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NCT00004188 · CITED IN SOURCE DOCUMENTS

Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With 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
2013-05-17

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: This randomized phase III trial is studying peripheral stem cell transplantation with treated peripheral stem cells following combination chemotherapy to see how well it works compared to peripheral stem cell transplantation with untreated peripheral stem cells following combination chemotherapy in treating patients with neuroblastoma.

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.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
DISEASE CHARACTERISTICS: * Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma, and/or evidence of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites, meeting 1 of the following criteria: * Age greater than 18 months with stage IV disease, regardless of biologic factors * Age 12-18 months with stage IV disease meeting one of the following criteria: * Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable pathology, and/or DNA index = 1) * Any biologic feature that is indeterminate, unsatisfactory, or unknown * At least 1 year old with the following: * Stage IIa/IIb with MYCN amplification (\> 10) AND unfavorable pathology * Stage III with MYCN amplification (\> 10) OR unfavorable pathology * Stage I, II, or IVS with disease progression to stage IV without interval chemotherapy * No more than 3 weeks since progression * Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047 * Less than 1 year old with the following: * Stage III, IV, or IVS disease with MYCN amplification (\> 10) * Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis PATIENT CHARACTERISTICS: Age: * See Disease Characteristics * 30 and under at time of diagnosis Performance status: * Not specified Life expectancy: * Not specified Hematopoietic: * Absolute neutrophil count ≥ 1,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Inadequate hematopoiesis secondary to bone marrow involvement with \> 10% tumor infiltration allowed Hepatic: * Bilirubin ≤ 1.5 mg/dL * ALT ≤ 300 units/L Renal: * Creatinine ≤ 1.5 mg/dL * Creatinine clearance or glomerular filtration rate ≥ 60 mL/min Cardiovascular: * ECG normal * Ejection fraction ≥ 55% by echocardiogram or MUGA OR * Fractional shortening ≥ 28% by echocardiogram Other: * Able to tolerate peripheral blood stem cell collection * HIV negative * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception for at least 1 month prior to, during, and for 1 month after study participation PRIOR CONCURRENT THERAPY: Biologic therapy: * Not specified Chemotherapy: * See Disease Characteristics * No more than 1 prior course of chemotherapy on the Intergroup low/intermediate risk neuroblastoma study (P9641, A3961) Endocrine therapy: * Not specified Radiotherapy: * Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed Surgery: * Not specified Other * No other prior systemic therapy
healthy Volunteers
false
maximum Age
30 Years
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    Induction-3 wks (cyclophosphamide day 0\&1, doxorubicin hydrochloride \& vincristine sulfate day 0-2 \& filgrastim(G-CSF) day 3 crs 1,2,4 \& 6.) Crs 3 \& 5 (etoposide day 0-2, cisplatin day 0-3, G-CSF day 4). Pts undergo unpurged PBSC collection until the target cell count is reached. Surgical resection of the tumor after crs 5 of induct. CR, VGPR, PR after induct receive consolidation (melphalan day -7 to -5, carboplatin \& etoposide day -7 to -4. purged peripheral blood stem cell transplantation infusion day 0, G-CSF 4 hrs post transplant. Day 66, isotretinoin 2x day/14 days. Isotretinoin every 4 wks 6 crs. After consol (28 days from stem cell infusion), radiation therapy 1x day/7 days. Not undergoing autologous bone marrow transplantation receive maintenance(cyclophosphamide 30 mins, topotecan hydrochloride days 0-4, G-CSF day 5). Maint every 3 wks/3 crs. Radiation therapy and Isotretinoin 2x day/14 days then every 4 wks for 6 crs.
    intervention Names
    1. Biological: filgrastim
    2. Drug: carboplatin
    3. Drug: cisplatin
    4. Drug: cyclophosphamide
    5. Drug: doxorubicin hydrochloride
    6. Drug: etoposide
    7. Drug: isotretinoin
    8. Drug: melphalan
    9. Drug: topotecan hydrochloride
    10. Drug: vincristine sulfate
    11. Procedure: autologous bone marrow transplantation
    12. Procedure: bone marrow ablation with stem cell support
    label
    Arm I (unpurged PBSC collection)
    type
    EXPERIMENTAL
  2. description
    Induction-3 wks (cyclophosphamide day 0\&1, doxorubicin hydrochloride \& vincristine sulfate day 0-2 \& filgrastim(G-CSF) day 3 crs 1,2,4 \& 6.) Crs 3 \& 5 (etoposide day 0-2, cisplatin day 0-3, G-CSF day 4). Immunocytology + PBSC undergo purged autologous bone marrow collection or repeat purged or unpurged PBSC collection. Surgical resection of the tumor after crs 5 of induct. CR, VGPR, PR after induct receive consolidation (melphalan day -7 to -5, carboplatin \& etoposide day -7 to -4. Unpurged peripheral blood stem cell transplantation infusion day 0, G-CSF 4 hrs post transplant. Day 66, isotretinoin 2x day/14 days. Isotretinoin every 4 wks 6 crs. After consol (28 days from stem cell infusion), radiation therapy 1x day/7 days. Not undergoing autologous bone marrow transplantation receive maintenance(cyclophosphamide 30 mins, topotecan hydrochloride days 0-4, G-CSF day 5). Maint every 3 wks/3 crs. Radiation therapy and Isotretinoin 2x day/14 days then every 4 wks for 6 crs.
    intervention Names
    1. Drug: carboplatin
    2. Drug: cisplatin
    3. Drug: cyclophosphamide
    4. Drug: doxorubicin hydrochloride
    5. Drug: etoposide
    6. Drug: isotretinoin
    7. Drug: melphalan
    8. Drug: topotecan hydrochloride
    9. Drug: vincristine sulfate
    10. Procedure: autologous bone marrow transplantation
    11. Procedure: bone marrow ablation with stem cell support
    12. Procedure: conventional surgery
    label
    Arm II (unpurged PBSC collection)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    description
    Given IV
    name
    filgrastim
    other Names
    1. GRANULOCYTE COLONY-STIMULATING FACTOR
    2. r-metHuG-CSF
    3. G-CSF
    4. Neupogen
    5. NSC 614629
    type
    BIOLOGICAL
  2. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    carboplatin
    other Names
    1. Paraplatin
    2. NSC #241240
    type
    DRUG
  3. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    cisplatin
    other Names
    1. Cis-diamminedichloroplatinum II
    2. Platinol-AQ
    3. NSC #11987
    type
    DRUG
  4. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    cyclophosphamide
    other Names
    1. CTX
    2. Cytoxan
    3. NSC #026271
    type
    DRUG
  5. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    doxorubicin hydrochloride
    other Names
    1. Adriamycin
    2. NSC #123127
    3. IND #7038
    type
    DRUG
  6. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    etoposide
    other Names
    1. VP-16
    2. VePesid
    3. Etopophos
    4. NSC #141540
    type
    DRUG
  7. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    isotretinoin
    other Names
    1. 13-cis-retinoic acid
    2. RO-43
    3. 780
    4. Accutane
    5. Amnesteem
    6. Claravis
    7. NSC 329481
    type
    DRUG
  8. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    melphalan
    other Names
    1. L-phenylalanine mustard
    2. phenylalanine mustard
    3. L-PAM
    4. L-sarcolysin
    5. NSC 008806
    type
    DRUG
  9. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    topotecan hydrochloride
    other Names
    1. SKF-104864
    2. Hycamtin
    3. NSC #609699
    type
    DRUG
  10. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    description
    Given IV
    name
    vincristine sulfate
    other Names
    1. VCR
    2. Oncovin
    3. NSC #067574
    type
    DRUG
  11. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    name
    autologous bone marrow transplantation
    type
    PROCEDURE
  12. arm Group Labels
    1. Arm I (unpurged PBSC collection)
    2. Arm II (unpurged PBSC collection)
    name
    bone marrow ablation with stem cell support
    type
    PROCEDURE
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
495
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. measure
    Event-free survival rate
    time Frame
    Time from study registration until the time of the first occurrence of either relapse, progression, secondary malignancy, or death, or until the time of last contact with the patient if none of these events occurs, assessed up to 6 years
  2. measure
    Rate of occurrence of toxic (non disease-related) deaths where a toxic death will be "counted" if it occurs prior to the initiation of the immunotherapy
    time Frame
    Up to day 42
secondary Outcomes
  1. description
    Engraftment is defined as three consecutive measurements of ANC \> 500.
    measure
    Time to engraftment
    time Frame
    Up to 6 years
  2. measure
    CD34 content
    time Frame
    Up to 6 years
  3. measure
    Tumor content as measured by reverse transcriptase polymerase chain reaction
    time Frame
    Up to 6 years
Full study description
brief Summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: This randomized phase III trial is studying peripheral stem cell transplantation with treated peripheral stem cells following combination chemotherapy to see how well it works compared to peripheral stem cell transplantation with untreated peripheral stem cells following combination chemotherapy in treating patients with neuroblastoma.
detailed Description
OBJECTIVES: Primary * Compare the event-free survival in patients with newly diagnosed high risk neuroblastoma or ganglioneuroblastoma treated with myeloablative consolidation chemotherapy and autologous purged versus unpurged peripheral blood stem cells (PBSC). * Compare the time to engraftment and CD34 content and tumor content by reverse transcriptase polymerase chain reaction (RT-PCR) of purged versus unpurged PBSC in patients treated with these regimens. * Determine event-free survival of patients treated with dose intensive induction chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin and etoposide. * Determine the toxicity of this dose-intensive induction chemotherapy regimen in these patients. * Evaluate tumor resectability at second look or delayed surgery, response (complete response and very good partial response) at completion of induction therapy, tumor content of peripheral blood and bone marrow, and the comparison of historical data from CCG-3891 induction therapy in these patients. Secondary * Compare the toxicity of this myeloablative consolidation regimen using purged vs unpurged PBSC in these patients. * Determine if event-free survival is predictable by RT-PCR positivity of the stem cell, minimal residual disease in bone marrow and peripheral blood after transplantation by immunocytology, and extent of disease as measured by MIBG after transplantation in patients treated with these regimens. * Evaluate the prognostic impact of tumor biology on event free survival in patients treated with these regimens. * Determine the incidence of relapse in the primary site after radiotherapy and in irradiated versus unirradiated metastatic sites in these patients. * Assess the toxicity and tolerability of maintenance therapy with topotecan and cyclophosphamide after intensive induction therapy in patients who decline or are unable to receive myeloablative therapy. * Determine the health-related quality of life of patients treated with these regimens. * Compare late effects of these regimens on the growth, endocrine, pulmonary, and cardiac function of these patients vs general population standards. * Determine the incidence of second malignant neoplasms in patients treated with these regimens. * Determine the variability of isotretinoin pharmacokinetics and relationship to pharmacogenomic parameters in these patients. * Correlate the isotretinoin pharmacokinetics and pharmacogenomic parameters and/or genetic variations in isotretinoin metabolic enzymes with event-free survival or systemic toxicity in these patients. OUTLINE: This is a randomized study. Patients are randomized to one of two treatment arms for peripheral blood stem cell (PBSC) collection. All patients receive induction chemotherapy comprising cyclophosphamide IV over 6 hours on days 0 and 1, doxorubicin IV and vincristine IV continuously over 72 hours on days 0-2, and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 3 and continuing until blood counts recover for courses 1, 2, 4, and 6. Treatment alternates with courses 3 and 5 comprising etoposide IV over 2 hours on days 0-2, cisplatin IV over 1 hour on days 0-3, and G-CSF SC or IV beginning on day 4 and continuing until blood counts recover. Induction chemotherapy repeats every 3 weeks or when blood counts recover in the absence of disease progression or unacceptable toxicity. After course 2 or 3 of induction chemotherapy, patients undergo PBSC collection, either purged or unpurged, depending on randomization. Patients continue on daily G-CSF until cell collection is complete. * Arm I: Patients undergo unpurged PBSC collection until the target cell count is reached. * Arm II: Patients undergo purged PBSC collection until the target cell count is reached. Patients with immunocytology positive PBSC undergo purged autologous bone marrow collection or repeat purged or unpurged PBSC collection depending on individual patient characteristics. All patients undergo delayed surgical resection of the residual tumor after course 5 of induction chemotherapy. After induction therapy, patients achieving complete response, very good partial response, or partial response receive consolidation therapy comprising melphalan IV on days -7 to -5 followed by carboplatin IV and etoposide IV continuously over days -7 to -4. Patients receive purged or unpurged PBSC infusion or purged autologous bone marrow transplantation on day 0 followed by G-CSF SC or IV beginning 4 hours after completion of transplantation and continuing until blood counts recover. Beginning on day 66, patients receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6 courses. After completion of consolidation (at least 28 days from stem cell infusion), all patients receive local radiotherapy daily over 7 days. Patients not undergoing transplantation or who are ineligible for consolidation therapy receive maintenance therapy comprising cyclophosphamide IV over 30 minutes followed by topotecan IV over 30 minutes on days 0-4. Patients receive G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Maintenance therapy repeats every 3 weeks for 3 courses. After completion of maintenance therapy, patients receive radiotherapy as outlined above. Patients then receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6 courses. Quality of life is assessed at 1\* and 5 years. Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter or until disease progression. NOTE: \* Patients under 5 years of age at 1 year are not assessed until 5 years. PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study within 4 years.
Source references
references
  1. citation
    Dubois SG, Geier E, Batra V, Yee SW, Neuhaus J, Segal M, Martinez D, Pawel B, Yanik G, Naranjo A, London WB, Kreissman S, Baker D, Attiyeh E, Hogarty MD, Maris JM, Giacomini K, Matthay KK. Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group. Int J Mol Imaging. 2012;2012:250834. doi: 10.1155/2012/250834. Epub 2012 Sep 25.
    pmid
    23050139
    type
    BACKGROUND
  2. citation
    Cantos MF, Gerstle JT, Irwin MS, Pappo A, Farley S, Cheang T, Kim PC. Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg. 2006 May;41(5):960-5. doi: 10.1016/j.jpedsurg.2006.01.059.
    pmid
    16677893
    type
    BACKGROUND
  3. citation
    Kushner BH, Budnick A, Kramer K, Modak S, Cheung NK. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006 Jul 15;107(2):417-22. doi: 10.1002/cncr.22004.
    pmid
    16779793
    type
    BACKGROUND
  4. citation
    Landier W, Knight K, Wong FL, Lee J, Thomas O, Kim H, Kreissman SG, Schmidt ML, Chen L, London WB, Gurney JG, Bhatia S. Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group. J Clin Oncol. 2014 Feb 20;32(6):527-34. doi: 10.1200/JCO.2013.51.2038. Epub 2014 Jan 13.
    pmid
    24419114
    type
    RESULT
  5. citation
    Naranjo A, Parisi MT, Shulkin BL, London WB, Matthay KK, Kreissman SG, Yanik GA. Comparison of (1)(2)(3)I-metaiodobenzylguanidine (MIBG) and (1)(3)(1)I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Jul 1;56(7):1041-5. doi: 10.1002/pbc.22991. Epub 2011 Feb 15.
    pmid
    21328522
    type
    RESULT
  6. citation
    Yanik GA, Parisi MT, Naranjo A, et al.: MIBG scoring as a prognostic indicator in patients with stage IV neuroblastoma: A COG study. [Abstract] J Clin Oncol 28 (Suppl 15): A-9516, 2010.
    type
    RESULT
  7. citation
    Kreissman SG, Villablanca JG, Diller L, et al.: Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): a Children's Oncology Group (COG A3973) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-9505, 527s, 2007.
    type
    RESULT
  8. citation
    Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013 Sep;14(10):999-1008. doi: 10.1016/S1470-2045(13)70309-7. Epub 2013 Jul 25.
    pmid
    23890779
    type
    DERIVED
Source notices and limitations
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        ents with MIBG-avid, stage 4, newly diagnosed, high-risk neuroblastoma (N = 280), treated on the COG protocol <a href="/clinicaltrials/NCT00004188">COG-A3973 (NCT00004188)</a>. For patients with <em class="gene-name">MYCN</em>-nonamplified neuroblastoma, a postinduction chemotherapy Curie score greater than 2 was associated with
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        apy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (<a href="/clinicaltrials/NCT00004188">A3973 [NCT00004188]</a>), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the p
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        h gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (<a href="/clinicaltrials/NCT00004188">A3973 [NCT00004188]</a>), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary
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      source update dates
      1. context
        Updated: April 28, 2025
        datetime
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        display
        April 28, 2025

    Preserved source evidence · Not medical advice