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
1 Year
21 Years
Both
Brain and Central Nervous System Tumors
Trial Information
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
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.
Inclusion 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
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
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose of erlotinib hydrochloride when given alone and in combination with radiotherapy
Safety Issue:
Yes
Principal Investigator
Darren Hargrave, MD
Investigator Affiliation:
Royal Marsden NHS Foundation Trust
Authority:
United States: Federal Government
Study ID:
CDR0000481539
NCT ID:
NCT00360854
Start Date:
May 2005
Completion Date:
Related Keywords:
- Brain and Central Nervous System Tumors
- untreated childhood brain stem glioma
- recurrent childhood cerebellar astrocytoma
- recurrent childhood cerebral astrocytoma
- recurrent childhood ependymoma
- recurrent childhood medulloblastoma
- recurrent childhood supratentorial primitive neuroectodermal tumor
- recurrent childhood visual pathway and hypothalamic glioma
- childhood central nervous system germ cell tumor
- childhood choroid plexus tumor
- childhood craniopharyngioma
- childhood grade I meningioma
- childhood grade II meningioma
- childhood grade III meningioma
- childhood low-grade cerebral astrocytoma
- childhood infratentorial ependymoma
- childhood supratentorial ependymoma
- recurrent childhood brain tumor
- recurrent childhood subependymal giant cell astrocytoma
- recurrent childhood pineoblastoma
- Brain Neoplasms
- Glioma
- Nervous System Neoplasms
- Central Nervous System Neoplasms
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