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

Sponsor

Children's Cancer and Leukaemia Group (Other)

Overall Status

Unknown status

CT.gov ID

NCT00360854

Collaborator

(none)

Enrollment

Locations

2.3

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving erlotinib together with radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of erlotinib when given alone or together with radiation therapy in treating young patients with refractory or relapsed malignant brain tumors or newly diagnosed brain stem glioma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: erlotinib hydrochloride Genetic: mutation analysis Genetic: polymorphism analysis Other: laboratory biomarker analysis Other: pharmacological study Radiation: radiation therapy	Phase 1

Detailed Description

OBJECTIVES:

Primary

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

Determine dose-limiting toxicities of these regimens.
Define the safety profile of these regimens.
Characterize the pharmacokinetic behavior of erlotinib hydrochloride in these patients.
Evaluate the efficacy of these regimens.
Correlate 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.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

48 participants

Allocation:

Non-Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

May 1, 2005

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Our Lady's Hospital for Sick Children Crumlin	Dublin		Ireland	12
2	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
3	Institute of Child Health at University of Bristol	Bristol	England	United Kingdom	BS2 8AE
4	Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust	Cambridge	England	United Kingdom	CB2 2QQ
5	Leeds Cancer Centre at St. James's University Hospital	Leeds	England	United Kingdom	LS9 7TF
6	Leicester Royal Infirmary	Leicester	England	United Kingdom	LE1 5WW
7	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England	United Kingdom	L12 2AP
8	Middlesex Hospital	London	England	United Kingdom	W1T 3AA
9	Great Ormond Street Hospital for Children NHS Trust	London	England	United Kingdom	WC1N 3JH
10	Central Manchester and Manchester Children's University Hospitals NHS Trust	Manchester	England	United Kingdom	M27 4HA
11	Sir James Spence Institute of Child Health	Newcastle-Upon-Tyne	England	United Kingdom	NE1 4LP
12	Queen's Medical Centre	Nottingham	England	United Kingdom	NG7 2UH
13	Oxford Radcliffe Hospital	Oxford	England	United Kingdom	0X3 9DU
14	Children's Hospital - Sheffield	Sheffield	England	United Kingdom	S10 2TH
15	Southampton University Hospital NHS Trust	Southampton	England	United Kingdom	SO16 6YD
16	Royal Marsden NHS Foundation Trust - Surrey	Sutton	England	United Kingdom	SM2 5PT
17	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland	United Kingdom	BT12 6BE
18	Royal Aberdeen Children's Hospital	Aberdeen	Scotland	United Kingdom	AB25 2ZG
19	Royal Hospital for Sick Children	Edinburgh	Scotland	United Kingdom	EH9 1LF
20	Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G3 8SJ
21	Childrens Hospital for Wales	Cardiff	Wales	United Kingdom	CF14 4XW