N2003-01: Irinotecan, Temozolomide, and Cefixime in Treating Young Patients With Recurrent or Resistant Neuroblastoma

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.

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