Isotretinoin With or Without Dinutuximab, Aldesleukin, and Sargramostim Following Stem Cell Transplant in Treating Patients With Neuroblastoma

Phase III Randomized Study of Chimeric Antibody 14.18 (Ch14.18) in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue

This partially randomized phase III trial studies isotretinoin with dinutuximab, aldesleukin, and sargramostim to see how well it works compared to isotretinoin alone following stem cell transplant in treating patients with neuroblastoma. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may block tumor growth in different ways by targeting certain cells. Aldesleukin and sargramostim may stimulate a person's white blood cells to kill cancer cells. It is not yet known if chemotherapy is more effective with or without dinutuximab, aldesleukin, and sargramostim following stem cell transplant in treating neuroblastoma.

Study Overview

• Status: Completed
• Conditions: Recurrent Neuroblastoma; Localized Resectable Neuroblastoma; Localized Unresectable Neuroblastoma; Regional Neuroblastoma; Stage 4S Neuroblastoma; Stage 4 Neuroblastoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Other: Pharmacological Study; Biological: Aldesleukin; Drug: Isotretinoin; Biological: Dinutuximab; Biological: Sargramostim

Detailed Description

PRIMARY OBJECTIVES:

I. Determine if monoclonal antibody Ch14.18 (dinutuximab) + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-autologous stem cell transplant (ASCT) response of complete response (CR), very good partial response (VGPR), or partial response (PR).

SECONDARY OBJECTIVES:

I. Determine if monoclonal antibody Ch14.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

II. Determine if immunotherapy + RA improves event free survival and overall survival as compared to RA alone, in the subgroup of high risk International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

III. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines.

IV. To compare the outcome data of the patients with persistent disease documented by biopsy (Stratum 07) to the historical data for the analogous patients from Children's Cancer Group (CCG)-3981.

V. To further describe and refine the event free survival (EFS) and overall survival (OS) estimates and baseline characteristics for subjects receiving Ch14.18 + cytokines + RA, following cessation of the randomized portion of the study.

VI. To further describe the safety and toxicity of Ch14.18 + cytokines + RA under the new administration guidelines implemented following cessation of the randomized portion of the study with focus on: a) number of courses delivered per subject; b) number of dose reductions or stoppage (ch14.18 and/or interleukin [IL]-2); and c) number of toxic deaths.

TERTIARY OBJECTIVES:

I. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR, determine if there is a difference between the two randomized regimens in reducing the minimal residual disease (MRD) burden as detected by the following parameters: meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples, reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosine hydroxylase, phosphoglycolate phosphatase (PGP) 9.5, and melanoma antigen family A, 1 (MAGE-1) in blood and bone marrow.

II. Determine if change from baseline of MRD is associated with event free and overall survival.

III. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens.

IV. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and EFS.

V. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.

VI. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if these levels and/or genetic variations correlate with EFS or systemic toxicity.

VII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate ch14.18 plasma levels.

VIII. To determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions and blood levels of ch14.18.

IX. To determine if the genotype of Fc receptor (FcR) and killer cell immunoglobulin-like receptor (Kir)/Kir-ligand correlate with EFS.

X. To determine if natural killer cell p30-related protein (NKp30) isoform expression and single nucleotide polymorphism (SNP), and circulating ligand B7-H6 are prognostic of EFS or OS.

OUTLINE: Patients stratified with biopsy-confirmed post-ASCT persistent disease who are also enrolled on Children's Oncology Group (COG)-A3973 or COG-ANBL0532 are assigned to treatment Arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms.

ARM I: Beginning on day 56-85 post-ASCT, patients receive isotretinoin orally (PO) twice daily (BID) for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy. (closed to accrual as of 4/16/2009)

ARM II: Beginning on day 56-85 post-ASCT, patients receive immunotherapy comprising sargramostim (GM-CSF) subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.

After completion of study treatment, patients are followed up periodically for 10 years.

• Study Type: Interventional
• Enrollment (Actual): 1449
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Hunter Regional Mail Centre, New South Wales, Australia, 2310
      • John Hunter Children's Hospital
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
    • Westmead, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Children's Hospital-Brisbane
    • South Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Women's and Children's Hospital-Adelaide
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • Québec, Canada, G1V 4G2
    • CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Child Health Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • The Montreal Children's Hospital of the MUHC
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• New Zealand
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1145
      • Starship Children's Hospital
• Puerto Rico
  • San Juan, Puerto Rico, 00912
    • San Jorge Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Kaiser Permanente Downey Medical Center
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's and Women's Hospital Long Beach
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93636
      • Valley Children's Hospital
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • Sacramento, California, United States, 95816
      • Sutter Medical Center Sacramento
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
    • San Francisco, California, United States, 94143
      • UCSF Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward Health Medical Center
    • Fort Myers, Florida, United States, 33908
      • Golisano Children's Hospital of Southwest Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Memorial Health System
    • Gainesville, Florida, United States, 32610
      • UF Health Cancer Institute - Gainesville
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Hospital/Joe DiMaggio Children's Hospital
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute
    • Orlando, Florida, United States, 32806
      • Orlando Health Cancer Institute
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic - Orlando
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • St. Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
    • Tampa, Florida, United States, 33607
      • Saint Joseph's Hospital/Children's Hospital-Tampa
    • West Palm Beach, Florida, United States, 33407
      • Saint Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta - Arthur M Blank Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
    • Savannah, Georgia, United States, 31404
      • Memorial Health University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
    • Honolulu, Hawaii, United States, 96859
      • Tripler Army Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Children's Hospital-Oak Lawn
    • Peoria, Illinois, United States, 61637
      • Saint Jude Midwest Affiliate
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Indianapolis, Indiana, United States, 46260
      • Ascension Saint Vincent Indianapolis Hospital
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Children's Hospital
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
    • Louisville, Kentucky, United States, 40202
      • Norton Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital New Orleans
  • Maine
    • Scarborough, Maine, United States, 04074
      • Maine Children's Cancer Program
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Boston, Massachusetts, United States, 02111
      • Tufts Children's Hospital
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • Detroit, Michigan, United States, 48236
      • Henry Ford Health Saint John Hospital
    • East Lansing, Michigan, United States, 48823
      • Michigan State University
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri Children's Hospital
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
    • St Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center of Omaha
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Alliance for Childhood Diseases/Cure 4 the Kids Foundation
    • Las Vegas, Nevada, United States, 89120
      • Nevada Cancer Research Foundation NCORP
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Mineola, New York, United States, 11501
      • NYU Langone Hospital - Long Island
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center/Levine Cancer Institute
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Broadway Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
    • Toledo, Ohio, United States, 43606
      • ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
    • Toledo, Ohio, United States, 43608
      • Mercy Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Children's Hospital
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134
      • Saint Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Prisma Health Richland Hospital
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Cancer Treatment Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T C Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Childrens Hospital
    • Memphis, Tennessee, United States, 38105
      • Saint Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont and State Agricultural College
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Falls Church, Virginia, United States, 22042
      • INOVA Fairfax Hospital
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Portsmouth, Virginia, United States, 23708-2197
      • Naval Medical Center - Portsmouth
    • Richmond, Virginia, United States, 23298
      • VCU Massey Comprehensive Cancer Center
    • Roanoke, Virginia, United States, 24014
      • Carilion Children's
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center and Children's Hospital
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Healthcare
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital Cancer Center Green Bay
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center - University Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center-Marshfield
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All patients must be diagnosed with neuroblastoma, and categorized as high risk at the time of diagnosis; exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible

• All patients must have completed therapy including intensive induction followed by ASCT and radiotherapy to be eligible for ANBL0032; radiotherapy may be waived for patients who either have small adrenal masses which are completely resected up front, or who never have an identifiable primary tumor; examples of such therapies include:

  • Following treatment per A3973 protocol
  • Following treatment per Pediatric Oncology Group (POG)-9341/9342 protocol
  • Following treatment per CCG3891
  • Following treatment on New Approaches to Neuroblastoma Therapy (NANT) 2001-02
  • Enrollment on or following treatment per ANBL02P1
  • Enrollment on or following treatment per ANBL07P1

  • Tandem transplant patients are eligible:

    • Following treatment on or per ANBL0532
    • Following treatment per POG 9640
    • Following treatment per COG ANBL00P1
    • Following treatment per CHP 594/Dana-Farber Cancer Institute (DFCI) 34-DAT
• No more than 12 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma, the 12 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT

• At pre-ASCT evaluation patients must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases and bone metastases; patients who meet those criteria must also meet the protocol specified criteria for bone marrow response as outlined below:

  • =< 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy
  • Patient who have no tumor seen on the prior bone marrow, and then have =< 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible (note that per INRC this would have been defined as "overall" response of progressive disease [PD])

• Prior to enrollment on ANBL0032, a determination of mandatory disease staging must be performed (tumor imaging studies including computed tomography [CT] or magnetic resonance imaging [MRI], MIBG scan, and vanillylmandelic acid [VMA]/homovanillic acid [HVA]; bone marrow aspirates are required but biopsy may be omitted if negative prior to ASCT); this disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before enrollment

  • For those with residual disease before radiotherapy, re-evaluation of irradiated residual tumors is preferably performed at the earliest 5 days after completing radiotherapy; patients with residual disease are eligible; biopsy is not required; patients who have biopsy proven residual disease after ASCT will be enrolled on Stratum 07
  • Patients must not have progressive disease at the time of study enrollment except for protocol specified bone marrow response and except for elevations of catecholamines as the only sign of disease in a patient who had normal catecholamines at pre-ASCT evaluation
• Patients must be enrolled before treatment begins; the date protocol therapy is projected to start must be no later than ten (10) calendar days after the date of study enrollment; patients should be enrolled preferably between day 56 and day 85 after peripheral blood stem cell (PBSC) infusion (day from 2nd stem cell infusion for tandem transplant); patients must be enrolled no later than day 200 after PBSC infusion; enrollment must occur after completion of radiotherapy, and after completion of tumor assessment post-ASCT and radiotherapy; informed consent should be obtained within 3 weeks pre-ASCT up to the time of registration
• Patients must not have received prior anti-disialoganglioside (GD2) antibody therapy
• Patients must have a Lansky or Karnofsky performance scale score of >= 50% and patients must have a life expectancy of >= 2 months
• Total absolute phagocyte count (APC = %neutrophils + %monocytes) X white blood cell (WBC) is at least 1000/uL

• 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:

  • No greater than 0.4 mg/dL (1 month to < 6 months)
  • No greater than 0.5 mg/dL (6 months to < 1 year)
  • No greater than 0.6 mg/dL (1 to < 2 years)
  • No greater than 0.8 mg/dL (2 to < 6 years)
  • No greater than 1.0 mg/dL (6 to < 10 years)
  • No greater than 1.2 mg/dL (10 to < 13 years)
  • No greater than 1.4 mg/dL (>= 13 years [female])
  • No greater than 1.5 mg/dL (13 to < 16 years [male])
  • No greater than 1.7 mg/dL (>= 16 years [male])
• Total bilirubin =< 1.5 x normal
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x normal
• Veno-occlusive disease, if present, should be stable or improving
• Shortening fraction of >= 27% by echocardiogram, or if shortening fraction abnormal, ejection fraction of >= 55% by gated radionuclide study or echocardiogram; note: the echocardiogram or gated radionuclide study must be performed within 4 weeks prior to enrollment
• Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) > 60% predicted by pulmonary function test; for children who are unable to do pulmonary function tests (PFTs), no evidence of dyspnea at rest and no exercise intolerance should be documented; note: the pulmonary function test must be performed within 4 weeks prior to enrollment
• Patients with seizure disorder may be enrolled if on anticonvulsants and well-controlled; central nervous system (CNS) toxicity < grade 2
• Written informed consent in accordance with institutional and Food and Drug Administration (FDA) guidelines must be obtained from parent or legal guardian
• Females of childbearing potential must have a negative pregnancy test; patients of childbearing potential must agree to use an effective birth control method; female patients who are lactating must agree to stop breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I (isotretinoin) (closed to accrual as of 4/16/2009); Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive isotretinoin PO BID for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Pharmacological Study; Correlative studies; Drug: Isotretinoin; Given PO; Other Names: Amnesteem; Cistane; Claravis; Sotret; 13-cis retinoic acid; 13-cis-Retinoate; 13-cis-Retinoic Acid; 13-cis-Vitamin A Acid; 13-cRA; Absorica; Accure; Accutane; cis-Retinoic Acid; Isotretinoinum; Isotrex; Isotrexin; Myorisan; Neovitamin A; Neovitamin A Acid; Oratane; Retinoicacid-13-cis; Ro 4-3780; Ro-4-3780; Roaccutan; Roaccutane; Roacutan; ZENATANE
Experimental: Arm II (sargramostim, dinutuximab, aldesleukin, isotretinoin); Beginning preferably between day 56 and day 85 post-ASCT, but may be delayed up to day 200, patients receive immunotherapy comprising sargramostim SC or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Pharmacological Study; Correlative studies; Biological: Aldesleukin; Given IV; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2; Drug: Isotretinoin; Given PO; Other Names: Amnesteem; Cistane; Claravis; Sotret; 13-cis retinoic acid; 13-cis-Retinoate; 13-cis-Retinoic Acid; 13-cis-Vitamin A Acid; 13-cRA; Absorica; Accure; Accutane; cis-Retinoic Acid; Isotretinoinum; Isotrex; Isotrexin; Myorisan; Neovitamin A; Neovitamin A Acid; Oratane; Retinoicacid-13-cis; Ro 4-3780; Ro-4-3780; Roaccutan; Roaccutane; Roacutan; ZENATANE; Biological: Dinutuximab; Given IV; Other Names: Ch14.18; Qarziba; Ch 14.18UTC; MOAB Ch14.18; monoclonal antibody Ch14.18; Unituxin; Dinutuximab Beta; Biological: Sargramostim; Given IV or SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS)	Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only	Three years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS)	Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only for the subgroup of randomized patients with INSS Stage 4 disease. Descriptive comparison of outcome data for patients with persistent disease documented by biopsy to historical data for the analogous patients from CCG-3981.	Three years
Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial	EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.	Three years
Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0	Proportion of patients experiencing at least one Grade 3 or higher toxicity.	From enrollment to follow-up
Number of Courses of Therapy Delivered	Number of courses of therapy delivered for patients randomized to RA + Immunotherapy vs. patients non-randomly assigned to RA + Immunotherapy, excluding patients with persistent disease.	Courses 1-6
Overall Survival (OS)	Comparison to determine if RA + Immunotherapy improves OS as compared to RA Only. Comparison to determine if RA + Immunotherapy improves OS as compared to RA only and for the subgroup of randomized patients with INSS Stage 4 disease.	Three years
Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial	OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.	Three years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Level of HACA	The average level of HACA at each collection time point during immunotherapy will be calculated.	Up to 10 years
Cardiac Repolarization	In general, descriptive summaries will include n, mean, standard deviation, median, minimum, maximum and 90% confidence intervals for continuous variables, and n and percent for categorical variables. Summaries will present data by assessment time when appropriate.	Up to 10 years
Change in MRD	A descriptive analysis of the change from baseline of MRD will be performed. Also, a Wilcoxon rank-sum test will be performed to compare the median change from baseline of MRD between the two treatment arms. A multivariate Cox proportional hazards regression model will test to see if the change in MRD burden is associated with EFS or OS.	Baseline to up to 10 years
Change in Tumor Biology	A multivariate Cox proportional hazards regression model will test to see if the dinutuximab serum level, HACA titer, effector cell function, or serum marker for effector cell activation are associated with EFS or OS.	Baseline to up to 10 years
Circulating B7-H6 Levels	Kaplan-Meier plots of EFS and OS will be generated after dichotomization using the median value for the cohort. To determine the prognostic value of circulating B7-H6 level, univariate analysis will be performed using a log rank test for EFS and OS. In multivariable analysis of EFS and OS, Cox models will be used to test for the independent prognostic ability of circulating B7-H6 level, adjusting for significant prognostic factors including MYCN status, INSS stage, histology and age at diagnosis.	1 week before first sargramostim injection (day -1 of course 1)
Genotype of FcR	Kaplan-Meier plots of EFS will be generated for the three genotype subgroups of FcR as well as for the three genotype subgroups of Kir/Kir-ligand. In addition, a log rank test comparison will be made in a pairwise fashion of each of the genotypes within FcR and within Kir/Kir-ligand.	Up to 10 years
Genotype of Kir/Kir-ligand	Kaplan-Meier plots of EFS will be generated for the three genotype subgroups of FcR as well as for the three genotype subgroups of Kir/Kir-ligand. In addition, a log rank test comparison will be made in a pairwise fashion of each of the genotypes within FcR and within Kir/Kir-ligand.	Up to 10 years
Isotretinoin Pharmacokinetic Parameters	To determine if there is a relationship of the peak serum concentration level with EFS, the term for this level will be tested in a Cox proportional hazards model. To determine if there is a relationship of the peak serum concentration level with toxicity rates, Kendall's Tau statistic will be calculated.	At 4 hours after administration on day 14 of course 1
Levels of ADCC	Will be descriptively compared.	Up to 10 years
NKp30 Isoform Expression and SNP	Kaplan-Meier plots of EFS and OS will be generated after dichotomization using the median value for the cohort. To determine the prognostic value of NKp30 isoform expression and SNP, univariate analysis will be performed using a log rank test for EFS and OS. In multivariable analysis of EFS and OS, Cox models will be used to test for the independent prognostic ability of NKp30 isoform expression and SNP, adjusting for significant prognostic factors including v-MYC myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (MYCN) status, INSS stage, histology and age at diagnosis.	1 week before first sargramostim injection (day -1 of course 1)
Presence of Naturally Occurring Anti-glycan Antibodies	A Fisher's exact test will be performed to determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions. A Wilcoxon test will be performed to determine if the presence of naturally occurring anti-glycan antibodies correlates with blood levels of dinutuximab.	Up to 10 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alice L Yu, Children's Oncology Group

Publications and helpful links

General Publications

• Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
• Oesterheld J, Ferguson W, Kraveka JM, Bergendahl G, Clinch T, Lorenzi E, Berry D, Wada RK, Isakoff MS, Eslin DE, Brown VI, Roberts W, Zage P, Harrod VL, Mitchell DS, Hanson D, Saulnier Sholler GL. Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons. J Clin Oncol. 2024 Jan 1;42(1):90-102. doi: 10.1200/JCO.22.02875. Epub 2023 Oct 26.
• Desai AV, Gilman AL, Ozkaynak MF, Naranjo A, London WB, Tenney SC, Diccianni M, Hank JA, Parisi MT, Shulkin BL, Smith M, Moscow JA, Shimada H, Matthay KK, Cohn SL, Maris JM, Bagatell R, Sondel PM, Park JR, Yu AL. Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children's Oncology Group. J Clin Oncol. 2022 Dec 10;40(35):4107-4118. doi: 10.1200/JCO.21.02478. Epub 2022 Jul 15.

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2001
• Primary Completion (Actual): January 12, 2012
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: November 9, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimated): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neuroblastoma; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Carbohydrates; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Isotretinoin; aldesleukin; dinutuximab; sargramostim; Colony-Stimulating Factors
• Other Study ID Numbers: NCI-2009-01064 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180886 (U.S. NIH Grant/Contract); U10CA098543 (U.S. NIH Grant/Contract); s14-01661; COG-ANBL0032; PANBL0032_A33PAMDREVW01; CDR0000069018; ANBL0032 (Other Identifier: CTEP); U10CA030969 (U.S. NIH Grant/Contract)