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

Alternate Title

Erlotinib Alone or in Combination With Radiation therapy in Treating Young Patients With Refractory or Relapsed Malignant Brain Tumors or Newly Diagnosed Brain Stem Glioma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Closed	1 to 21	Other	CCLG-NAG-2005-09 ITCC-003, EU-20617, CCLG-CPP-05-07, ROCHE-MO18461, EUDRACT-2004-005247-10, NCT00360854

Objectives

Primary

1. Establish the maximum tolerated dose of single-agent erlotinib hydrochloride in pediatric patients with refractory or relapsed malignant brain tumors and in combination with radiotherapy in pediatric patients with newly diagnosed brain stem glioma.

Secondary

1. Determine dose-limiting toxicities of these regimens.
2. Define the safety profile of these regimens.
3. Characterize the pharmacokinetic behavior of erlotinib hydrochloride in these patients.
4. Evaluate the efficacy of these regimens.
5. Correlate expression and mutations of epidermal growth factor receptor with treatment response.

Entry Criteria

Disease Characteristics:

• Diagnosis of 1 of the following:
  • Histologically or cytologically confirmed malignant brain tumor
    • Refractory to first-line therapy or relapsed after conventional therapy
    • No effective conventional therapy exists
  • Histologically confirmed brain stem glioma
    • Newly diagnosed disease
    • No pilocytic glioma
• Measurable or evaluable disease

Prior/Concurrent Therapy:

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)
• More than 6 weeks since prior radiotherapy
• No concurrent warfarin
• No other concurrent anticancer or investigational agents

Patient Characteristics:

• WHO performance status 0-2 OR Lansky play scale 50-100%
  • Patients with motor paresis due to disease are eligible
  • Neurological deficits must be stable for ≥ 1 week
• Life expectancy ≥ 8 weeks
• Absolute neutrophil count > 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8 g/dL
• AST/ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• Creatinine < 1.5 times ULN OR creatinine clearance ≥ 70 mL/min
• No other serious, uncontrolled illness
• No active infection
• No organ toxicity ≥ grade 2 except alopecia and neurological symptoms due to disease
• Must be able to take oral medication
  • Patients with newly diagnosed brain stem glioma with difficulty swallowing may be eligible
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No evidence of pulmonary dysfunction or pre-existing lung disease
• No myocardial infarction within the past year
• No severe cardiac pathology
• No significant ophthalmologic abnormality including, but not limited to, any of the following:
  • Severe dry eye syndrome
  • Keratoconjunctivitis sicca
  • Sjögren's syndrome
  • Severe exposure keratitis
  • Any other disorder likely to increase the risk of corneal epithelial lesions

Expected Enrollment

A total of 48 patients will be accrued for this study.

Outcomes

Maximum tolerated dose of erlotinib hydrochloride when given alone and in combination with radiotherapy

Dose-limiting toxicities
Safety
Pharmacokinetic behavior of erlotinib hydrocloride
Efficacy
Correlation of expression and mutations of epidermal growth factor receptor with treatment response

Outline

This is a multicenter, nonrandomized, open-label, dose-escalation study of erlotinib hydrochloride. Patients are assigned to 1 of 2 treatment groups according to disease.

• Group 1 (refractory or relapsed malignant brain tumors): Patients receive oral erlotinib hydrochloride once daily on days 1-21. Treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression.

  Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride 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 (DLT).

• Group 2 (newly diagnosed brain stem glioma): Patients receive oral erlotinib hydrochloride once daily on days 1-21. Treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression. Beginning on day 1, patients also undergo radiotherapy 5 days a week for 6 weeks .

  Cohorts of 1-2 patients receive escalating doses of erlotinib hydrochloride until the MTD is determined. The MTD is defined as the dose resulting in 25% of patients experiencing DLT at 6 weeks.

Blood is collected for pharmacokinetic assessments and pharmacogenetic genotyping for analysis of enzyme polymorphisms. Tumor tissue may be assessed for epidermal growth factor receptor mutations.

After completion of study treatment, patients are followed every 3 months.

Trial Contact Information

Trial Lead Organizations

Children's Cancer and Leukaemia Group

Darren Hargrave, MD, Study coordinator		Ph: 44-20-8661-3455

Registry Information
Official Title		Phase I Studies of TARCEVA™ (ERLOTINIB HYDROCHLORIDE, OSI-774) as Single Agent in Children with Refractory and Relapsed Malignant Brain Tumors and in Combination with Irradiation in Newly Diagnosed Brain Stem Glioma
Trial Start Date		2005-05-27
Registered in ClinicalTrials.gov		NCT00360854
Date Submitted to PDQ		2006-04-18
Information Last Verified		2007-06-03

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