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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Neuroblastoma

Intervention: 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); iobenguane I 131 (Radiation); radiation therapy (Radiation)

Phase: N/A

Status: Recruiting

Sponsored by: Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany

Official(s) and/or principal investigator(s):
Frank Berthold, MD, Study Chair, Affiliation: Children's Hospital Medical Center, Cincinnati


RATIONALE: Giving chemotherapy before an autologous stem cell transplant stops the growth of tumor cells by stopping them from dividing or by killing them. It also prepares the patient's bone marrow for the stem cell transplant. The stem cells are given to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving isotretinoin after transplant may kill any remaining tumor cells. It is not yet known which combination chemotherapy regimen is more effective when given before a stem cell transplant and isotretinoin in treating neuroblastoma. PURPOSE: This randomized clinical trial is studying two different combination chemotherapy regimens to compare how well they work when given before a stem cell transplant and isotretinoin in treating young patients with high-risk neuroblastoma.

Clinical Details

Official title: Trial Protocol for the Treatment of Children With High Risk Neuroblastoma (NB2004-HR)

Study design: Allocation: Randomized, Primary Purpose: Treatment

Primary outcome: Event-free survival (EFS)

Secondary outcome:

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)

Detailed description: OBJECTIVES: Primary

- 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

- Compare the overall survival of patients treated with these regimens.

- 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).

- Compare response to standard vs experimental induction chemotherapy before autologous

stem cell transplantation (or after 280 days if induction chemotherapy is not yet finished).

- 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.

- 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).

- Compare the acute and long-term side effects of external-beam radiotherapy.

- Correlate the activity of MIBG and whole-body radiation dose.

- 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. 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.


Minimum age: N/A. Maximum age: 21 Years. Gender(s): Both.



- 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)


- Not pregnant or nursing

- Fertile patients must use effective contraception (hormonal contraception or

intra-uterine device [IUD]) 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

Locations and Contacts

Kinderklinik - Universitaetsklinikum Aachen, Aachen D-52074, Germany; Recruiting
R. Mertens, MD, PhD, Phone: 49-241-808-9902, Email: rmertens@ukaachen.de

Klinikum Augsburg, Augsburg DOH-86156, Germany; Recruiting
Astrid Gnekow, Phone: 49-821-400-3603

Klinikum Bayreuth, Bayreuth D-95445, Germany; Recruiting
T. Rupprecht, Phone: 49-921-400-1400

Charite University Hospital - Campus Virchow Klinikum, Berlin D-13353, Germany; Recruiting
Gunter Henze, Phone: 49-30-450-660-31

Helios Klinikum Berlin, Berlin 13125, Germany; Recruiting
Lothar Schweigerer, MD, Phone: 49-30-9401-2345

Evangelisches Krankenhauus Bielfeld, Biefeld 33617, Germany; Recruiting
N. Jorch, MD, Phone: 49-52-177-278-050

Kinderklinik der Universitaet Bonn, Bonn D-53113, Germany; Recruiting
Udo Bode, MD, Phone: 49-228-2873-3215, Email: udo.bode@ukb.uni-bonn.de

Staedtisches Klinikum - Howedestrase, Braunschweig 38118, Germany; Recruiting
Wolfgang Eberl, MD, Phone: 49-531-595-1222, Email: w.eberl@kliniklum-braunschweig.de

Klinikum Bremen-Mitte, Bremen D-28205, Germany; Recruiting
Arnulf Pekrun, MD, PhD, Phone: 49-421-497-3656, Email: arnulf.pekrun@klinikum-bremen-mitte.de

Klinikum Chemnitz gGmbH, Chemnitz D-09116, Germany; Recruiting
Krause, MD, Phone: 49-371-3332-4124

Klinikum Coburg, Coburg 96450, Germany; Recruiting
Roland Frank, MD, Phone: 49-9561-22-5547

Children's Hospital, Cologne D-50924, Germany; Recruiting
Frank Berthold, MD, Phone: 49-221-478-4380, Email: frank.berthold@uk-koeln.de

Carl - Thiem - Klinkum Cottbus, Cottbus D-03048, Germany; Recruiting
D Mobius, MD, Phone: 49-355-462336

Vestische Kinderklinik, Datteln 45704, Germany; Recruiting
W. Andler, MD, Phone: 49-023-63-9750, Email: w.andler@kinderklinik-datteln.de

Klinikum Lippe - Detmold, Detmold D-32756, Germany; Recruiting
Klaus Wesseler, MD, Phone: 49-523-172-4511

Klinikum Dortmund, Dortmund D-44137, Germany; Recruiting
Dominik T. Schneider, MD, Phone: 49-231-953-2-1670, Email: dominik.schneider@klinikumdo.de

Universitatsklinikum Carl Gustav Carus, Dresden D-01307, Germany; Recruiting
M. Suttorp, MD, Phone: 49-351-458-0, Email: meinolf.suttorp@uniklinikum-dresden.de

Universitaetsklinikum Duesseldorf, Duesseldorf D-40225, Germany; Recruiting
Arndt Borkhardt, Phone: 49-211-311-7990

Klinikum Duisburg, Duisburg D-47055, Germany; Recruiting
Ruef, MD, Phone: 49-203-733-2421

Helios Klinikum Erfurt, Erfurt 99089, Germany; Recruiting
Axel Sauerbrey, MD, Phone: 49-361-781-3729, Email: asauerbrey@erfurt.helios-kliniken.de

Universitaets - Kinderklinik, Erlangen 91054, Germany; Recruiting
W. Holter, MD, Phone: 49-9131-853-3118

Universitaetsklinikum Essen, Essen D-45147, Germany; Recruiting
Bernhard Kremens, MD, Phone: 49-201-723-2453

Klinikum der J.W. Goethe Universitaet, Frankfurt D-60590, Germany; Recruiting
Thomas Klingebiel, MD, Phone: 49-69-6301-5094, Email: thomas.klingebiel@kgu.de

Universitaetskinderklinik - Universitaetsklinikum Freiburg, Freiburg D-79106, Germany; Recruiting
Charlotte Niemeyer, MD, Phone: 49-761-270-4506, Email: charlotte.niemeyer@uniklinik-freiburg.de

Kinderklinik, Giessen D-35385, Germany; Recruiting
Alfred Reiter, MD, Phone: 49-641-994-3420

Universitaetsklinikum Goettingen, Goettingen D-37075, Germany; Recruiting
M. Lakomek, MD, Phone: 49-551-398-600

Universitats - Kinderklinik, Greiswald 17487, Germany; Recruiting
James F. Beck, MD, Phone: 49-383-486-6325, Email: beck@uni-greifswald.de

Krankenhaus St. Elisabeth und St. Barbara, Halle D-06110, Germany; Recruiting
G. Guenther, MD, Phone: 49-345-482-50

Universitaetsklinikum Halle, Halle D-06097, Germany; Recruiting
Dieter Koerholz, MD, Phone: 49-345-557-2387

University Medical Center Hamburg - Eppendorf, Hamburg D-20246, Germany; Recruiting
Rudolf Erttmann, MD, Phone: 49-40-4717-4270, Email: erttmann@uke.uni-hamburg.de

Medizinische Hochschule Hannover, Hannover D-30625, Germany; Recruiting
Karl Welte, MD, Phone: 49-511-532-6710, Email: welte.karl.h@mh-hannover.de

Universitaets-Kinderklinik Heidelberg, Heidelberg D-69120, Germany; Recruiting
Andreas E. Kulozik, MD, PhD, Phone: 49-6221-564-555, Email: andreas.kulozik@med.uni-heidelberg.de

Gemeinschaftskrankenhaus, Herdecke 58313, Germany; Recruiting
Christoph Tautz, MD, Phone: 49-2330-62-3914, Email: ctautz@yahoo.de

Universitaetsklinikum des Saarlandes, Homburg 66421, Germany; Recruiting
Norbert Graf, Phone: 49-6841-162-4000

Universitaets - Kinderklinik, Jena D-07745, Germany; Recruiting
Felix Zintl, MD, Phone: 49-3641-938-270

Staedtisches Klinikum Karlsruhe gGmbH, Karlsruhe 76133, Germany; Recruiting
A. Leipold, Phone: 49-721-974-3311

Klinikum Kassel, Kassel D-34125, Germany; Recruiting
Martina Rodehueser, MD, Phone: 49-561-980-3066

University Hospital Schleswig-Holstein - Kiel Campus, Kiel D-24105, Germany; Recruiting
A. Claviez, MD, Phone: 49-431-597-1622, Email: a.claviez@pediatrics.uni-kiel.de

Klinikum Kemperhof Koblenz, Koblenz D-56065, Germany; Recruiting
M. Rister, MD, Phone: 49-261-499-2602

Klinikum Krefeld GmbH, Krefeld D-47805, Germany; Recruiting
S. Volpel, MD, Phone: 49-2151-32-2375

St. Annastift Krankenhaus, Ludwigshafen 67065, Germany; Recruiting
Barbara Selle, MD, Phone: 49-621-5702-4449

Universitaets - Kinderklinik - Luebeck, Luebeck D-23538, Germany; Recruiting
Peter P. Bucsky, MD, Phone: 49-451-500-2956, Email: bucsky@paedia.ukl.mu-luebeck.de

Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg, Magdeburg D-39120, Germany; Recruiting
P. Vorwerk, MD, Phone: 49-394-672-791

Johannes Gutenberg University, Mainz D-55101, Germany; Recruiting
P. Gutjahr, MD, Phone: 49-6131-17-2112

Staedtisches Klinik - Kinderklinik, Mannheim D-68167, Germany; Recruiting
M. Duerken, Phone: 49-621-383-2243

Universitaetsklinikum Giessen und Marburg GmbH - Marburg, Marburg D-35043, Germany; Recruiting
H. Christiansen, MD, Phone: 49-6421-286-2671

Klinikum Minden, Minden D-32423, Germany; Recruiting
Bernhard Erdlenbruch, MD, Phone: 49-57-1801-4601, Email: bernhard.erdlenbruch@klinikum-minden.de

Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster, Muenster D-48149, Germany; Recruiting
Heribert F. Juergens, MD, Phone: 49-251-834-7742, Email: jurgh@uni-muenster.de

Dr. von Haunersches Kinderspital der Universitaet Muenchen, Munich D-80337, Germany; Recruiting
Irene Schmid, MD, Phone: 49-89-5160-7978

Krankenhaus Muenchen Schwabing, Munich 80804, Germany; Recruiting
Stefan Burdach, MD, PhD, Phone: 49-89-3068-2352

Klinikum Neubrandenburg, Neubrandenburg 17036, Germany; Recruiting
H. J. Feickert, MD, PhD, Phone: 49-395-775-2901, Email: feickerthj@dbk-nb.de

Cnopf'sche Kinderklinik, Nuremberg 90419, Germany; Recruiting
W. Scheurlen, Phone: 49-911-334-002

Klinikum Oldenburg, Oldenburg 26133, Germany; Recruiting
Hermann Mueller, MD, Phone: 49-441-403-2013, Email: mueller.hermann@klinikum-oldenburg.de

Klinik St. Hedwig-Kinderklinik, Regensburg 93049, Germany; Recruiting
Ove Peters, Phone: 49-941-369-5404

Kinderklinik - Universitaetsklinikum Rostock, Rostock D-18057, Germany; Recruiting
Carl Friedrich Classen, MD, PD, Phone: 49-381-494-0, Email: carl-friedrich.classen@med.uni-rostock.de

Kinderklink Siegen Deutsches Rotes Kreuz, Siegen D-57072, Germany; Recruiting
Rainer Burghard, MD, Phone: 49-271-2345-0, Email: rainer.burghard@drk-kinderklinik.de

Johanniter-Kinderklinik, St. Augustin 53757, Germany; Recruiting
Roswitha Dickerhoff, MD, Phone: 49-22-41-2491, Email: roswitha.dickerhoft@uni-bonn.de

Olgahospital, Stuttgart D-70176, Germany; Recruiting
Stefan Bielack, MD, Phone: 49-711-99-24-61, Email: st.bielack@olgahospital.de

Krankenanstalt Mutterhaus der Borromaerinnen, Trier D-54290, Germany; Recruiting
Wolfgang Rauh, MD, Phone: 49-651-947-2654

Universitaetsklinikum Tuebingen, Tuebingen D-72076, Germany; Recruiting
Rupert Handgretinger, MD, Phone: 49-7071-298-2087

Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm, Ulm D-89075, Germany; Recruiting
Klaus M. Debatin, MD, Phone: 49-731-5002-7790, Email: klaus-michael.debatin@medizin.uni-ulm.de

Universitaets - Kinderklinik Wuerzburg, Wuerzburg D-97080, Germany; Recruiting
P. G. Schlegel, MD, Phone: 49-931-201-27-831, Email: schlegel@mail.uni-wuerzburg.de

Helios Kliniken Wuppertal University Hospital, Wuppertal D-42283, Germany; Recruiting
K. Sinha, MD, Phone: 49-202-896-2441

Kantonsspital Aarau, Aarau CH-5001, Switzerland; Recruiting
R. Angst, Phone: 41-62-838-4906

Universitaets-Kinderspital beider Basel, Basel CH-4005, Switzerland; Recruiting
Thomas Kuhne, MD, Phone: 41-61-685-6565, Email: thomas.kuehne@ukbb.ch

Kinderspital Luzern, Lucerne 16 CH-6000, Switzerland; Recruiting
U. Caflisch, MD, Phone: 41-41-205-11-11

Ostschweizer Kinderspital, St. Gallen CH-9006, Switzerland; Recruiting
Jeanette Greiner, MD, Phone: 41-71-243-13-60, Email: jeanette.greiner@kispisg.ch

University Children's Hospital, Zurich CH-8032, Switzerland; Recruiting
Felix Niggli, MD, Phone: 41-44-266-7823

Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: January 2007
Last updated: July 15, 2015

Page last updated: August 23, 2015

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