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

Alternate Title

Induction Chemotherapy Using Cyclophosphamide and Topotecan in Treating Patients Who Are Undergoing Autologous Peripheral Stem Cell Transplantation for Newly Diagnosed or Progressive Neuroblastoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	30 and under at initial diagnosis	NCI	COG-ANBL02P1 NCT00070200, ANBL02P1

Objectives

Primary

1. Determine the toxicity and feasibility of adding cyclophosphamide and topotecan to induction therapy in patients with newly diagnosed or progressive high-risk neuroblastoma undergoing autologous peripheral blood stem cell (PBSC) transplantation.
2. Determine the feasibility of PBSC mobilization and in vivo PBSC tumor purging in these patients after treatment with this regimen.

Secondary

1. Determine tumor response rate in patients treated with this regimen.
2. Determine the pharmacokinetics of this regimen in these patients.
3. Determine whether topotecan affects cyclophosphamide pharmacokinetics in these patients.
4. Correlate host DNA with toxicity and cyclophosphamide and topotecan pharmacokinetics in patients treated with this regimen.
5. Determine toxicity in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed neuroblastoma or ganglioneuroblastoma meeting 1 of the following staging criteria:
  • Newly diagnosed disease, at least 1 year of age, and meets criteria for 1 of the following:
    • International Neuroblastoma Staging System (INSS) stage 2a/2b with MYCN amplification (greater than 10) AND unfavorable pathology
    • INSS stage 3 with MYCN amplification OR unfavorable pathology
  • Newly diagnosed INSS stage 4 disease meeting criteria for 1 of the following:
    • Over 18 months of age
    • Age 12 to 18 months with any unfavorable biologic feature (MYCN amplification, unfavorable pathology, and/or DNA index=1) or any biologic feature that is indeterminant, unsatisfactory, or unknown
      • No INSS stage 4 disease and age 12 to 18 months with all 3 favorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNA index greater than 1)
  • Newly diagnosed INSS stage 3, 4, or 4S disease AND under 1 year of age with MYCN amplification
  • At least 1 year of age and initially diagnosed with INSS stage 1, 2, or 4S disease that progressed to stage 4 without interval chemotherapy
    • Must have been enrolled on COG-ANBL00B1 at initial diagnosis

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics
• No more than 1 prior chemotherapy course on the low- or intermediate-risk neuroblastoma studies (COG-P9641, COG-A3961) prior to determination of MYCN amplification and Shimada histology

Endocrine therapy

• Not specified

Radiotherapy

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

Surgery

• Not specified

Other

• No other prior systemic therapy

Patient Characteristics:

Age

• 30 and under at initial diagnosis

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,000/mm³*
• Platelet count at least 100,000/mm³* (transfusion independent)
• Hemoglobin at least 10.0 g/dL* (red blood cell transfusions allowed)

 [Note: *Granulocytopenia, anemia, and/or thrombocytopenia allowed for patients with tumor metastatic to the bone marrow]

Hepatic

• Bilirubin no greater than 1.5 mg/dL
• ALT less than 300 IU/L

Renal

• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min

Cardiovascular

• ECG normal
• Shortening fraction at least 27% by echocardiogram

  OR

• Ejection fraction at least 50% by MUGA

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative

Expected Enrollment

A total of 10-29 patients will be accrued for this study within 2 years.

Outline

This is a pilot, multicenter study. Patients are stratified according to diagnosis (newly diagnosed vs initially stage 1, 2, or 4S that progressed to stage 4 without interval chemotherapy).

• Induction therapy: Patients receive 6 courses of induction therapy.
  • Courses 1 and 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover.
  
  
  
  • Course 3: Patients receive etoposide IV over 2 hours on days 1-3, cisplatin IV over 1 hour on days 1-4, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.
  
  
  
  • Course 4: Patients receive cyclophosphamide IV over 6 hours on day 1 and doxorubicin IV and vincristine IV continuously over 24 hours on days 1-3. Patients also receive G-CSF SC or IV beginning on day 4 and continuing until blood counts recover.
  
  
  
  • Course 5: Patients receive etoposide, cisplatin, and G-CSF as in course 3.
  
  
  
  • Course 6: Patients receive cyclophosphamide, doxorubicin, vincristine, and G-CSF as in course 4.
  
  
  

  Treatment repeats every 21 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity.




• Consolidation therapy: Within 4-6 weeks after completing induction therapy, patients receive melphalan IV on days -7 to -5 and etoposide IV and carboplatin IV continuously over 24 hours on days -7 to -4.



• Stem cell transplantation: Peripheral blood stem cells are collected after course 2 of induction therapy and infused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover.



• Surgery: After course 5 of induction therapy, patients undergo surgery.



• Radiotherapy: Beginning 28-42 days after transplantation, patients receive 12 fractions of local radiotherapy to all areas of residual soft tissue disease and the primary tumor site, even if completely resected.



• Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.

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

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Julie Park, MD, Protocol chair		Ph: 206-987-2106

Registry Information
Official Title		A Pilot Induction Regimen Incorporating Topotecan for Treatment of Newly Diagnosed High Risk Neuroblastoma
Trial Start Date		2004-03-29
Registered in ClinicalTrials.gov		NCT00070200
Date Submitted to PDQ		2003-08-14
Information Last Verified		2005-12-05
NCI Grant/Contract Number		CA98543