Erlotinib and Radiation Therapy in Treating Young Patients With Newly Diagnosed Glioma

Official Title: “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.

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.

Intervention(s) in this Clinical Trial

• Drug: Erlotinib hydrochloride
  • 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).

Arms, Groups and Cohorts in this Clinical Trial

• 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.

Primary Measures

• estimate the MTD and determine the DLT of erlotinib when given once a day continuously during and after RT in children, adolescents, and young adults with newly diagnosed high-grade glioma and unfavorable low-grade glioma
  • Time Frame: 5 Years
    Safety Issue?: Yes
• estimate the 1- and 2-year PFS of children, adolescents, and young adults with intracranial anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) treated with a combination of maximum safe surgical resection, local RT, and erlotinib (Tarceva™)
  • Time Frame: 5 Years
    Safety Issue?: No

Secondary Measures

• To determine the toxicities associated with the chronic use of erlotinib in these patients
  • Time Frame: 5 Years
    Safety Issue?: No
• To analyze the EGFR and some of the components of downstream pathways for specific genetic abnormalities (e.g., amplification, mutation), and to investigate their influence on treatment response
  • Time Frame: 5 Years
    Safety Issue?: No
• To test the ability of erlotinib to inhibit the EGFR signaling in patients with high-grade glioma who require second surgery
  • Time Frame: 5 Years
    Safety Issue?: No
• To prospectively investigate the correlation between standard (magnetic resonance imaging [MRI]) and investigational (MR spectroscopy, perfusion/diffusion, PET scan, DEMRI/BLAST) radiologic techniques in assessing tumor response to this treatment
  • Time Frame: 5 Years
    Safety Issue?: No
• 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
  • Time Frame: 5 Years
    Safety Issue?: No
• 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
    Safety Issue?: No
• To identify genomic regions of gains and losses and to perform a global analysis of gene expression in pediatric high-grade glioma. Based on our results, validation studies are also planned.
  • Time Frame: 5 Years
    Safety Issue?: No

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 25
• Performance status
• Karnofsky 40-100% (age 17 to 25 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 3 Years

Maximum Age for this Clinical Trial: 25 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: St. Jude Children's Research Hospital Other

Overall Clinical Trial Officials and Contacts

Alberto Broniscer, MD Principal Investigator St. Jude Children's Research Hospital  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00124657

Study ID Number: SJHG04

ClinicalTrials.gov Identifier: NCT00124657

Health Authority: United States: Food and Drug Administration

St. Jude Children's Research Hospital