- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00124657
Erlotinib and Radiation Therapy in Treating Young Patients With Newly Diagnosed Glioma
A Phase I/II Trial of a New Tyrosine Kinase Inhibitor (Tarceva; Erlotinib Hydrochloride; OSI-774) During and After Radiotherapy in the Treatment of Patients With Newly Diagnosed High Grade Glioma and Unfavorable Low-Grade Glioma
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It may also make tumor cells more sensitive to radiation therapy. Giving radiation therapy together with erlotinib may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with radiation therapy and to see how well they work in treating young patients with newly diagnosed glioma.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
OBJECTIVES:
Primary
- Determine the maximum tolerated dose and dose-limiting toxicity of erlotinib when administered during and after radiotherapy in young patients with newly diagnosed high-grade glioma and unfavorable low-grade glioma.
- Determine the 1- and 2-year progression-free survival of patients treated with this regimen.
Secondary
- Determine the toxic effects of this regimen in these patients.
- Correlate genetic abnormalities in epidermal growth factor receptor (EGFR) and components of downstream pathways with treatment response in patients treated with this regimen.
- Determine the ability of erlotinib to inhibit EGFR signaling in patients with high-grade glioma who require second surgery.
- Determine the pharmacokinetics of erlotinib and its metabolites in these patients.
- Correlate plasma and cerebrospinal fluid levels of vascular endothelial growth factor and basic fibroblast growth factor with tumor response in patients treated with this regimen.
- Correlate irradiation dosimetry with patterns of failure, standard and investigational imaging, and toxicity in patients treated with this regimen.
OUTLINE: This is a phase I dose-escalation study of erlotinib followed by a phase II study.
- Phase I: Patients undergo radiotherapy once daily, 5 days week, for approximately 6½ weeks. Beginning on the first day of radiotherapy, patients receive oral erlotinib once daily for up to 2 years.
Cohorts of patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined.
- Phase II: Patients will receive erlotinib as in phase I at the MTD and undergo radiotherapy as in phase I.
PROJECTED ACCRUAL: A total of 75-80 patients (15-20 for the phase I portion and 60 for the phase II portion) will be accrued for this study.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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California
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San Diego, California, United States, 92123-4282
- University of California San Diego
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North Carolina
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Durham, North Carolina, United States, 27710
- Duke Children's Hospital and Health Center
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Tennessee
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Memphis, Tennessee, United States, 38105
- St. Jude Children's Research Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
DISEASE CHARACTERISTICS:
Diagnosis of high-grade glioma of 1 of the following types:
Unfavorable low-grade glioma
- Gliomatosis cerebri or bithalamic involvement
Histologically confirmed high-grade glioma (WHO grade III or IV) of 1 of the following subtypes:
- Anaplastic astrocytoma
- Anaplastic oligodendroglioma
- Anaplastic oligoastrocytoma
- Anaplastic ganglioglioma
- Pleomorphic xanthoastrocytoma with anaplastic features
- Malignant glioneuronal tumor
- Glioblastoma multiforme
- Gliosarcoma
- Newly diagnosed disease
- Intracranial or spinal cord tumors allowed
PATIENT CHARACTERISTICS:
Age
- 3 to 21
Performance status
- Karnofsky 40-100% (age 17 to 21 years) OR
- Lansky 40-100% (age 3 to 16 years)
Life expectancy
- Not specified
Hematopoietic
- Absolute neutrophil count ≥ 1,000/mm^3
- Platelet count ≥ 100,000/mm^3 (transfusion independent)
- Hemoglobin ≥ 8 g/dL (transfusion allowed)
Hepatic
- Bilirubin < 1.5 times upper limit of normal (ULN)
- SGPT < 5 times ULN
- Albumin ≥ 2 g/dL
Renal
- Creatinine < 2 times normal OR
- Glomerular filtration rate > 70 mL/min
Cardiovascular
- No significant cardiovascular problem
Pulmonary
- No significant pulmonary problem
Other
- Not pregnant or nursing
- Fertile patients must use effective contraception
- No uncontrolled infection
- No significant medical illness
PRIOR CONCURRENT THERAPY:
Biologic therapy
- No prior or concurrent biologic agents
Chemotherapy
- No prior or concurrent chemotherapy
Endocrine therapy
- Not specified
Radiotherapy
- No prior radiotherapy
Surgery
- No more than 42 days since prior surgery
Other
- No other prior or concurrent anticancer or experimental treatment
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Patients with High-Grade/Low-Grade Glioma
Patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age.
Patients receiving enzyme-inducing anticonvulsants (EIACs) are not eligible for this study.
Patients with spinal cord tumors will be eligible for the Phase I and Phase II component of this study, but they will not be taken into consideration to estimate PFS in the Phase II component of this trial because of their notoriously worse prognosis.
Patients receive erlotinib hydrochloride.
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This study has 2 components: a Phase I component which estimated the MTD and DLT(s) of erlotinib given once a day during and after conventionally fractionated RT for a period of 8 weeks (DLT-evaluation period), followed by continuous administration of this medication for up to 3 years; and a Phase II component where erlotinib will be given at the MTD during and after RT for 2 years.
The recommended dose of erlotinib for the Phase II component of the current study is 120mg/m2 per day (maximum dose of 200mg per day).
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Dose-limiting Toxicity (DLT)
Time Frame: During the first 8 weeks of therapy
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DLT was defined as any of the following toxicities attributable to erlotinib therapy: thrombocytopenia grade 3 and 4; neutropenia grade 4; or any grade 3 and 4 non-hematologic toxicity except for grade 3 diarrhea and grade 3 nausea and vomiting lasting ≤48 hours in participants not receiving optimal supportive therapy, grade 3 skin rash, which did not affect normal daily activities, grade 3 fever or nonneutropenic infection, grade 3 seizures, grade 3 weight gain or loss, and grade 3 transaminase elevation that returned to grade 1 or baseline within 7 days.
After enrollment of the first 4 participants, grade 3 and 4 electrolyte abnormalities that resolved to ≤grade 2 within 7 days were excluded as DLT.
Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0.
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During the first 8 weeks of therapy
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Maximum Tolerated Dose (MTD) of Erlotinib
Time Frame: During the first 8 weeks of therapy.
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MTD was defined as the highest dosage level in which no more than one of six assessable participants experienced dose-limiting toxicities (DLT).
The dosage of erlotinib was increased by approximately 30% in each dosage level starting at 80% of the MTD in adults with solid tumors.
A traditional 3+3 dose escalation scheme was used to estimate the MTD.
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During the first 8 weeks of therapy.
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Progression Free Survival (PFS)
Time Frame: 1 and 2 years after end of therapy
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Progression-free survival (PFS) distributions for the Phase II participants with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were calculated using Kaplan-Meier estimates (n=41). PFS was defined as the interval between treatment start and initial failure, including clinical or radiologic progression or death from any cause. PFS was not calculated for the other disease types. |
1 and 2 years after end of therapy
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cmax of Erlotinib and Its Metabolite OSI-420
Time Frame: After first dose of therapy, and Day 8 of therapy
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Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient.
The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.
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After first dose of therapy, and Day 8 of therapy
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Erlotinib Tmax
Time Frame: After first dose of therapy
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Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient.
The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.
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After first dose of therapy
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AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420
Time Frame: After first dose of therapy, and Day 8 of therapy
|
Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient.
The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.
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After first dose of therapy, and Day 8 of therapy
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Number of Positive Mutations of EGFR and Downstream Pathways
Time Frame: Once at tumor resection and diagnosis
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Statistical analyses of genomic changes, expression profiles and validation studies should be considered in an exploratory and hypothesis-generating context. Fresh frozen tumor tissue was obtained at the time of tumor resection and diagnosis. DNA was extracted from formalin-fixed, paraffin-embedded tissue. The entire PTEN coding sequence (exons 1-9), exons 1, 9 and 20 of PIK3CA, and exons 17-24 of EGFR were evaluated using exon-specific PCR amplification, and immunohistochemistry was done. Tumor lesions were considered positive if >25% cells were immunoreactive. |
Once at tumor resection and diagnosis
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Ability of Erlotinib to Inhibit EGFR Signaling
Time Frame: 5 Years
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The objective was to test the ability of erlotinib to inhibit the EGFR signaling in patients with high-grade glioma who required a second surgery. This outcome was not assessed due to insufficient availability of tumor and control samples for analysis. |
5 Years
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Correlation Between Standard Magnetic Resonance Imaging and Investigational Radiologic Techniques in Assessing Tumor Response to This Treatment
Time Frame: at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)
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This objective was to prospectively investigate the correlation between standard magnetic resonance imaging (MRI) and investigational radiologic techniques (MR spectroscopy, perfusion/diffusion, PET scan, DEMRI/BLAST) in assessing tumor response to this treatment.
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at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)
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To Prospectively Investigate the Technical Factors Involved in Planning and Administering Conformal Fractionated RT as Outlined in This Study, and to Correlate RT Dosimetry With Patterns of Failure, Standard and Investigational Imaging and Toxicity
Time Frame: 5 Years
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5 Years
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Plasma and CSF Levels of VEGF, bFGF, and SDF1
Time Frame: at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)
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This objective was to determine the plasma and CSF levels of the VEGF, bFGF, and SDF1 at diagnosis, and the plasma levels of these factors at regular intervals during therapy, and to analyze the association of these results with tumor response.
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at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)
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Number of Participants Experiencing Grade 3 or 4 Toxicity Events
Time Frame: From start of therapy through 2 years.
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Adverse events were collected systematically for each of the 44 Phase II participants from the time of enrollment to the completion of therapy (approximately 2 years from start of therapy).
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From start of therapy through 2 years.
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Collaborators and Investigators
Investigators
- Principal Investigator: Alberto Broniscer, MD, St. Jude Children's Research Hospital
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
- childhood high-grade cerebral astrocytoma
- adult glioblastoma
- adult giant cell glioblastoma
- adult gliosarcoma
- adult anaplastic astrocytoma
- adult anaplastic oligodendroglioma
- adult mixed glioma
- untreated childhood cerebellar astrocytoma
- childhood oligodendroglioma
- childhood low-grade cerebral astrocytoma
- childhood spinal cord neoplasm
- childhood mixed glioma
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Glioma
- Nervous System Neoplasms
- Central Nervous System Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Erlotinib Hydrochloride
Other Study ID Numbers
- SJHG04
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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