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

Sponsor

Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany (Other)

Overall Status

Unknown status

CT.gov ID

NCT00526318

Collaborator

(none)

360

Enrollment

Locations

5.3

Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Biological: filgrastim Drug: 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 Procedure: autologous hematopoietic stem cell transplantation Radiation: iobenguane I 131 Radiation: radiation therapy	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

360 participants

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2007

Anticipated Primary Completion Date :

Dec 1, 2016

Outcome Measures

Primary Outcome Measures

Event-free survival (EFS) []

Secondary Outcome Measures

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) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

PATIENT CHARACTERISTICS:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Kinderklinik - Universitaetsklinikum Aachen	Aachen	Germany	D-52074
2	Klinikum Augsburg	Augsburg	Germany	DOH-86156
3	Klinikum Bayreuth	Bayreuth	Germany	D-95445
4	Helios Klinikum Berlin	Berlin	Germany	13125
5	Charite University Hospital - Campus Virchow Klinikum	Berlin	Germany	D-13353
6	Evangelisches Krankenhauus Bielfeld	Biefeld	Germany	33617
7	Kinderklinik der Universitaet Bonn	Bonn	Germany	D-53113
8	Staedtisches Klinikum - Howedestrase	Braunschweig	Germany	38118
9	Klinikum Bremen-Mitte	Bremen	Germany	D-28205
10	Klinikum Chemnitz gGmbH	Chemnitz	Germany	D-09116
11	Klinikum Coburg	Coburg	Germany	96450
12	Children's Hospital	Cologne	Germany	D-50924
13	Carl - Thiem - Klinkum Cottbus	Cottbus	Germany	D-03048
14	Vestische Kinderklinik	Datteln	Germany	45704
15	Klinikum Lippe - Detmold	Detmold	Germany	D-32756
16	Klinikum Dortmund	Dortmund	Germany	D-44137
17	Universitatsklinikum Carl Gustav Carus	Dresden	Germany	D-01307
18	Universitaetsklinikum Duesseldorf	Duesseldorf	Germany	D-40225
19	Klinikum Duisburg	Duisburg	Germany	D-47055
20	Helios Klinikum Erfurt	Erfurt	Germany	99089
21	Universitaets - Kinderklinik	Erlangen	Germany	91054
22	Universitaetsklinikum Essen	Essen	Germany	D-45147
23	Klinikum der J.W. Goethe Universitaet	Frankfurt	Germany	D-60590
24	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
25	Kinderklinik	Giessen	Germany	D-35385
26	Universitaetsklinikum Goettingen	Goettingen	Germany	D-37075
27	Universitats - Kinderklinik	Greiswald	Germany	17487
28	Universitaetsklinikum Halle	Halle	Germany	D-06097
29	Krankenhaus St. Elisabeth und St. Barbara	Halle	Germany	D-06110
30	University Medical Center Hamburg - Eppendorf	Hamburg	Germany	D-20246
31	Medizinische Hochschule Hannover	Hannover	Germany	D-30625
32	Universitaets-Kinderklinik Heidelberg	Heidelberg	Germany	D-69120
33	Gemeinschaftskrankenhaus	Herdecke	Germany	58313
34	Universitaetsklinikum des Saarlandes	Homburg	Germany	66421
35	Universitaets - Kinderklinik	Jena	Germany	D-07745
36	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe	Germany	76133
37	Klinikum Kassel	Kassel	Germany	D-34125
38	University Hospital Schleswig-Holstein - Kiel Campus	Kiel	Germany	D-24105
39	Klinikum Kemperhof Koblenz	Koblenz	Germany	D-56065
40	Klinikum Krefeld GmbH	Krefeld	Germany	D-47805
41	St. Annastift Krankenhaus	Ludwigshafen	Germany	67065
42	Universitaets - Kinderklinik - Luebeck	Luebeck	Germany	D-23538
43	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg	Germany	D-39120
44	Johannes Gutenberg University	Mainz	Germany	D-55101
45	Staedtisches Klinik - Kinderklinik	Mannheim	Germany	D-68167
46	Universitaetsklinikum Giessen und Marburg GmbH - Marburg	Marburg	Germany	D-35043
47	Klinikum Minden	Minden	Germany	D-32423
48	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster	Muenster	Germany	D-48149
49	Krankenhaus Muenchen Schwabing	Munich	Germany	80804
50	Dr. von Haunersches Kinderspital der Universitaet Muenchen	Munich	Germany	D-80337
51	Klinikum Neubrandenburg	Neubrandenburg	Germany	17036
52	Cnopf'sche Kinderklinik	Nuremberg	Germany	90419
53	Klinikum Oldenburg	Oldenburg	Germany	26133
54	Klinik St. Hedwig-Kinderklinik	Regensburg	Germany	93049
55	Kinderklinik - Universitaetsklinikum Rostock	Rostock	Germany	D-18057
56	Kinderklink Siegen Deutsches Rotes Kreuz	Siegen	Germany	D-57072
57	Johanniter-Kinderklinik	St. Augustin	Germany	53757
58	Olgahospital	Stuttgart	Germany	D-70176
59	Krankenanstalt Mutterhaus der Borromaerinnen	Trier	Germany	D-54290
60	Universitaetsklinikum Tuebingen	Tuebingen	Germany	D-72076
61	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm	Germany	D-89075
62	Universitaets - Kinderklinik Wuerzburg	Wuerzburg	Germany	D-97080
63	Helios Kliniken Wuppertal University Hospital	Wuppertal	Germany	D-42283
64	Kantonsspital Aarau	Aarau	Switzerland	CH-5001
65	Universitaets-Kinderspital beider Basel	Basel	Switzerland	CH-4005
66	Kinderspital Luzern	Lucerne 16	Switzerland	CH-6000
67	Ostschweizer Kinderspital	St. Gallen	Switzerland	CH-9006
68	University Children's Hospital	Zurich	Switzerland	CH-8032