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

Brain and Central Nervous System Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00124657
• Other study ID #: SJHG04
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 26, 2005
• Last updated: October 29, 2015
• Start date: March 2005
• Est. completion date: September 2014

Study information

• Verified date: October 2015
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: September 2014
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 21 Years

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

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).

Locations

Country	Name	City	State
United States	Duke Children's Hospital and Health Center	Durham	North Carolina
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	University of California San Diego	San Diego	California

Sponsors (3)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	Duke University, Rady Children's Hospital, San Diego

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose-limiting Toxicity (DLT)	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.	During the first 8 weeks of therapy	Yes
Primary	Maximum Tolerated Dose (MTD) of Erlotinib	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.	During the first 8 weeks of therapy.	Yes
Primary	Progression Free Survival (PFS)	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	No
Secondary	Cmax of Erlotinib and Its Metabolite OSI-420	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.	After first dose of therapy, and Day 8 of therapy	No
Secondary	Erlotinib Tmax	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.	After first dose of therapy	No
Secondary	AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420	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.	After first dose of therapy, and Day 8 of therapy	No
Secondary	Number of Positive Mutations of EGFR and Downstream Pathways	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	No
Secondary	Ability of Erlotinib to Inhibit EGFR Signaling	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	No
Secondary	Correlation Between Standard Magnetic Resonance Imaging and Investigational Radiologic Techniques in Assessing Tumor Response to This Treatment	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.	at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)	No
Secondary	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		5 Years	No
Secondary	Plasma and CSF Levels of VEGF, bFGF, and SDF1	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.	at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)	No
Secondary	Number of Participants Experiencing Grade 3 or 4 Toxicity Events	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).	From start of therapy through 2 years.	Yes

External Links

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