RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow doctors to give higher doses of chemotherapy drugs and kill more tumor cells. Radiation therapy uses high-energy x-rays to damage tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combination chemotherapy plus peripheral stem cell transplantation followed by surgery and/or radiation therapy in treating young patients who have newly diagnosed advanced neuroblastoma.

Condition	Treatment or Intervention	Phase
disseminated neuroblastoma	Drug: carboplatin  Drug: cyclophosphamide  Drug: doxorubicin  Drug: etoposide  Drug: filgrastim  Drug: mesna  Drug: vincristine	Phase I

Further Study Details: 

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.

PROTOCOL 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.

Ages Eligible for Study:  1 Year   -   21 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Newly diagnosed stage IV neuroblastoma by one of the following: Histologic verification; Demonstration of tumor cell clumps in bone marrow with elevated urinary catecholamine metabolites
• Initial presentation with low-stage disease allowed if followed by progression to stage IV disease

--Prior/Concurrent Therapy--

• No prior systemic chemotherapy
• No prior radiotherapy except as emergency treatment

--Patient Characteristics--

• Age: 1 to 21
• Performance status: Not specified
• Hematopoietic: (unless bone marrow involvement by tumor) Absolute neutrophil count greater than 1,000/mm3; Platelet count greater than 100,000/mm3
• Hepatic: Bilirubin less than 3.0 mg/dL
• Renal: Creatinine less than 1.5 mg/dL; Creatinine clearance or radionuclide GFR greater than 60 mL/min
• Cardiovascular: EKG normal; Ejection fraction at least 55% by radionuclide MUGA OR Fractional shortening at least 28% by echocardiogram
• Other: No other significant organ dysfunction that precludes study treatment; Body weight at least 10 kg; Not pregnant or nursing; Effective contraception required of fertile patients

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94115-0128,  United States
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5265,  United States
Minnesota
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
Ohio
      Children's Hospital Medical Center - Cincinnati, Cincinnati,  Ohio,  45229-3039,  United States
      Children's Hospital of Columbus, Columbus,  Ohio,  43205-2696,  United States
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States

Study chairs or principal investigators

Susan G. Kreissman,  Study Chair,  Children's Cancer Group   

Study ID Numbers:  CDR0000064656; CCG-3951
Record last reviewed:  June 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002740
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08