Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00004799

Trial Description

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Title

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

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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.

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Organizational Data

  •   DRKS00004799
  •   2013/04/24
  •   2007/09/05
  •   yes
  •   [---]*
  •   [---]*
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Secondary IDs

  •   NCT00526318  (ClinicalTrials.gov)
  •   GPOH-NB2004-HR  (Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany)
  •   UNI-KOELN-161 
  •   EU-20661 
  •   CDR0000564820 
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Health Condition or Problem studied

  •   Neuroblastoma
  •   C74 -  Malignant neoplasm of adrenal gland
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Interventions/Observational Groups

  •   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
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
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  •   Treatment
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  •   N/A
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Primary Outcome

- Event-free survival (EFS)

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Secondary Outcome

- 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)

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Countries of Recruitment

  •   Germany
  •   Switzerland
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Locations of Recruitment

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Recruitment

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  •   2007/01/31
  •   360
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   21   Years
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Additional Inclusion 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

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Exclusion Criteria

[---]*

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Addresses

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    • Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany
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    • Children's Hospital Medical Center, Cincinnati
    • Frank Berthold, MD 
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    • Children's Hospital Medical Center, Cincinnati
    • Frank Berthold, MD 
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Sources of Monetary or Material Support

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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   4
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.