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NCT00567567 · CITED IN SOURCE DOCUMENTS

Comparing Two Different Myeloablation Therapies in Treating Young Patients Who Are Undergoing a Stem Cell Transplant for High-Risk Neuroblastoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2022-04-28

This randomized phase III trial compares two different high-dose chemotherapy regimens followed by a stem cell transplant in treating younger patients with high-risk neuroblastoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments before a peripheral blood stem cell transplant helps kill any tumor cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. High-dose chemotherapy and radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the high- chemotherapy. It is not yet known which regimen of high-dose chemotherapy is more effective for patients with high-risk neuroblastoma undergoing a peripheral blood stem cell transplant.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-free Survival Rate

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outcome · POSTED

Response After Induction Therapy

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outcome · POSTED

Incidence Rate of Local Recurrence

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outcome · POSTED

Duration of Greater Than or Equal to Grade 3 Neutropenia

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outcome · POSTED

Duration of Greater Than or Equal to Grade 3 Thrombocytopenia

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outcome · POSTED

Proportion of Patients With a Polymorphism

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outcome · POSTED

Surgical Response

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outcome · POSTED

Type of Surgical or Radiotherapy Complication

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outcome · POSTED

Intraspinal Extension

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outcome · POSTED

Peak Serum Concentration of Isotretinoin in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies

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outcome · POSTED

Pharmacogenetic Variants in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies

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outcome · POSTED

Topotecan Systemic Clearance

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outcome · POSTED

Presence and Function of T Cells Capable of Recognizing Neuroblastoma

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outcome · POSTED

Enumeration of Peripheral Blood Cluster of Differentiation (CD)3, CD4, and CD8 Cells

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outcome · POSTED

Proportion of Patients With Neuroblastoma Detected in Bone Marrow and Peripheral Blood Using RT-PCR Technique

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outcome · POSTED

EFS Pts Non-randomly Assigned to Single CEM (12-18 Mths, Stg. 4, MYCN Nonamplified Tumor/Unfavorable or Indeterminant Histopathology/Diploid DNA Content & Pts>547 Days, Stg.3, MYCN Nonamplified Tumor AND Unfavorable or Indeterminant Histopathology).

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outcome · POSTED

OS in Patients 12-18 Months, Stage 4, MYCN Nonamplified Tumor/Unfavorable Histopathology/Diploid DNA Content/Indeterminant Histology/Ploidy and Patients > 547 Days, Stage 3, MYCN Nonamplified Tumor AND Unfavorable Histopathology/Indeterminant Histology

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: * Diagnosis of neuroblastoma or ganglioneuroblastoma by histology or as evidenced by the presence of clumps of tumor cells in bone marrow and elevated catecholamine metabolites in urine meeting any of the following criteria: * Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) stage 4 disease are eligible with the following: * MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features * Age \> 18 months (i.e., \> 547 days) regardless of biologic features * Age 12-18 months (i.e., 365-547 days) with none of the following three favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and deoxyribonucleic acid \[DNA\] index \> 1) * Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following: * MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features * Age \> 18 months (i.e., \> 547 days) with unfavorable pathology, regardless of MYCN status * Patients with newly diagnosed INSS stage 2a or 2b with MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features * Patients with newly diagnosed INSS stage 4s with MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features * Patients \>= 365 days initially diagnosed with INSS stage 1, 2, or 4S and who progressed to a stage 4 without interval chemotherapy * Must have been enrolled on COG-ANBL00B1 * Creatinine clearance or radioisotope glomerular filtration rate ? 70mL/min OR serum creatinine based on age/gender as follows: * 1 month to \< 6 months: 0.4 mg/dL * 6 months to \< 1 year: 0.5 mg/dL * 1 to \< 2 years: 0.6 mg/dL * 2 to \< 6 years: 0.8 mg/dL * 6 to \< 10 years: 1 mg/dL * 10 to \< 13 years: 1.2 mg/dL * 10 to \< 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) * \>= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female) * Total bilirubin ? 1.5 times upper limit of normal (ULN) for age * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 10 times ULN for age * Not pregnant or nursing * Negative pregnancy test * Shortening fraction \>= 27% by echocardiogram (ECHO) OR left ventricular ejection fraction (LVEF) \>= 50% by radionuclide angiogram * No known contraindication (e.g., size, weight or physical condition) to peripheral blood stem cell collection * No prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease * No more than one course of chemotherapy per low- or intermediate-risk neuroblastoma therapy prior to determination of MYCN amplification and histology
healthy Volunteers
false
maximum Age
30 Years
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    Patients receive melphalan IV over 15-30 minutes on days -7 to -5, etoposide IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo autologous PBSCT on day 0.
    intervention Names
    1. Procedure: Autologous Hematopoietic Stem Cell Transplantation
    2. Drug: Carboplatin
    3. Drug: Cisplatin
    4. Drug: Cyclophosphamide
    5. Drug: Doxorubicin Hydrochloride
    6. Drug: Etoposide
    7. Radiation: External Beam Radiation Therapy
    8. Biological: Filgrastim
    9. Drug: Isotretinoin
    10. Other: Laboratory Biomarker Analysis
    11. Drug: Melphalan
    12. Procedure: Peripheral Blood Stem Cell Transplantation
    label
    Consolidation Arm A: single myeloablative consolidation
    type
    ACTIVE_COMPARATOR
  2. description
    Patients receive thiotepa IV over 2 hours on days -7 to -5, cyclophosphamide IV over 1 hour on days -5 to -2, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A. Patients undergo autologous PBSCT on day 0.
    intervention Names
    1. Procedure: Autologous Hematopoietic Stem Cell Transplantation
    2. Drug: Carboplatin
    3. Drug: Cisplatin
    4. Drug: Cyclophosphamide
    5. Drug: Doxorubicin Hydrochloride
    6. Drug: Etoposide
    7. Radiation: External Beam Radiation Therapy
    8. Biological: Filgrastim
    9. Drug: Isotretinoin
    10. Other: Laboratory Biomarker Analysis
    11. Drug: Melphalan
    12. Procedure: Peripheral Blood Stem Cell Transplantation
    label
    Consolidation Arm B: tandem myeloablative consolidation
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Undergo autologous peripheral blood stem cell transplant
    name
    Autologous Hematopoietic Stem Cell Transplantation
    other Names
    1. Autologous Hematopoietic Cell Transplantation
    2. autologous stem cell transplantation
    type
    PROCEDURE
  2. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV
    name
    Carboplatin
    other Names
    1. Blastocarb
    2. Carboplat
    3. Carboplatin Hexal
    4. Carboplatino
    5. Carbosin
    6. Carbosol
    7. Carbotec
    8. CBDCA
    9. Displata
    10. Ercar
    11. JM-8
    12. Nealorin
    type
    DRUG
  3. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV
    name
    Cisplatin
    other Names
    1. Abiplatin
    2. Blastolem
    3. Briplatin
    4. CDDP
    5. Cis-diammine-dichloroplatinum
    6. Cis-diamminedichloridoplatinum
    7. Cis-diamminedichloro Platinum (II)
    8. Cis-diamminedichloroplatinum
    9. Cis-dichloroammine Platinum (II)
    10. Cis-platinous Diamine Dichloride
    11. Cis-platinum
    12. Cis-platinum II
    type
    DRUG
  4. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV
    name
    Cyclophosphamide
    other Names
    1. (-)-Cyclophosphamide
    2. 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    3. Carloxan
    4. Ciclofosfamida
    5. Ciclofosfamide
    6. Cicloxal
    7. Clafen
    8. Claphene
    9. CP monohydrate
    10. CTX
    11. CYCLO-cell
    12. Cycloblastin
    type
    DRUG
  5. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV
    name
    Doxorubicin Hydrochloride
    other Names
    1. 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    2. ADM
    3. Adriacin
    4. Adriamycin
    5. Adriamycin Hydrochloride
    6. Adriamycin PFS
    7. Adriamycin RDF
    8. ADRIAMYCIN, HYDROCHLORIDE
    9. Adriamycine
    10. Adriblastina
    11. Adriblastine
    12. Adrimedac
    type
    DRUG
  6. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV
    name
    Etoposide
    other Names
    1. Demethyl Epipodophyllotoxin Ethylidine Glucoside
    2. EPEG
    3. Lastet
    4. Toposar
    5. Vepesid
    6. VP 16-213
    7. VP-16
    8. VP-16-213
    type
    DRUG
  7. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Undergo EBRT
    name
    External Beam Radiation Therapy
    other Names
    1. Definitive Radiation Therapy
    2. EBRT
    3. External Beam Radiotherapy
    4. External Beam RT
    5. external radiation
    6. External Radiation Therapy
    7. external-beam radiation
    type
    RADIATION
  8. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV or SC
    name
    Filgrastim
    other Names
    1. FILGRASTIM, LICENSE HOLDER UNSPECIFIED
    2. G-CSF
    3. Neupogen
    4. r-metHuG-CSF
    5. Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    6. rG-CSF
    7. Tevagrastim
    type
    BIOLOGICAL
  9. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given orally
    name
    Isotretinoin
    other Names
    1. 13-cis retinoic acid
    2. 13-cis-Retinoate
    3. 13-cis-Retinoic Acid
    4. 13-cis-Vitamin A Acid
    5. 13-cRA
    6. Accure
    7. Accutane
    8. Amnesteem
    9. cis-Retinoic Acid
    10. Cistane
    11. Claravis
    12. Isotretinoinum
    type
    DRUG
  10. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Correlative studies
    name
    Laboratory Biomarker Analysis
    type
    OTHER
  11. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Given IV
    name
    Melphalan
    other Names
    1. Alanine Nitrogen Mustard
    2. CB-3025
    3. L-PAM
    4. L-Phenylalanine Mustard
    5. L-sarcolysin
    6. L-Sarcolysin Phenylalanine mustard
    7. L-Sarcolysine
    8. Melphalanum
    9. Phenylalanine Mustard
    10. Phenylalanine nitrogen mustard
    11. Sarcoclorin
    12. Sarkolysin
    type
    DRUG
  12. arm Group Labels
    1. Consolidation Arm A: single myeloablative consolidation
    2. Consolidation Arm B: tandem myeloablative consolidation
    description
    Undergo autologous peripheral blood stem cell transplant
    name
    Peripheral Blood Stem Cell Transplantation
    other Names
    1. PBPC transplantation
    2. PBSCT
    3. Peripheral Blood Progenitor Cell Transplantation
    4. Peripheral Stem Cell Support
    5. Peripheral Stem Cell Transplant
    6. Peripheral Stem Cell Transplantation
    type
    PROCEDURE
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
665
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    Comparison of EFS curves, starting from the time of randomization, by treatment group (single CEM vs. tandem CEM)
    measure
    Event-free Survival Rate
    time Frame
    Three years, from time of randomization
  2. description
    Per the International Response Criteria: measurable tumor defined as product of longest x widest perpendicular diameter. Elevated catecholamine levels, tumor cell invasion of bone marrow also considered measurable tumor. Complete Response (CR)-no evidence of primary tumor or metastases. Very Good Partial Response (VGPR)-\>90% reduction of primary tumor; no metastases; no new bone lesions, all pre-existing lesions improved. Partial Response (PR)-50-90% reduction of primary tumor; \>50% reduction in measurable sites of metastases; 0-1 bone marrow samples with tumor; number of positive bone sites decreased by \>50%. Mixed Response (MR)-\>50% reduction of any measurable lesion (primary or metastases) with \<50% reduction in other sites; no new lesions; \<25% increase in any existing lesion. No Response (NR)-no new lesions; \<50% reduction but \<25% increase in any existing legions. Progressive Disease (PD)-any new/increased measurable lesion by \>25%; previous negative marrow positive.
    measure
    Response After Induction Therapy
    time Frame
    Study enrollment to the end of induction therapy
  3. description
    Cumulative incidence rate of local recurrence comparison between ANBL0532 patients randomized or assigned to receive single CEM transplant and boost radiation versus the historical A3973 patients who were transplanted and received boost radiation.
    measure
    Incidence Rate of Local Recurrence
    time Frame
    Up to 3 years
secondary Outcomes
  1. description
    A logistic regression model will be used to test the ability of the number of days of neutropenia to predict the presence of a polymorphism.
    measure
    Duration of Greater Than or Equal to Grade 3 Neutropenia
    time Frame
    Through completion of a participant's first cycle during induction, including treatment delays, assessed up to 39 days
  2. description
    A logistic regression model will be used to test the ability of the number of days of thrombocytopenia to predict the presence of a polymorphism.
    measure
    Duration of Greater Than or Equal to Grade 3 Thrombocytopenia
    time Frame
    Through completion of a participant's first cycle during induction, including treatment delays, assessed up to 46 days
  3. description
    A chi-square test will be used to test whether the response rate after two cycles of induction therapy and the presence of a polymorphism are independent in the study population.
    measure
    Proportion of Patients With a Polymorphism
    time Frame
    Through completion of a participant's first two cycles during induction, including treatment delays, assessed up to 69 days
  4. description
    Percentage of patients who achieved a surgical complete resection
    measure
    Surgical Response
    time Frame
    Up to 3 years
  5. description
    The Percentage of patients who experienced surgical or radiotherapy complications will be calculated. The complications are: bowel obstruction, chylous leaf, renal injury/atrophy/loss and diarrhea.
    measure
    Type of Surgical or Radiotherapy Complication
    time Frame
    Up to 3 years
  6. description
    Percentage of patients with primary tumors with intraspinal extension.
    measure
    Intraspinal Extension
    time Frame
    Up to 5 years
  7. description
    Median peak serum concentration level of isotretinoin for patients enrolled on ANBL0532
    measure
    Peak Serum Concentration of Isotretinoin in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies
    time Frame
    Day 1 of each course
  8. description
    To determine if pharmacogenomic variations are predictive of EFS, a logrank test comparison of patients with vs without a given polymorphism will be made. A Fisher's exact test will test for association of the presence of a polymorphism with the occurrence of systemic toxicity (CTC grade 3 or 4 skin, hypercalcemia, or hepatic toxicity). These tests will be performed for UGT1A1, UGT2B7, CYP2C8 and CYP3A7 alleles.
    measure
    Pharmacogenetic Variants in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies
    time Frame
    At baseline
  9. description
    Median topotecan systemic clearance for courses 1 and 2.
    measure
    Topotecan Systemic Clearance
    time Frame
    Day 1 of courses 1-2
  10. measure
    Presence and Function of T Cells Capable of Recognizing Neuroblastoma
    time Frame
    Up to 6 months (end of therapy)
  11. description
    A descriptive comparison of the median number of T-cells (CD3, CD4, CD8) between treatment arms (single vs. tandem myeloablative regimens) will be performed.
    measure
    Enumeration of Peripheral Blood Cluster of Differentiation (CD)3, CD4, and CD8 Cells
    time Frame
    Up to 6 months after completion of assigned myeloablation therapy
  12. description
    Will be calculated overall and by treatment arm.
    measure
    Proportion of Patients With Neuroblastoma Detected in Bone Marrow and Peripheral Blood Using RT-PCR Technique
    time Frame
    Baseline
Full study description
brief Summary
This randomized phase III trial compares two different high-dose chemotherapy regimens followed by a stem cell transplant in treating younger patients with high-risk neuroblastoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments before a peripheral blood stem cell transplant helps kill any tumor cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. High-dose chemotherapy and radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the high- chemotherapy. It is not yet known which regimen of high-dose chemotherapy is more effective for patients with high-risk neuroblastoma undergoing a peripheral blood stem cell transplant.
detailed Description
PRIMARY OBJECTIVES: I. To improve the 3-year event-free survival (EFS) rate of high-risk neuroblastoma patients through treatment with a tandem consolidation of thiotepa/cyclophosphamide followed by carboplatin/etoposide/melphalan (CEM) as compared to single CEM consolidation. II. To improve the rate of end-induction complete response and very good partial response, compared to historical controls, by use of a topotecan-containing induction regimen. III. To improve the 3-year local control rate, compared to historical controls, by increasing the local dose of radiation to the residual primary tumor for patients with less than a gross total resection. SECONDARY OBJECTIVES: I. To evaluate the pharmacogenetic relationship of cyclophosphamide metabolizing enzymes (CYP2B6, CYP2C9, and GSTA1 genotypes) with toxicity and response following dose-intensive cyclophosphamide and topotecan induction chemotherapy. II. To determine if resection completeness is predictive of a) local control rate; or b) EFS rate in patients with high-risk neuroblastoma. III. To prospectively describe the complications related to efforts at local control (surgery and radiation therapy) in patients with high-risk neuroblastoma. IV. To describe the neurologic outcome of patients with paraspinal primary neuroblastoma tumors. V. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if pharmacokinetics and/or genetic variations correlate with EFS or systemic toxicity as follows: a) To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters. b) To determine if 13-cis-retinoic-acid pharmacokinetic levels are predictive of the EFS rate or associated with systemic toxicity following 13-cis-retinoic acid. c) To determine if pharmacogenomic variations are predictive of the EFS rate or associated with systemic toxicity following 13-cis-retinoic acid. VI. To evaluate total topotecan pharmacokinetics and correlate with patient specific data for use in an ongoing topotecan population pharmacokinetic analysis. VII. To evaluate the presence and function of T cells capable of recognizing neuroblastoma by assessing: a) if T cells recognizing the neuroblastoma antigen, survivin, circulate at diagnosis; b) if these T cells can be expanded using autologous antigen presenting cells (APCs); c) if these T cells will kill neuroblastoma cells as detected in functional assays; and d) if the presence and activity of anti-neuroblastoma immunity is decreased by stem cell transplantation. VIII. To characterize the recovery of T- cell numbers after myeloablative consolidation and hematopoietic stem cell transplant (HSCT) and assess the impact of tandem myeloablative consolidation on T- cell recovery. IX. To characterize minimal residual disease burden using reverse transcriptase-polymerase chain reaction (RT-PCR) evaluation of a panel of neuroblastoma specific transcripts in patient bone marrow and peripheral blood following induction chemotherapy and after single versus tandem myeloablative chemotherapy and to evaluate impact on EFS. X. To evaluate the EFS and overall survival (OS) rate for patients 12-18 months with Stage 4, MYCN nonamplified tumor with unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy and patients who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant histology following treatment with single myeloablative transplant. OUTLINE: INDUCTION CHEMOTHERAPY: COURSES 1 AND 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients undergo peripheral blood stem cell (PBSC) mobilization and harvest after course 2. COURSES 3 AND 5: Patients receive cisplatin IV over 1 hour on days 1-4, etoposide IV over 1 hour on days 1-3, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients undergo surgical resection of soft tissue disease after course 5 (or after course 6 if medically necessary). COURSES 4 AND 6: Patients receive cyclophosphamide IV over 6 hours on days 1-2, doxorubicin hydrochloride IV over 24 hours on days 1-3, vincristine IV on days 1-3, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients are then stratified by initial stage of disease and MYCN status, biologic characteristics, and response to induction chemotherapy (complete response/very good partial response vs partial response vs mixed response/no response). Patients are randomized to 1 of 2 arms. Patients 12?18 months old (i.e., 365-547 days) with stage IV, MYCN nonamplified tumor with unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy AND patients who are 547 days of age with stage III, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant histology will be nonrandomly assigned to Arm A. Patients begin consolidation chemotherapy no later than 8 weeks after the start of induction course 6. CONSOLIDATION THERAPY: ARM A (single myeloablative consolidation): Patients receive melphalan IV over 15-30 minutes on days -7 to -5, etoposide IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0. ARM B (tandem myeloablative consolidation): Patients receive thiotepa IV over 2 hours on days -7 to -5, cyclophosphamide IV over 1 hour on days -5 to -2, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A. Patients undergo autologous PBSCT on day 0. RADIOTHERAPY: Patients undergo external beam radiation therapy (EBRT) to primary site of disease as well as to MIBG-avid sites seen at pre-transplantation (i.e., end-induction) evaluation between 28-42 days post-transplant. Additional radiotherapy is administered to residual tumor at primary site. MAINTENANCE THERAPY: Patients are encouraged to enroll onto Children?s Oncology Group (COG)-ANBL0032 following assessment of tumor response after completion of the consolidation phase and radiotherapy. Beginning on day 60 post-transplantation patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tissue sample collection periodically for the following analyses; correlation between peak serum concentration level and the existence of polymorphisms, event-free survival, and toxicity rates; pharmacogenomics for uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), UGT2B7, CYP2C8 and CYP3A7 alleles; topotecan systemic clearance; survivin-specific cytotoxic T-lymphocytes (CTLs) detected using peptide/major histocompatibility complex (MHC) tetramers in human leukocyte antigen (HLA)-A2+ patients; interferon (IFN)-gamma production in enzyme-linked immunospot (ELISPOT) assays to APCs loaded with tumor ribonucleic acid (RNA), survivin RNA, or control RNA; response of APC-stimulated CTL response to neuroblastoma cells; rate of T cell recovery; and proportion of patients with neuroblastoma detected in bone marrow and peripheral blood using RT-PCR and immunohistochemistry (IHC). After completion of study treatment, patients are followed up periodically for 5 years and then annually for 5 years.
Source references
references
  1. citation
    Berko ER, Naranjo A, Daniels AA, McNulty SN, Krytska K, Druley T, Zelley K, Koneru B, Chen L, Polkosnik G, Irwin MS, Bagatell R, Maris JM, Reynolds CP, DuBois SG, Park JR, Mosse YP. Frequency and Clinical Significance of Clonal and Subclonal Driver Mutations in High-Risk Neuroblastoma at Diagnosis: A Children's Oncology Group Study. J Clin Oncol. 2025 May 10;43(14):1673-1684. doi: 10.1200/JCO-24-02407. Epub 2025 Mar 4.
    pmid
    40036726
    type
    DERIVED
  2. citation
    Liu KX, Naranjo A, Zhang FF, DuBois SG, Braunstein SE, Voss SD, Khanna G, London WB, Doski JJ, Geiger JD, Kreissman SG, Grupp SA, Diller LR, Park JR, Haas-Kogan DA. Prospective Evaluation of Radiation Dose Escalation in Patients With High-Risk Neuroblastoma and Gross Residual Disease After Surgery: A Report From the Children's Oncology Group ANBL0532 Study. J Clin Oncol. 2020 Aug 20;38(24):2741-2752. doi: 10.1200/JCO.19.03316. Epub 2020 Jun 12.
    pmid
    32530765
    type
    DERIVED
  3. citation
    Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, Tenney SC, Haas-Kogan D, Shaw PJ, Kraveka JM, Roberts SS, Geiger JD, Doski JJ, Voss SD, Maris JM, Grupp SA, Diller L. Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA. 2019 Aug 27;322(8):746-755. doi: 10.1001/jama.2019.11642.
    pmid
    31454045
    type
    DERIVED
see Also Links
  1. label
    Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive
Source notices and limitations
    Discovery and provenance
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        ction_6.1">1</a>] Statistically significant improvement in event-free survival (EFS) was observed in a randomized phase III COG study (<a href="/clinicaltrials/NCT00567567">ANBL0532 [NCT00567567]</a>) with tandem cycles of myeloablative therapy and HSCT, compared with a single cycle of myeloablative therapy and HSCT. The 3-year E
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        stically significant improvement in event-free survival (EFS) was observed in a randomized phase III COG study (<a href="/clinicaltrials/NCT00567567">ANBL0532 [NCT00567567]</a>) with tandem cycles of myeloablative therapy and HSCT, compared with a single cycle of myeloablative therapy and HSCT. The 3-year EFS rate for patients wh
        end
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        start
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        an resulted in an improved EFS, without an effect on OS or severe adverse events.</li></ul></div></li><li>A randomized clinical study (<a href="/clinicaltrials/NCT00567567">COG-ANBL0532</a>) tested the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue.[<a href="#cit/section_8.30">30</a>][
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        ence C1</a>] Boost radiation therapy for gross-residual disease did not show improved local control when studied prospectively in the <a href="/clinicaltrials/NCT00567567">ANBL0532 (NCT00567567)</a> trial.[<a href="#cit/section_8.38">38</a>][<a href="/Common/PopUps/popDefinition.aspx?id=810035&amp;version=HealthProfessional&amp;
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        iation therapy for gross-residual disease did not show improved local control when studied prospectively in the <a href="/clinicaltrials/NCT00567567">ANBL0532 (NCT00567567)</a> trial.[<a href="#cit/section_8.38">38</a>][<a href="/Common/PopUps/popDefinition.aspx?id=810035&amp;version=HealthProfessional&amp;language=English" oncli
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        class="pdq-content-list"><ol id="_2046"><li>Because of the high rates of local recurrence after incomplete surgical resection, the COG <a href="/clinicaltrials/NCT00567567">ANBL0532 (NCT00567567)</a> trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared
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        "><ol id="_2046"><li>Because of the high rates of local recurrence after incomplete surgical resection, the COG <a href="/clinicaltrials/NCT00567567">ANBL0532 (NCT00567567)</a> trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the pr
        end
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      source update dates
      1. context
        Updated: April 28, 2025
        datetime
        2025-04-28T12:00:00Z
        display
        April 28, 2025

    Preserved source evidence · Not medical advice