Trial Information

A Pilot Study Of Tandem High Dose Chemotherapy With Stem Cell Rescue Following Induction Therapy In Children With High Risk Neuroblastoma

OBJECTIVES:

- Determine the toxicity and feasibility of high-dose thiotepa and cyclophosphamide with
autologous peripheral blood stem cell (PBSC) transplantation and sargramostim (GM-CSF)
followed by high-dose carboplatin, etoposide, and melphalan with second PBSC
transplantation, GM-CSF, and isotretinoin after induction in children with newly
diagnosed high-risk neuroblastoma.

- Determine the role of the meta-iodobenzylguanidine (MIBG) scan in assessing response to
tandem transplantation and minimal residual disease therapy in these patients.

- Determine the feasibility of quantitative polymerase chain reaction for
neuroblastoma-specific ribonucleic acids at specific stages of treatment as a
prognostic indicator of outcome in these patients.

- Determine the immune recovery by quantitation of lymphocyte subsets in these patients
and limited functional analysis after completion of this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to peripheral blood
stem cell (PBSC) selection (selected PBSCs vs unselected PBSCs). (Selected PBSC stratum
closed to accrual as of 7/17/02.)

- Induction/harvest:

- Course 1: Patients receive etoposide (VP-16) IV over 1 hour on days 2-4, cisplatin
IV over 6 hours (beginning after VP-16 infusion) on days 1-5, and filgrastim
(G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts
recover.

- Course 2: Patients receive vincristine IV and doxorubicin IV over 15 minutes on
day 1, cyclophosphamide IV over 6 hours on days 1 and 2, and sargramostim (GM-CSF)
SC beginning on day 3 and continuing until PBSC are harvested. Beginning after
completion of course 2 and when blood counts recover, autologous PBSC are
harvested.

- Course 3: Patients receive VP-16 IV over 1 hour and ifosfamide IV over 1 hour on
days 1-5 and G-CSF SC beginning on day 6 and continuing until blood counts
recover.

- Course 4: Patients receive VP-16 IV over 1 hour on days 1-3, carboplatin IV over 2
hours (beginning after VP-16 infusion) on days 1 and 2, and G-CSF SC beginning on
day 4 and continuing until blood counts recover.

- Course 5: Patients receive treatment as in course 2 but supported by G-CSF.
Courses 1-5 each last 3-4 weeks. Patients undergo resection of the primary tumor
after course 4 or 5 unless primary resection was completed at diagnosis (which is
not recommended), no primary site is found, or the primary site is unresectable.
Patients complete courses 1-5 and then proceed to the first conditioning/PBSC
transplantation (PBSCT) in the absence of disease progression or unacceptable
toxicity.

- First conditioning/PBSCT: Patients receive high-dose thiotepa IV on days -7 to -5 and
cyclophosphamide IV over 1 hour on days -5 to -2. CD34+ PBSC are reinfused on day 0.
GM-CSF is administered SC beginning on day 5 and continuing until blood counts recover.
If blood counts have not recovered by day 28, unselected PBSC are reinfused. In the
absence of disease progression or unacceptable toxicity, patients proceed to the second
conditioning/PBSCT.

- Second conditioning/PBSCT: Beginning within 6-8 weeks after initiating the first
conditioning, patients receive high-dose carboplatin IV continuously and etoposide
phosphate IV continuously on days -7 to -4 and melphalan IV on days -7 to -5. PBSC and
GM-CSF are administered as in the first PBSCT.

Beginning no earlier than day 28 after the second PBSCT, patients undergo local radiotherapy
to the primary site and sites that are positive by meta-iodobenzylguanidine scan after
induction twice a day for 7 days (or once a day for 12 days if twice daily dosing is not
possible). Beginning on day 90 after the second PBSCT, patients receive oral isotretinoin
twice a day for 2 weeks. Treatment repeats every 4 weeks for 6 courses in the absence of
disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then
annually thereafter.

PROJECTED ACCRUAL: A total of 31-39 patients will be accrued for this study within 22
months.