Trial Information

Therapy for Children With Advanced Stage High Risk Neuroblastoma

In this prospective phase II trial, topotecan is administered intravenously daily for 5 days
for each of 2 consecutive weeks for two cycles in an upfront treatment window. Patients
subsequently will receive standard treatment during induction and intensification phases.

The objectives of this trial are:

- To estimate the response rate to an upfront window of two cycles of IV topotecan when
given in doses adjusted to attain a targeted systemic exposure in children with
advanced stage neuroblastoma.

- To determine the feasibility and toxicity of an intensification phase of high-dose
chemotherapy with topotecan and cyclophosphamide followed by autologous peripheral
blood stem cell transplant

- To estimate the 3-year overall survival and progression-free survival in patients
treated with this approach

- To characterize the phenotype of neuroblastoma tumor cells

- To evaluate the disposition of topotecan in previously untreated patients with
neuroblastoma

Details for chemotherapy intervention:

Window Phase Topotecan description, window therapy-Topotecan given intravenously daily as a
30 minute infusion for five consecutive days, off two days, and then five consecutive days.
The dose for day 1 and 2 was 3.0 mg/m2 and subsequent doses were adjusted to attain a target
systemic exposure. A second course of Topotecan was given approximately 16 days from the end
of the first cycle, with the initial dose for the second course of Topotecan based on the
dose required in the preceding course to attain the target AUC.

Induction Phase

Cyclophosphamide, MESNA, Adriamycin, Cisplatin, Carboplatin, and Etoposide description,
Induction Phase (after completion of window) consists of 4 cycles of therapy:

Cycle 1:Cyclophosphamide 1 gm/m2 daily x 2 I.V. day 1 and 2 Adriamycin 35 mg/m2 I.V. day 1
only, MESNA: 250 mg/m2 I.V. immediately following cyclophosphamide infusion and at 3 and 6
hours post-infusion, and Etoposide: 30 mg/m2 over 30 minutes, followed by 250 mg/m2/day x 3
days I.V. by continuous infusion (days 2-5) Cycles 2 and 4- Cisplatin 40 mg/m2/day x 5 I.V.
over 1 hour (days 1-5) Etoposide 200 mg/m2/day x 3 I.V. over 1 hour (days 2,3,4) Cycle 3:
Carboplatin: dose adapted from GFR on day 1. Dose in mg/m2 = 8 x [(0.93 GFR) + 15]
Ifosfamide: 2 gm/m2 I.V. over 1 hour daily x 3 (days 2, 3, 4) MESNA: 500 mg/m2 I.V.
immediately after ifosfamide and 3 and 6 hours later Etoposide: 100 mg/m2 IV daily x 3 over
1 hour (days 2, 3, 4).

Intensification Phase

Topotecan, Cyclophosphamide, and MESNA- Intensification Therapy:

Topotecan - targeted dose - daily x 5 days for two weeks. Cyclophosphamide 750 mg/m2 IV over
1 hour on days 8 through 12. MESNA 175 mg/m2 IV immediately after cyclophosphamide and 3 and
6 hours later. Infusion of previously collected peripheral blood stem cells on day 14.

Subjects that do not respond to the Topotecan window will not receive topotecan during
intensification, but instead will receive the following intensification therapy:

Carboplatin 700 mg/m2/day IV, over one hour q.o.d. x 3 Etoposide 500 mg/m2/day IV, over 6
hours q.o.d. x 3. Infusion of previously collected peripheral blood stem cells on day 8

Details for Intervention: Procedure/Surgery: Surgery Surgical resection will be performed
after the window therapy in feasible subjects. If surgery was not possible after the
Topotecan window resection of the primary tumor mass and careful lymph node staging was done
after recovery from induction and re-evaluation of tumor status.