recruiting
C S Mott Children's Hospital	Ann Arbor	Michigan	Recruiting
Mission Hospital	Asheville	North Carolina	Recruiting
Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	Recruiting
Grady Health System	Atlanta	Georgia	Recruiting
Emory Proton Therapy Center	Atlanta	Georgia	Recruiting
Emory University Hospital Midtown	Atlanta	Georgia	Recruiting
Emory Saint Joseph's Hospital	Atlanta	Georgia	Recruiting
Children's Healthcare of Atlanta - Arthur M Blank Hospital	Atlanta	Georgia	Recruiting
Augusta University Medical Center	Augusta	Georgia	Recruiting
Rush-Copley Medical Center	Aurora	Illinois	Recruiting
UCHealth University of Colorado Hospital	Aurora	Colorado	Recruiting
Children's Hospital Colorado	Aurora	Colorado	Recruiting
Dell Children's Medical Center of Central Texas	Austin	Texas	Recruiting
Saint Alphonsus Cancer Care Center-Baker City	Baker City	Oregon	Recruiting
University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	Recruiting
Sinai Hospital of Baltimore	Baltimore	Maryland	Recruiting
Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	Recruiting
Eastern Maine Medical Center	Bangor	Maine	Recruiting
Advocate Good Shepherd Hospital	Barrington	Illinois	Recruiting
MaineHealth Coastal Cancer Treatment Center	Bath	Maine	Recruiting
Bronson Battle Creek	Battle Creek	Michigan	Recruiting
Nebraska Medicine-Bellevue	Bellevue	Nebraska	Recruiting
Walter Reed National Military Medical Center	Bethesda	Maryland	Recruiting
Children's Hospital of Alabama	Birmingham	Alabama	Recruiting
Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina	Recruiting
Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	Recruiting
Saint Luke's Cancer Institute - Boise	Boise	Idaho	Recruiting

365 further sites are listed in the registry record.

Study documents

No documents are linked in this registry record.

Changes over time

September 18, 2026
Site added
1 site added (415 total)
414415
September 17, 2026
Site added
5 sites added (414 total)
409414
September 2, 2026
Site added
1 site added (409 total)
408409
August 11, 2026
Site added
1 site added (408 total)
407408

Registry: ClinicalTrials.gov · NCT########

https://xmedica.io/trials/ctgov/NCT05675410

Categories

Registered in 1 registry

Interested in this study?

How this study is set up

Summary

Conditions

Eligibility

Eligibility as written in the registry

Eligibility in plain statements

Study design

Sponsor and collaborators

Arms and interventions

Interventions

Outcome measures

Dates

Locations

Canada

Puerto Rico

United States

Study documents

Changes over time