Trial Information

Neuroblastoma Study Phase II Study of Various Therapies in Patients With Neuroblastoma

OBJECTIVES:

- Determine the frequency of spontaneous remission in pediatric patients with localized
neuroblastoma.

- Determine the course of regression in patients with spontaneous remission.

- Determine the event-free survival rate of patients with high-risk neuroblastoma treated
with maintenance chemotherapy OR consolidation chemotherapy followed by autologous stem
cell rescue.

- Determine if a correlation exists between long-term overall survival and catecholamine
response in these high-risk patients.

- Determine if a correlation exists between cytotoxic and conditioning chemotherapies, in
terms of bone marrow toxicity, in these high-risk patients.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (low vs
standard vs high).

- Observation stratum (low risk): Patients undergo surgical biopsy followed by
observation for 6-12 months. Patients may also undergo second-look surgery. Patients
with tumor regression receive no further therapy. Patients with disease progression or
no tumor regression receive standard-risk chemotherapy as in the standard-risk stratum.

- Standard-risk stratum: Patients undergo surgical biopsy. Patients at least 6 months of
age receive 1 course of chemotherapy comprising cisplatin IV and etoposide IV
continuously on days 1-4 and vindesine IV over 1 hour on day 1. Patients then receive 1
course of chemotherapy comprising vincristine IV over 1 hour on days 1 and 8,
dacarbazine IV over 1 hour on days 1-5, ifosfamide IV continuously on days 1-5, and
doxorubicin IV over 4 hours on days 6 and 7.

Patients under 6 months of age receive doxorubicin IV over 30 minutes and vincristine IV on
days 1, 3, and 5 and cyclophosphamide IV over 5 minutes on days 1-7. Treatment repeats every
3 weeks for 2 courses in the absence of unacceptable toxicity.

After chemotherapy, patients may undergo second-look surgery followed by 2 additional
courses of chemotherapy as above. Patients with complete response or very good partial
response receive no further therapy. Patients with partial response, minimal response, no
response, or progressive disease undergo local radiotherapy daily 5 days a week for
approximately 6 weeks. Patients with no response after radiotherapy may then receive therapy
as in the high-risk stratum.

- High-risk stratum: Patients undergo surgical biopsy. Patients at least 6 months of age
receive induction chemotherapy comprising cisplatin, etoposide, and vindesine as in the
standard-risk stratum combined with filgrastim (G-CSF) subcutaneously (SC) daily
beginning on day 8 and continuing until blood counts recover. Patients also receive
alternating courses of vincristine, dacarbazine, ifosfamide, and doxorubicin as in the
standard-risk stratum combined with G-CSF SC daily beginning on day 9 and continuing
until blood counts recover. Treatment repeats every 3 weeks for up to 6 courses in the
absence of unacceptable toxicity.

Patients under 6 months of age receive 2 courses of induction chemotherapy as in the
standard-risk stratum followed by 4 courses of alternating chemotherapy as above.

Patients may also undergo second-look surgery.

Patients then receive consolidation chemotherapy comprising melphalan IV over 30 minutes on
days -8 to -5, etoposide IV over 4 hours on day -4, and carboplatin IV over 1 hour on days
-4 to -2. Patients undergo autologous stem cell transplantation (ASCT) on day 0. Patients
also receive G-CSF SC or IV over 2 hours daily beginning on day 0. Patients may then undergo
radiotherapy daily 5 days a week for 6 weeks.

Patients who were diagnosed less than 1 year ago and who do not demonstrate MYCN amplication
receive maintenance chemotherapy comprising oral cyclophosphamide on days 1-8 (instead of
consolidation chemotherapy and ASCT as above). Treatment repeats every 3 weeks for 4
courses.

Beginning 4-6 weeks after transplantation or 4 weeks after initiation of the last course of
maintenance chemotherapy, all patients receive consolidation therapy with oral tretinoin 3
times daily on days 1-14. Treatment repeats every 28 days for 6 courses followed by a
3-month rest. Patients then receive 3 additional courses.

Patients are followed at 6 weeks, every 3 months for 5 years, and then every 6 months
thereafter.

PROJECTED ACCRUAL: Approximately 130 patients (50 in high-risk stratum, 15 in standard-risk
stratum, and 65 in observation stratum) will be accrued for this study within 1 year.