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

Cancer Categories

Hematologic (Blood Cancers)

Karmanos Trial ID

AHOD2131

NCT ID

NCT05675410

Age Group

Both

Scope

National

Phase

Phase III

Principal Investigator

Dipenkumar
Modi, M.D.
Oncology - Hematology, Oncology - Medical View Profile

Objective:

Primary Objectives:

To compare the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL who have a rapid early response (RER) as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy.
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:

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.
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.
To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients.
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.
To evaluate the EFS at 12 years of patients undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab). 1.2.6 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.
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 RT over time.
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.
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).
To evaluate FDG-PET measurements of metabolic tumor burden (MTV and TLG) at PET1 as a predictive marker of PFS. 1.2.11 To evaluate the associations between race/ethnicity and key outcomes including early response to therapy, PFS and OS.

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Eligibility

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/gender 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 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

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