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Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB or Stage IIIB-IVB Hodgkin Lymphoma

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02166463
First Posted: June 18, 2014
Last Update Posted: November 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
June 16, 2014
June 18, 2014
November 21, 2017
March 16, 2015
November 30, 2019   (Final data collection date for primary outcome measure)
Event free survival (EFS), where events include disease progression or relapse, second malignancy, or death [ Time Frame: Up to 48 months ]
Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle.
EFS where events include disease progression or relapse, second malignancy, or death [ Time Frame: Up to 48 months ]
Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle.
Complete list of historical versions of study NCT02166463 on ClinicalTrials.gov Archive Site
  • Proportion of patients experiencing grade 3+ peripheral neuropathy assessed by modified Balis scale [ Time Frame: After 42 days of chemotherapy ]
    Will be estimated for Bv-AVEPC arm and for ABVE-PC arm along with the corresponding. The proportion will be compared between the 2 arms by two-sample Z test of proportions at 1-sided alpha level of 0.05.
  • Proportion of patients experiencing grade 3+ peripheral neuropathy assessed by modified Balis scale [ Time Frame: After 105 days of chemotherapy ]
    Will be estimated for Bv-AVEPC arm and for ABVE-PC arm along with the corresponding 95% confidence intervals. The proportion will be compared between the 2 arms by two-sample Z test of proportions at 1-sided alpha level of 0.05.
  • Proportion of patients needing protocol-directed radiation therapy (RT) defined as patients with slow responding lesions (SRL) or progressive disease (PD) [ Time Frame: After 42 days of chemotherapy ]
    The proportion of patients needing protocol radiation therapy (RT) (including PD) will be compared between the two arms to see if Bv-AVEPC arm has a lower rate for RT compared to ABVE-PC arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons.
  • Proportion of patients with early response defined as no slow responding lesions (SRL) and no progressive disease (PD) at all sites determined by positron emission tomography (PET) per Deauville criteria through central review [ Time Frame: After 42 days of chemotherapy ]
    The proportion of patients 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.
  • Proportion of patients with early response defined at no slow responding lesions (SRL) determined by PET per Deauville criteria through central review [ Time Frame: After 42 days of chemotherapy ]
    The proportion of patients with no SRL will be compared between the two randomized arms to see if Bv-AVEPC arm has a higher rate of early response compared to ABVE-PC arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons.
  • Proportion of patients needing protocol-directed RT defined as patients with SRL [ Time Frame: After 42 days of chemotherapy ]
    The proportion of patients needing protocol RT will be compared between the two arms to see if Bv-AVEPC arm has a lower rate for RT compared to ABVE-PC arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons.
  • Proportion of patients experiencing grade 3+ peripheral neuropathy assessed by modified Balis scale [ Time Frame: After 42 days of chemotherapy ]
    Will be estimated for Bv-AVEPC arm and for ABVE-PC arm along with the corresponding. The proportion will be compared between the 2 arms by two-sample Z test of proportions at 1-sided alpha level of 0.05.
  • Proportion of patients experiencing grade 3+ peripheral neuropathy assessed by modified Balis scale [ Time Frame: After 105 days of chemotherapy ]
    Will be estimated for Bv-AVEPC arm and for ABVE-PC arm along with the corresponding. The proportion will be compared between the 2 arms by two-sample Z test of proportions at 1-sided alpha level of 0.05.
  • Childhood International Prognostic Score (CHIPS) score [ Time Frame: Baseline ]
    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. EFS by CHIPS within each arm and combining both arms will be estimated by Kaplan-Meier curves, and compared by log rank test. Subset analyses and Cox proportional hazards models will also be used.
  • Dose of radiation received by normal tissues for doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC) arm [ Time Frame: Up to 48 months ]
    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.
  • Efficacy of Iinvolved site radiotherapy (ISRT) by analyzing the event-free survival of patients treated with response-adapted ISRT and by evaluating patterns of relapse following ISRT [ Time Frame: Up to 3 years ]
    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.
  • Frequency of patients with persistent Deauville score of 3 [ Time Frame: Up to end of course 5 ]
    Will be calculated with corresponding standard deviation. EFS and risk of relapse of patients with or without radiation will be compared at same Deauville score level (2 or 3) and perform Cox multivariate models to include other possible covariates besides of the Deauville score.
  • Pharmacokinetic (PK) analyses [ Time Frame: Pre-dose and end of infusion on day 1, days 2, 3, 8, and 15 of course 4 and pre-dose on day 1 and day 22 of course 5 ]
    PK concentration time profile will be evaluated.
  • CHIPS score [ Time Frame: Baseline ]
    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. EFS by CHIPS within each arm and combining both arms will be estimated by Kaplan-Meier curves, and compared by log rank test. Subset analyses and Cox proportional hazards models will also be used.
  • Dose of radiation received by normal tissues for ABVE-PC arm [ Time Frame: Up to 48 months ]
    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.
  • Efficacy of ISRT by analyzing the event-free survival of patients treated with response-adapted ISRT and by evaluating patterns of relapse following ISRT [ Time Frame: Up to 3 years ]
    EFS for patients on each arm as well as those receiving ISRT or those with SER on each arm will be estimated.
 
Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB or Stage IIIB-IVB Hodgkin Lymphoma
A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults
This randomized 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 or stage IIIB-IVB Hodgkin lymphoma. Combinations of biological substances in brentuximab vedotin may be able to carry cancer-killing substances directly to Hodgkin lymphoma cells. Drugs used in chemotherapy, 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 Hodgkin lymphoma.

PRIMARY OBJECTIVES:

I. To assess the event free survival (EFS) of a novel regimen incorporating brentuximab vedotin (Bv; Adcetris) in the chemotherapy backbone of doxorubicin (Adriamycin) (doxorubicin hydrochloride), vincristine (vincristine sulfate), 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).

TERTIARY 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 1-15 minutes on days 1-2, bleomycin sulfate IV over 10 minutes or subcutaneously (SC) on days 1 and 8, vincristine sulfate IV over 1 minute on days 1 and 8, etoposide IV over 60-120 minutes on days 1-3, prednisone orally (PO) twice daily (BID) on days 1-7, and cyclophosphamide IV over 30-60 minutes on days 1 and 2.

ARM II (Bv-AVEPC): Patients receive brentuximab vedotin IV over 30 minutes on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone, and cyclophosphamide as in Arm I and vincristine sulfate IV over 1 minute on day 8.

In both arms, treatment repeats every 21 days for 5 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 30, 36, and 48 months.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
  • Ann Arbor Stage IIB Hodgkin Lymphoma
  • Ann Arbor Stage IIIB Hodgkin Lymphoma
  • Ann Arbor Stage IV Hodgkin Lymphoma
  • Ann Arbor Stage IVA Hodgkin Lymphoma
  • Ann Arbor Stage IVB Hodgkin Lymphoma
  • Childhood Hodgkin Lymphoma
  • Classical Hodgkin Lymphoma
  • Biological: Bleomycin Sulfate
    Given IV or SC
    Other Names:
    • Blanoxan
    • BleMomycine
    • Blenoxane
    • Bleo-cell
    • Bleo-S
    • Bleocin
    • Bleolem
    • Bleomycin Sulfas
    • Bleomycin Sulphate
    • Bleomycini Sulfas
    • Blexane
    • Oil Bleo
  • Drug: Brentuximab Vedotin
    Given IV
    Other Names:
    • ADC SGN-35
    • Adcetris
    • Anti-CD30 Antibody-Drug Conjugate SGN-35
    • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
    • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
    • cAC10-vcMMAE
    • SGN-35
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    • ADM
    • Adriacin
    • Adriamycin
    • Adriamycin hydrochloride
    • Adriamycin PFS
    • Adriamycin RDF
    • ADRIAMYCIN, HYDROCHLORIDE
    • Adriamycine
    • Adriblastina
    • Adriblastine
    • Adrimedac
    • Chloridrato de Doxorrubicina
    • DOX
    • DOXO-CELL
    • Doxolem
    • Doxorubicin.HCl
    • Doxorubin
    • Farmiblastina
    • FI 106
    • FI-106
    • hydroxydaunorubicin
    • Rubex
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Drug: Prednisone
    Given PO
    Other Names:
    • .delta.1-Cortisone
    • 1, 2-Dehydrocortisone
    • Adasone
    • Cortancyl
    • Dacortin
    • DeCortin
    • Decortisyl
    • Decorton
    • Delta 1-Cortisone
    • Delta-Dome
    • Deltacortene
    • Deltacortisone
    • Deltadehydrocortisone
    • Deltasone
    • Deltison
    • Deltra
    • Econosone
    • Lisacort
    • Meprosona-F
    • Metacortandracin
    • Meticorten
    • Ofisolona
    • Orasone
    • Panafcort
    • Panasol-S
    • Paracort
    • PRED
    • Predicor
    • Predicorten
    • Prednicen-M
    • Prednicort
    • Prednidib
    • Prednilonga
    • Predniment
    • Prednisonum
    • Prednitone
    • Promifen
    • Servisone
    • SK-Prednisone
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Drug: Vincristine Sulfate
    Given IV
    Other Names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate
  • Active Comparator: Arm I (ABVE-PC)
    Patients receive doxorubicin hydrochloride IV over 1-15 minutes on days 1-2, bleomycin sulfate IV over 10 minutes or SC on days 1 and 8, vincristine sulfate IV over 1 minute on days 1 and 8, etoposide IV over 60-120 minutes on days 1-3, prednisone PO BID on days 1-7, and cyclophosphamide IV over 30-60 minutes on days 1 and 2. Treatment repeats every 21 days for 5 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: Bleomycin Sulfate
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin Hydrochloride
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Drug: Prednisone
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Drug: Vincristine Sulfate
  • Experimental: ARM II (Bv-AVEPC)
    Patients receive brentuximab vedotin IV over 30 minutes on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone, and cyclophosphamide as in Arm I and vincristine sulfate IV over 1 minute on day 8. Treatment repeats every 21 days for 5 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Brentuximab Vedotin
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin Hydrochloride
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Drug: Prednisone
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Drug: Vincristine Sulfate
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
600
November 30, 2019
November 30, 2019   (Final data collection date for primary outcome measure)

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:

    • 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
  • 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
  • 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; (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
Sexes Eligible for Study: All
2 Years to 22 Years   (Child, Adult)
No
Canada,   Puerto Rico,   United States
 
 
NCT02166463
NCI-2014-01223
NCI-2014-01223 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
s15-00950
AHOD1331 ( Other Identifier: Childrens Oncology Group )
AHOD1331 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Sharon Castellino Children's Oncology Group
National Cancer Institute (NCI)
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP