Trial Information

PHASE I PILOT STUDY OF MULTIPLE CYCLES OF HIGH DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD STEM CELL INFUSIONS IN ADVANCED STAGE NEUROBLASTOMA

OBJECTIVES: I. Estimate the maximum tolerated dose of carboplatin that can be given in
combination with cyclophosphamide (CTX) and etoposide following high dose CTX, doxorubicin,
and vincristine in patients with newly diagnosed stage IV neuroblastoma. II. Determine the
hematologic and nonhematologic toxic effects of this regimen in this patient population.
III. Determine the change in neuroblastoma tumor cell content in peripheral blood stem cells
(PBSC) collected following chemotherapy. IV. Assess the feasibility of repetitive
collection, storage, and infusion of PBSC with multicycle high-dose chemotherapy in
pediatric patients. V. Assess hematopoietic recovery following PBSC infusion as well as the
CD34 content and CFU-GM yield of the PBSC products. VI. Assess the response rate and
disease-free survival in the context of a phase I pilot study. VII. Determine the
feasibility of administering twice-daily radiotherapy fractions to post-chemotherapy
residual tumor volumes in neuroblastoma patients.

OUTLINE: This is a dose escalation study of carboplatin. Patients receive induction
chemotherapy consisting of vincristine IV over 24 hours, cyclophosphamide IV over 4 hours,
and doxorubicin IV over 24 hours on days 0, 1, 21, and 22. Patients receive filgrastim
(G-CSF) subcutaneously (SQ) or IV beginning on days 3 and 24 and continuing until blood
counts recover. Patients undergo peripheral blood stem cell (PBSC) collection after course 2
of induction chemotherapy. Patients receive G-CSF SQ or IV for 2 days prior to and during
collection. PBSC are collected daily for 1-3 days. Patients may undergo autologous bone
marrow collection after course 1 of consolidation therapy (after PBSC collection). Following
mobilization, patients receive consolidation chemotherapy consisting of etoposide IV over 4
hours on days 0, 1, and 2 and carboplatin IV over 1 hour and cyclophosphamide IV over 4
hours on days 0 and 1. Patients receive G-CSF SQ or IV beginning on day 3 (within 4 hours of
PBSC infusion) and continuing until blood counts recover. Patients receive PBSC reinfusion
at 48-72 hours following completion of each chemotherapy course. Treatment repeats every 3
weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Upon
recovery from consolidation chemotherapy, patients with no disease progression undergo tumor
resection with or without radiotherapy. Patients undergoing radiotherapy receive therapy
twice daily over 7 days. Patients with no disease progression, less than 2% detectable bone
marrow disease, and adequate bone marrow cellularity may undergo additional therapy
consisting of autologous bone marrow transplantation per appropriate transplant protocol.
Cohorts of 6-12 patients receive escalating doses of carboplatin until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 6 or 4
of 12 patients experience dose limiting toxicity. Patients are followed every 3 months for 2
years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 24-30 patients will be accrued for this study within
approximately 2 years.