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

Alternate Title

Irinotecan, Temozolomide, and Cefixime in Treating Young Patients With Recurrent or Resistant Neuroblastoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Supportive care, Treatment	Completed	1 to 30 at diagnosis	NCI	NANT-2003-01 NCT00093353

Objectives

Primary

1. 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.
2. Determine the toxic effects of this regimen in these patients.

Secondary

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

Entry 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)]

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

Patient Characteristics:

Age

• 1 to 30 at diagnosis

Performance status

• ECOG 0-2

Life expectancy

• At least 2 months

Hematopoietic

• Absolute neutrophil count ≥ 750/mm³
• Platelet count ≥ 75,000/mm³ (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

Expected Enrollment

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

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.

Wagner LM, Villablanca JG, Stewart CF, et al.: Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. J Clin Oncol 27 (8): 1290-6, 2009.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

New Approaches to Neuroblastoma Therapy Consortium

Lars Wagner, MD, Protocol chair		Ph: 513-636-1849; 800-344-2462
Katherine Matthay, MD, Protocol co-chair		Ph: 415-476-0603; 800-888-8664

Registry Information
Official Title		A Phase I Study Of Oral Irinotecan, Temozolomide, Cefixime In Children With Recurrent/Resistant High-Risk Neuroblastoma
Trial Start Date		2004-05-24
Trial Completion Date		2006-07-17
Registered in ClinicalTrials.gov		NCT00093353
Date Submitted to PDQ		2004-05-25
Information Last Verified		2009-05-28
NCI Grant/Contract Number		CA81403

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