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

Phase 3
30 Years
Not Enrolling

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Trial Information

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



- 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

- 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.


- 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

- 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

- 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

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

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.

Inclusion Criteria


- Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma,
and/or evidence of clumps of tumor cells in bone marrow with elevated urinary
catecholamine metabolites, meeting 1 of the following criteria:

- Age greater than 18 months with stage IV disease, regardless of biologic factors

- Age 12-18 months with stage IV disease meeting one of the following criteria:

- Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable
pathology, and/or DNA index = 1)

- Any biologic feature that is indeterminate, unsatisfactory, or unknown

- At least 1 year old with the following:

- Stage IIa/IIb with MYCN amplification (> 10) AND unfavorable pathology

- Stage III with MYCN amplification (> 10) OR unfavorable pathology

- Stage I, II, or IVS with disease progression to stage IV without interval

- No more than 3 weeks since progression

- Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047

- Less than 1 year old with the following:

- Stage III, IV, or IVS disease with MYCN amplification (> 10)

- Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis



- See Disease Characteristics

- 30 and under at time of diagnosis

Performance status:

- Not specified

Life expectancy:

- Not specified


- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- Inadequate hematopoiesis secondary to bone marrow involvement with > 10% tumor
infiltration allowed


- Bilirubin ≤ 1.5 mg/dL

- ALT ≤ 300 units/L


- Creatinine ≤ 1.5 mg/dL

- Creatinine clearance or glomerular filtration rate ≥ 60 mL/min


- ECG normal

- Ejection fraction ≥ 55% by echocardiogram or MUGA OR

- Fractional shortening ≥ 28% by echocardiogram


- Able to tolerate peripheral blood stem cell collection

- HIV negative

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception for at least 1 month prior to,
during, and for 1 month after study participation


Biologic therapy:

- Not specified


- See Disease Characteristics

- No more than 1 prior course of chemotherapy on the Intergroup low/intermediate risk
neuroblastoma study (P9641, A3961)

Endocrine therapy:

- Not specified


- Prior localized emergency radiotherapy to sites of life-threatening or
function-threatening disease allowed


- Not specified


- No other prior systemic therapy

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival rate

Outcome Time Frame:

Time from study registration until the time of the first occurrence of either relapse, progression, secondary malignancy, or death, or until the time of last contact with the patient if none of these events occurs, assessed up to 6 years

Safety Issue:


Principal Investigator

Susan G. Kreissman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Duke Cancer Institute


United States: Federal Government

Study ID:




Start Date:

February 2001

Completion Date:

Related Keywords:

  • Neuroblastoma
  • localized resectable neuroblastoma
  • regional neuroblastoma
  • disseminated neuroblastoma
  • stage 4S neuroblastoma
  • localized unresectable neuroblastoma
  • Neuroblastoma



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