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

Neuroblastoma Clinical Trial

Official title:

NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00410631
• Other study ID #: GPOH-NB2004
• Secondary ID: CDR0000517312EU-
• Status: Recruiting
• Phase: Phase 3
• First received: December 11, 2006
• Last updated: August 6, 2013
• Start date: October 2004

Study information

• Verified date: January 2008
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 642
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

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

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neuroblastoma

Intervention

Biological:
• filgrastim

Drug:
• carboplatin

• cisplatin

• cyclophosphamide

• dacarbazine

• doxorubicin hydrochloride

• etoposide phosphate

• ifosfamide

• isotretinoin

• melphalan

• topotecan hydrochloride

• vincristine sulfate

• vindesine

Procedure:
• autologous hematopoietic stem cell transplantation

• conventional surgery

• peripheral blood stem cell transplantation

Radiation:
• iobenguane I 131

• radiation therapy

Locations

Country	Name	City	State
Germany	Kinderklinik - Universitaetsklinikum Aachen	Aachen
Germany	Klinikum Augsburg	Augsburg
Germany	Klinikum am Bamberg	Bamberg
Germany	Klinikum Bayreuth	Bayreuth
Germany	Charite University Hospital - Campus Virchow Klinikum	Berlin
Germany	Helios Klinikum Berlin	Berlin
Germany	Evangelisches Krankenhauus Bielfeld	Biefeld
Germany	Kinderklinik der Universitaet Bonn	Bonn
Germany	Staedtisches Klinikum - Howedestrase	Braunschweig
Germany	Klinikum Bremen-Mitte	Bremen
Germany	Allgemeinen Krankenhaus Celle Kinderklinik	Celle
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Klinikum Coburg	Coburg
Germany	Children's Hospital	Cologne
Germany	Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl	Cologne
Germany	Carl - Thiem - Klinkum Cottbus	Cottbus
Germany	Vestische Kinderklinik	Datteln
Germany	Klinikum Lippe - Detmold	Detmold
Germany	Klinikum Dortmund	Dortmund
Germany	Universitatsklinikum Carl Gustav Carus	Dresden
Germany	Universitaets - Frauenklinik, Duesseldorf	Duesseldorf
Germany	Klinikum Duisburg	Duisburg
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Universitaets - Kinderklinik	Erlangen
Germany	Universitaetsklinikum Essen	Essen
Germany	Klinikum der J.W. Goethe Universitaet	Frankfurt
Germany	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg
Germany	Kinderklinik	Giessen
Germany	Universitaetsklinikum Goettingen	Goettingen
Germany	Universitats - Kinderklinik	Greiswald
Germany	Krankenhaus St. Elisabeth und St. Barbara	Halle
Germany	Universitaetsklinikum Halle	Halle
Germany	University Medical Center Hamburg - Eppendorf	Hamburg
Germany	Kinderkrankenhaus auf der Bult	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitaets-Kinderklinik Heidelberg	Heidelberg
Germany	SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen	Heilbronn
Germany	Gemeinschaftskrankenhaus	Herdecke
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Universitaets - Kinderklinik	Jena
Germany	Universitaets - Kinderklinik	Jena
Germany	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe
Germany	Kinderkrankenhaus Park Schoenfeld	Kassel
Germany	Klinikum Kassel	Kassel
Germany	University Hospital Schleswig-Holstein - Kiel Campus	Kiel
Germany	Klinikum Kemperhof Koblenz	Koblenz
Germany	Klinikum Krefeld GmbH	Krefeld
Germany	St. Annastift Krankenhaus	Ludwigshafen
Germany	Universitaets - Kinderklinik - Luebeck	Luebeck
Germany	Universitatsklinikum der MA	Magdeburg
Germany	Johannes Gutenberg University	Mainz
Germany	Staedtisches Klinik - Kinderklinik	Mannheim
Germany	Universitaets - Kinderklinik	Marburg
Germany	Klinikum Minden	Minden
Germany	University of Muenster	Muenster
Germany	Dr. von Haunersches Kinderspital der Universitaet Muenchen	Munich
Germany	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich
Germany	Krankenhaus Muenchen Schwabing	Munich
Germany	Staedtisches Krankenhaus Muenchen - Harlaching	Munich
Germany	Klinikum Neubrandenburg	Neubrandenburg
Germany	Kinderklinik Kohlhof	Neunkirchen
Germany	Cnopf'sche Kinderklinik	Nuremberg
Germany	Klinikum Oldenburg	Oldenburg
Germany	Klinik St. Hedwig-Kinderklinik	Regensburg
Germany	Kinderklinik - Universitaetsklinikum Rostock	Rostock
Germany	Kinderklink Siegen Deutsches Rotes Kreuz	Siegen
Germany	Johanniter-Kinderklinik	St. Augustin
Germany	Olgahospital	Stuttgart
Germany	Krankenanstalt Mutterhaus der Borromaerinnen	Trier
Germany	Universitaets-Kinderklinik	Tuebingen
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm
Germany	Reinhard-Nieter-Krankenhaus	Wilhelmshaven
Germany	Universitaets - Kinderklinik Wuerzburg	Wuerzburg
Germany	Helios Kliniken Wuppertal University Hospital	Wuppertal
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitaets-Kinderspital beider Basel	Basel
Switzerland	Kinderspital Luzern	Lucerne 16
Switzerland	Ostschweizer Kinderspital	St. Gallen
Switzerland	University Children's Hospital	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany

Countries where clinical trial is conducted

Germany,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival (EFS)			No
Primary	Locoregional EFS			No
Secondary	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)			No
Secondary	Overall survival			No
Secondary	Time to the beginning of primary tumor regression (in patients in the low-risk group [LRG])			No
Secondary	Time to the normalization of tumor markers HVA and VMA in urine			No
Secondary	Time to no evidence of disease (in patients in the LRG with stage 4S disease)			No
Secondary	Status of the primary tumor 12 months after diagnosis (LRG)			No
Secondary	Best status of the primary tumor within the first 12 months (LRG)			No
Secondary	Status of chromosome 1p (unblinded) and status of chromosome 11q (blinded)			No
Secondary	Comparison of the extent of initial surgery (incomplete resection vs macroscopic complete resection) (LRG)			No
Secondary	Comparison of the extent of best surgery during protocol treatment (incomplete resection vs macroscopic complete resection)			No
Secondary	Surgery-related complications (i.e., bleeding, infection, intestinal obstruction, or other)			No
Secondary	Disease progression and symptoms controlled after the first, second, third, and fourth N4 course (LRG)			No
Secondary	Disease progression and symptoms not controlled after four N4 courses (LRG)			No
Secondary	Transition to stage 4 disease at any time (LRG)			No
Secondary	Acute and late side effects of external-beam radiotherapy (medium-risk group [MRG] and high-risk group [HRG])			Yes
Secondary	Early response after 2 courses of induction therapy (N5 and N6 or two courses of N8) (HRG)			No
Secondary	Response to induction therapy prior to conditioning therapy or after 280 days (HRG)			No
Secondary	Grade of toxicity observed during induction therapy course 1 (N5 or N8) (HRG)			Yes
Secondary	Grade of toxicity observed during induction therapy course 2 (N6 or N8) (HRG)			Yes
Secondary	Frequency of grade 3 or 4 toxicity observed during the last 6 courses of induction therapy (3 courses of N5 and N6) (HRG)			Yes
Secondary	Activity and whole body dose of radiotherapy			No