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

Neuroblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00093353
• Other study ID #: CDR0000373759
• Secondary ID: P01CA081403N2003
• Status: Completed
• Phase: Phase 1
• First received: October 6, 2004
• Last updated: October 14, 2010
• Start date: May 2004

Study information

• Verified date: May 2009
• Source: Children's Hospital Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. primary completion date: July 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 30 Years

Eligibility

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

Study Design

Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diarrhea
• Drug/Agent Toxicity by Tissue/Organ
• Neuroblastoma

Intervention

Drug:
• cefixime

• irinotecan hydrochloride

• temozolomide

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Lucile Packard Children's Hospital at Stanford University Medical Center	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital Los Angeles	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Wagner LM, Villablanca JG, Stewart CF, Crews KR, Groshen S, Reynolds CP, Park JR, Maris JM, Hawkins RA, Daldrup-Link HE, Jackson HA, Matthay KK. Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new ap — View Citation