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A Phase I Study Of Oral Irinotecan, Temozolomide, Cefixime In Children With Recurrent/Resistant High-Risk Neuroblastoma

Phase 1
1 Year
30 Years
Not Enrolling
Diarrhea, Drug/Agent Toxicity by Tissue/Organ, Neuroblastoma

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Trial Information

A Phase I Study Of Oral Irinotecan, Temozolomide, Cefixime In Children With Recurrent/Resistant High-Risk Neuroblastoma



- 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.


- 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

- Correlate p53 status in tumor cells with response in patients treated with this

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

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

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

Inclusion Criteria


- 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

- 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)



- 1 to 30 at diagnosis

Performance status

- ECOG 0-2

Life expectancy

- At least 2 months


- Absolute neutrophil count ≥ 750/mm^3

- Platelet count ≥ 75,000/mm^3 (without transfusion)

- Hemoglobin ≥ 8.0 g/dL (transfusion allowed)


- SGPT and SGOT < 5 times normal

- Bilirubin ≤ 1.5 times normal


- 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)


- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No allergy to cephalosporins

- No active diarrhea

- No uncontrolled infection


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

- No concurrent immunomodulating agents except steroids to control intracranial


- 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


- 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

- At least 4 weeks since prior radiotherapy to biopsied lesions (for study entry) and

- At least 6 weeks since prior MIBG therapy

- Concurrent radiotherapy to painful lesions allowed provided the lesions are not used
to assess treatment response


- Not specified


- No concurrent enzyme-inducing anticonvulsants (e.g., phenobarbital, phenytoin, or

- No other concurrent anticancer agents

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Lars M. Wagner, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital Medical Center, Cincinnati


United States: Food and Drug Administration

Study ID:




Start Date:

May 2004

Completion Date:

Related Keywords:

  • Diarrhea
  • Drug/Agent Toxicity by Tissue/Organ
  • Neuroblastoma
  • diarrhea
  • drug/agent toxicity by tissue/organ
  • disseminated neuroblastoma
  • recurrent neuroblastoma
  • Diarrhea
  • Neuroblastoma



University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan  48109-0752
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Indiana University Cancer Center Indianapolis, Indiana  46202-5265
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
UCSF Comprehensive Cancer Center San Francisco, California  94115
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Lucile Packard Children's Hospital at Stanford University Medical Center Palo Alto, California  95798
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Atlanta, Georgia  30322
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital Houston, Texas  77030-2399
Children's Hospital Boston Boston, Massachusetts  02115