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.
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
