A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab
A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab
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 cells deoxyribonucleic acid (DNA) and may kill cancer cells. It may also lower the bodys 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.
Pediatric Lymphoma,
Pediatrics
Phase III
Both
Chemotherapy - cytotoxic,
Mol. targeted/Immunotherapy/Biologics,
Radiotherapy
Bleomycin,
Brentuximab Vedotin,
Cyclophosphamide,
Dacarbazine (DTIC),
Doxorubicin,
Etoposide,
Nivolumab,
Prednisone,
Procarbazine,
Vinblastine (Velban),
Vincristine
Smith, Christine
National
Vanderbilt University
11-02-2023
Eligibility
5 Years
BOTH
NO
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 Gilberts 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 Gilberts 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 Gilberts 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 patients 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
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 Gilberts 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 Gilberts 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 Gilberts 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 patients 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
