Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy Followed by Stem Cell Transplant and Isotretinoin in Treating Young Patients With High-Risk Neuroblastoma

Basic Trial Information

Objectives

Primary

1. Compare the event-free survival of pediatric patients with high-risk neuroblastoma treated with standard induction chemotherapy vs topotecan hydrochloride-containing induction chemotherapy followed by myeloablative autologous stem cell transplantation and consolidation therapy with isotretinoin.

Secondary

1. Compare the overall survival of patients treated with these regimens.
2. Compare early response (complete response, very good partial response, partial response, mixed response, stable disease, and progression/relapse) after 2 courses of standard vs experimental induction chemotherapy (or after 60 days if the second course is not yet finished).
3. Compare response to standard vs experimental induction chemotherapy before autologous stem cell transplantation (or after 280 days if induction chemotherapy is not yet finished).
4. Compare the toxicity of standard vs experimental induction chemotherapy during courses 1 and 2 and the frequency of ≥ grade 3 toxicity during the last 6 courses of induction chemotherapy.
5. Compare the extent of initial surgery and best surgery (biopsy vs incomplete resection vs macroscopic complete resection) and the frequency of complications related to surgery (e.g., nephrectomy, bleeding, infection, or intestinal obstruction).
6. Compare the acute and long-term side effects of external-beam radiotherapy.
7. Correlate the activity of MIBG and whole-body radiation dose.
8. Collect and store tumor material in the tumor bank for future evaluation of other molecular markers (MYCN and status of chromosome 1p and 11q) and prognostic significant gene signatures.

Entry Criteria

Disease Characteristics:

• Diagnosis of neuroblastoma according to any of the following criteria:
  • Histological diagnosis from tumor tissue
  • Presence of distinct neuroblastoma cells in the bone marrow and elevated catecholamine metabolites (HVA, VMA) in blood or urine

• High-risk disease, meeting 1 of the following criteria:
  • Stage 4 disease, regardless of the MYCN status (1-21 years of age)
  • Stage 1-3 or 4S disease with MYCN amplification (6 months -21 years of age)

Prior/Concurrent Therapy:

• No concurrent participation in another clinical trial that would preclude the interventions or outcome assessment of this clinical trial
• No other concurrent anticancer therapy

Patient Characteristics:

• Not pregnant or nursing
• Fertile patients must use effective contraception (hormonal contraception or intra-uterine device [IUD])

Expected Enrollment

Outcomes

Event-free survival (EFS)

Overall survival (OS)
Impact of well established clinical and molecular risk factors on EFS and OS
Early response, measured after 2 courses of induction chemotherapy
Response to induction therapy, measured before autologous stem cell transplantation
Toxicity during the first 2 courses and the last 6 courses of induction chemotherapy
Impact of the extent of initial and best surgery on outcome and frequency of complications
Acute and late toxicity of radiotherapy
Correlation of MIBG activity with whole-body radiation dose
Molecular markers (MYCN and status of chromosome 1p and 11q)

Outline

This is a multicenter study. Patients are stratified according to disease stage, lactate dehydrogenase (LDH) status, MYCN status, and age at diagnosis (stage 4 disease; LDH not elevated; any MYCN status; age at diagnosis 1-21 years vs stage 4 disease; LDH elevated; any MYCN status; age at diagnosis ≥ 1 but < 2 years vs stage 4 disease; LDH elevated; any MYCN status; age at diagnosis 2-21 years vs localized disease; MYCN amplification; age at diagnosis ≥ 6 months)

• Induction chemotherapy: Patients are randomized to 1 of 2 induction chemotherapy arms.
  • Arm I (standard): Patients receive N5 chemotherapy comprising cisplatin IV continuously over 96 hours and etoposide phosphate IV continuously over 96 hours on days 1-4 and vindesine IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily 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 on days 1-5, ifosfamide IV continuously over 120 hours on days 1-5, and doxorubicin hydrochloride IV over 4 hours on days 6 and 7. Patients also receive G-CSF SC once daily beginning on day 10 and continuing until blood counts recover. Treatment with N5 and N6 chemotherapy alternates every 21 days for 6 courses (N5 chemotherapy is given in courses 1, 3, and 5 and N6 chemotherapy is given in courses 2, 4, and 6).

  • Arm II (experimental): Patients receive N8 chemotherapy comprising cyclophosphamide IV over 1 hour on days 1-7, topotecan hydrochloride IV continuously over 168 hours on days 1-7, and etoposide phosphate IV over 1 hour on days 8-10. Patients also receive G-CSF SC once daily beginning on day 12 and continuing until blood counts recover. Treatment with N8 chemotherapy repeats every 21 days for 2 courses. Patients then receive N5 chemotherapy alternating with N6 chemotherapy as in arm I.

• Surgery: Patients may undergo secondary surgery after completion of 4 or 6 courses of induction chemotherapy but prior to radiotherapy.

• Radiotherapy (¹³¹I-MIBG therapy and external-beam radiotherapy [EBRT]): Patients with active residual primary tumor after the completion of induction chemotherapy undergo ¹³¹I-MIBG therapy* prior to autologous stem cell transplantation (ASCT) and EBRT after ASCT.

   [Note: *Patients with MIBG negative neuroblastoma at initial diagnosis will only receive EBRT.]

• Myeloablative 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 reinfusion of CD34+ stem cells on day 0. Patients also receive G-CSF SC or IV over 4 hours once daily beginning on day 2 and continuing until blood counts recover.

• Consolidation therapy (isotretinoin)*: Beginning 30 days after ASCT, patients receive oral isotretinoin once daily on days 1-14. Treatment repeats every 28 days for up to 6 courses. Beginning 3 months later, patients receive an additional 3 courses of isotretinoin.

   [Note: *Isotretinoin must not be given concurrently with radiotherapy]

After completion of study treatment, patients are followed every 6 weeks for 1 year, every 3 months for 4 years, and then every 6 months thereafter.

Trial Contact Information

Trial Lead Organizations

Gesellschaft fuer Paediatrische Onkologie und Haematologie - Germany

Frank Berthold, MD, Protocol chair		Ph: 49-221-478-4380 Email: frank.berthold@uk-koeln.de

Germany
	Aachen
	Kinderklinik - Universitaetsklinikum Aachen
		R. Mertens, MD, PhD	Ph:  49-241-808-9902
			Email: rmertens@ukaachen.de
	Augsburg
	Klinikum Augsburg
		Astrid Gnekow	Ph:  49-821-400-3603
	Bayreuth
	Klinikum Bayreuth
		T. Rupprecht	Ph:  49-921-400-1400
	Berlin
	Charite University Hospital - Campus Virchow Klinikum
		Gunter Henze	Ph:  49-30-450-660-31
	Helios Klinikum Berlin
		Lothar Schweigerer, MD	Ph:  49-30-9401-2345
	Biefeld
	Evangelisches Krankenhauus Bielfeld
		N. Jorch, MD	Ph:  49-52-177-278-050
	Bonn
	Kinderklinik der Universitaet Bonn
		Udo Bode, MD	Ph:  49-228-2873-3215
			Email: udo.bode@ukb.uni-bonn.de
	Braunschweig
	Staedtisches Klinikum - Howedestrase
		Wolfgang Eberl, MD	Ph:  49-531-595-1222
			Email: w.eberl@kliniklum-braunschweig.de
	Bremen
	Klinikum Bremen-Mitte
		Arnulf Pekrun, MD, PhD	Ph:  49-421-497-3656
			Email: arnulf.pekrun@klinikum-bremen-mitte.de
	Chemnitz
	Klinikum Chemnitz gGmbH
		Krause, MD	Ph:  49-371-3332-4124
	Coburg
	Klinikum Coburg
		Roland Frank, MD	Ph:  49-9561-22-5547
	Cologne
	Children's Hospital
		Frank Berthold, MD	Ph:  49-221-478-4380
			Email: frank.berthold@uk-koeln.de
	Cottbus
	Carl - Thiem - Klinkum Cottbus
		D Mobius, MD	Ph:  49-355-462336
	Datteln
	Vestische Kinderklinik
		W. Andler, MD	Ph:  49-023-63-9750
			Email: w.andler@kinderklinik-datteln.de
	Detmold
	Klinikum Lippe - Detmold
		Klaus Wesseler, MD	Ph:  49-523-172-4511
	Dortmund
	Klinikum Dortmund
		Dominik Schneider, MD	Ph:  49-231-953-2-1670
			Email: dominik.schneider@klinikumdo.de
	Dresden
	Universitatsklinikum Carl Gustav Carus
		M. Suttorp, MD	Ph:  49-351-458-0
			Email: meinolf.suttorp@uniklinikum-dresden.de
	Duesseldorf
	Universitaetsklinikum Duesseldorf
		Arndt Borkhardt	Ph:  49-211-311-7990
	Duisburg
	Klinikum Duisburg
		Ruef, MD	Ph:  49-203-733-2421
	Erfurt
	Helios Klinikum Erfurt
		Axel Sauerbrey, MD	Ph:  49-361-781-3729
			Email: asauerbrey@erfurt.helios-kliniken.de
	Erlangen
	Universitaets - Kinderklinik
		W. Holter, MD	Ph:  49-9131-853-3118
	Essen
	Universitaetsklinikum Essen
		Bernhard Kremens, MD	Ph:  49-201-723-2453
	Frankfurt
	Klinikum der J.W. Goethe Universitaet
		Thomas Klingebiel, MD	Ph:  49-69-6301-5094
			Email: thomas.klingebiel@kgu.de
	Freiburg
	Universitaetskinderklinik - Universitaetsklinikum Freiburg
		Charlotte Niemeyer, MD	Ph:  49-761-270-4506
			Email: charlotte.niemeyer@uniklinik-freiburg.de
	Giessen
	Kinderklinik
		Alfred Reiter, MD	Ph:  49-641-994-3420
	Goettingen
	Universitaetsklinikum Goettingen
		M. Lakomek, MD	Ph:  49-551-398-600
	Greiswald
	Universitats - Kinderklinik
		James Beck, MD	Ph:  49-383-486-6325
			Email: beck@uni-greifswald.de
	Halle
	Krankenhaus St. Elisabeth und St. Barbara
		G. Guenther, MD	Ph:  49-345-482-50
	Universitaetsklinikum Halle
		Dieter Koerholz, MD	Ph:  49-345-557-2387
	Hamburg
	University Medical Center Hamburg - Eppendorf
		Rudolf Erttmann, MD	Ph:  49-40-4717-4270
			Email: erttmann@uke.uni-hamburg.de
	Hannover
	Medizinische Hochschule Hannover
		Karl Welte, MD	Ph:  49-511-532-6710
			Email: welte.karl.h@mh-hannover.de
	Heidelberg
	Universitaets-Kinderklinik Heidelberg
		Andreas Kulozik, MD, PhD	Ph:  49-6221-564-555
			Email: andreas.kulozik@med.uni-heidelberg.de
	Herdecke
	Gemeinschaftskrankenhaus
		Christoph Tautz, MD	Ph:  49-2330-62-3914
			Email: ctautz@yahoo.de
	Homburg
	Universitaetsklinikum des Saarlandes
		Norbert Graf	Ph:  49-6841-162-4000
	Jena
	Universitaets - Kinderklinik
		Felix Zintl, MD	Ph:  49-3641-938-270
	Karlsruhe
	Staedtisches Klinikum Karlsruhe gGmbH
		A. Leipold	Ph:  49-721-974-3311
	Kassel
	Klinikum Kassel
		Martina Rodehueser, MD	Ph:  49-561-980-3066
	Kiel
	University Hospital Schleswig-Holstein - Kiel Campus
		A. Claviez, MD	Ph:  49-431-597-1622
			Email: a.claviez@pediatrics.uni-kiel.de
	Koblenz
	Klinikum Kemperhof Koblenz
		M. Rister, MD	Ph:  49-261-499-2602
	Krefeld
	Klinikum Krefeld GmbH
		S. Volpel, MD	Ph:  49-2151-32-2375
	Leipzig
	Universitaets - Kinderklinik
		U. Bierbach, MD
	Ludwigshafen
	St. Annastift Krankenhaus
		Barbara Selle, MD	Ph:  49-621-5702-4449
	Luebeck
	Universitaets - Kinderklinik - Luebeck
		Peter Bucsky, MD	Ph:  49-451-500-2956
			Email: bucsky@paedia.ukl.mu-luebeck.de
	Magdeburg
	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
		P. Vorwerk, MD	Ph:  49-394-672-791
	Mainz
	Johannes Gutenberg University
		P. Gutjahr, MD	Ph:  49-6131-17-2112
	Mannheim
	Staedtisches Klinik - Kinderklinik
		M. Duerken	Ph:  49-621-383-2243
	Marburg
	Universitaetsklinikum Giessen und Marburg GmbH - Marburg
		H. Christiansen, MD	Ph:  49-6421-286-2671
	Minden
	Klinikum Minden
		Bernhard Erdlenbruch, MD	Ph:  49-57-1801-4601
			Email: bernhard.erdlenbruch@klinikum-minden.de
	Muenster
	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
		Heribert Juergens, MD	Ph:  49-251-834-7742
			Email: jurgh@uni-muenster.de
	Munich
	Dr. von Haunersches Kinderspital der Universitaet Muenchen
		Irene Schmid, MD	Ph:  49-89-5160-7978
	Krankenhaus Muenchen Schwabing
		Stefan Burdach, MD, PhD	Ph:  49-89-3068-2352
	Neubrandenburg
	Klinikum Neubrandenburg
		H. J. Feickert, MD, PhD	Ph:  49-395-775-2901
			Email: feickerthj@dbk-nb.de
	Nuremberg
	Cnopf'sche Kinderklinik
		W. Scheurlen	Ph:  49-911-334-002
	Oldenburg
	Klinikum Oldenburg
		Hermann Mueller, MD	Ph:  49-441-403-2013
			Email: mueller.hermann@klinikum-oldenburg.de
	Regensburg
	Klinik St. Hedwig-Kinderklinik
		Ove Peters	Ph:  49-941-369-5404
	Rostock
	Kinderklinik - Universitaetsklinikum Rostock
		Carl Friedrich Classen, MD, PD	Ph:  49-381-494-0
			Email: carl-friedrich.classen@med.uni-rostock.de
	Siegen
	Kinderklink Siegen Deutsches Rotes Kreuz
		Rainer Burghard, MD	Ph:  49-271-2345-0
			Email: rainer.burghard@drk-kinderklinik.de
	St. Augustin
	Johanniter-Kinderklinik
		Roswitha Dickerhoff, MD	Ph:  49-22-41-2491
			Email: roswitha.dickerhoft@uni-bonn.de
	Stuttgart
	Olgahospital
		Stefan Bielack, MD	Ph:  49-711-99-24-61
			Email: st.bielack@olgahospital.de
	Trier
	Krankenanstalt Mutterhaus der Borromaerinnen
		Wolfgang Rauh, MD	Ph:  49-651-947-2654
	Tuebingen
	Universitaetsklinikum Tuebingen
		Rupert Handgretinger, MD	Ph:  49-7071-298-2087
	Ulm
	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
		Klaus Debatin, MD	Ph:  49-731-5002-7790
			Email: klaus-michael.debatin@medizin.uni-ulm.de
	Wuerzburg
	Universitaets - Kinderklinik Wuerzburg
		P. G. Schlegel, MD	Ph:  49-931-201-27-831
			Email: schlegel@mail.uni-wuerzburg.de
	Wuppertal
	Helios Kliniken Wuppertal University Hospital
		K. Sinha, MD	Ph:  49-202-896-2441
Switzerland
	Aarau
	Kantonsspital Aarau
		R. Angst	Ph:  41-62-838-4906
	Basel
	Universitaets-Kinderspital beider Basel
		Thomas Kuhne, MD	Ph:  41-61-685-6565
			Email: thomas.kuehne@ukbb.ch
	Lucerne 16
	Kinderspital Luzern
		U. Caflisch, MD	Ph:  41-41-205-11-11
	St. Gallen
	Ostschweizer Kinderspital
		Jeanette Greiner, MD	Ph:  41-71-243-13-60
			Email: jeanette.greiner@kispisg.ch
	Zurich
	University Children's Hospital
		Felix Niggli, MD	Ph:  41-44-266-7823

Registry Information
Official Title		Trial Protocol for the Treatment of Children with High Risk Neuroblastoma (NB2004-HR)
Trial Start Date		2007-01-01
Trial Completion Date		2012-12-31 (estimated)
Registered in ClinicalTrials.gov		NCT00526318
Date Submitted to PDQ		2007-08-28
Information Last Verified		2011-08-31

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