Clinical Trials /

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

NCT02166463

Description:

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.

Related Conditions:
  • Hodgkin Lymphoma
Recruiting Status:

Suspended

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB or Stage IIIB-IVB Hodgkin Lymphoma
  • Official Title: A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01223
  • SECONDARY ID: NCI-2014-01223
  • SECONDARY ID: AHOD1331
  • SECONDARY ID: AHOD1331
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02166463

Conditions

  • Childhood Hodgkin Lymphoma
  • Classical Hodgkin Lymphoma
  • Stage IIB Hodgkin Lymphoma
  • Stage IIIB Hodgkin Lymphoma
  • Stage IV Hodgkin Lymphoma
  • Stage IVA Hodgkin Lymphoma
  • Stage IVB Hodgkin Lymphoma

Interventions

DrugSynonymsArms
Bleomycin SulfateBlanoxan, BleMomycine, Blenoxane, Bleo-cell, Bleo-S, Bleocin, Bleolem, Bleomycin Sulfas, Bleomycin Sulphate, Bleomycini Sulfas, Blexane, Oil BleoArm I (ABVE-PC)
Brentuximab VedotinADC 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-35ARM II (Bv-AVEPC)
Cyclophosphamide(-)-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- 138719Arm I (ABVE-PC)
Doxorubicin Hydrochloride5,12-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, RubexArm I (ABVE-PC)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Arm I (ABVE-PC)
Prednisone.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-PrednisoneArm I (ABVE-PC)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm I (ABVE-PC)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ABVE-PC)Active ComparatorPatients 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.
  • Cyclophosphamide
  • Doxorubicin Hydrochloride
  • Etoposide
  • Prednisone
  • Vincristine Sulfate
ARM II (Bv-AVEPC)ExperimentalPatients 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.
  • Brentuximab Vedotin
  • Cyclophosphamide
  • Doxorubicin Hydrochloride
  • Etoposide
  • Prednisone
  • Vincristine Sulfate

Eligibility Criteria

        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
      
Maximum Eligible Age:22 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event free survival (EFS), where events include disease progression or relapse, second malignancy, or death
Time Frame:Up to 48 months
Safety Issue:
Description:Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle.

Secondary Outcome Measures

Measure:Proportion of patients experiencing grade 3+ peripheral neuropathy assessed by modified Balis scale
Time Frame:After 42 days of chemotherapy
Safety Issue:
Description: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.
Measure:Proportion of patients experiencing grade 3+ peripheral neuropathy assessed by modified Balis scale
Time Frame:After 105 days of chemotherapy
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 13, 2017