Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Neuroblastoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	30 and under at original diagnosis	NCI	COG-ANBL00P1 NCT00017368

Objectives

1. 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.
2. Determine the role of the meta-iodobenzylguanidine (MIBG) scan in assessing response to tandem transplantation and minimal residual disease therapy in these patients.
3. 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.
4. Determine the immune recovery by quantitation of lymphocyte subsets in these patients and limited functional analysis after completion of this regimen.

Entry Criteria

Disease Characteristics:

• Newly diagnosed high-risk neuroblastoma
  • Histologically proven

    AND/OR

  • Bone marrow specimen showing clumps of tumor cells accompanied by elevated urinary catecholamines
  • Age 1-30:
    • Must meet one of the following INSS staging criteria:
      • Stage IV regardless of biologic factors
      • Stage IIa/IIb with MYCN oncogene amplification (greater than 10) and unfavorable pathology
      • Stage III with MYCN oncogene amplification (greater than 10) or unfavorable pathology
      • Initially stage I, II, or IVS, that has progressed without interval chemotherapy
  • Under age 1:
    • INSS stage III, IV, or IVS with MYCN amplification (greater than 10)



• Must enter neuroblastoma biology study COG-ANBL00B1 within 2 weeks of diagnosis and before entry on this study

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• No more than 1 prior course of chemotherapy on the intergroup low- or intermediate-risk neuroblastoma studies prior to determination of MYCN status and Shimada histology

Endocrine therapy:

• Not specified

Radiotherapy:

• Prior emergent radiotherapy to sites of function- or life-threatening neuroblastoma allowed

Surgery:

• Not specified

Other:

• No other prior systemic therapy for neuroblastoma

Patient Characteristics:

Age:

• 30 and under at original diagnosis

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

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

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.

Marcus KJ, Shamberger R, Litman H, et al.: Primary tumor control in patients with stage 3/4 unfavorable neuroblastoma treated with tandem double autologous stem cell transplants. J Pediatr Hematol Oncol 25 (12): 934-40, 2003.[PUBMED Abstract]

Kletzel M, Katzenstein HM, Haut PR, et al.: Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 20 (9): 2284-92, 2002.[PUBMED Abstract]

Donovan J, Temel J, Zuckerman A, et al.: CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies. Med Pediatr Oncol 35 (6): 677-82, 2000.[PUBMED Abstract]

Grupp SA, Stern JW, Bunin N, et al.: Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Med Pediatr Oncol 35 (6): 696-700, 2000.[PUBMED Abstract]

Grupp SA, Stern JW, Bunin N, et al.: Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol 18 (13): 2567-75, 2000.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Stephan A. Grupp, MD, PhD, Protocol chair		Ph: 215-590-5476

Registry Information
Official Title		A Pilot Study Of Tandem High Dose Chemotherapy With Stem Cell Rescue Following Induction Therapy In Children With High Risk Neuroblastoma
Trial Start Date		2001-04-11
Registered in ClinicalTrials.gov		NCT00017368
Date Submitted to PDQ		2001-04-24
Information Last Verified		2004-04-27
NCI Grant/Contract Number		CA13539

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