RATIONALE: Drugs used in chemotherapy, such as irinotecan and temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Temozolomide may help irinotecan kill more tumor cells by making them more sensitive to the drug. Cefixime may be effective in preventing diarrhea that is caused by treatment with irinotecan.

PURPOSE: This phase I trial is studying the side effects and best dose of irinotecan when given together with temozolomide and cefixime in treating young patients with recurrent or resistant neuroblastoma.

Condition	Treatment or Intervention	Phase
Diarrhea Drug Toxicity disseminated neuroblastoma recurrent neuroblastoma	Drug: cefixime  Drug: irinotecan  Drug: temozolomide  Procedure: antibiotic therapy  Procedure: chemoprotection  Procedure: chemosensitization/potentiation  Procedure: chemotherapy  Procedure: complications of therapy assessment/management  Procedure: infection prophylaxis/management  Procedure: supportive care/therapy	Phase I

Further Study Details: 

OBJECTIVES: Primary

• Determine the maximum tolerated dose of oral irinotecan when administered with fixed-dose temozolomide and cefixime in pediatric patients with recurrent or resistant high-risk neuroblastoma.
• Determine the toxic effects of this regimen in these patients.

Secondary

• Determine the response rate in patients treated with this regimen.
• Determine the pharmacokinetics of this regimen in these patients.
• Correlate UGT1A1 genotype with the occurrence of dose-limiting diarrhea in patients treated with this regimen.
• Correlate BCRP genotype with pharmacokinetic phenotype in patients treated with this regimen.
• Correlate p53 status in tumor cells with response in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of irinotecan.

Patients receive oral cefixime once daily beginning 5 days before the start of fixed-dose temozolomide and irinotecan and continuing for the duration of the study. Patients also receive oral temozolomide once daily on days 1-5 and oral irinotecan once daily on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of irinotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A maximum of 12 patients are treated at the MTD.

Patients are followed for toxicity, response, and survival.

PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for this study within 1.25 years.

Ages Eligible for Study:  1 Year   -   30 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed neuroblastoma AND/OR demonstration of tumor cells in the bone marrow with increased urinary catecholamines
• High-risk disease meeting 1 of the following criteria:
• Recurrent or progressive disease
• Resistant or refractory disease (i.e., never achieved a complete response to therapy AND never had new sites of disease or progression of initial sites)
• Measurable disease meeting at least 1 of the following criteria:
• Unidimensionally measurable tumor ≥ 20 mm by MRI, CT scan, or x-ray OR ≥ 10 mm by spiral CT scan*
• At least 1 site with positive uptake by metaiodobenzylguanidine (MIBG) scan*
• Bone marrow with tumor cells seen on routine morphology (not by NSE staining only) of bilateral aspirate AND/OR biopsy on 1 bone marrow sample NOTE: *Patients who never experienced disease recurrence or progression must demonstrate viable neuroblastoma in a biopsy of either bone marrow or bone and/or soft tissue site (biopsy must be performed ≥ 4 weeks after completion of prior radiotherapy if lesion was irradiated)

PATIENT CHARACTERISTICS: Age

• 1 to 30 at diagnosis

Performance status

• ECOG 0-2

Life expectancy

• At least 2 months

Hematopoietic

• Absolute neutrophil count ≥ 750/mm^3
• Platelet count ≥ 75,000/mm^3 (without transfusion)
• Hemoglobin ≥ 8.0 g/dL (transfusion allowed)

Hepatic

• SGPT and SGOT < 5 times normal
• Bilirubin ≤ 1.5 times normal

Renal

• Creatinine ≤ 1.5 times normal for age
• No greater than 0.8 mg/dL (≤ 5 years of age)
• No greater than 1.0 mg/dL (6 to 10 years of age)
• No greater than 1.2 mg/dL (11 to 15 years of age)
• No greater than 1.5 mg/dL (> 15 years of age)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No allergy to cephalosporins
• No active diarrhea
• No uncontrolled infection

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Chemotherapy
• Recovered from prior immunotherapy
• More than 3 weeks since prior biologic therapy and recovered
• More than 2 days since prior hematopoietic growth factors
• No concurrent epoetin alfa
• No concurrent prophylactic hematopoietic growth factors during the first treatment course
• No concurrent immunomodulating agents except steroids to control intracranial pressure

Chemotherapy

• Prior myeloablative therapy and autologous stem cell transplantation allowed
• No prior allogeneic stem cell transplantation
• More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• Prior temozolomide, irinotecan, or topotecan allowed
• No prior temozolomide and irinotecan as combination therapy
• No other concurrent chemotherapy

Endocrine therapy

• See Biologic therapy

Radiotherapy

• At least 6 weeks since prior large field radiotherapy (e.g., total body irradiation, craniospinal therapy, whole abdomen, total lung, or > 50% bone marrow space) and recovered
• At least 4 weeks since prior radiotherapy to biopsied lesions (for study entry) and recovered
• At least 6 weeks since prior MIBG therapy
• Concurrent radiotherapy to painful lesions allowed provided the lesions are not used to assess treatment response

Surgery

• Not specified

Other

• No concurrent enzyme-inducing anticonvulsants (e.g., phenobarbital, phenytoin, or carbamazepine)
• No other concurrent anticancer agents

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States; Recruiting
      Lucile Packard Children's Hospital at Stanford University Medical Center, Palo Alto,  California,  94304,  United States; Recruiting
      UCSF Comprehensive Cancer Center, San Francisco,  California,  94143,  United States; Recruiting
Ohio
      Cincinnati Children's Hospital Medical Center, Cincinnati,  Ohio,  45229-3039,  United States; Recruiting
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting
Texas
      Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital, Houston,  Texas,  77030-2399,  United States; Recruiting

Study chairs or principal investigators

Lars Martin Wagner, MD,  Study Chair,  Children's Hospital Medical Center - Cincinnati   
Katherine K. Matthay, MD,  University of California, San Francisco   

Study ID Numbers:  CDR0000373759; NANT-2003-01; NCT00093353
Record last reviewed:  October 2004
Last Updated:  March 10, 2005
Record first received:  October 6, 2004
ClinicalTrials.gov Identifier:  NCT00093353
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08