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

Neuroblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00526318
• Other study ID #: GPOH-NB2004-HR
• Secondary ID: CDR0000564820UNI
• Status: Recruiting
• Phase: N/A
• First received: September 5, 2007
• Last updated: July 15, 2015
• Start date: January 2007

Study information

• Verified date: July 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 360
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

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

Study Design

Allocation: Randomized, 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

Radiation:
• iobenguane I 131

• radiation therapy

Locations

Country	Name	City	State
Germany	Kinderklinik - Universitaetsklinikum Aachen	Aachen
Germany	Klinikum Augsburg	Augsburg
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	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Klinikum Coburg	Coburg
Germany	Children's Hospital	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	Universitaetsklinikum 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	Medizinische Hochschule Hannover	Hannover
Germany	Universitaets-Kinderklinik Heidelberg	Heidelberg
Germany	Gemeinschaftskrankenhaus	Herdecke
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Universitaets - Kinderklinik	Jena
Germany	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe
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	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg
Germany	Johannes Gutenberg University	Mainz
Germany	Staedtisches Klinik - Kinderklinik	Mannheim
Germany	Universitaetsklinikum Giessen und Marburg GmbH - Marburg	Marburg
Germany	Klinikum Minden	Minden
Germany	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster	Muenster
Germany	Dr. von Haunersches Kinderspital der Universitaet Muenchen	Munich
Germany	Krankenhaus Muenchen Schwabing	Munich
Germany	Klinikum Neubrandenburg	Neubrandenburg
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	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm
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
Secondary	Overall survival (OS)			No
Secondary	Impact of well established clinical and molecular risk factors on EFS and OS			No
Secondary	Early response, measured after 2 courses of induction chemotherapy			No
Secondary	Response to induction therapy, measured before autologous stem cell transplantation			No
Secondary	Toxicity during the first 2 courses and the last 6 courses of induction chemotherapy			Yes
Secondary	Impact of the extent of initial and best surgery on outcome and frequency of complications			No
Secondary	Acute and late toxicity of radiotherapy			Yes
Secondary	Correlation of MIBG activity with whole-body radiation dose			No
Secondary	Molecular markers (MYCN and status of chromosome 1p and 11q)			No