Observation, Combination Chemotherapy, Radiation Therapy, and/or Autologous Stem Cell Transplant in Treating Young Patients With Neuroblastoma

Sponsor

Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany (Other)

Overall Status

Unknown status

CT.gov ID

NCT00410631

Collaborator

(none)

642

Enrollment

Locations

Patients Per Site

Study Details

Study Description

Brief 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. 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.

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 Procedure: conventional surgery Procedure: peripheral blood stem cell transplantation Radiation: iobenguane I 131 Radiation: radiation therapy	Phase 3

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

Study Type:

Interventional

Anticipated Enrollment :

642 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma

Study Start Date :

Oct 1, 2004

Anticipated Primary Completion Date :

Dec 1, 2010

Outcome Measures

Primary Outcome Measures

Event-free survival (EFS) []
Locoregional EFS []

Secondary Outcome Measures

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 []

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 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

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 am Bamberg	Bamberg	Germany	96049
4	Klinikum Bayreuth	Bayreuth	Germany	D-95445
5	Helios Klinikum Berlin	Berlin	Germany	D-13125
6	Charite University Hospital - Campus Virchow Klinikum	Berlin	Germany	D-13353
7	Evangelisches Krankenhauus Bielfeld	Biefeld	Germany	33617
8	Kinderklinik der Universitaet Bonn	Bonn	Germany	D-53113
9	Staedtisches Klinikum - Howedestrase	Braunschweig	Germany	38118
10	Klinikum Bremen-Mitte	Bremen	Germany	D-28205
11	Allgemeinen Krankenhaus Celle Kinderklinik	Celle	Germany	29223
12	Klinikum Chemnitz gGmbH	Chemnitz	Germany	D-09116
13	Klinikum Coburg	Coburg	Germany	96450
14	Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl	Cologne	Germany	D-50735
15	Children's Hospital	Cologne	Germany	D-50924
16	Carl - Thiem - Klinkum Cottbus	Cottbus	Germany	D-03048
17	Vestische Kinderklinik	Datteln	Germany	45704
18	Klinikum Lippe - Detmold	Detmold	Germany	D-32756
19	Klinikum Dortmund	Dortmund	Germany	D-44137
20	Universitatsklinikum Carl Gustav Carus	Dresden	Germany	D-01307
21	Universitaets - Frauenklinik, Duesseldorf	Duesseldorf	Germany	D-40225
22	Klinikum Duisburg	Duisburg	Germany	D-47055
23	Helios Klinikum Erfurt	Erfurt	Germany	99089
24	Universitaets - Kinderklinik	Erlangen	Germany	91054
25	Universitaetsklinikum Essen	Essen	Germany	D-45147
26	Klinikum der J.W. Goethe Universitaet	Frankfurt	Germany	D-60590
27	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
28	Kinderklinik	Giessen	Germany	D-35385
29	Universitaetsklinikum Goettingen	Goettingen	Germany	D-37075
30	Universitats - Kinderklinik	Greiswald	Germany	17487
31	Universitaetsklinikum Halle	Halle	Germany	D-06097
32	Krankenhaus St. Elisabeth und St. Barbara	Halle	Germany	D-06110
33	University Medical Center Hamburg - Eppendorf	Hamburg	Germany	D-20246
34	Kinderkrankenhaus auf der Bult	Hannover	Germany	30173
35	Medizinische Hochschule Hannover	Hannover	Germany	D-30625
36	Universitaets-Kinderklinik Heidelberg	Heidelberg	Germany	D-69120
37	SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen	Heilbronn	Germany	D-74064
38	Gemeinschaftskrankenhaus	Herdecke	Germany	58313
39	Universitaetsklinikum des Saarlandes	Homburg	Germany	66421
40	Universitaets - Kinderklinik	Jena	Germany	D-07440
41	Universitaets - Kinderklinik	Jena	Germany	D-07745
42	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe	Germany	76133
43	Kinderkrankenhaus Park Schoenfeld	Kassel	Germany	D-34121
44	Klinikum Kassel	Kassel	Germany	D-34125
45	University Hospital Schleswig-Holstein - Kiel Campus	Kiel	Germany	D-24105
46	Klinikum Kemperhof Koblenz	Koblenz	Germany	D-56065
47	Klinikum Krefeld GmbH	Krefeld	Germany	D-47805
48	St. Annastift Krankenhaus	Ludwigshafen	Germany	67065
49	Universitaets - Kinderklinik - Luebeck	Luebeck	Germany	D-23538
50	Universitatsklinikum der MA	Magdeburg	Germany	39120
51	Johannes Gutenberg University	Mainz	Germany	D-55101
52	Staedtisches Klinik - Kinderklinik	Mannheim	Germany	D-68167
53	Universitaets - Kinderklinik	Marburg	Germany	35033
54	Klinikum Minden	Minden	Germany	D-32423
55	University of Muenster	Muenster	Germany	D-48129
56	Krankenhaus Muenchen Schwabing	Munich	Germany	80804
57	Dr. von Haunersches Kinderspital der Universitaet Muenchen	Munich	Germany	D-80337
58	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich	Germany	D-81377
59	Staedtisches Krankenhaus Muenchen - Harlaching	Munich	Germany	D-81545
60	Klinikum Neubrandenburg	Neubrandenburg	Germany	17036
61	Kinderklinik Kohlhof	Neunkirchen	Germany	D-66539
62	Cnopf'sche Kinderklinik	Nuremberg	Germany	90419
63	Klinikum Oldenburg	Oldenburg	Germany	26133
64	Klinik St. Hedwig-Kinderklinik	Regensburg	Germany	93049
65	Kinderklinik - Universitaetsklinikum Rostock	Rostock	Germany	D-18057
66	Kinderklink Siegen Deutsches Rotes Kreuz	Siegen	Germany	D-57072
67	Johanniter-Kinderklinik	St. Augustin	Germany	53757
68	Olgahospital	Stuttgart	Germany	D-70176
69	Krankenanstalt Mutterhaus der Borromaerinnen	Trier	Germany	D-54290
70	Universitaets-Kinderklinik	Tuebingen	Germany	D-72070
71	Universitaetsklinikum Tuebingen	Tuebingen	Germany	D-72076
72	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm	Germany	D-89075
73	Reinhard-Nieter-Krankenhaus	Wilhelmshaven	Germany	D-26389
74	Universitaets - Kinderklinik Wuerzburg	Wuerzburg	Germany	D-97080
75	Helios Kliniken Wuppertal University Hospital	Wuppertal	Germany	D-42283
76	Kantonsspital Aarau	Aarau	Switzerland	CH-5001
77	Universitaets-Kinderspital beider Basel	Basel	Switzerland	CH-4005
78	Kinderspital Luzern	Lucerne 16	Switzerland	CH-6000
79	Ostschweizer Kinderspital	St. Gallen	Switzerland	CH-9006
80	University Children's Hospital	Zurich	Switzerland	CH-8032