Clinical trial NCT00526318: Combination Chemotherapy Followed by Stem Cell Transplant and Isotretinoin in Treating Young Patients With High-Risk Neuroblastoma
Official title: Trial Protocol for the Treatment of Children With High Risk Neuroblastoma (NB2004-HR)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Neuroblastoma
Keywords: localized resectable neuroblastoma
localized unresectable neuroblastoma
regional neuroblastoma
stage 4S neuroblastoma
disseminated neuroblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2007-09-10
Enrollment: 360
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Event-free survival (EFS)
Secondary outcomes:
measure: Overall survival (OS)
measure: Impact of well established clinical and molecular risk factors on EFS and OS
measure: Early response, measured after 2 courses of induction chemotherapy
measure: Response to induction therapy, measured before autologous stem cell transplantation
measure: Toxicity during the first 2 courses and the last 6 courses of induction chemotherapy
measure: Impact of the extent of initial and best surgery on outcome and frequency of complications
measure: Acute and late toxicity of radiotherapy
measure: Correlation of MIBG activity with whole-body radiation dose
measure: Molecular markers (MYCN and status of chromosome 1p and 11q)
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Kinderklinik - Universitaetsklinikum Aachen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Biefeld
country: Germany
facility: Evangelisches Krankenhauus Bielfeld
city: Bonn
country: Germany
facility: Kinderklinik der Universitaet Bonn
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum - Howedestrase
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Coburg
country: Germany
facility: Klinikum Coburg
city: Cologne
country: Germany
facility: Children's Hospital
city: Cottbus
country: Germany
facility: Carl - Thiem - Klinkum Cottbus
city: Datteln
country: Germany
facility: Vestische Kinderklinik
city: Detmold
country: Germany
facility: Klinikum Lippe - Detmold
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Duesseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Duisburg
country: Germany
facility: Klinikum Duisburg
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erlangen
country: Germany
facility: Universitaets - Kinderklinik
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetskinderklinik - Universitaetsklinikum Freiburg
city: Giessen
country: Germany
facility: Kinderklinik
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greiswald
country: Germany
facility: Universitats - Kinderklinik
city: Halle
country: Germany
facility: Universitaetsklinikum Halle
city: Halle
country: Germany
facility: Krankenhaus St. Elisabeth und St. Barbara
city: Hamburg
country: Germany
facility: University Medical Center Hamburg - Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitaets-Kinderklinik Heidelberg
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitaets - Kinderklinik
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Koblenz
country: Germany
facility: Klinikum Kemperhof Koblenz
city: Krefeld
country: Germany
facility: Klinikum Krefeld GmbH
city: Ludwigshafen
country: Germany
facility: St. Annastift Krankenhaus
city: Luebeck
country: Germany
facility: Universitaets - Kinderklinik - Luebeck
city: Magdeburg
country: Germany
facility: Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
city: Mainz
country: Germany
facility: Johannes Gutenberg University
city: Mannheim
country: Germany
facility: Staedtisches Klinik - Kinderklinik
city: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH - Marburg
city: Minden
country: Germany
facility: Klinikum Minden
city: Muenster
country: Germany
facility: Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Krankenhaus Muenchen Schwabing
city: Munich
country: Germany
facility: Dr. von Haunersches Kinderspital der Universitaet Muenchen
city: Neubrandenburg
country: Germany
facility: Klinikum Neubrandenburg
city: Nuremberg
country: Germany
facility: Cnopf'sche Kinderklinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Regensburg
country: Germany
facility: Klinik St. Hedwig-Kinderklinik
city: Rostock
country: Germany
facility: Kinderklinik - Universitaetsklinikum Rostock
city: Siegen
country: Germany
facility: Kinderklink Siegen Deutsches Rotes Kreuz
city: St. Augustin
country: Germany
facility: Johanniter-Kinderklinik
city: Stuttgart
country: Germany
facility: Olgahospital
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Wuppertal
country: Germany
facility: Helios Kliniken Wuppertal University Hospital
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitaets-Kinderspital beider Basel
city: Lucerne 16
country: Switzerland
facility: Kinderspital Luzern
city: St. Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Zurich
country: Switzerland
facility: University Children's Hospital
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Frank Berthold, MD
role: STUDY_CHAIR
References: