Observation, Combination Chemotherapy, Radiation Therapy, and/or Autologous Stem Cell Transplant in Treating Young Patients With Neuroblastoma
NCT ID: NCT00410631
Last Updated: 2013-08-07
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE3
642 participants
INTERVENTIONAL
2004-10-31
Brief Summary
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PURPOSE: This randomized phase III and phase IV trial is studying observation, combination chemotherapy, radiation therapy, and/or autologous stem cell transplant to compare how well they work in treating young patients with neuroblastoma.
Detailed Description
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Primary
* Determine the event-free survival (EFS) of younger patients with newly diagnosed neuroblastoma categorized in the low-risk group (LRG) who undergo observation only or receive combination chemotherapy.
* Compare the EFS rate in patients with neuroblastoma categorized in the medium-risk group (MRG) treated with combination induction therapy, maintenance therapy, and consolidation therapy with that of a historical control group.
* Compare the EFS in patients with neuroblastoma categorized in the high-risk group (HRG) treated with standard vs experimental induction therapy followed by autologous stem cell transplantation and consolidation therapy.
Secondary
* Determine the locoregional EFS of patients in the LRG, MRG, or HRG.
* Determine the overall survival of these patients.
* Determine the extent of initial surgery, the extent or impact of best surgery, and surgery-related complications in these patients.
* Determine the time to transition to stage 4 disease in patients in the LRG or MRG.
* Determine the time to a locoregional event in patients in the LRG or HRG.
* Determine the time from diagnosis to an event in patients in the LRG.
* Determine the time from the beginning of regression to an adverse event in patients in the LRG.
* Determine the time to the beginning of primary tumor regression in patients in the LRG.
* Determine the time to the normalization of tumor markers in patients in the LRG.
* Determine the time to no evidence of disease in patients in the LRG with stage 4S disease.
* Assess the status of the primary tumor at 12 months and the best status of the primary tumor within 12 months in patients in the LRG.
* Determine the need for chemotherapy to control progression and the intensity of therapy required in patients in the LRG.
* Determine the acute and late side effects of external-beam radiotherapy in patients in the MRG or HRG.
* Determine the response to induction therapy in patients in the HRG.
* Assess early response after 2 courses of induction therapy in patients in the HRG.
* Determine the toxicity during induction courses 1 and 2 and the frequency of grade 3 or 4 toxicity during induction therapy in patients in the HRG.
* Assess the efficacy of iodine I 131 metaiodobenzylguanidine (MIBG) therapy, in terms of activity and whole body dose, in patients in the HRG.
* Assess molecular markers (e.g., chromosome 1p, chromosome 11q, neuroblastoma gene chip) in these patients.
OUTLINE: This is a prospective, historically controlled, randomized, open-label, multicenter study. Patients are stratified according to disease risk (low-risk vs medium-risk vs high-risk).
* Low-risk group: Patients undergo complete staging 3 months after initial surgery. Patients with no progression are observed for 12 months (for patients over 1 year of age) or until the end of the second year of life (for patients 1 year of age or younger). Patients with localized progression or threatening symptoms undergo N4 chemotherapy comprising doxorubicin hydrochloride IV over 30 minutes and vincristine IV on days 1, 3, and 5 and cyclophosphamide IV over 30 minutes on days 1-7. Treatment repeats every 21 days for up to 4 courses. Patients are reassessed after each course of N4 chemotherapy. Patients achieving stable disease or tumor regression at any point discontinue N4 chemotherapy and undergo observation. Patients with persistent progressive disease after 4 courses of N4 chemotherapy proceed to treatment as in the medium-risk group. Patients who progress to stage 4 disease after initial surgery proceed to treatment as in the medium-risk group (for patients 1 year of age or younger and no indication of stage 4S disease) or high-risk group (for patients over 1 year of age).
* Medium-risk group: Patients receive induction therapy followed by maintenance therapy and consolidation therapy.
* Induction therapy: Patients\* receive N5 chemotherapy comprising cisplatin IV continuously over 96 hours and etoposide phosphate IV continuously over 96 hours on days 1-4, vindesine IV over 1 hour on day 1, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 9 and continuing until blood counts recover. Patients then receive N6 chemotherapy comprising vincristine IV over 1 hour on days 1 and 8, dacarbazine IV over 1 hour and ifosfamide IV continuously over 120 hours on days 1-5, doxorubicin hydrochloride IV over 4 hours on days 6 and 7, and G-CSF beginning on day 10 and continuing until blood counts recover. Treatment repeats every 21 days alternating between N5 and N6 chemotherapy for up to 6 total courses (3 courses of N5 and N6 each). Patients then proceed to maintenance therapy.
NOTE: \*Patients under 6 months of age receive up to 4 courses of N4 chemotherapy (as in the low-risk group) instead of N5/N6 chemotherapy until they reach 6 months of age.
Patients with active residual tumor after induction chemotherapy undergo external-beam radiotherapy (EBRT) for up to 25 fractions concurrently with maintenance chemotherapy. Secondary surgery for resection of the primary tumor is attempted after course 4 or 6 of the induction therapy and before EBRT.
* Maintenance therapy: Patients receive N7 chemotherapy comprising cyclophosphamide orally or IV over 1 hour on days 1-8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
* Consolidation therapy: Beginning 21 days after completion of maintenance therapy, patients receive oral isotretinoin 2-3 times daily on days 1-14. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity. Patients then receive 3 additional courses after 3-months of rest.
* High-risk group: Patients receive induction therapy followed by autologous stem cell transplantation (ASCT) and consolidation therapy.
* Induction therapy: Patients 1 year of age and over are randomized to 1 of 2 treatment arms. Patients under 1 year of age do not undergo randomization; instead they are assigned to arm I.
* Arm I (standard): Patients\* receive N5 and N6 chemotherapy as in induction therapy for the medium-risk group.
* Arm II (experimental): Patients receive N8 chemotherapy comprising topotecan hydrochloride IV continuously over 168 hours and cyclophosphamide IV over 1 hour on days 1-7, etoposide IV over 1 hour on days 8-10, and G-CSF SC beginning on day 12 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients then receive N5 and N6 chemotherapy as in induction therapy for the medium-risk group.
In both arms, patients with active residual primary tumor after 6 courses of induction therapy undergo iodine I 131 metaiodobenzylguanidine (MIBG)\*\* radiotherapy (before ASCT). Patients also undergo EBRT for up to 25 fractions after ASCT. Secondary surgery for resection of the primary tumor is attempted after course 4 or 6 of induction therapy and before radiotherapy.
NOTE: \*Patients under 6 months of age receive up to 4 courses of N4 chemotherapy (as in the low-risk group) instead of N5/N6 chemotherapy until they reach 6 months of age.
NOTE: \*\*Patients with MIBG-negative disease undergo EBRT only.
* Conditioning followed by ASCT: Patients receive melphalan IV over 30 minutes on days -8 to -5, etoposide phosphate IV over 4 hours on day -4, and carboplatin IV over 1 hour on days -4 to -2. Patients undergo ASCT on day 0. Patients receive G-CSF SC beginning on day 2 and continuing until blood counts recover.
* Consolidation therapy: Beginning 30 days after ASCT, patients receive isotretinoin\* as in consolidation therapy for the medium-risk group.
NOTE: \*Isotretinoin is discontinued during EBRT and restarted 1 week after completion of EBRT.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A total of 642 patients will be accrued for this study.
Conditions
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Keywords
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Study Design
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RANDOMIZED
TREATMENT
NONE
Interventions
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filgrastim
carboplatin
cisplatin
cyclophosphamide
dacarbazine
doxorubicin hydrochloride
etoposide phosphate
ifosfamide
isotretinoin
melphalan
topotecan hydrochloride
vincristine sulfate
vindesine
autologous hematopoietic stem cell transplantation
conventional surgery
peripheral blood stem cell transplantation
iobenguane I 131
radiation therapy
Eligibility Criteria
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Inclusion Criteria
* Diagnosis of neuroblastoma by histology using tumor tissue or as evidenced by the presence of distinct neuroblastoma cells in the bone marrow AND elevated catecholamine metabolites (i.e., homovanillic acid \[HVA\] and vanillylmandelic acid \[VMA\]) in blood or urine
* Newly diagnosed disease (for patients in the low-risk group)
* Diagnosis from tumor tissue (for patients in the medium-risk group)
* Meets criteria for 1 of the following risk groups:
* Low-risk group
* No MYCN amplification AND meets 1 of the following criteria:
* Stage 1 disease
* Stage 2 disease with no chromosome 1p deletion or imbalance
* Stage 3 disease with no chromosome 1p deletion or imbalance (for patients \< 2 years of age)
* Stage 4S disease (for patients \< 1 year of age)
* Medium-risk group
* No MYCN amplification AND meets 1 of the following criteria:
* Stage 2 disease with chromosome 1p deletion or imbalance
* Stage 3 disease with chromosome 1p deletion or imbalance
* Any chromosome 1p status (for patients ≥ 2 years of age)
* Stage 4 disease (for patients \< 1 year of age)
* High-risk group, meeting 1 of the following criteria:
* Any stage disease with MYCN amplification
* Any MYCN status (for patients ≥ 1 year of age)
PATIENT CHARACTERISTICS:
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY:
* No prior nephrectomy or other mutilating surgery as initial surgery (for patients in the low-risk group)
* No other concurrent anticancer therapy
21 Years
ALL
No
Sponsors
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German Society for Pediatric Oncology and Hematology GPOH gGmbH
OTHER
Principal Investigators
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Frank Berthold, MD
Role: STUDY_CHAIR
Children's Hospital Medical Center, Cincinnati
Locations
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Kinderklinik - Universitaetsklinikum Aachen
Aachen, , Germany
Klinikum Augsburg
Augsburg, , Germany
Klinikum am Bamberg
Bamberg, , Germany
Klinikum Bayreuth
Bayreuth, , Germany
Helios Klinikum Berlin
Berlin, , Germany
Charite University Hospital - Campus Virchow Klinikum
Berlin, , Germany
Evangelisches Krankenhauus Bielfeld
Biefeld, , Germany
Kinderklinik der Universitaet Bonn
Bonn, , Germany
Staedtisches Klinikum - Howedestrase
Braunschweig, , Germany
Klinikum Bremen-Mitte
Bremen, , Germany
Allgemeinen Krankenhaus Celle Kinderklinik
Celle, , Germany
Klinikum Chemnitz gGmbH
Chemnitz, , Germany
Klinikum Coburg
Coburg, , Germany
Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
Cologne, , Germany
Children's Hospital
Cologne, , Germany
Carl - Thiem - Klinkum Cottbus
Cottbus, , Germany
Vestische Kinderklinik
Datteln, , Germany
Klinikum Lippe - Detmold
Detmold, , Germany
Klinikum Dortmund
Dortmund, , Germany
Universitatsklinikum Carl Gustav Carus
Dresden, , Germany
Klinikum Duisburg
Duisburg, , Germany
Universitaets - Frauenklinik, Duesseldorf
Düsseldorf, , Germany
Helios Klinikum Erfurt
Erfurt, , Germany
Universitaets - Kinderklinik
Erlangen, , Germany
Universitaetsklinikum Essen
Essen, , Germany
Klinikum der J.W. Goethe Universitaet
Frankfurt, , Germany
Universitaetskinderklinik - Universitaetsklinikum Freiburg
Freiburg im Breisgau, , Germany
Kinderklinik
Giessen, , Germany
Universitaetsklinikum Goettingen
Göttingen, , Germany
Universitats - Kinderklinik
Greiswald, , Germany
Universitaetsklinikum Halle
Halle, , Germany
Krankenhaus St. Elisabeth und St. Barbara
Halle, , Germany
University Medical Center Hamburg - Eppendorf
Hamburg, , Germany
Kinderkrankenhaus auf der Bult
Hanover, , Germany
Medizinische Hochschule Hannover
Hanover, , Germany
Universitaets-Kinderklinik Heidelberg
Heidelberg, , Germany
SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen
Heilbronn, , Germany
Gemeinschaftskrankenhaus
Herdecke, , Germany
Universitaetsklinikum des Saarlandes
Homburg, , Germany
Universitaets - Kinderklinik
Jena, , Germany
Universitaets - Kinderklinik
Jena, , Germany
Staedtisches Klinikum Karlsruhe gGmbH
Karlsruhe, , Germany
Kinderkrankenhaus Park Schoenfeld
Kassel, , Germany
Klinikum Kassel
Kassel, , Germany
University Hospital Schleswig-Holstein - Kiel Campus
Kiel, , Germany
Klinikum Kemperhof Koblenz
Koblenz, , Germany
Klinikum Krefeld GmbH
Krefeld, , Germany
St. Annastift Krankenhaus
Ludwigshafen, , Germany
Universitaets - Kinderklinik - Luebeck
Lübeck, , Germany
Universitatsklinikum der MA
Magdeburg, , Germany
Johannes Gutenberg University
Mainz, , Germany
Staedtisches Klinik - Kinderklinik
Mannheim, , Germany
Universitaets - Kinderklinik
Marburg, , Germany
Klinikum Minden
Minden, , Germany
Krankenhaus Muenchen Schwabing
Munich, , Germany
Dr. von Haunersches Kinderspital der Universitaet Muenchen
Munich, , Germany
Klinikum der Universitaet Muenchen - Grosshadern Campus
Munich, , Germany
Staedtisches Krankenhaus Muenchen - Harlaching
Munich, , Germany
University of Muenster
Münster, , Germany
Klinikum Neubrandenburg
Neubrandenburg, , Germany
Kinderklinik Kohlhof
Neunkirchen, , Germany
Cnopf'sche Kinderklinik
Nuremberg, , Germany
Klinikum Oldenburg
Oldenburg, , Germany
Klinik St. Hedwig-Kinderklinik
Regensburg, , Germany
Kinderklinik - Universitaetsklinikum Rostock
Rostock, , Germany
Johanniter-Kinderklinik
Sankt Augustin, , Germany
Kinderklink Siegen Deutsches Rotes Kreuz
Siegen, , Germany
Olgahospital
Stuttgart, , Germany
Krankenanstalt Mutterhaus der Borromaerinnen
Trier, , Germany
Universitaets-Kinderklinik
Tübingen, , Germany
Universitaetsklinikum Tuebingen
Tübingen, , Germany
Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
Ulm, , Germany
Reinhard-Nieter-Krankenhaus
Wilhelmshaven, , Germany
Helios Kliniken Wuppertal University Hospital
Wuppertal, , Germany
Universitaets - Kinderklinik Wuerzburg
Würzburg, , Germany
Kantonsspital Aarau
Aarau, , Switzerland
Universitaets-Kinderspital beider Basel
Basel, , Switzerland
Kinderspital Luzern
Lucerne, , Switzerland
Ostschweizer Kinderspital
Sankt Gallen, , Switzerland
University Children's Hospital
Zurich, , Switzerland
Countries
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Facility Contacts
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R. Mertens, MD, PhD
Role: primary
Astrid Gnekow
Role: primary
Gloeckel, MD
Role: primary
T. Rupprecht
Role: primary
L. Wickmann, MD
Role: primary
Gunter Henze
Role: primary
N. Jorch, MD
Role: primary
Udo Bode, MD
Role: primary
Contact Person
Role: primary
Arnulf Pekrun, MD, PhD
Role: primary
Martin Kirschstein, MD
Role: primary
Krause, MD
Role: primary
Roland Frank, MD
Role: primary
Contact Person
Role: primary
Frank Berthold, MD
Role: primary
D Mobius, MD
Role: primary
W. Andler, MD
Role: primary
Klaus Wesseler, MD
Role: primary
Heidi Olscheswski, MD
Role: primary
M. Suttorp, MD
Role: primary
Ruef, MD
Role: primary
Dilloo, MD
Role: primary
Axel Sauerbrey, MD
Role: primary
W. Holter, MD
Role: primary
Bernhard Kremens, MD
Role: primary
Thomas Klingebiel, MD
Role: primary
Charlotte Niemeyer, MD
Role: primary
Alfred Reiter, MD
Role: primary
Lothar Schweigerer, MD
Role: primary
James F. Beck, MD
Role: primary
Dieter Koerholz, MD
Role: primary
G. Guenther, MD
Role: primary
Rudolf Erttmann, MD
Role: primary
U. Hofmann, MD
Role: primary
Karl Welte, MD
Role: primary
Andreas E. Kulozik, MD, PhD
Role: primary
Full, MD
Role: primary
Christoph Tautz, MD
Role: primary
Norbert Graf
Role: primary
Contact Peron
Role: primary
Felix Zintl, MD
Role: primary
A. Leipold
Role: primary
M. L. Wright, MD
Role: primary
Martina Rodehueser, MD
Role: primary
A. Claviez, MD
Role: primary
M. Rister, MD
Role: primary
S. Volpel, MD
Role: primary
Barbara Selle, MD
Role: primary
Peter P. Bucsky, MD
Role: primary
Uwe Mittler, MD
Role: primary
P. Gutjahr, MD
Role: primary
M. Duerken
Role: primary
H. Christiansen, MD
Role: primary
W Tilmann, MD
Role: primary
Stefan Burdach, MD, PhD
Role: primary
Arndt Borkhardt
Role: primary
Schulz, MD
Role: primary
Contact Person
Role: primary
Contact Person
Role: primary
H. J. Feickert, MD, PhD
Role: primary
Contact Person
Role: primary
W. Scheurlen
Role: primary
Hermann Mueller, MD
Role: primary
Ove Peters
Role: primary
Carl Friedrich Classen, MD, PD
Role: primary
Roswitha Dickerhoff, MD
Role: primary
Rainer Burghard, MD
Role: primary
Stefan Bielack, MD
Role: primary
Wolfgang Rauh, MD
Role: primary
Contact Person
Role: primary
Rupert Handgretinger, MD
Role: primary
Klaus M. Debatin, MD
Role: primary
Liebner, MD
Role: primary
K. Sinha, MD
Role: primary
P. G. Schlegel, MD
Role: primary
R. Angst
Role: primary
Thomas Kuhne, MD
Role: primary
U. Caflisch, MD
Role: primary
Jeanette Greiner, MD
Role: primary
Felix Niggli, MD
Role: primary
References
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Decarolis B, Simon T, Krug B, Leuschner I, Vokuhl C, Kaatsch P, von Schweinitz D, Klingebiel T, Mueller I, Schweigerer L, Berthold F, Hero B. Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed. BMC Cancer. 2016 Jul 27;16:542. doi: 10.1186/s12885-016-2513-9.
Other Identifiers
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CDR0000517312
Identifier Type: REGISTRY
Identifier Source: secondary_id
EU-20661
Identifier Type: -
Identifier Source: secondary_id
GPOH-NB2004
Identifier Type: -
Identifier Source: org_study_id