NeuroblastomaPhase 3NCT00410631
Observation, Combination Chemotherapy, Radiation Therapy, and/or Autologous Stem Cell Transplant in Treating Young Patients With Neuroblastoma
A Phase 3 study testing filgrastim, carboplatin and cisplatin in people with Neuroblastoma, run by German Society for Pediatric Oncology and Hematology GPOH gGmbH at 80 sites in 2 countries.
Trial summary
RATIONALE: 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 may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. Read more about this study
- Who is it for?
- Ages Up to 21 years
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- filgrastim, carboplatin and cisplatin
- Type of treatment
- Surgery or procedure
- How many people
- 642 participants
- Where
- 80 sitesin 2 countries
- Study dates
- Oct 2004to Dec 2010
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
DISEASE CHARACTERISTICS:
- 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
Trial locations and contacts
80 sites in 2 countries.
80 sites in 2 countries
Germany75 sites, 75 recruiting
- Recruiting
Kinderklinik - Universitaetsklinikum Aachen
Aachen, D-52074
R. Mertens, MD, PhD, 49-241-809-222, rmertens@ukaachen.de
- Recruiting
Klinikum Augsburg
Augsburg, DOH-86156
Astrid Gnekow, 49-821-400-3603
- Recruiting
Klinikum am Bamberg
Bamberg, 96049
Gloeckel, MD, 49-951-506-0
- Recruiting
Klinikum Bayreuth
Bayreuth, D-95445
T. Rupprecht, 49-921-400-6202
- Recruiting
Helios Klinikum Berlin
Berlin, D-13125
L. Wickmann, MD, 49-30-9401-2353, lwickmann@berlin.helios-kliniken.de
- Recruiting
Charite University Hospital - Campus Virchow Klinikum
Berlin, D-13353
Gunter Henze, 49-30-450-566-004
- Recruiting
Evangelisches Krankenhauus Bielfeld
Biefeld, 33617
N. Jorch, MD, 49-521-7727-8050
- Recruiting
Kinderklinik der Universitaet Bonn
Bonn, D-53113
Udo Bode, MD, 49-228-2873-3215, udo.bode@ukb.uni-bonn.de
- Recruiting
Staedtisches Klinikum - Howedestrase
Braunschweig, 38118
Contact Person, 49-531-595-1222
- Recruiting
Klinikum Bremen-Mitte
Bremen, D-28205
Arnulf Pekrun, MD, PhD, 49-421-497-3656, arnulf.pekrun@klinikum-bremen-mitte.de
- Recruiting
Allgemeinen Krankenhaus Celle Kinderklinik
Celle, 29223
Martin Kirschstein, MD, 49-241-809-222, martin.kirschstein@akh-celle.de
- Recruiting
Klinikum Chemnitz gGmbH
Chemnitz, D-09116
Krause, MD, 49-371-3332-4124
- Recruiting
Klinikum Coburg
Coburg, 96450
Roland Frank, MD, 49-8561-225-547
- Recruiting
Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
Cologne, D-50735
Contact Person, 49-221-8907-5243
- Recruiting
Children's Hospital
Cologne, D-50924
Frank Berthold, MD, 49-221-478-4380, frank.berthold@uk-koeln.de
- Recruiting
Carl - Thiem - Klinkum Cottbus
Cottbus, D-03048
D Mobius, MD, 49-355-462-336
- Recruiting
Vestische Kinderklinik
Datteln, 45704
W. Andler, MD, 49-2363-9750, w.andler@kinderklinik-datteln.de
- Recruiting
Klinikum Lippe - Detmold
Detmold, D-32756
Klaus Wesseler, MD, 49-5231-724-510
- Recruiting
Klinikum Dortmund
Dortmund, D-44137
Heidi Olscheswski, MD, 49-231-9532-1721
- Recruiting
Universitatsklinikum Carl Gustav Carus
Dresden, D-01307
M. Suttorp, MD, 49-351-458-5035, meinolf.suttorp@uniklinikum-dresden.de
- Recruiting
Klinikum Duisburg
Duisburg, D-47055
Ruef, MD, 49-203-733-2421
- Recruiting
Universitaets - Frauenklinik, Duesseldorf
Düsseldorf, D-40225
Dilloo, MD, 49-211-811-7680
- Recruiting
Helios Klinikum Erfurt
Erfurt, 99089
Axel Sauerbrey, MD, 49-361-781-3702, asauerbrey@erfurt.helios-kliniken.de
- Recruiting
Universitaets - Kinderklinik
Erlangen, 91054
W. Holter, MD, 49-9131-853-3118
- Recruiting
Universitaetsklinikum Essen
Essen, D-45147
Bernhard Kremens, MD, 49-201-723-2453
- Recruiting
Klinikum der J.W. Goethe Universitaet
Frankfurt, D-60590
Thomas Klingebiel, MD, 49-69-6301-5243, thomas.klingebiel@kgu.de
- Recruiting
Universitaetskinderklinik - Universitaetsklinikum Freiburg
Freiburg im Breisgau, D-79106
Charlotte Niemeyer, MD, 49-761-270-4552, charlotte.niemeyer@uniklinik-freiburg.de
- Recruiting
Kinderklinik
Giessen, D-35385
Alfred Reiter, MD, 49-641-994-3400
- Recruiting
Universitaetsklinikum Goettingen
Göttingen, D-37075
Lothar Schweigerer, MD, 49-551-396-210
- Recruiting
Universitats - Kinderklinik
Greiswald, 17487
James F. Beck, MD, 49-3834-866-325, beck@uni-greifswald.de
- Recruiting
Universitaetsklinikum Halle
Halle, D-06097
Dieter Koerholz, MD, 49-345-557-2911
- Recruiting
Krankenhaus St. Elisabeth und St. Barbara
Halle, D-06110
G. Guenther, MD, 49-345-213-4514
- Recruiting
University Medical Center Hamburg - Eppendorf
Hamburg, D-20246
Rudolf Erttmann, MD, 49-40-428-034-270, erttmann@uke.uni-hamburg.de
- Recruiting
Kinderkrankenhaus auf der Bult
Hanover, 30173
U. Hofmann, MD, 49-511-811-5424
- Recruiting
Medizinische Hochschule Hannover
Hanover, D-30625
Karl Welte, MD, 49-511-532-9123, welte.karl.h@mh-hannover.de
- Recruiting
Universitaets-Kinderklinik Heidelberg
Heidelberg, D-69120
Andreas E. Kulozik, MD, PhD, 49-6221-562-311, andreas.kulozik@med.uni-heidelberg.de
- Recruiting
SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen
Heilbronn, D-74064
Full, MD, 49-7131-493-702
- Recruiting
Gemeinschaftskrankenhaus
Herdecke, 58313
Christoph Tautz, MD, 49-233-0620, ctautz@yahoo.de
- Recruiting
Universitaetsklinikum des Saarlandes
Homburg, 66421
Norbert Graf, 49-6841-162-4000
- Recruiting
Universitaets - Kinderklinik
Jena, D-07440
Contact Peron, 49-3641-938-270
- Recruiting
Universitaets - Kinderklinik
Jena, D-07745
Felix Zintl, MD, 49-3641-9300
- Recruiting
Staedtisches Klinikum Karlsruhe gGmbH
Karlsruhe, 76133
A. Leipold, 49-721-974-3230
- Recruiting
Kinderkrankenhaus Park Schoenfeld
Kassel, D-34121
M. L. Wright, MD, 49-561-928-5108
- Recruiting
Klinikum Kassel
Kassel, D-34125
Martina Rodehueser, MD, 49-561-9800
- Recruiting
University Hospital Schleswig-Holstein - Kiel Campus
Kiel, D-24105
A. Claviez, MD, 49-431-597-1620, a.claviez@pediatrics.uni-kiel.de
- Recruiting
Klinikum Kemperhof Koblenz
Koblenz, D-56065
M. Rister, MD, 49-261-499-2602
- Recruiting
Klinikum Krefeld GmbH
Krefeld, D-47805
S. Volpel, MD, 49-2151-322-375
- Recruiting
Universitaets - Kinderklinik - Luebeck
Lübeck, D-23538
Peter P. Bucsky, MD, 49-451-500-2956, bucsky@paedia.ukl.mu-luebeck.de
- Recruiting
St. Annastift Krankenhaus
Ludwigshafen, 67065
Barbara Selle, MD, 49-621-57021
- Recruiting
Universitatsklinikum der MA
Magdeburg, 39120
Uwe Mittler, MD, 49-391-671-7210
- Recruiting
Johannes Gutenberg University
Mainz, D-55101
P. Gutjahr, MD, 49-6131-172-112
- Recruiting
Staedtisches Klinik - Kinderklinik
Mannheim, D-68167
M. Duerken, 49-621-383-2244
- Recruiting
Universitaets - Kinderklinik
Marburg, 35033
H. Christiansen, MD, 49-6421-286-2650
- Recruiting
Klinikum Minden
Minden, D-32423
W Tilmann, MD, 49-571-801-4601
- Recruiting
Krankenhaus Muenchen Schwabing
Munich, 80804
Stefan Burdach, MD, PhD, 49-89-3068-2276
- Recruiting
Dr. von Haunersches Kinderspital der Universitaet Muenchen
Munich, D-80337
Arndt Borkhardt, 49-89-5160-2842
- Recruiting
Klinikum der Universitaet Muenchen - Grosshadern Campus
Munich, D-81377
Schulz, MD, 49-89-7095-2404
- Recruiting
Staedtisches Krankenhaus Muenchen - Harlaching
Munich, D-81545
Contact Person, 49-89-6210-2443
- Recruiting
University of Muenster
Münster, D-48129
Contact Person, 44-251-834-7742
- Recruiting
Klinikum Neubrandenburg
Neubrandenburg, 17036
H. J. Feickert, MD, PhD, 49-395-775-2901, feickerthj@dbk-nb.de
- Recruiting
Kinderklinik Kohlhof
Neunkirchen, D-66539
Contact Person, 49-681-3630
- Recruiting
Cnopf'sche Kinderklinik
Nuremberg, 90419
W. Scheurlen, 49-911-334-002
- Recruiting
Klinikum Oldenburg
Oldenburg, 26133
Hermann Mueller, MD, 49-441-403-2013, mueller.hermann@klinikum-oldenburg.de
- Recruiting
Klinik St. Hedwig-Kinderklinik
Regensburg, 93049
Ove Peters, 49-941-3690
- Recruiting
Kinderklinik - Universitaetsklinikum Rostock
Rostock, D-18057
Carl Friedrich Classen, MD, PD, 49-381-4940, carl-friedrich.classen@med.uni-rostock.de
- Recruiting
Johanniter-Kinderklinik
Sankt Augustin, 53757
Roswitha Dickerhoff, MD, 49-2241-2490, roswitha.dickerhoft@uni-bonn.de
- Recruiting
Kinderklink Siegen Deutsches Rotes Kreuz
Siegen, D-57072
Rainer Burghard, MD, 49-271-23450, rainer.burghard@drk-kinderklinik.de
- Recruiting
Olgahospital
Stuttgart, D-70176
Stefan Bielack, MD, 49-711-992-460, st.bielack@olgahospital.de
- Recruiting
Krankenanstalt Mutterhaus der Borromaerinnen
Trier, D-54290
Wolfgang Rauh, MD, 49-651-947-2620
- Recruiting
Universitaets-Kinderklinik
Tübingen, D-72070
Contact Person, 49-707-1298-3781
- Recruiting
Universitaetsklinikum Tuebingen
Tübingen, D-72076
Rupert Handgretinger, MD, 49-7071-298-3781
- Recruiting
Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
Ulm, D-89075
Klaus M. Debatin, MD, 49-731-5002-7790, klaus-michael.debatin@medizin.uni-ulm.de
- Recruiting
Reinhard-Nieter-Krankenhaus
Wilhelmshaven, D-26389
Liebner, MD, 49-4421-891-840
- Recruiting
Helios Kliniken Wuppertal University Hospital
Wuppertal, D-42283
K. Sinha, MD, 49-202-896-2441
- Recruiting
Universitaets - Kinderklinik Wuerzburg
Würzburg, D-97080
P. G. Schlegel, MD, 49-931-2010, schlegel@mail.uni-wuerzburg.de
Switzerland5 sites, 5 recruiting
- Recruiting
Kantonsspital Aarau
Aarau, CH-5001
R. Angst, 49-41-628-384-941
- Recruiting
Universitaets-Kinderspital beider Basel
Basel, CH-4005
Thomas Kuhne, MD, 49-41-616-856-565, thomas.kuehne@ukbb.ch
- Recruiting
Kinderspital Luzern
Lucerne, CH-6000
U. Caflisch, MD, 49-41-412-051-111
- Recruiting
Ostschweizer Kinderspital
Sankt Gallen, CH-9006
Jeanette Greiner, MD, 49-41-712-437-111, jeanette.greiner@kispisg.ch
- Recruiting
University Children's Hospital
Zurich, CH-8032
Felix Niggli, MD, 49-41-1266-7111
About this study
Official title: NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma
RATIONALE: 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 may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. An autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. This may allow more chemotherapy to be given so that more tumor cells are killed. Sometimes, after surgery, the tumor may not need more treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether observation is more effective than combination chemotherapy, radiation therapy, and/or autologous stem cell transplant in treating neuroblastoma.
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.
Read the detailed description
OBJECTIVES:
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
- Neuroblastoma
- Being tested
- filgrastim, carboplatin, cisplatin, cyclophosphamide, dacarbazine
- Keywords
- localized resectable neuroblastoma, localized unresectable neuroblastoma, regional neuroblastoma, stage 4S neuroblastoma, disseminated neuroblastoma, recurrent neuroblastoma
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
filgrastimBiological
carboplatinDrug
cisplatinDrug
cyclophosphamideDrug
dacarbazineDrug
etoposide phosphateDrug
ifosfamideDrug
isotretinoinDrug
melphalanDrug
topotecan hydrochlorideDrug
vindesineDrug
autologous hematopoietic stem cell transplantationProcedure or surgery
conventional surgeryProcedure or surgery
peripheral blood stem cell transplantationProcedure or surgery
iobenguane I 131Radiation
radiation therapyRadiation
What is being measured
The primary outcome is the main question the study is designed to answer.
Event-free survival (EFS)
Locoregional EFS
Secondary outcomes (21)
Time from diagnosis to transition to stage 4 disease, to death from disease, or to the last follow-up (if no transition to stage 4 disease is observed)
Overall survival
Time to the beginning of primary tumor regression (in patients in the low-risk group [LRG])
Time to the normalization of tumor markers HVA and VMA in urine
Time to no evidence of disease (in patients in the LRG with stage 4S disease)
Status of the primary tumor 12 months after diagnosis (LRG)
Best status of the primary tumor within the first 12 months (LRG)
Status of chromosome 1p (unblinded) and status of chromosome 11q (blinded)
Comparison of the extent of initial surgery (incomplete resection vs macroscopic complete resection) (LRG)
Comparison of the extent of best surgery during protocol treatment (incomplete resection vs macroscopic complete resection)
Surgery-related complications (i.e., bleeding, infection, intestinal obstruction, or other)
Disease progression and symptoms controlled after the first, second, third, and fourth N4 course (LRG)
Disease progression and symptoms not controlled after four N4 courses (LRG)
Transition to stage 4 disease at any time (LRG)
Acute and late side effects of external-beam radiotherapy (medium-risk group [MRG] and high-risk group [HRG])
Early response after 2 courses of induction therapy (N5 and N6 or two courses of N8) (HRG)
Response to induction therapy prior to conditioning therapy or after 280 days (HRG)
Grade of toxicity observed during induction therapy course 1 (N5 or N8) (HRG)
Grade of toxicity observed during induction therapy course 2 (N6 or N8) (HRG)
Frequency of grade 3 or 4 toxicity observed during the last 6 courses of induction therapy (3 courses of N5 and N6) (HRG)
Activity and whole body dose of radiotherapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Dec 2006 (estimated)
- Study startOct 2004
- Primary completionDec 2010 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Masking
- None (open label)
- Enrolment
- 642 participants (estimated)
Sponsor and investigators
- Lead sponsor
- German Society for Pediatric Oncology and Hematology GPOH gGmbH
- Sponsor type
- University, hospital or other
- Investigators
- Frank Berthold, MD, Study chair, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00410631
- Sponsor's protocol ID
- GPOH-NB2004
- Other IDs
- CDR0000517312, EU-20661
- Status last verified
- Jan 2008
- First submitted
- 11 Dec 2006
- Last updated
- 7 Aug 2013
- Results posted
- No
Publications
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.
PubMed 27465021
Study at a glance
From the registry record, last updated by the sponsor on 7 Aug 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma
- ClinicalTrials.gov ID
- NCT00410631
- Acronym / sponsor ID
- GPOH-NB2004
- Conditions
- Neuroblastoma
- Keywords
- localized resectable neuroblastoma, localized unresectable neuroblastoma, regional neuroblastoma, stage 4S neuroblastoma, disseminated neuroblastoma, recurrent neuroblastoma
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 642 participants (estimated)
- Lead sponsor
- German Society for Pediatric Oncology and Hematology GPOH gGmbHUniversity, hospital or other
- Study start
- Oct 2004
- Primary completion
- Dec 2010 (estimated)
- First posted
- 13 Dec 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
RATIONALE: 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 may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. An autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. This may allow more chemotherapy to be given so that more tumor cells are killed. Sometimes, after surgery, the tumor may not need more treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether observation is more effective than combination chemotherapy, radiation therapy, and/or autologous stem cell transplant in treating neuroblastoma.
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
OBJECTIVES:
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Masking
- None (open label)
Who may qualify
- Ages
- Up to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| filgrastim | Biological | – |
| carboplatin | Drug | – |
| cisplatin | Drug | – |
| cyclophosphamide | Drug | – |
| dacarbazine | Drug | – |
| doxorubicin hydrochloride | Drug | – |
| etoposide phosphate | Drug | – |
| ifosfamide | Drug | – |
| isotretinoin | Drug | – |
| melphalan | Drug | – |
| topotecan hydrochloride | Drug | – |
| vincristine sulfate | Drug | – |
| vindesine | Drug | – |
| autologous hematopoietic stem cell transplantation | Procedure or surgery | – |
| conventional surgery | Procedure or surgery | – |
| peripheral blood stem cell transplantation | Procedure or surgery | – |
| iobenguane I 131 | Radiation | – |
| radiation therapy | Radiation | – |
Primary outcome
Event-free survival (EFS)
Locoregional EFS
21 secondary outcomes
Time from diagnosis to transition to stage 4 disease, to death from disease, or to the last follow-up (if no transition to stage 4 disease is observed)
Overall survival
Time to the beginning of primary tumor regression (in patients in the low-risk group [LRG])
Time to the normalization of tumor markers HVA and VMA in urine
Time to no evidence of disease (in patients in the LRG with stage 4S disease)
Status of the primary tumor 12 months after diagnosis (LRG)
Best status of the primary tumor within the first 12 months (LRG)
Status of chromosome 1p (unblinded) and status of chromosome 11q (blinded)
Comparison of the extent of initial surgery (incomplete resection vs macroscopic complete resection) (LRG)
Comparison of the extent of best surgery during protocol treatment (incomplete resection vs macroscopic complete resection)
Surgery-related complications (i.e., bleeding, infection, intestinal obstruction, or other)
Disease progression and symptoms controlled after the first, second, third, and fourth N4 course (LRG)
Disease progression and symptoms not controlled after four N4 courses (LRG)
Transition to stage 4 disease at any time (LRG)
Acute and late side effects of external-beam radiotherapy (medium-risk group [MRG] and high-risk group [HRG])
Early response after 2 courses of induction therapy (N5 and N6 or two courses of N8) (HRG)
Response to induction therapy prior to conditioning therapy or after 280 days (HRG)
Grade of toxicity observed during induction therapy course 1 (N5 or N8) (HRG)
Grade of toxicity observed during induction therapy course 2 (N6 or N8) (HRG)
Frequency of grade 3 or 4 toxicity observed during the last 6 courses of induction therapy (3 courses of N5 and N6) (HRG)
Activity and whole body dose of radiotherapy
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Aug 2013.
- Derived from this study: PubMed 27465021Decarolis 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Frank Berthold, MD study chair
Children's Hospital Medical Center, Cincinnati
80 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing filgrastim, carboplatin and cisplatin in people with Neuroblastoma, run by German Society for Pediatric Oncology and Hematology GPOH gGmbH at 80 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 7 Aug 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 80 sites in Germany, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Event-free survival (EFS). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00410631, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Aug 2013; AzTrials last refreshed its copy on 7 Nov 2026.