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European Infant Neuroblastoma Study Final Protocol


Phase 3
N/A
1 Year
Open (Enrolling)
Both
Neuroblastoma

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Trial Information

European Infant Neuroblastoma Study Final Protocol


OBJECTIVES:

Primary

- Determine the outcome, in terms of survival and morbidity, in infants with localized,
unresectable, non-MYCN-amplified neuroblastoma treated with reduced-intensity
chemotherapy.

- Determine the survival of infants with stage 4S neuroblastoma, no MYCN amplification,
and no bone, CNS, or pleural/lung metastases treated with short-course intensive
chemotherapy.

- Determine the survival of infants with stage 4S neuroblastoma, no MYCN amplification,
and bone, CNS, or pleural/lung metastases not treated with intensive high-dose
chemotherapy consolidation.

- Determine the survival of infants with any stage (except stage 1) neuroblastoma and
MYCN amplification treated with intensive consolidation high-dose chemotherapy followed
by autologous bone marrow or stem cell support.

Secondary

- Correlate outcome with factors other than stage and MYCN status in infants with
neuroblastoma.

- Define the behavior of neuroblastoma in infants treated with these regimens.

- Determine prognostic criteria in infants treated with these regimens.

- Determine whether deletion of chromosome 1p or diploidy/tetraploidy are prognostic
factors in infants who do not have other adverse features, such as MYCN amplification.

OUTLINE: This is a nonrandomized, multicenter study. Patients are assigned to 1 of 4
treatment regimens according to disease criteria. Patients who are not eligible for any of
these regimens (stage 1 or resectable stage 2 disease) undergo surgical resection followed
by observation.

- Regimen NB 99.1 (unresectable stage 2 or 3): Patients are treated according to spinal
cord involvement and presence of neurological symptoms.

- Group I (no evidence of spinal cord involvement):

- CO therapy: Patients receive cyclophosphamide IV on days 1-5 and vincristine
IV on day 1. Treatment repeats every 14 days for up to 4 courses in the
absence of disease progression. Resectability is assessed after every 2
courses of chemotherapy; if tumor is resectable, then patients undergo
surgery followed by observation only. If, after 4 courses of CO, the tumor is
still not resectable or disease has progressed, then patients proceed to
VP-CARBO therapy.

- VP-CARBO therapy: Patients receive carboplatin IV over 1 hour and etoposide
phosphate IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2
courses. If the tumor is then deemed resectable, the patient undergoes
surgery. If the tumor is not resectable or disease has progressed, then
patients proceed to CADO therapy.

- CADO therapy: Patients receive cyclophosphamide IV over 1 hour on days 1-5,
doxorubicin hydrochloride IV over 6 hours on days 4 and 5, and vincristine IV
on days 1 and 5. Treatment repeats every 21 days for 2 courses. Patients then
proceed to resection or biopsy.

- Group II (dumbbell tumors, spinal cord compression symptoms or life-threatening
symptoms [e.g., respiratory obstruction]): Patients receive 2 courses of VP-CARBO
therapy. Patients who achieve a response proceed to surgery or biopsy if the
extraspinal portion is resectable. Patients with nonresponding disease or an
unresectable extraspinal portion of the tumor receive 2 courses of CADO therapy
and then undergo surgery or biopsy. Patients with dumbbell tumors but no spinal
cord compression symptoms are treated as in group I.

- Regimen NB 99.2 (stage 4S or stage 4 without bone, pleura/lung, or CNS metastases and
no MYCN amplification): Patients who do not have severe or life-threatening symptoms
are observed for spontaneous regression of disease. Patients with severe symptoms
receive 1 course of VP-CARBO therapy. Patients with a Philadelphia score ≥ 2 (or ≥ 1
for neonates [< 1 month old]) receive a second course of VP-CARBO therapy. If disease
does not respond to 2 courses of VP-CARBO therapy, patients receive up to 4 courses of
CADO therapy. Treatment ceases after response is obtained. Surgery is allowed but not
required.

- Regimen NB 99.3 (skeletal bone, pleural, and/or CNS metastases, no MYCN amplification):
Patients receive 2 courses of VP-CARBO therapy. Patients with responding disease
receive 2 more courses and then proceed to surgery (if possible). Patients with disease
progression or no response after the first 2 courses of VP-CARBO therapy and patients
who do not experience metastatic complete response (CR) after 4 courses of VP-CARBO
therapy receive up to 4 courses of CADO therapy. Patients proceed to surgery, if
possible, after 2-4 courses of CADO therapy.

- Regimen NB 99.4 (stages 2-4 disease with MYCN amplification): Patients receive 2
courses of VP-CARBO therapy followed by 2 courses of CADO therapy and then surgery (if
not already performed). Patients receive filgrastim (G-CSF) subcutaneously for 5 days
between the second course of CADO therapy and surgery. Patients also undergo collection
of their bone marrow or peripheral blood stem cells (PBSC). Patients who undergo
surgery receive 1 course of VP-CARBO therapy followed by 1 course of CADO therapy
postsurgery. At least 3 weeks after the third course of CADO therapy, patients receive
high-dose chemotherapy comprising busulfan every 6 hours on days -7 to -3 and melphalan
IV on day -2 followed by autologous bone marrow or PBSC infusion on day 0. At least 2
months later, patients undergo radiotherapy to the primary tumor site, even if complete
surgical resection has been accomplished. Patients with stage 4 disease who do not
achieve metastatic CR after chemotherapy (before surgery) go off study.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 330 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed neuroblastoma or ganglioblastoma

- Newly diagnosed disease

- MYCN status known

- Patients are assigned to different study treatment regimens* according to the
following disease criteria:

- Regimen NB 99.1

- Localized unresectable tumor

- If open surgery is considered too hazardous due to the site of the
tumor or condition of the infant, then cytological confirmation is
allowed, provided adequate material is obtained for study procedures

- No MYCN amplification (i.e., < 10 copies)

- No metastatic deposits in the bone marrow

- No MIBG or technetium uptake or radiological bone lesions in the skeleton

- No liver disease by ultrasound

- Regimen NB 99.2

- Stage 4 or 4S with metastases confined to the skin, marrow, nodes, or liver

- No bone involvement by radiographs

- No pleural or lung involvement

- No CNS involvement

- No MYCN amplification (i.e., < 10 copies)

- Regimen NB 99.3

- Stage 4 disease, metastases must meet ≥ 1 of the following criteria:

- Skeletal bone metastases by plain x-ray or CT scan

- Pleural or lung metastases

- CNS involvement

- No MYCN amplification (i.e., < 10 copies)

- Regimen NB 99.4

- Stage 2-4 disease

- MYCN amplification (i.e., ≥ 10 copies) NOTE: *Patients with stage 1 or
resectable stage 2 disease with no MYCN amplification ( i.e., < 10 copies)
are not eligible for a study treatment regimen but may be enrolled on the
study for observation only

PATIENT CHARACTERISTICS:

- Not specified

PRIOR CONCURRENT THERAPY:

- No prior therapy

Type of Study:

Interventional

Study Design:

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

Principal Investigator

Mary P. Gerrard, MBChB, FRCP, FRCPCH

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital - Sheffield

Authority:

United States: Federal Government

Study ID:

CDR0000454507

NCT ID:

NCT00417053

Start Date:

Completion Date:

Related Keywords:

  • Neuroblastoma
  • disseminated neuroblastoma
  • localized resectable neuroblastoma
  • localized unresectable neuroblastoma
  • regional neuroblastoma
  • stage 4S neuroblastoma
  • Neuroblastoma

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