Trial Information

A Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma

OBJECTIVES:

Primary

- Compare the event-free survival in patients with newly diagnosed high risk
neuroblastoma or ganglioneuroblastoma treated with myeloablative consolidation
chemotherapy and autologous purged versus unpurged peripheral blood stem cells (PBSC).

- Compare the time to engraftment and CD34 content and tumor content by reverse
transcriptase polymerase chain reaction (RT-PCR) of purged versus unpurged PBSC in
patients treated with these regimens.

- Determine event-free survival of patients treated with dose intensive induction
chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine alternating with
cisplatin and etoposide.

- Determine the toxicity of this dose-intensive induction chemotherapy regimen in these
patients.

- Evaluate tumor resectability at second look or delayed surgery, response (complete
response and very good partial response) at completion of induction therapy, tumor
content of peripheral blood and bone marrow, and the comparison of historical data from
CCG-3891 induction therapy in these patients.

Secondary

- Compare the toxicity of this myeloablative consolidation regimen using purged vs
unpurged PBSC in these patients.

- Determine if event-free survival is predictable by RT-PCR positivity of the stem cell,
minimal residual disease in bone marrow and peripheral blood after transplantation by
immunocytology, and extent of disease as measured by MIBG after transplantation in
patients treated with these regimens.

- Evaluate the prognostic impact of tumor biology on event free survival in patients
treated with these regimens.

- Determine the incidence of relapse in the primary site after radiotherapy and in
irradiated versus unirradiated metastatic sites in these patients.

- Assess the toxicity and tolerability of maintenance therapy with topotecan and
cyclophosphamide after intensive induction therapy in patients who decline or are
unable to receive myeloablative therapy.

- Determine the health-related quality of life of patients treated with these regimens.

- Compare late effects of these regimens on the growth, endocrine, pulmonary, and cardiac
function of these patients vs general population standards.

- Determine the incidence of second malignant neoplasms in patients treated with these
regimens.

- Determine the variability of isotretinoin pharmacokinetics and relationship to
pharmacogenomic parameters in these patients.

- Correlate the isotretinoin pharmacokinetics and pharmacogenomic parameters and/or
genetic variations in isotretinoin metabolic enzymes with event-free survival or
systemic toxicity in these patients.

OUTLINE: This is a randomized study. Patients are randomized to one of two treatment arms
for peripheral blood stem cell (PBSC) collection.

All patients receive induction chemotherapy comprising cyclophosphamide IV over 6 hours on
days 0 and 1, doxorubicin IV and vincristine IV continuously over 72 hours on days 0-2, and
filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 3 and continuing until blood
counts recover for courses 1, 2, 4, and 6. Treatment alternates with courses 3 and 5
comprising etoposide IV over 2 hours on days 0-2, cisplatin IV over 1 hour on days 0-3, and
G-CSF SC or IV beginning on day 4 and continuing until blood counts recover. Induction
chemotherapy repeats every 3 weeks or when blood counts recover in the absence of disease
progression or unacceptable toxicity.

After course 2 or 3 of induction chemotherapy, patients undergo PBSC collection, either
purged or unpurged, depending on randomization. Patients continue on daily G-CSF until cell
collection is complete.

- Arm I: Patients undergo unpurged PBSC collection until the target cell count is
reached.

- Arm II: Patients undergo purged PBSC collection until the target cell count is reached.

Patients with immunocytology positive PBSC undergo purged autologous bone marrow collection
or repeat purged or unpurged PBSC collection depending on individual patient
characteristics.

All patients undergo delayed surgical resection of the residual tumor after course 5 of
induction chemotherapy.

After induction therapy, patients achieving complete response, very good partial response,
or partial response receive consolidation therapy comprising melphalan IV on days -7 to -5
followed by carboplatin IV and etoposide IV continuously over days -7 to -4. Patients
receive purged or unpurged PBSC infusion or purged autologous bone marrow transplantation on
day 0 followed by G-CSF SC or IV beginning 4 hours after completion of transplantation and
continuing until blood counts recover. Beginning on day 66, patients receive oral
isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6
courses.

After completion of consolidation (at least 28 days from stem cell infusion), all patients
receive local radiotherapy daily over 7 days.

Patients not undergoing transplantation or who are ineligible for consolidation therapy
receive maintenance therapy comprising cyclophosphamide IV over 30 minutes followed by
topotecan IV over 30 minutes on days 0-4. Patients receive G-CSF SC or IV beginning on day 5
and continuing until blood counts recover. Maintenance therapy repeats every 3 weeks for 3
courses. After completion of maintenance therapy, patients receive radiotherapy as outlined
above. Patients then receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy
repeats every 4 weeks for 6 courses.

Quality of life is assessed at 1* and 5 years.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then
annually thereafter or until disease progression.

NOTE: * Patients under 5 years of age at 1 year are not assessed until 5 years.

PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study within 4 years.