Ann Arbor Stage IIB Hodgkin Lymphoma, Ann Arbor Stage IIIB Hodgkin Lymphoma, Ann Arbor Stage IVA Hodgkin Lymphoma, Ann Arbor Stage IVB Hodgkin Lymphoma, Childhood Hodgkin Lymphoma, Classic Hodgkin Lymphoma
Conditions
Brief summary
This phase III trial studies brentuximab vedotin and combination chemotherapy to see how well they work compared to combination chemotherapy alone in treating children and young adults with stage IIB with bulk, stage IIIB, IVA, or IVB Hodgkin lymphoma. Combinations of biological substances in brentuximab vedotin may be able to carry cancer-killing substances directly to Hodgkin lymphoma cells. Chemotherapy drugs, such as doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide, 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. It is not yet known if combination chemotherapy is more effective with or without brentuximab vedotin in treating children with high-risk Hodgkin lymphoma.
Detailed description
PRIMARY OBJECTIVE: I. To assess the event free survival (EFS) of a novel regimen incorporating brentuximab vedotin (Bv; Adcetris) in the chemotherapy backbone of doxorubicin hydrochloride (doxorubicin) (Adriamycin), vincristine sulfate (vincristine), etoposide, prednisone and cyclophosphamide (Bv-AVEPC) in newly diagnosed high-risk classical Hodgkin lymphoma (cHL) compared to those treated with Adriamycin, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC). SECONDARY OBJECTIVES: I. To determine whether children/young adults with high-risk cHL treated with Bv-AVEPC have a higher rate of early response (determined by fludeoxyglucose F 18 \[FDG\]-positron emission tomography \[PET\]) and a reduction in protocol directed radiation therapy (RT) compared to those treated with ABVE-PC. II. To compare the rate of neuropathy (\>= grade 3) among patients treated on the Bv-AVEPC (experimental arm) to patients treated on the ABVE-PC (standard arm). EXPLORATORY OBJECTIVES: I. To validate and compare the Childhood Hodgkin International Prognostic Score (CHIPS) to conventional Ann Arbor stage (stages II B with bulk, III B, IV A or B) in predicting outcome in high-risk childhood cHL. II. To determine the incidence of preferentially expressed antigen in melanoma (PRAME) and testis-specific antigens in Epstein-Barr virus (EBV)- cHL tumors and the incidence of EBV antigens (Epstein-Barr nuclear antigen 1 \[EBNA1\], Epstein-Barr virus latent membrane protein 1 \[LMP1\], large multifunctional peptidase 2 \[LMP2\]) in EBV+ cHL tumors, with the goal of developing strategies to integrate cellular therapy into treatment for newly diagnosed high-risk cHL. (Biology) III. To incorporate qualitative visual FDG-PET into response-directed treatment algorithms and explore quantitative FDG-PET and computed tomography (CT) definitions of tumor burden and response for incorporation into next generation pediatric cHL risk-stratification schemes, exploring the extension of these algorithms to young adults. (Imaging) IV. To evaluate the reduction in normal tissue irradiation associated with the current treatment approach compared to the volume of historic involved field radiation therapy (IFRT) fields. (Radiation Therapy) V. To evaluate EFS and patterns of relapse following protocol-specified RT utilization and treatment volumes. (Radiation Therapy) VI. To characterize the extent of chemotherapy induced peripheral neuropathy (CIPN), as reported by patients and parent proxies, through serial administration of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX). (Patient Reported Outcomes \[PRO\] of Peripheral Neuropathy and Health-Related Quality of Life) VII. To describe the Health-Related Quality of Life (HRQL) consequences of peripheral neuropathy over time by correlating total neuropathy scale scores with the individual items with the Child Health Ratings Inventories (CHRIs)-Global scale (e.g., physical health, pain, emotional functioning). (PRO of Peripheral Neuropathy and Health-Related Quality of Life) VIII. To perform a cross validation of the FACT-GOG-NTX with the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) to determine the performance of both measures with the use of brentuximab vedotin in a limited institutional approach in children and adolescents with cHL. (PRO of Peripheral Neuropathy and Health-Related Quality of Life) IX. To assess the resource use and cost implications of Bv in combination with chemotherapy and radiotherapy (RT) for newly diagnosed high-risk cHL in children and young adults. (Economic) X. To estimate the risk of relapse among rapidly responding lesions (RRL) subjects that have at least one lesion that is Deauville 3 at PET 2. (Follow-up of Deauville score 3 lesions on FDG-PET imaging \[confirmed by central imaging review\]) XI. To characterize the pharmacokinetics of brentuximab vedotin in children \< 13 years of age. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (ABVE-PC): Patients receive doxorubicin hydrochloride intravenously (IV) over on days 1-2, bleomycin sulfate IV or subcutaneously (SC) on days 1 and 8, vincristine sulfate IV on days 1 and 8, etoposide IV on days 1-3, prednisone orally (PO) twice daily (BID) or methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2. ARM II (Bv-AVEPC): Patients receive brentuximab vedotin IV on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone or methylprednisolone, and cyclophosphamide as in Arm I and vincristine sulfate IV on day 8. In both arms, treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte simulating factor (GCSF) or equivalent is given on both arms. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 30, 36, and 48 months.
Interventions
BIOLOGICALBleomycin Sulfate
Given IV or SC
DRUGBrentuximab Vedotin
Given IV
DRUGCyclophosphamide
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMethylprednisolone
Given IV
OTHERPharmacological Study
Correlative studies
DRUGPrednisone
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
DRUGVincristine Sulfate
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 22 Years
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed, pathologically confirmed cHL meeting one of the following Ann Arbor stages are eligible: * Stage IIB with bulk * Stage IIIB * Stage IVA * Stage IVB * If study eligibility by staging is uncertain, consultation with Imaging and Radiation Oncology Core (IROC) Rhode Island (RI) may be obtained prior to study enrollment * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows (performed within 14 days prior to enrollment): * 2 to \< 6 years: male 0.8 mg/dL, female 0.8 mg/dL * 6 to \< 10 years: male 1 mg/dL, female 1 mg/dL * 10 to \< 13 years: male 1.2 mg/dL, female 1.2 mg/dL * 13 to \< 16 years: male 1.5 mg/dL, female 1.4 mg/dL * \>= 16 years: male 1.7 mg/dL, female 1.4 mg/dL * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (performed within 14 days prior to enrollment) * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine transaminase \[ALT\]) \< 2.5 x upper limit of normal (ULN) for age (performed within 14 days prior to enrollment) * Shortening fraction of \>= 27% by echocardiogram, or ejection fraction of \>= 50% by radionuclide angiogram * Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) \> 60% by pulmonary function test (PFT), unless due to large mediastinal mass from Hodgkin lymphoma (HL) * For children who are unable to cooperate for PFTs, the criteria are: no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry reading of \> 92% on room air * 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
Exclusion criteria
* Patients with nodular lymphocyte-predominant HL * Patients with an immunodeficiency that existed prior to diagnosis, such as primary immunodeficiency syndromes, organ transplant recipients and children on current systemic immunosuppressive agents are not eligible * Patients who are pregnant; (since fetal toxicities and teratogenic effects have been noted for several of the study drugs, a negative pregnancy test is required for female patients of childbearing potential) * Lactating females who plan to breastfeed * Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 30 days after the last dose of chemotherapy * Patients known to be positive for human immunodeficiency virus (HIV) are not eligible * Patients who have received any previous chemotherapy or radiation therapy are not eligible * Patients who received systemic corticosteroids within 28 days of enrollment on this protocol, except as specified, are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS), Where Events Include Disease Progression or Relapse, Second Malignancy, or Death | Up to 48 months after the last enrollment | Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle. Progression is defined as an ≥50% increase of in the product of the perpendicular diameters of any of the involved nodes or nodal masses or focal organ lesions in sites that were persistently PET positive; or recurrent PET positive lesions (Deauville 4, 5) in sites that had previously been PET negative regardless of change of size, as was the development of new PET avid measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Relapse is defined in patients who achieved a prior CR but subsequently has an increase of ≥50% of the PPD in prior nodal or extranodal sites in a recurrently PET positive lesion(s), or the development of new measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Second malignancy is defined based on report of a cancer that is not considered to be classic Hodgkin Lymphoma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentages of Patients With Early Response Defined as no Slow Responding Lesions (SRL) and no Progressive Disease (PD) at Any Disease Sites Determined by Positron Emission Tomography (PET) Per Deauville Criteria Through Central Review | After 42 days of chemotherapy | The percentages of patients (with available PET scan) with no SRL and no PD will be compared between the two randomized arms to see if brentuximab vedotin in the chemotherapy backbone of doxorubicin hydrochloride, vincristine sulfate, etoposide, prednisone and cyclophosphamide (Bv-AVEPC) arm has a higher rate of early response compared to doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC) arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons. |
| Percentages of Patients Experiencing Grade 3+ Peripheral Neuropathy Assessed by Modified Balis Scale | From the enrollment of the patient to the time of analysis or the last follow-up; an average of 3.6 years. | The percentages of patients experiencing grade 3+ peripheral neuropathy assessed by the treating clinician using the modified Balis scale. The "Modified Balis scale of Pediatric Neuropathy" allows clinicians to assign a score for sensory or motor neuropathy symptoms separately. Scores range from 1 to 4 with 1 being the least symptomatic state and 4 indicating a severe debility. The percentages of patients (with a score \>/=3) will be compared between the 2 arms by two-sample Z test at 1-sided alpha level of 0.05. |
Countries
Canada, Puerto Rico, United States
Contacts
PRINCIPAL_INVESTIGATORSharon M Castellino
Children's Oncology Group
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (ABVE-PC) Patients receive doxorubicin hydrochloride IV over on days 1-2, bleomycin sulfate IV or SC on days 1 and 8, vincristine sulfate IV on days 1 and 8, etoposide IV on days 1-3, prednisone orally PO BID or methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. | 300 |
| ARM II (Bv-AVEPC) Patients receive brentuximab vedotin IV on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone or methylprednisolone, and cyclophosphamide as in Arm I and vincristine sulfate IV on day 8. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. | 300 |
| Total | 600 |
Baseline characteristics
| Characteristic | Arm I (ABVE-PC) | ARM II (Bv-AVEPC) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 285 Participants | 290 Participants | 575 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 10 Participants | 25 Participants |
| Age, Continuous | 15.3 years STANDARD_DEVIATION 3 | 14.8 years STANDARD_DEVIATION 3.1 | 15 years STANDARD_DEVIATION 3.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 57 Participants | 63 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 228 Participants | 220 Participants | 448 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 17 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 34 Participants | 67 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 34 Participants | 27 Participants | 61 Participants |
| Race (NIH/OMB) White | 221 Participants | 224 Participants | 445 Participants |
| Region of Enrollment Canada | 19 participants | 23 participants | 42 participants |
| Region of Enrollment United States | 281 participants | 277 participants | 558 participants |
| Sex: Female, Male Female | 142 Participants | 139 Participants | 281 Participants |
| Sex: Female, Male Male | 158 Participants | 161 Participants | 319 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 289 | 2 / 298 |
| other Total, other adverse events | 206 / 287 | 209 / 295 |
| serious Total, serious adverse events | 11 / 287 | 66 / 295 |
Outcome results
Primary
Event Free Survival (EFS), Where Events Include Disease Progression or Relapse, Second Malignancy, or Death
Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle. Progression is defined as an ≥50% increase of in the product of the perpendicular diameters of any of the involved nodes or nodal masses or focal organ lesions in sites that were persistently PET positive; or recurrent PET positive lesions (Deauville 4, 5) in sites that had previously been PET negative regardless of change of size, as was the development of new PET avid measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Relapse is defined in patients who achieved a prior CR but subsequently has an increase of ≥50% of the PPD in prior nodal or extranodal sites in a recurrently PET positive lesion(s), or the development of new measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Second malignancy is defined based on report of a cancer that is not considered to be classic Hodgkin Lymphoma.
Time frame: Up to 48 months after the last enrollment
Population: All the eligible patients who had undergone randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (ABVE-PC) | Event Free Survival (EFS), Where Events Include Disease Progression or Relapse, Second Malignancy, or Death | 82.5 percentage of participants |
| ARM II (Bv-AVEPC) | Event Free Survival (EFS), Where Events Include Disease Progression or Relapse, Second Malignancy, or Death | 92.1 percentage of participants |
Comparison: Assuming a 3-year EFS of 82% (5-year EFS of 78.4%, long term EFS of 76%) for standard arm, the study will have approximately 86% power for detecting an 8% improvement in 3-year EFS in the Bv-AVEPC arm (3-year EFS of 90%, 5-year EFS of 88.0%, long term EFS of 86.7%) in log rank test.p-value: 0.0001Log Rank
Secondary
Percentages of Patients Experiencing Grade 3+ Peripheral Neuropathy Assessed by Modified Balis Scale
The percentages of patients experiencing grade 3+ peripheral neuropathy assessed by the treating clinician using the modified Balis scale. The Modified Balis scale of Pediatric Neuropathy allows clinicians to assign a score for sensory or motor neuropathy symptoms separately. Scores range from 1 to 4 with 1 being the least symptomatic state and 4 indicating a severe debility. The percentages of patients (with a score \>/=3) will be compared between the 2 arms by two-sample Z test at 1-sided alpha level of 0.05.
Time frame: From the enrollment of the patient to the time of analysis or the last follow-up; an average of 3.6 years.
Population: All the eligible patients who had undergone randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (ABVE-PC) | Percentages of Patients Experiencing Grade 3+ Peripheral Neuropathy Assessed by Modified Balis Scale | 5.5 Percentage of patients |
| ARM II (Bv-AVEPC) | Percentages of Patients Experiencing Grade 3+ Peripheral Neuropathy Assessed by Modified Balis Scale | 6.7 Percentage of patients |
Secondary
Percentages of Patients With Early Response Defined as no Slow Responding Lesions (SRL) and no Progressive Disease (PD) at Any Disease Sites Determined by Positron Emission Tomography (PET) Per Deauville Criteria Through Central Review
The percentages of patients (with available PET scan) with no SRL and no PD will be compared between the two randomized arms to see if brentuximab vedotin in the chemotherapy backbone of doxorubicin hydrochloride, vincristine sulfate, etoposide, prednisone and cyclophosphamide (Bv-AVEPC) arm has a higher rate of early response compared to doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC) arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons.
Time frame: After 42 days of chemotherapy
Population: All the eligible patients who had undergone randomization and had PET result by central review after completed cycle 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (ABVE-PC) | Percentages of Patients With Early Response Defined as no Slow Responding Lesions (SRL) and no Progressive Disease (PD) at Any Disease Sites Determined by Positron Emission Tomography (PET) Per Deauville Criteria Through Central Review | 80.7 Percentage of patients |
| ARM II (Bv-AVEPC) | Percentages of Patients With Early Response Defined as no Slow Responding Lesions (SRL) and no Progressive Disease (PD) at Any Disease Sites Determined by Positron Emission Tomography (PET) Per Deauville Criteria Through Central Review | 81.2 Percentage of patients |
Other Pre-specified
Childhood International Prognostic Score (CHIPS) Score
CHIPS will be computed for all patients and summarized by descriptive statistics. Will examine the association between CHIPS and early response by cross-tabulations and Chi-square tests within each arm separately, as well as logistic regression model where early response is the outcome variable and CHIPS the predictor variable combining the 2 arms with adjustment for randomized chemotherapy.
Time frame: Baseline
Other Pre-specified
Dose of Radiation Received by Normal Tissues Following Chemotherapy on Either Study Arm
Descriptive statistics will be used to summarize RT doses received by normal tissues on this study. Two-sample t-test will be used to compare the doses received on this study to those on prior studies.
Time frame: Up to 48 months
Other Pre-specified
Efficacy of Involved Site Radiotherapy (ISRT) by Analyzing the Event-free Survival of Patients Treated With Response-adapted ISRT and by Evaluating Patterns of Relapse Following ISRT
EFS for patients on each arm as well as those receiving ISRT or those with slow early response (SER) on each arm will be estimated. One-sample log rank test will be used to compare the observed EFS to the assumed baseline of 82% at 3 years to see if the observed EFS is significantly lower than the projection in these subsets.
Time frame: Up to 3 years
Other Pre-specified
Pharmacokinetic (PK) Analyses
PK concentration time profile will be evaluated.
Time frame: Pre-dose and end of infusion on day 1, days 2, 3, 8, and 15 of cycle 4 and pre-dose on day 1 and day 22 of cycle 5 (each cycle = 21 days)
Other Pre-specified
Risk of Relapse Among RRL Subjects That Have at Least One Lesion That is Deauville 3 at PET 2
The risk of relapse for cases that are RRL, but have Deauville 3 lesions, will be compared to those that are classified as complete metabolic response at PET2 with solely Deauville 1 or 2 lesions with K-sample test.
Time frame: Up to 48 months after the last enrollment