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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT00026312
Collaborator
(none)
1,449
Enrollment
197
Locations
2
Arms
7.4
Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: Aldesleukin
  • Biological: Dinutuximab
  • Drug: Isotretinoin
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Biological: Sargramostim
 Phase 3

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:

  1. 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.

  2. 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.

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

  4. 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.

  5. 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.

  6. 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:

  1. 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.

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

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

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

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

  6. 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.

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

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

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

  10. 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 Design

Study Type:
Interventional
Actual Enrollment :
1449 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase III Randomized Study of Chimeric Antibody 14.18 (Ch14.18) in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue
Actual Study Start Date :
Oct 18, 2001
Actual Primary Completion Date :
Jan 12, 2012

Arms and Interventions

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.

Drug: Isotretinoin
Given PO
Other Names:
  • 13-cis retinoic acid
  • 13-cis-Retinoate
  • 13-cis-Retinoic Acid
  • 13-cis-Vitamin A Acid
  • 13-cRA
  • Absorica
  • Accure
  • Accutane
  • Amnesteem
  • cis-Retinoic Acid
  • Cistane
  • Claravis
  • Isotretinoinum
  • Isotrex
  • Isotrexin
  • Myorisan
  • Neovitamin A
  • Neovitamin A Acid
  • Oratane
  • Retinoicacid-13-cis
  • Ro 4-3780
  • Ro-4-3780
  • Roaccutan
  • Roaccutane
  • Roacutan
  • Sotret
  • ZENATANE

    • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment

    		•
    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.

    Biological: Aldesleukin
    Given IV
    Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2

    • Biological: Dinutuximab
    Given IV
    Other Names:
  • Ch 14.18UTC
  • Ch14.18
  • MOAB Ch14.18
  • monoclonal antibody Ch14.18
  • Unituxin

    • Drug: Isotretinoin
    Given PO
    Other Names:
  • 13-cis retinoic acid
  • 13-cis-Retinoate
  • 13-cis-Retinoic Acid
  • 13-cis-Vitamin A Acid
  • 13-cRA
  • Absorica
  • Accure
  • Accutane
  • Amnesteem
  • cis-Retinoic Acid
  • Cistane
  • Claravis
  • Isotretinoinum
  • Isotrex
  • Isotrexin
  • Myorisan
  • Neovitamin A
  • Neovitamin A Acid
  • Oratane
  • Retinoicacid-13-cis
  • Ro 4-3780
  • Ro-4-3780
  • Roaccutan
  • Roaccutane
  • Roacutan
  • Sotret
  • ZENATANE

    • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment

    • Biological: Sargramostim
    Given IV or SC
    Other Names:
  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Event-Free Survival (EFS) [Three years]

      Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only

    Secondary Outcome Measures

    1. Event-Free Survival (EFS) [Three years]

      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.

    2. Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial [Three years]

      EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.

    3. Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0 [From enrollment to follow-up]

      Proportion of patients experiencing at least one Grade 3 or higher toxicity.

    4. Number of Courses of Therapy Delivered [Courses 1-6]

      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.

    5. Overall Survival (OS) [Three years]

      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.

    6. Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial [Three years]

      OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.

    Other Outcome Measures

    1. Average Level of HACA [Up to 10 years]

      The average level of HACA at each collection time point during immunotherapy will be calculated.

    2. Cardiac Repolarization [Up to 10 years]

      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.

    3. Change in MRD [Baseline to up to 10 years]

      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.

    4. Change in Tumor Biology [Baseline to up to 10 years]

      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.

    5. Circulating B7-H6 Levels [1 week before first sargramostim injection (day -1 of course 1)]

      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.

    6. Genotype of FcR [Up to 10 years]

      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.

    7. Genotype of Kir/Kir-ligand [Up to 10 years]

      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.

    8. Isotretinoin Pharmacokinetic Parameters [At 4 hours after administration on day 14 of course 1]

      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.

    9. Levels of ADCC [Up to 10 years]

      Will be descriptively compared.

    10. NKp30 Isoform Expression and SNP [1 week before first sargramostim injection (day -1 of course 1)]

      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.

    11. Presence of Naturally Occurring Anti-glycan Antibodies [Up to 10 years]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 University of Alabama at Birmingham Cancer Center Birmingham Alabama United States 35233
    3 Providence Alaska Medical Center Anchorage Alaska United States 99508
    4 Phoenix Childrens Hospital Phoenix Arizona United States 85016
    5 Banner University Medical Center - Tucson Tucson Arizona United States 85719
    6 Arkansas Children's Hospital Little Rock Arkansas United States 72202-3591
    7 University of Arkansas for Medical Sciences Little Rock Arkansas United States 72205
    8 Kaiser Permanente Downey Medical Center Downey California United States 90242
    9 City of Hope Comprehensive Cancer Center Duarte California United States 91010
    10 Loma Linda University Medical Center Loma Linda California United States 92354
    11 Miller Children's and Women's Hospital Long Beach Long Beach California United States 90806
    12 Children's Hospital Los Angeles Los Angeles California United States 90027
    13 Valley Children's Hospital Madera California United States 93636
    14 UCSF Benioff Children's Hospital Oakland Oakland California United States 94609
    15 Kaiser Permanente-Oakland Oakland California United States 94611
    16 Children's Hospital of Orange County Orange California United States 92868
    17 Lucile Packard Children's Hospital Stanford University Palo Alto California United States 94304
    18 Sutter Medical Center Sacramento Sacramento California United States 95816
    19 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    20 Rady Children's Hospital - San Diego San Diego California United States 92123
    21 UCSF Medical Center-Parnassus San Francisco California United States 94143
    22 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    23 Children's Hospital Colorado Aurora Colorado United States 80045
    24 Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado United States 80218
    25 Connecticut Children's Medical Center Hartford Connecticut United States 06106
    26 Yale University New Haven Connecticut United States 06520
    27 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    28 MedStar Georgetown University Hospital Washington District of Columbia United States 20007
    29 Children's National Medical Center Washington District of Columbia United States 20010
    30 Broward Health Medical Center Fort Lauderdale Florida United States 33316
    31 Lee Memorial Health System Fort Myers Florida United States 33901
    32 Golisano Children's Hospital of Southwest Florida Fort Myers Florida United States 33908
    33 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    34 Memorial Regional Hospital/Joe DiMaggio Children's Hospital Hollywood Florida United States 33021
    35 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    36 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    37 Nicklaus Children's Hospital Miami Florida United States 33155
    38 Miami Cancer Institute Miami Florida United States 33176
    39 AdventHealth Orlando Orlando Florida United States 32803
    40 Arnold Palmer Hospital for Children Orlando Florida United States 32806
    41 Nemours Children's Clinic - Orlando Orlando Florida United States 32806
    42 Orlando Health Cancer Institute Orlando Florida United States 32806
    43 Nemours Children's Hospital Orlando Florida United States 32827
    44 Nemours Children's Clinic - Pensacola Pensacola Florida United States 32504
    45 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    46 Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida United States 33607
    47 Saint Mary's Hospital West Palm Beach Florida United States 33407
    48 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    49 Augusta University Medical Center Augusta Georgia United States 30912
    50 Memorial Health University Medical Center Savannah Georgia United States 31404
    51 University of Hawaii Cancer Center Honolulu Hawaii United States 96813
    52 Kapiolani Medical Center for Women and Children Honolulu Hawaii United States 96826
    53 Tripler Army Medical Center Honolulu Hawaii United States 96859
    54 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    55 University of Illinois Chicago Illinois United States 60612
    56 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    57 Advocate Children's Hospital-Oak Lawn Oak Lawn Illinois United States 60453
    58 Saint Jude Midwest Affiliate Peoria Illinois United States 61637
    59 Southern Illinois University School of Medicine Springfield Illinois United States 62702
    60 Riley Hospital for Children Indianapolis Indiana United States 46202
    61 Saint Vincent Hospital and Health Care Center Indianapolis Indiana United States 46260
    62 Blank Children's Hospital Des Moines Iowa United States 50309
    63 University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa United States 52242
    64 University of Kentucky/Markey Cancer Center Lexington Kentucky United States 40536
    65 Norton Children's Hospital Louisville Kentucky United States 40202
    66 Children's Hospital New Orleans New Orleans Louisiana United States 70118
    67 Maine Children's Cancer Program Scarborough Maine United States 04074
    68 University of Maryland/Greenebaum Cancer Center Baltimore Maryland United States 21201
    69 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
    70 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    71 Walter Reed National Military Medical Center Bethesda Maryland United States 20889-5600
    72 Tufts Children's Hospital Boston Massachusetts United States 02111
    73 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 02114
    74 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    75 Baystate Medical Center Springfield Massachusetts United States 01199
    76 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    77 Wayne State University/Karmanos Cancer Institute Detroit Michigan United States 48201
    78 Ascension Saint John Hospital Detroit Michigan United States 48236
    79 Michigan State University Clinical Center East Lansing Michigan United States 48824-7016
    80 Hurley Medical Center Flint Michigan United States 48503
    81 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    82 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    83 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    84 University of Minnesota/Masonic Cancer Center Minneapolis Minnesota United States 55455
    85 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    86 University of Mississippi Medical Center Jackson Mississippi United States 39216
    87 Columbia Regional Columbia Missouri United States 65201
    88 Children's Mercy Hospitals and Clinics Kansas City Missouri United States 64108
    89 Cardinal Glennon Children's Medical Center Saint Louis Missouri United States 63104
    90 Washington University School of Medicine Saint Louis Missouri United States 63110
    91 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    92 Children's Hospital and Medical Center of Omaha Omaha Nebraska United States 68114
    93 University of Nebraska Medical Center Omaha Nebraska United States 68198
    94 Alliance for Childhood Diseases/Cure 4 the Kids Foundation Las Vegas Nevada United States 89135
    95 Nevada Cancer Research Foundation NCORP Las Vegas Nevada United States 89169
    96 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    97 Hackensack University Medical Center Hackensack New Jersey United States 07601
    98 Morristown Medical Center Morristown New Jersey United States 07960
    99 Saint Peter's University Hospital New Brunswick New Jersey United States 08901
    100 Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital New Brunswick New Jersey United States 08903
    101 Newark Beth Israel Medical Center Newark New Jersey United States 07112
    102 Overlook Hospital Summit New Jersey United States 07902
    103 University of New Mexico Cancer Center Albuquerque New Mexico United States 87102
    104 Albany Medical Center Albany New York United States 12208
    105 Montefiore Medical Center - Moses Campus Bronx New York United States 10467
    106 Roswell Park Cancer Institute Buffalo New York United States 14263
    107 NYU Winthrop Hospital Mineola New York United States 11501
    108 The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park New York United States 11040
    109 Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York United States 10016
    110 Mount Sinai Hospital New York New York United States 10029
    111 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    112 University of Rochester Rochester New York United States 14642
    113 State University of New York Upstate Medical University Syracuse New York United States 13210
    114 New York Medical College Valhalla New York United States 10595
    115 Mission Hospital Asheville North Carolina United States 28801
    116 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    117 Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina United States 28203
    118 Novant Health Presbyterian Medical Center Charlotte North Carolina United States 28204
    119 Duke University Medical Center Durham North Carolina United States 27710
    120 Wake Forest University Health Sciences Winston-Salem North Carolina United States 27157
    121 Sanford Broadway Medical Center Fargo North Dakota United States 58122
    122 Children's Hospital Medical Center of Akron Akron Ohio United States 44308
    123 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    124 Rainbow Babies and Childrens Hospital Cleveland Ohio United States 44106
    125 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    126 Nationwide Children's Hospital Columbus Ohio United States 43205
    127 Dayton Children's Hospital Dayton Ohio United States 45404
    128 ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital Toledo Ohio United States 43606
    129 Mercy Children's Hospital Toledo Ohio United States 43608
    130 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    131 Legacy Emanuel Children's Hospital Portland Oregon United States 97227
    132 Legacy Emanuel Hospital and Health Center Portland Oregon United States 97227
    133 Oregon Health and Science University Portland Oregon United States 97239
    134 Lehigh Valley Hospital - Muhlenberg Bethlehem Pennsylvania United States 18017
    135 Geisinger Medical Center Danville Pennsylvania United States 17822
    136 Penn State Children's Hospital Hershey Pennsylvania United States 17033
    137 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    138 Saint Christopher's Hospital for Children Philadelphia Pennsylvania United States 19134
    139 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    140 Rhode Island Hospital Providence Rhode Island United States 02903
    141 Medical University of South Carolina Charleston South Carolina United States 29425
    142 Prisma Health Richland Hospital Columbia South Carolina United States 29203
    143 BI-LO Charities Children's Cancer Center Greenville South Carolina United States 29605
    144 Greenville Cancer Treatment Center Greenville South Carolina United States 29605
    145 Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota United States 57117-5134
    146 T C Thompson Children's Hospital Chattanooga Tennessee United States 37403
    147 East Tennessee Childrens Hospital Knoxville Tennessee United States 37916
    148 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    149 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    150 Dell Children's Medical Center of Central Texas Austin Texas United States 78723
    151 Driscoll Children's Hospital Corpus Christi Texas United States 78411
    152 Medical City Dallas Hospital Dallas Texas United States 75230
    153 UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas United States 75390
    154 Cook Children's Medical Center Fort Worth Texas United States 76104
    155 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas United States 77030
    156 Methodist Children's Hospital of South Texas San Antonio Texas United States 78229
    157 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    158 Primary Children's Hospital Salt Lake City Utah United States 84113
    159 University of Vermont and State Agricultural College Burlington Vermont United States 05405
    160 University of Virginia Cancer Center Charlottesville Virginia United States 22908
    161 Inova Fairfax Hospital Falls Church Virginia United States 22042
    162 Children's Hospital of The King's Daughters Norfolk Virginia United States 23507
    163 Naval Medical Center - Portsmouth Portsmouth Virginia United States 23708-2197
    164 Virginia Commonwealth University/Massey Cancer Center Richmond Virginia United States 23298
    165 Carilion Children's Roanoke Virginia United States 24014
    166 Seattle Children's Hospital Seattle Washington United States 98105
    167 Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington United States 99204
    168 West Virginia University Healthcare Morgantown West Virginia United States 26506
    169 Saint Vincent Hospital Cancer Center Green Bay Green Bay Wisconsin United States 54301
    170 University of Wisconsin Carbone Cancer Center Madison Wisconsin United States 53792
    171 Marshfield Medical Center-Marshfield Marshfield Wisconsin United States 54449
    172 Children's Hospital of Wisconsin Milwaukee Wisconsin United States 53226
    173 John Hunter Children's Hospital Hunter Regional Mail Centre New South Wales Australia 2310
    174 Sydney Children's Hospital Randwick New South Wales Australia 2031
    175 The Children's Hospital at Westmead Westmead New South Wales Australia 2145
    176 Royal Brisbane and Women's Hospital Herston Queensland Australia 4029
    177 Royal Children's Hospital-Brisbane Herston Queensland Australia 4029
    178 Queensland Children's Hospital South Brisbane Queensland Australia 4101
    179 Women's and Children's Hospital-Adelaide North Adelaide South Australia Australia 5006
    180 Royal Children's Hospital Parkville Victoria Australia 3052
    181 Princess Margaret Hospital for Children Perth Western Australia Australia 6008
    182 Alberta Children's Hospital Calgary Alberta Canada T3B 6A8
    183 University of Alberta Hospital Edmonton Alberta Canada T6G 2B7
    184 British Columbia Children's Hospital Vancouver British Columbia Canada V6H 3V4
    185 CancerCare Manitoba Winnipeg Manitoba Canada R3E 0V9
    186 Janeway Child Health Centre Saint John's Newfoundland and Labrador Canada A1B 3V6
    187 IWK Health Centre Halifax Nova Scotia Canada B3K 6R8
    188 McMaster Children's Hospital at Hamilton Health Sciences Hamilton Ontario Canada L8N 3Z5
    189 Children's Hospital London Ontario Canada N6A 5W9
    190 Children's Hospital of Eastern Ontario Ottawa Ontario Canada K1H 8L1
    191 Hospital for Sick Children Toronto Ontario Canada M5G 1X8
    192 The Montreal Children's Hospital of the MUHC Montreal Quebec Canada H3H 1P3
    193 Centre Hospitalier Universitaire Sainte-Justine Montreal Quebec Canada H3T 1C5
    194 Centre Hospitalier Universitaire de Quebec Quebec Canada G1V 4G2
    195 Starship Children's Hospital Grafton Auckland New Zealand 1145
    196 Christchurch Hospital Christchurch New Zealand 8011
    197 San Jorge Children's Hospital San Juan Puerto Rico 00912

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Alice L Yu, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00026312
    Other Study ID Numbers:
    • NCI-2009-01064
    • NCI-2009-01064
    • s14-01661
    • COG-ANBL0032
    • PANBL0032_A33PAMDREVW01
    • CDR0000069018
    • ANBL0032
    • ANBL0032
    • ANBL0032
    • U10CA180886
    • U10CA030969
    • U10CA098543
    First Posted:
    Jan 27, 2003
    Last Update Posted:
    Jul 28, 2022
    Last Verified:
    Mar 1, 2022
    Additional relevant MeSH terms:
    Neuroblastoma
    Vitamin A
    Aldesleukin
    Interleukin-2
    Tretinoin
    Dinutuximab
    Isotretinoin
    Sargramostim

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Regimen A Regimen B
    Arm/Group Description Randomized to Regimen A - RA Only Regimen B - RA + Immunotherapy
    Period Title: Overall Study
    STARTED 116 1333
    COMPLETED 82 1064
    NOT COMPLETED 34 269

    Baseline Characteristics

    Arm/Group Title Regimen A Regimen B Total
    Arm/Group Description Randomized to Regimen A - RA Only Regimen B - RA + Immunotherapy Total of all reporting groups
    Overall Participants 116 1333 1449
    Age (Count of Participants)
    <=18 years
    116
    100%
    1325
    99.4%
    1441
    99.4%
    Between 18 and 65 years
    0
    0%
    8
    0.6%
    8
    0.6%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    3.22
    (2.12)
    3.64
    (2.77)
    3.61
    (2.73)
    Sex: Female, Male (Count of Participants)
    Female
    49
    42.2%
    534
    40.1%
    583
    40.2%
    Male
    67
    57.8%
    799
    59.9%
    866
    59.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    11
    9.5%
    142
    10.7%
    153
    10.6%
    Not Hispanic or Latino
    99
    85.3%
    1159
    86.9%
    1258
    86.8%
    Unknown or Not Reported
    6
    5.2%
    32
    2.4%
    38
    2.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    3
    0.2%
    3
    0.2%
    Asian
    4
    3.4%
    62
    4.7%
    66
    4.6%
    Native Hawaiian or Other Pacific Islander
    2
    1.7%
    2
    0.2%
    4
    0.3%
    Black or African American
    8
    6.9%
    153
    11.5%
    161
    11.1%
    White
    89
    76.7%
    942
    70.7%
    1031
    71.2%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    13
    11.2%
    171
    12.8%
    184
    12.7%
    Region of Enrollment (participants) [Number]
    New Zealand
    0
    0%
    17
    1.3%
    17
    1.2%
    Canada
    13
    11.2%
    135
    10.1%
    148
    10.2%
    United States
    100
    86.2%
    1092
    81.9%
    1192
    82.3%
    Australia
    3
    2.6%
    89
    6.7%
    92
    6.3%

    Outcome Measures

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

    Outcome Measure Data

    Analysis Population Description
    Eligible, randomized patients.
    Arm/Group Title Regimen A Regimen B
    Arm/Group Description Randomized to Regimen A - RA Only Randomized to Regimen B - RA + Immunotherapy
    Measure Participants 112 114
    Number (95% Confidence Interval) [Percentage of participants]
    48.1
    41.5%
    62.9
    4.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen A, Regimen B
    Comments The event-free survival distributions of patients randomized to Regimen A - RA Only and randomized to Regimen B - RA + Immunotherapy were compared using the log-rank test.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1016
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Log Rank Test Statistic
    Estimated Value 2.6803
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Event-Free Survival (EFS)
    Description 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.
    Time Frame Three years

    Outcome Measure Data

    Analysis Population Description
    Eligible, randomized patients with INSS Stage 4 disease. Eligible patients with persistent disease.
    Arm/Group Title Regimen A Regimen B
    Arm/Group Description Randomized to Regimen A - RA Only Regimen B - RA + Immunotherapy
    Measure Participants 93 127
    Randomized patients with INSS Stage 4 disease
    43.2
    37.2%
    59.7
    4.5%
    Eligible patients with persistent disease
    35.1
    30.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen A, Regimen B
    Comments The event-free survival distributions of patients randomized to Regimen A - RA Only and randomized to Regimen B - RA + Immunotherapy for the subgroup of patients with INSS Stage 4 disease were compared using the log-rank test.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1057
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Log Rank Test Statistic
    Estimated Value 2.6176
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial
    Description EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
    Time Frame Three years

    Outcome Measure Data

    Analysis Population Description
    Eligible patients non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease.
    Arm/Group Title Regimen B
    Arm/Group Description Non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease
    Measure Participants 1177
    Number (95% Confidence Interval) [Percentage of participants]
    64.0
    55.2%
    4. Secondary Outcome
    Title Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0
    Description Proportion of patients experiencing at least one Grade 3 or higher toxicity.
    Time Frame From enrollment to follow-up

    Outcome Measure Data

    Analysis Population Description
    Eligible patients enrolled prior to halting of randomization.
    Arm/Group Title Regimen A Regimen B
    Arm/Group Description Randomized to Regimen A - RA Only Patients that received RA + Immunotherapy before halting of randomization
    Measure Participants 112 141
    Number (95% Confidence Interval) [Proportion]
    0.64
    0.94
    5. Secondary Outcome
    Title Number of Courses of Therapy Delivered
    Description 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.
    Time Frame Courses 1-6

    Outcome Measure Data

    Analysis Population Description
    Eligible patients assigned to Regimen B, excluding patients with persistent disease.
    Arm/Group Title Regimen B
    Arm/Group Description Regimen B- RA + Immunotherapy
    Measure Participants 1291
    Randomized to Regimen B - RA + Immunotherapy
    6
    Non-randomly assigned after halting randomization
    6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen A
    Comments The number of courses of therapy delivered or patients randomized to Regimen B - RA + Immunotherapy and non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease, were compared using the Wilcoxon rank-sum test.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0262
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Overall Survival (OS)
    Description 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.
    Time Frame Three years

    Outcome Measure Data

    Analysis Population Description
    Eligible, randomized patients. Eligible, randomized patients with INSS Stage 4 disease.
    Arm/Group Title Regimen A Regimen B
    Arm/Group Description Randomized to Regimen A - RA Only Randomized to Regimen B - RA + Immunotherapy
    Measure Participants 112 114
    Randomized patients
    67.4
    58.1%
    78.8
    5.9%
    Randomized patients with INSS Stage 4 disease
    64.0
    55.2%
    78.7
    5.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen A, Regimen B
    Comments The overall survival distributions of patients randomized to Regimen A - RA Only and randomized to Regimen B - RA + Immunotherapy were compared using the log-rank test.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0634
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Log Rank Test Statistic
    Estimated Value 3.4471
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Regimen A, Regimen B
    Comments The overall survival distributions of patients randomized to Regimen A - RA Only and randomized to Regimen B - RA + Immunotherapy for the subgroup of patients with INSS Stage 4 disease were compared using the log-rank test.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.042
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Log-Rank Test Statistic
    Estimated Value 4.1362
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial
    Description OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
    Time Frame Three years

    Outcome Measure Data

    Analysis Population Description
    Eligible patients non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease
    Arm/Group Title Regimen B
    Arm/Group Description Non-randomly assigned to Regimen B after halting of randomization, excluding patients with persistent disease
    Measure Participants 1177
    Number (95% Confidence Interval) [Percentage of participants]
    78.4
    67.6%
    8. Other Pre-specified Outcome
    Title Average Level of HACA
    Description The average level of HACA at each collection time point during immunotherapy will be calculated.
    Time Frame Up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    Title Cardiac Repolarization
    Description 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.
    Time Frame Up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Other Pre-specified Outcome
    Title Change in MRD
    Description 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.
    Time Frame Baseline to up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Other Pre-specified Outcome
    Title Change in Tumor Biology
    Description 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.
    Time Frame Baseline to up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Other Pre-specified Outcome
    Title Circulating B7-H6 Levels
    Description 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.
    Time Frame 1 week before first sargramostim injection (day -1 of course 1)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Other Pre-specified Outcome
    Title Genotype of FcR
    Description 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.
    Time Frame Up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Other Pre-specified Outcome
    Title Genotype of Kir/Kir-ligand
    Description 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.
    Time Frame Up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    15. Other Pre-specified Outcome
    Title Isotretinoin Pharmacokinetic Parameters
    Description 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.
    Time Frame At 4 hours after administration on day 14 of course 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    16. Other Pre-specified Outcome
    Title Levels of ADCC
    Description Will be descriptively compared.
    Time Frame Up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    17. Other Pre-specified Outcome
    Title NKp30 Isoform Expression and SNP
    Description 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.
    Time Frame 1 week before first sargramostim injection (day -1 of course 1)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    18. Other Pre-specified Outcome
    Title Presence of Naturally Occurring Anti-glycan Antibodies
    Description 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.
    Time Frame Up to 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame
    Adverse Event Reporting Description Ineligible patients were excluded from the adverse event analysis, so only eligible patients are reported.
    Arm/Group Title Regimen A Regimen B
    Arm/Group Description Randomized to Regimen A - RA Only Regimen B - RA + Immunotherapy
    All Cause Mortality
    Regimen A Regimen B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Regimen A Regimen B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/112 (8.9%) 785/1328 (59.1%)
    Blood and lymphatic system disorders
    Anemia 0/112 (0%) 0 42/1328 (3.2%) 49
    Blood and lymphatic system disorders - Other specify 0/112 (0%) 0 3/1328 (0.2%) 3
    Disseminated intravascular coagulation 0/112 (0%) 0 3/1328 (0.2%) 3
    Febrile neutropenia 0/112 (0%) 0 4/1328 (0.3%) 4
    Hemolysis 0/112 (0%) 0 2/1328 (0.2%) 2
    Hemolytic uremic syndrome 0/112 (0%) 0 2/1328 (0.2%) 2
    Cardiac disorders
    Atrial fibrillation 0/112 (0%) 0 1/1328 (0.1%) 2
    Cardiac arrest 0/112 (0%) 0 3/1328 (0.2%) 3
    Cardiac disorders - Other specify 1/112 (0.9%) 1 5/1328 (0.4%) 5
    Heart failure 0/112 (0%) 0 3/1328 (0.2%) 3
    Left ventricular systolic dysfunction 0/112 (0%) 0 7/1328 (0.5%) 7
    Pericardial effusion 0/112 (0%) 0 3/1328 (0.2%) 3
    Right ventricular dysfunction 0/112 (0%) 0 1/1328 (0.1%) 1
    Sinus bradycardia 0/112 (0%) 0 2/1328 (0.2%) 2
    Sinus tachycardia 0/112 (0%) 0 13/1328 (1%) 16
    Supraventricular tachycardia 0/112 (0%) 0 1/1328 (0.1%) 1
    Ventricular arrhythmia 0/112 (0%) 0 2/1328 (0.2%) 2
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Ear pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Hearing impaired 0/112 (0%) 0 1/1328 (0.1%) 1
    Endocrine disorders
    Adrenal insufficiency 0/112 (0%) 0 1/1328 (0.1%) 1
    Endocrine disorders - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypothyroidism 0/112 (0%) 0 4/1328 (0.3%) 4
    Eye disorders
    Blurred vision 0/112 (0%) 0 7/1328 (0.5%) 7
    Eye disorders - Other specify 1/112 (0.9%) 1 16/1328 (1.2%) 16
    Optic nerve disorder 0/112 (0%) 0 2/1328 (0.2%) 2
    Papilledema 0/112 (0%) 0 2/1328 (0.2%) 2
    Photophobia 0/112 (0%) 0 5/1328 (0.4%) 5
    Gastrointestinal disorders
    Abdominal distension 0/112 (0%) 0 7/1328 (0.5%) 7
    Abdominal pain 0/112 (0%) 0 41/1328 (3.1%) 60
    Ascites 0/112 (0%) 0 5/1328 (0.4%) 5
    Colitis 0/112 (0%) 0 9/1328 (0.7%) 10
    Colonic obstruction 0/112 (0%) 0 2/1328 (0.2%) 2
    Diarrhea 0/112 (0%) 0 35/1328 (2.6%) 36
    Duodenal obstruction 0/112 (0%) 0 1/1328 (0.1%) 1
    Esophageal hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Esophageal perforation 0/112 (0%) 0 1/1328 (0.1%) 1
    Esophageal stenosis 0/112 (0%) 0 3/1328 (0.2%) 3
    Esophageal ulcer 0/112 (0%) 0 1/1328 (0.1%) 1
    Esophagitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Gastric hemorrhage 0/112 (0%) 0 3/1328 (0.2%) 3
    Gastritis 0/112 (0%) 0 2/1328 (0.2%) 2
    Gastrointestinal disorders - Other specify 0/112 (0%) 0 2/1328 (0.2%) 3
    Gastrointestinal fistula 0/112 (0%) 0 1/1328 (0.1%) 1
    Ileal obstruction 0/112 (0%) 0 1/1328 (0.1%) 1
    Ileus 0/112 (0%) 0 10/1328 (0.8%) 10
    Intra-abdominal hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Jejunal obstruction 0/112 (0%) 0 2/1328 (0.2%) 2
    Lower gastrointestinal hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Malabsorption 0/112 (0%) 0 1/1328 (0.1%) 1
    Nausea 1/112 (0.9%) 1 3/1328 (0.2%) 3
    Proctitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Rectal hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Small intestinal obstruction 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Typhlitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Vomiting 1/112 (0.9%) 1 14/1328 (1.1%) 16
    General disorders
    Chills 0/112 (0%) 0 5/1328 (0.4%) 5
    Death NOS 0/112 (0%) 0 3/1328 (0.2%) 3
    Edema face 0/112 (0%) 0 12/1328 (0.9%) 13
    Edema limbs 0/112 (0%) 0 2/1328 (0.2%) 2
    Edema trunk 0/112 (0%) 0 3/1328 (0.2%) 3
    Fatigue 0/112 (0%) 0 8/1328 (0.6%) 8
    Fever 0/112 (0%) 0 121/1328 (9.1%) 148
    Flu like symptoms 0/112 (0%) 0 1/1328 (0.1%) 1
    Gait disturbance 0/112 (0%) 0 1/1328 (0.1%) 1
    General disorders and administration site conditions - Other specify 0/112 (0%) 0 4/1328 (0.3%) 4
    Infusion related reaction 0/112 (0%) 0 4/1328 (0.3%) 4
    Injection site reaction 0/112 (0%) 0 2/1328 (0.2%) 2
    Irritability 0/112 (0%) 0 6/1328 (0.5%) 6
    Localized edema 0/112 (0%) 0 1/1328 (0.1%) 1
    Non-cardiac chest pain 0/112 (0%) 0 6/1328 (0.5%) 6
    Pain 0/112 (0%) 0 47/1328 (3.5%) 68
    Hepatobiliary disorders
    Hepatic failure 0/112 (0%) 0 1/1328 (0.1%) 1
    Hepatobiliary disorders - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Immune system disorders
    Allergic reaction 1/112 (0.9%) 3 141/1328 (10.6%) 185
    Anaphylaxis 1/112 (0.9%) 1 153/1328 (11.5%) 180
    Cytokine release syndrome 0/112 (0%) 0 23/1328 (1.7%) 35
    Immune system disorders - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Serum sickness 0/112 (0%) 0 5/1328 (0.4%) 7
    Infections and infestations
    Abdominal infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Anorectal infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Bladder infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Bone infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Bronchial infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Catheter related infection 1/112 (0.9%) 1 88/1328 (6.6%) 105
    Device related infection 0/112 (0%) 0 4/1328 (0.3%) 4
    Enterocolitis infectious 0/112 (0%) 0 11/1328 (0.8%) 11
    Eye infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Infections and infestations - Other specify 0/112 (0%) 0 113/1328 (8.5%) 145
    Kidney infection 0/112 (0%) 0 2/1328 (0.2%) 2
    Lung infection 0/112 (0%) 0 13/1328 (1%) 14
    Mucosal infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Otitis externa 0/112 (0%) 0 1/1328 (0.1%) 1
    Peripheral nerve infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Sepsis 0/112 (0%) 0 33/1328 (2.5%) 35
    Skin infection 0/112 (0%) 0 4/1328 (0.3%) 4
    Upper respiratory infection 0/112 (0%) 0 9/1328 (0.7%) 10
    Urinary tract infection 0/112 (0%) 0 11/1328 (0.8%) 13
    Wound infection 0/112 (0%) 0 2/1328 (0.2%) 2
    Injury, poisoning and procedural complications
    Fracture 0/112 (0%) 0 2/1328 (0.2%) 2
    Vascular access complication 0/112 (0%) 0 2/1328 (0.2%) 2
    Investigations
    Activated partial thromboplastin time prolonged 0/112 (0%) 0 2/1328 (0.2%) 2
    Alanine aminotransferase increased 2/112 (1.8%) 3 36/1328 (2.7%) 45
    Alkaline phosphatase increased 0/112 (0%) 0 6/1328 (0.5%) 7
    Aspartate aminotransferase increased 1/112 (0.9%) 1 28/1328 (2.1%) 30
    Blood bilirubin increased 0/112 (0%) 0 21/1328 (1.6%) 21
    Cardiac troponin I increased 0/112 (0%) 0 1/1328 (0.1%) 1
    Creatinine increased 0/112 (0%) 0 14/1328 (1.1%) 15
    Fibrinogen decreased 0/112 (0%) 0 2/1328 (0.2%) 2
    GGT increased 0/112 (0%) 0 14/1328 (1.1%) 18
    INR increased 0/112 (0%) 0 2/1328 (0.2%) 2
    Investigations - Other specify 0/112 (0%) 0 5/1328 (0.4%) 5
    Lipase increased 0/112 (0%) 0 3/1328 (0.2%) 3
    Lymphocyte count decreased 2/112 (1.8%) 2 17/1328 (1.3%) 22
    Neutrophil count decreased 0/112 (0%) 0 30/1328 (2.3%) 31
    Platelet count decreased 0/112 (0%) 0 29/1328 (2.2%) 44
    Serum amylase increased 0/112 (0%) 0 2/1328 (0.2%) 2
    Urine output decreased 0/112 (0%) 0 27/1328 (2%) 37
    Weight gain 0/112 (0%) 0 8/1328 (0.6%) 8
    Weight loss 0/112 (0%) 0 5/1328 (0.4%) 6
    White blood cell decreased 0/112 (0%) 0 15/1328 (1.1%) 17
    Metabolism and nutrition disorders
    Acidosis 0/112 (0%) 0 10/1328 (0.8%) 10
    Anorexia 0/112 (0%) 0 16/1328 (1.2%) 18
    Dehydration 0/112 (0%) 0 22/1328 (1.7%) 22
    Hypercalcemia 0/112 (0%) 0 24/1328 (1.8%) 35
    Hyperglycemia 0/112 (0%) 0 1/1328 (0.1%) 1
    Hyperkalemia 0/112 (0%) 0 10/1328 (0.8%) 10
    Hypermagnesemia 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypernatremia 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypertriglyceridemia 1/112 (0.9%) 1 6/1328 (0.5%) 6
    Hypoalbuminemia 0/112 (0%) 0 23/1328 (1.7%) 25
    Hypocalcemia 0/112 (0%) 0 23/1328 (1.7%) 25
    Hypoglycemia 0/112 (0%) 0 6/1328 (0.5%) 6
    Hypokalemia 0/112 (0%) 0 65/1328 (4.9%) 71
    Hypomagnesemia 0/112 (0%) 0 4/1328 (0.3%) 5
    Hyponatremia 0/112 (0%) 0 66/1328 (5%) 76
    Hypophosphatemia 0/112 (0%) 0 38/1328 (2.9%) 40
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/112 (0%) 0 5/1328 (0.4%) 8
    Back pain 0/112 (0%) 0 9/1328 (0.7%) 12
    Bone pain 0/112 (0%) 0 4/1328 (0.3%) 4
    Chest wall pain 0/112 (0%) 0 3/1328 (0.2%) 3
    Muscle weakness lower limb 0/112 (0%) 0 2/1328 (0.2%) 2
    Musculoskeletal and connective tissue disorder - Other specify 0/112 (0%) 0 2/1328 (0.2%) 2
    Myalgia 0/112 (0%) 0 1/1328 (0.1%) 1
    Neck pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Pain in extremity 0/112 (0%) 0 20/1328 (1.5%) 29
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign malignant and unspecified (incl cysts and polyps) - Other specify 0/112 (0%) 0 4/1328 (0.3%) 4
    Nervous system disorders
    Depressed level of consciousness 0/112 (0%) 0 7/1328 (0.5%) 7
    Dysphasia 0/112 (0%) 0 1/1328 (0.1%) 1
    Encephalopathy 0/112 (0%) 0 3/1328 (0.2%) 3
    Extrapyramidal disorder 0/112 (0%) 0 2/1328 (0.2%) 2
    Headache 0/112 (0%) 0 11/1328 (0.8%) 12
    Hydrocephalus 0/112 (0%) 0 4/1328 (0.3%) 4
    Intracranial hemorrhage 0/112 (0%) 0 6/1328 (0.5%) 6
    Myelitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Nervous system disorders - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Neuralgia 0/112 (0%) 0 11/1328 (0.8%) 12
    Oculomotor nerve disorder 0/112 (0%) 0 1/1328 (0.1%) 1
    Peripheral motor neuropathy 0/112 (0%) 0 4/1328 (0.3%) 4
    Peripheral sensory neuropathy 0/112 (0%) 0 5/1328 (0.4%) 5
    Reversible posterior leukoencephalopathy syndrome 0/112 (0%) 0 3/1328 (0.2%) 3
    Seizure 0/112 (0%) 0 10/1328 (0.8%) 10
    Somnolence 0/112 (0%) 0 1/1328 (0.1%) 1
    Syncope 0/112 (0%) 0 1/1328 (0.1%) 1
    Tremor 0/112 (0%) 0 1/1328 (0.1%) 1
    Psychiatric disorders
    Agitation 0/112 (0%) 0 3/1328 (0.2%) 3
    Anxiety 0/112 (0%) 0 1/1328 (0.1%) 1
    Confusion 0/112 (0%) 0 1/1328 (0.1%) 1
    Delirium 0/112 (0%) 0 2/1328 (0.2%) 2
    Depression 0/112 (0%) 0 1/1328 (0.1%) 1
    Euphoria 0/112 (0%) 0 1/1328 (0.1%) 1
    Insomnia 0/112 (0%) 0 1/1328 (0.1%) 1
    Personality change 0/112 (0%) 0 1/1328 (0.1%) 1
    Psychosis 0/112 (0%) 0 3/1328 (0.2%) 3
    Suicidal ideation 0/112 (0%) 0 1/1328 (0.1%) 1
    Suicide attempt 0/112 (0%) 0 1/1328 (0.1%) 1
    Renal and urinary disorders
    Acute kidney injury 0/112 (0%) 0 12/1328 (0.9%) 12
    Chronic kidney disease 0/112 (0%) 0 2/1328 (0.2%) 2
    Proteinuria 0/112 (0%) 0 9/1328 (0.7%) 12
    Renal and urinary disorders - Other specify 0/112 (0%) 0 3/1328 (0.2%) 4
    Urinary frequency 0/112 (0%) 0 1/1328 (0.1%) 1
    Urinary retention 0/112 (0%) 0 10/1328 (0.8%) 11
    Urinary tract obstruction 0/112 (0%) 0 1/1328 (0.1%) 1
    Reproductive system and breast disorders
    Scrotal pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome 0/112 (0%) 0 11/1328 (0.8%) 12
    Allergic rhinitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Apnea 0/112 (0%) 0 6/1328 (0.5%) 6
    Aspiration 0/112 (0%) 0 1/1328 (0.1%) 1
    Atelectasis 0/112 (0%) 0 1/1328 (0.1%) 1
    Bronchial obstruction 0/112 (0%) 0 1/1328 (0.1%) 1
    Bronchopulmonary hemorrhage 0/112 (0%) 0 2/1328 (0.2%) 2
    Bronchospasm 0/112 (0%) 0 30/1328 (2.3%) 34
    Cough 0/112 (0%) 0 16/1328 (1.2%) 18
    Dyspnea 0/112 (0%) 0 53/1328 (4%) 60
    Epistaxis 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypoxia 0/112 (0%) 0 69/1328 (5.2%) 85
    Laryngeal edema 0/112 (0%) 0 3/1328 (0.2%) 5
    Pharyngolaryngeal pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Pleural effusion 0/112 (0%) 0 8/1328 (0.6%) 8
    Pleural hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Pleuritic pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Pneumonitis 0/112 (0%) 0 2/1328 (0.2%) 2
    Pneumothorax 0/112 (0%) 0 1/1328 (0.1%) 1
    Pulmonary edema 0/112 (0%) 0 10/1328 (0.8%) 10
    Respiratory thoracic and mediastinal disorders - Other specify 0/112 (0%) 0 5/1328 (0.4%) 5
    Respiratory failure 0/112 (0%) 0 7/1328 (0.5%) 7
    Stridor 0/112 (0%) 0 6/1328 (0.5%) 7
    Wheezing 0/112 (0%) 0 6/1328 (0.5%) 6
    Skin and subcutaneous tissue disorders
    Dry skin 0/112 (0%) 0 2/1328 (0.2%) 2
    Erythema multiforme 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Hyperhidrosis 0/112 (0%) 0 1/1328 (0.1%) 1
    Pain of skin 0/112 (0%) 0 1/1328 (0.1%) 1
    Periorbital edema 0/112 (0%) 0 2/1328 (0.2%) 2
    Pruritus 0/112 (0%) 0 10/1328 (0.8%) 10
    Rash acneiform 0/112 (0%) 0 1/1328 (0.1%) 1
    Rash maculo-papular 0/112 (0%) 0 6/1328 (0.5%) 6
    Skin and subcutaneous tissue disorders - Other specify 0/112 (0%) 0 3/1328 (0.2%) 3
    Urticaria 0/112 (0%) 0 102/1328 (7.7%) 128
    Surgical and medical procedures
    Surgical and medical procedures - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Vascular disorders
    Capillary leak syndrome 0/112 (0%) 0 154/1328 (11.6%) 189
    Hypertension 0/112 (0%) 0 22/1328 (1.7%) 24
    Hypotension 0/112 (0%) 0 249/1328 (18.8%) 335
    Thromboembolic event 0/112 (0%) 0 4/1328 (0.3%) 4
    Vascular disorders - Other specify 0/112 (0%) 0 2/1328 (0.2%) 2
    Other (Not Including Serious) Adverse Events
    Regimen A Regimen B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 92/112 (82.1%) 1244/1328 (93.7%)
    Blood and lymphatic system disorders
    Anemia 22/112 (19.6%) 47 428/1328 (32.2%) 962
    Blood and lymphatic system disorders - Other specify 1/112 (0.9%) 1 16/1328 (1.2%) 24
    Disseminated intravascular coagulation 0/112 (0%) 0 3/1328 (0.2%) 3
    Febrile neutropenia 0/112 (0%) 0 19/1328 (1.4%) 23
    Hemolytic uremic syndrome 0/112 (0%) 0 1/1328 (0.1%) 1
    Cardiac disorders
    Atrial fibrillation 0/112 (0%) 0 1/1328 (0.1%) 1
    Cardiac disorders - Other specify 1/112 (0.9%) 1 36/1328 (2.7%) 49
    Chest pain - cardiac 0/112 (0%) 0 2/1328 (0.2%) 2
    Conduction disorder 0/112 (0%) 0 1/1328 (0.1%) 1
    Heart failure 0/112 (0%) 0 1/1328 (0.1%) 1
    Left ventricular systolic dysfunction 0/112 (0%) 0 1/1328 (0.1%) 1
    Mobitz type I 0/112 (0%) 0 1/1328 (0.1%) 1
    Paroxysmal atrial tachycardia 0/112 (0%) 0 5/1328 (0.4%) 6
    Pericardial effusion 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Sinus bradycardia 0/112 (0%) 0 2/1328 (0.2%) 4
    Sinus tachycardia 1/112 (0.9%) 1 49/1328 (3.7%) 82
    Supraventricular tachycardia 0/112 (0%) 0 8/1328 (0.6%) 13
    Ventricular arrhythmia 0/112 (0%) 0 2/1328 (0.2%) 2
    Ventricular tachycardia 0/112 (0%) 0 3/1328 (0.2%) 3
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other specify 0/112 (0%) 0 2/1328 (0.2%) 2
    Ear pain 1/112 (0.9%) 1 3/1328 (0.2%) 3
    External ear inflammation 1/112 (0.9%) 1 0/1328 (0%) 0
    Hearing impaired 6/112 (5.4%) 8 22/1328 (1.7%) 28
    Middle ear inflammation 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Tinnitus 0/112 (0%) 0 1/1328 (0.1%) 1
    Endocrine disorders
    Adrenal insufficiency 0/112 (0%) 0 3/1328 (0.2%) 3
    Endocrine disorders - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Hyperthyroidism 0/112 (0%) 0 4/1328 (0.3%) 6
    Hypothyroidism 2/112 (1.8%) 2 6/1328 (0.5%) 6
    Eye disorders
    Blurred vision 0/112 (0%) 0 12/1328 (0.9%) 14
    Conjunctivitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Dry eye 1/112 (0.9%) 1 2/1328 (0.2%) 2
    Extraocular muscle paresis 0/112 (0%) 0 1/1328 (0.1%) 1
    Eye disorders - Other specify 2/112 (1.8%) 2 20/1328 (1.5%) 24
    Eye pain 0/112 (0%) 0 2/1328 (0.2%) 3
    Flashing lights 0/112 (0%) 0 1/1328 (0.1%) 1
    Photophobia 2/112 (1.8%) 3 8/1328 (0.6%) 8
    Watering eyes 0/112 (0%) 0 1/1328 (0.1%) 2
    Gastrointestinal disorders
    Abdominal distension 0/112 (0%) 0 9/1328 (0.7%) 9
    Abdominal pain 11/112 (9.8%) 14 312/1328 (23.5%) 566
    Anal mucositis 0/112 (0%) 0 1/1328 (0.1%) 1
    Anal pain 0/112 (0%) 0 4/1328 (0.3%) 4
    Cheilitis 4/112 (3.6%) 7 16/1328 (1.2%) 29
    Colitis 0/112 (0%) 0 11/1328 (0.8%) 14
    Colonic stenosis 0/112 (0%) 0 1/1328 (0.1%) 1
    Constipation 2/112 (1.8%) 2 24/1328 (1.8%) 35
    Diarrhea 16/112 (14.3%) 26 196/1328 (14.8%) 311
    Dry mouth 0/112 (0%) 0 1/1328 (0.1%) 1
    Dysphagia 0/112 (0%) 0 1/1328 (0.1%) 1
    Esophageal stenosis 0/112 (0%) 0 1/1328 (0.1%) 1
    Esophagitis 0/112 (0%) 0 2/1328 (0.2%) 2
    Flatulence 0/112 (0%) 0 1/1328 (0.1%) 1
    Gastric ulcer 0/112 (0%) 0 1/1328 (0.1%) 1
    Gastritis 0/112 (0%) 0 3/1328 (0.2%) 3
    Gastrointestinal disorders - Other specify 0/112 (0%) 0 5/1328 (0.4%) 6
    Gastrointestinal pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Gastroparesis 0/112 (0%) 0 1/1328 (0.1%) 6
    Gingival pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Ileus 0/112 (0%) 0 3/1328 (0.2%) 3
    Lower gastrointestinal hemorrhage 0/112 (0%) 0 2/1328 (0.2%) 2
    Malabsorption 0/112 (0%) 0 2/1328 (0.2%) 5
    Mucositis oral 1/112 (0.9%) 1 6/1328 (0.5%) 6
    Nausea 2/112 (1.8%) 2 40/1328 (3%) 65
    Oral pain 0/112 (0%) 0 8/1328 (0.6%) 9
    Pancreatitis 1/112 (0.9%) 1 0/1328 (0%) 0
    Rectal hemorrhage 0/112 (0%) 0 2/1328 (0.2%) 2
    Rectal pain 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Small intestinal obstruction 0/112 (0%) 0 4/1328 (0.3%) 4
    Stomach pain 1/112 (0.9%) 1 16/1328 (1.2%) 23
    Toothache 0/112 (0%) 0 3/1328 (0.2%) 3
    Upper gastrointestinal hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Vomiting 21/112 (18.8%) 35 109/1328 (8.2%) 196
    General disorders
    Chills 0/112 (0%) 0 31/1328 (2.3%) 43
    Edema face 0/112 (0%) 0 49/1328 (3.7%) 82
    Edema limbs 0/112 (0%) 0 20/1328 (1.5%) 28
    Edema trunk 0/112 (0%) 0 3/1328 (0.2%) 3
    Facial pain 1/112 (0.9%) 1 3/1328 (0.2%) 3
    Fatigue 2/112 (1.8%) 3 33/1328 (2.5%) 39
    Fever 33/112 (29.5%) 43 536/1328 (40.4%) 991
    Flu like symptoms 0/112 (0%) 0 1/1328 (0.1%) 1
    Gait disturbance 0/112 (0%) 0 4/1328 (0.3%) 4
    General disorders and administration site conditions - Other specify 0/112 (0%) 0 6/1328 (0.5%) 8
    Hypothermia 0/112 (0%) 0 2/1328 (0.2%) 2
    Infusion site extravasation 0/112 (0%) 0 1/1328 (0.1%) 1
    Injection site reaction 0/112 (0%) 0 10/1328 (0.8%) 13
    Irritability 0/112 (0%) 0 13/1328 (1%) 17
    Localized edema 0/112 (0%) 0 1/1328 (0.1%) 1
    Non-cardiac chest pain 0/112 (0%) 0 10/1328 (0.8%) 12
    Pain 6/112 (5.4%) 14 441/1328 (33.2%) 941
    Hepatobiliary disorders
    Cholecystitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Hepatobiliary disorders - Other specify 0/112 (0%) 0 3/1328 (0.2%) 3
    Immune system disorders
    Allergic reaction 11/112 (9.8%) 29 655/1328 (49.3%) 1405
    Anaphylaxis 1/112 (0.9%) 2 71/1328 (5.3%) 92
    Cytokine release syndrome 1/112 (0.9%) 1 115/1328 (8.7%) 205
    Immune system disorders - Other specify 0/112 (0%) 0 4/1328 (0.3%) 4
    Serum sickness 1/112 (0.9%) 1 0/1328 (0%) 0
    Infections and infestations
    Abdominal infection 2/112 (1.8%) 2 8/1328 (0.6%) 11
    Anorectal infection 0/112 (0%) 0 4/1328 (0.3%) 4
    Bladder infection 0/112 (0%) 0 2/1328 (0.2%) 2
    Bone infection 0/112 (0%) 0 3/1328 (0.2%) 3
    Bronchial infection 2/112 (1.8%) 2 1/1328 (0.1%) 1
    Catheter related infection 8/112 (7.1%) 9 97/1328 (7.3%) 128
    Cecal infection 0/112 (0%) 0 2/1328 (0.2%) 2
    Conjunctivitis infective 0/112 (0%) 0 1/1328 (0.1%) 1
    Device related infection 1/112 (0.9%) 1 7/1328 (0.5%) 8
    Endocarditis infective 0/112 (0%) 0 1/1328 (0.1%) 1
    Enterocolitis infectious 2/112 (1.8%) 2 39/1328 (2.9%) 47
    Esophageal infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Eye infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Gum infection 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Infections and infestations - Other specify 29/112 (25.9%) 42 147/1328 (11.1%) 255
    Joint infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Lung infection 2/112 (1.8%) 2 13/1328 (1%) 13
    Lymph gland infection 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Nail infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Otitis externa 0/112 (0%) 0 1/1328 (0.1%) 1
    Otitis media 1/112 (0.9%) 1 6/1328 (0.5%) 6
    Ovarian infection 1/112 (0.9%) 1 0/1328 (0%) 0
    Pelvic infection 1/112 (0.9%) 1 0/1328 (0%) 0
    Peripheral nerve infection 1/112 (0.9%) 2 1/1328 (0.1%) 1
    Pharyngitis 0/112 (0%) 0 1/1328 (0.1%) 1
    Pleural infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Rash pustular 0/112 (0%) 0 1/1328 (0.1%) 1
    Rhinitis infective 0/112 (0%) 0 3/1328 (0.2%) 4
    Salivary gland infection 0/112 (0%) 0 1/1328 (0.1%) 1
    Sepsis 0/112 (0%) 0 6/1328 (0.5%) 6
    Sinusitis 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Skin infection 1/112 (0.9%) 1 9/1328 (0.7%) 9
    Small intestine infection 0/112 (0%) 0 1/1328 (0.1%) 2
    Tooth infection 0/112 (0%) 0 1/1328 (0.1%) 2
    Upper respiratory infection 2/112 (1.8%) 2 21/1328 (1.6%) 23
    Urinary tract infection 1/112 (0.9%) 1 27/1328 (2%) 35
    Wound infection 0/112 (0%) 0 4/1328 (0.3%) 4
    Injury, poisoning and procedural complications
    Bruising 0/112 (0%) 0 2/1328 (0.2%) 2
    Burn 0/112 (0%) 0 1/1328 (0.1%) 1
    Fracture 0/112 (0%) 0 5/1328 (0.4%) 5
    Injury poisoning and procedural complications - Other specify 0/112 (0%) 0 1/1328 (0.1%) 1
    Radiation recall reaction (dermatologic) 0/112 (0%) 0 3/1328 (0.2%) 3
    Vascular access complication 0/112 (0%) 0 6/1328 (0.5%) 6
    Investigations
    Activated partial thromboplastin time prolonged 1/112 (0.9%) 1 6/1328 (0.5%) 6
    Alanine aminotransferase increased 33/112 (29.5%) 79 281/1328 (21.2%) 560
    Alkaline phosphatase increased 7/112 (6.3%) 14 35/1328 (2.6%) 53
    Aspartate aminotransferase increased 6/112 (5.4%) 11 180/1328 (13.6%) 279
    Blood bilirubin increased 5/112 (4.5%) 7 28/1328 (2.1%) 40
    CD4 lymphocytes decreased 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Cholesterol high 1/112 (0.9%) 4 12/1328 (0.9%) 30
    Creatinine increased 6/112 (5.4%) 12 44/1328 (3.3%) 67
    Fibrinogen decreased 0/112 (0%) 0 1/1328 (0.1%) 1
    Forced expiratory volume decreased 1/112 (0.9%) 1 0/1328 (0%) 0
    GGT increased 0/112 (0%) 0 97/1328 (7.3%) 217
    INR increased 0/112 (0%) 0 2/1328 (0.2%) 2
    Investigations - Other specify 2/112 (1.8%) 4 18/1328 (1.4%) 28
    Lipase increased 0/112 (0%) 0 4/1328 (0.3%) 4
    Lymphocyte count decreased 40/112 (35.7%) 97 323/1328 (24.3%) 739
    Lymphocyte count increased 0/112 (0%) 0 2/1328 (0.2%) 2
    Neutrophil count decreased 18/112 (16.1%) 24 272/1328 (20.5%) 470
    Pancreatic enzymes decreased 0/112 (0%) 0 1/1328 (0.1%) 1
    Platelet count decreased 47/112 (42%) 144 356/1328 (26.8%) 876
    Serum amylase increased 0/112 (0%) 0 5/1328 (0.4%) 12
    Urine output decreased 0/112 (0%) 0 31/1328 (2.3%) 57
    Weight gain 0/112 (0%) 0 50/1328 (3.8%) 90
    Weight loss 0/112 (0%) 0 15/1328 (1.1%) 15
    White blood cell decreased 16/112 (14.3%) 37 158/1328 (11.9%) 297
    Metabolism and nutrition disorders
    Acidosis 0/112 (0%) 0 25/1328 (1.9%) 48
    Alkalosis 0/112 (0%) 0 3/1328 (0.2%) 4
    Anorexia 5/112 (4.5%) 12 100/1328 (7.5%) 189
    Dehydration 2/112 (1.8%) 2 14/1328 (1.1%) 14
    Glucose intolerance 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypercalcemia 8/112 (7.1%) 17 36/1328 (2.7%) 44
    Hyperglycemia 4/112 (3.6%) 5 77/1328 (5.8%) 129
    Hyperkalemia 4/112 (3.6%) 4 46/1328 (3.5%) 58
    Hypermagnesemia 1/112 (0.9%) 1 13/1328 (1%) 13
    Hypernatremia 1/112 (0.9%) 1 12/1328 (0.9%) 12
    Hypertriglyceridemia 11/112 (9.8%) 17 77/1328 (5.8%) 162
    Hyperuricemia 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypoalbuminemia 3/112 (2.7%) 4 156/1328 (11.7%) 359
    Hypocalcemia 1/112 (0.9%) 1 128/1328 (9.6%) 229
    Hypoglycemia 0/112 (0%) 0 29/1328 (2.2%) 35
    Hypokalemia 6/112 (5.4%) 12 409/1328 (30.8%) 664
    Hypomagnesemia 1/112 (0.9%) 1 40/1328 (3%) 55
    Hyponatremia 13/112 (11.6%) 31 262/1328 (19.7%) 466
    Hypophosphatemia 3/112 (2.7%) 7 114/1328 (8.6%) 141
    Iron overload 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/112 (2.7%) 7 14/1328 (1.1%) 18
    Arthritis 0/112 (0%) 0 1/1328 (0.1%) 1
    Back pain 1/112 (0.9%) 1 69/1328 (5.2%) 97
    Bone pain 2/112 (1.8%) 5 14/1328 (1.1%) 17
    Buttock pain 0/112 (0%) 0 4/1328 (0.3%) 4
    Chest wall pain 2/112 (1.8%) 2 16/1328 (1.2%) 19
    Flank pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Generalized muscle weakness 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Muscle weakness lower limb 0/112 (0%) 0 2/1328 (0.2%) 2
    Musculoskeletal and connective tissue disorder - Other specify 0/112 (0%) 0 2/1328 (0.2%) 2
    Myalgia 2/112 (1.8%) 4 9/1328 (0.7%) 11
    Neck pain 0/112 (0%) 0 26/1328 (2%) 36
    Osteoporosis 0/112 (0%) 0 1/1328 (0.1%) 1
    Pain in extremity 4/112 (3.6%) 7 132/1328 (9.9%) 207
    Pelvic soft tissue necrosis 0/112 (0%) 0 1/1328 (0.1%) 1
    Nervous system disorders
    Ataxia 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Depressed level of consciousness 0/112 (0%) 0 7/1328 (0.5%) 7
    Dizziness 0/112 (0%) 0 2/1328 (0.2%) 2
    Dysgeusia 0/112 (0%) 0 2/1328 (0.2%) 3
    Dysphasia 0/112 (0%) 0 1/1328 (0.1%) 1
    Headache 4/112 (3.6%) 5 56/1328 (4.2%) 73
    Hypoglossal nerve disorder 0/112 (0%) 0 1/1328 (0.1%) 1
    Intracranial hemorrhage 0/112 (0%) 0 1/1328 (0.1%) 1
    Memory impairment 0/112 (0%) 0 1/1328 (0.1%) 1
    Movements involuntary 0/112 (0%) 0 1/1328 (0.1%) 1
    Nervous system disorders - Other specify 1/112 (0.9%) 1 1/1328 (0.1%) 1
    Neuralgia 1/112 (0.9%) 1 53/1328 (4%) 119
    Oculomotor nerve disorder 0/112 (0%) 0 2/1328 (0.2%) 2
    Peripheral motor neuropathy 4/112 (3.6%) 5 12/1328 (0.9%) 17
    Peripheral sensory neuropathy 1/112 (0.9%) 4 19/1328 (1.4%) 27
    Seizure 1/112 (0.9%) 1 9/1328 (0.7%) 9
    Somnolence 0/112 (0%) 0 1/1328 (0.1%) 1
    Stroke 0/112 (0%) 0 2/1328 (0.2%) 2
    Syncope 1/112 (0.9%) 1 2/1328 (0.2%) 2
    Vasovagal reaction 0/112 (0%) 0 1/1328 (0.1%) 1
    Psychiatric disorders
    Agitation 2/112 (1.8%) 3 15/1328 (1.1%) 20
    Anxiety 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Confusion 0/112 (0%) 0 3/1328 (0.2%) 3
    Depression 0/112 (0%) 0 3/1328 (0.2%) 4
    Euphoria 0/112 (0%) 0 2/1328 (0.2%) 2
    Hallucinations 0/112 (0%) 0 2/1328 (0.2%) 2
    Personality change 4/112 (3.6%) 5 3/1328 (0.2%) 3
    Psychosis 0/112 (0%) 0 4/1328 (0.3%) 4
    Renal and urinary disorders
    Acute kidney injury 1/112 (0.9%) 1 1/1328 (0.1%) 2
    Bladder spasm 0/112 (0%) 0 1/1328 (0.1%) 1
    Chronic kidney disease 0/112 (0%) 0 1/1328 (0.1%) 1
    Hematuria 1/112 (0.9%) 1 17/1328 (1.3%) 22
    Hemoglobinuria 0/112 (0%) 0 2/1328 (0.2%) 2
    Proteinuria 3/112 (2.7%) 6 32/1328 (2.4%) 42
    Renal and urinary disorders - Other specify 1/112 (0.9%) 2 10/1328 (0.8%) 13
    Renal hemorrhage 1/112 (0.9%) 1 0/1328 (0%) 0
    Urinary frequency 2/112 (1.8%) 2 0/1328 (0%) 0
    Urinary retention 0/112 (0%) 0 30/1328 (2.3%) 47
    Urinary tract obstruction 0/112 (0%) 0 2/1328 (0.2%) 4
    Urinary tract pain 0/112 (0%) 0 4/1328 (0.3%) 4
    Urine discoloration 0/112 (0%) 0 2/1328 (0.2%) 4
    Reproductive system and breast disorders
    Pelvic pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Penile pain 0/112 (0%) 0 10/1328 (0.8%) 12
    Perineal pain 0/112 (0%) 0 1/1328 (0.1%) 1
    Vaginal pain 0/112 (0%) 0 2/1328 (0.2%) 2
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Allergic rhinitis 1/112 (0.9%) 4 5/1328 (0.4%) 7
    Apnea 0/112 (0%) 0 2/1328 (0.2%) 2
    Atelectasis 0/112 (0%) 0 5/1328 (0.4%) 5
    Bronchospasm 1/112 (0.9%) 2 29/1328 (2.2%) 36
    Chylothorax 0/112 (0%) 0 2/1328 (0.2%) 2
    Cough 2/112 (1.8%) 5 84/1328 (6.3%) 115
    Dyspnea 3/112 (2.7%) 3 111/1328 (8.4%) 146
    Epistaxis 3/112 (2.7%) 3 5/1328 (0.4%) 5
    Hypoxia 3/112 (2.7%) 3 179/1328 (13.5%) 275
    Laryngeal edema 0/112 (0%) 0 2/1328 (0.2%) 2
    Laryngeal obstruction 0/112 (0%) 0 1/1328 (0.1%) 1
    Pharyngolaryngeal pain 0/112 (0%) 0 12/1328 (0.9%) 16
    Pleural effusion 1/112 (0.9%) 1 4/1328 (0.3%) 4
    Pneumonitis 0/112 (0%) 0 4/1328 (0.3%) 4
    Pneumothorax 0/112 (0%) 0 1/1328 (0.1%) 1
    Pulmonary edema 0/112 (0%) 0 3/1328 (0.2%) 3
    Pulmonary fibrosis 0/112 (0%) 0 2/1328 (0.2%) 2
    Respiratory thoracic and mediastinal disorders - Other specify 0/112 (0%) 0 10/1328 (0.8%) 10
    Respiratory failure 0/112 (0%) 0 2/1328 (0.2%) 2
    Sinus disorder 1/112 (0.9%) 1 0/1328 (0%) 0
    Sore throat 0/112 (0%) 0 7/1328 (0.5%) 10
    Stridor 0/112 (0%) 0 4/1328 (0.3%) 4
    Voice alteration 0/112 (0%) 0 1/1328 (0.1%) 1
    Wheezing 0/112 (0%) 0 5/1328 (0.4%) 5
    Skin and subcutaneous tissue disorders
    Alopecia 0/112 (0%) 0 1/1328 (0.1%) 1
    Dry skin 16/112 (14.3%) 29 57/1328 (4.3%) 98
    Erythema multiforme 6/112 (5.4%) 7 6/1328 (0.5%) 7
    Hyperhidrosis 0/112 (0%) 0 6/1328 (0.5%) 6
    Nail loss 1/112 (0.9%) 1 0/1328 (0%) 0
    Pain of skin 0/112 (0%) 0 13/1328 (1%) 15
    Palmar-plantar erythrodysesthesia syndrome 0/112 (0%) 0 3/1328 (0.2%) 3
    Periorbital edema 0/112 (0%) 0 3/1328 (0.2%) 5
    Pruritus 2/112 (1.8%) 2 60/1328 (4.5%) 89
    Purpura 0/112 (0%) 0 3/1328 (0.2%) 4
    Rash acneiform 0/112 (0%) 0 1/1328 (0.1%) 1
    Rash maculo-papular 5/112 (4.5%) 8 41/1328 (3.1%) 48
    Skin and subcutaneous tissue disorders - Other specify 2/112 (1.8%) 2 22/1328 (1.7%) 35
    Skin induration 0/112 (0%) 0 3/1328 (0.2%) 4
    Skin ulceration 0/112 (0%) 0 1/1328 (0.1%) 1
    Urticaria 6/112 (5.4%) 9 606/1328 (45.6%) 1151
    Vascular disorders
    Capillary leak syndrome 2/112 (1.8%) 2 533/1328 (40.1%) 1089
    Flushing 0/112 (0%) 0 5/1328 (0.4%) 5
    Hematoma 0/112 (0%) 0 1/1328 (0.1%) 1
    Hypertension 7/112 (6.3%) 16 48/1328 (3.6%) 67
    Hypotension 6/112 (5.4%) 9 797/1328 (60%) 1824
    Thromboembolic event 0/112 (0%) 0 1/1328 (0.1%) 1
    Vascular disorders - Other specify 3/112 (2.7%) 5 17/1328 (1.3%) 24

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Results Reporting Coordinator
    Organization Children's Oncology Group
    Phone 626-447-0064
    Email resultsreportingcoordinator@childrensoncologygroup.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00026312
    Other Study ID Numbers:
    • NCI-2009-01064
    • NCI-2009-01064
    • s14-01661
    • COG-ANBL0032
    • PANBL0032_A33PAMDREVW01
    • CDR0000069018
    • ANBL0032
    • ANBL0032
    • ANBL0032
    • U10CA180886
    • U10CA030969
    • U10CA098543
    First Posted:
    Jan 27, 2003
    Last Update Posted:
    Jul 28, 2022
    Last Verified:
    Mar 1, 2022