Trial Information

N8: Dose-Intensive Chemotherapy Plus Biologics in the Treatment of Neuroblastoma

OBJECTIVES:

- Determine whether treatment with multimodality therapy comprising dose-intensive
induction chemotherapy, monoclonal antibody 3F8, surgery, myeloablative chemotherapy,
autologous or syngeneic bone marrow or peripheral blood stem cell transplantation,
radiotherapy, and isotretinoin improves the cure rate in patients with advanced
neuroblastoma.

- Determine whether the 2-year progression-free survival (PFS) rate improves to 70% in
patients with newly diagnosed advanced neuroblastoma treated with this regimen.

- Determine whether the 2-year PFS rate improves to 40% in patients with previously
treated advanced neuroblastoma treated with this regimen.

- Determine the biologic and clinical prognostic factors of neuroblastoma that may guide
future research of treatment approaches for this malignancy.

OUTLINE: Patients are stratified according to the following:

- Stratum 1: Patients with previously untreated stage IV disease who are over age 1 at
diagnosis, with or without N-myc amplification

- Stratum 2: Patients with previously treated stage IV disease who are over age 1 at
diagnosis; or patients with previously treated high-risk disease (e.g., N-myc amplified
stage III or IV disease, under age 1 at diagnosis, and with or without prior treatment)

- Intensive induction therapy (courses 1-5): During courses 1, 2, and 4, patients receive
cyclophosphamide IV over 6 hours on days 1 and 2 and doxorubicin and vincristine IV
continuously on days 1-3. Courses repeat every 21 days. During courses 3 and 5,
patients receive etoposide (VP-16) IV over 2 hours on days 1-3 and cisplatin IV over 1
hour on days 1-4. Courses repeat every 35 days. Before proceeding to myeloablative
therapy/transplantation, patients in stratum 2 must have received a minimum of 2
courses of chemotherapy if they achieved a complete response (CR) or very good partial
response (VGPR) or patients must have received a minimum of 3 courses of chemotherapy
if they achieved less than a CR or VGPR.

Patients undergo tumor resection either at diagnosis or after completion of a minimum of 3
courses of chemotherapy (approximately day 63).

Treatment with monoclonal antibody 3F8 (MOAB 3F8) starts after completion of course 3 of
intensive induction chemotherapy, preferably after surgical resection or debulking of the
primary tumor. Patients receive MOAB 3F8 IV over 90 minutes on days 1-5 of courses 3-5 and
on days 1-5 immediately prior to transplantation.

- Harvest: Autologous or syngeneic bone marrow or peripheral blood stem cells (PBSC) are
harvested. Patients undergoing PBSC collection receive filgrastim (G-CSF) beginning 2-3
days prior to collection and continuing through the end of collection. For patients
without bone marrow involvement at diagnosis, autologous bone marrow or PBSC are
harvested after completion of 1-2 courses of induction therapy. For patients with bone
marrow involvement at diagnosis, bone marrow or PBSC are harvested after completion of
4 courses of induction therapy, surgery, and completion of 1 course of MOAB 3F8, if
bone marrow is in remission. If a patient's bone marrow/PBSC cannot be collected or
harvested after completion of induction therapy because of hypoplasia or persistent
tumor, bone marrow/PBSC collected or harvested before starting protocol or syngeneic
bone marrow/PBSC may be used. If neither of these options is available, patients who do
not clear marrow by course 5 have the option of proceeding directly to the
posttransplantation therapy phase below, while delaying transplantation until bone
marrow is clear.

- Myeloablative therapy/transplantation: Patients receive thiotepa IV over 3 hours on
days -8 to -6, topotecan IV over 30 minutes on days -8 to -4, and carboplatin IV over 4
hours on days -5 to -3. Patients undergo autologous or syngeneic bone marrow
transplantation (BMT) or PBSC transplantation (PBSCT) on day 0.

- Posttransplantation therapy: Beginning 33 days after BMT/PBSCT, patients receive
sargramostim (GM-CSF) subcutaneously on days 1-15 and MOAB 3F8 IV within 90 minutes
(beginning approximately 1 hour after initiation of GM-CSF infusion) on days 6-15.
Treatment repeats every 28 days for 2 courses.

Beginning 47 days after BMT/PBSCT (on day 14 of course 1 of MOAB 3F8 and GM-CSF), patients
receive localized external beam radiotherapy twice daily for 7 consecutive weekdays.

Beginning 82 days after BMT/PBSCT, patients receive alternating courses of oral VP-16 and
MOAB 3F8 for a total of 8 courses (total of 4 courses of each drug). Patients receive oral
VP-16 3 times daily on days 1-21, with courses repeating every 28 days. Patients receive
MOAB 3F8 IV within 90 minutes on days 1-5, with courses repeating every 35 days.

Beginning 222 days after BMT/PBSCT (2-3 weeks after completion of course 4 of oral VP-16),
patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days
for 6 courses.

Beginning on day 243 after BMT/PBSCT, patients receive MOAB 3F8 IV within 90 minutes on days
1-5. Treatment repeats every 28 days for 6 courses.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 6 months for 2 years and then annually thereafter.

PROJECTED ACCRUAL: A maximum of 49 patients (34 for stratum 1 and 15 for stratum 2) will be
accrued for this study within 3 years.