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NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma


Phase 3
N/A
21 Years
Open (Enrolling)
Both
Neuroblastoma

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Trial Information

NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Event-free survival (EFS)

Safety Issue:

No

Principal Investigator

Frank Berthold, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital Medical Center, Cincinnati

Authority:

Unspecified

Study ID:

CDR0000517312

NCT ID:

NCT00410631

Start Date:

October 2004

Completion Date:

Related Keywords:

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

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