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

• ClinicalTrials.gov Identifier: NCT00124657
• Recruitment Status: Completed
• First Posted: July 28, 2005
• Results First Posted: April 29, 2014
• Last Update Posted: December 4, 2015
• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Rady Children's Hospital, San Diego; Duke University
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Brain and Central Nervous System Tumors	Drug: Erlotinib hydrochloride	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: March 2005
• Actual Primary Completion Date: July 2012
• Actual Study Completion Date: September 2014

Arms and Interventions

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.

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).; Other Names: Tarceva; OSI-774; NSC#718781

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose-limiting Toxicity (DLT) [ Time Frame: During the first 8 weeks of therapy ]
   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.
2. Maximum Tolerated Dose (MTD) of Erlotinib [ Time Frame: During the first 8 weeks of therapy. ]
   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.
3. Progression Free Survival (PFS) [ Time Frame: 1 and 2 years after end of therapy ]

   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.

Secondary Outcome Measures :

1. Cmax 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.
2. Erlotinib Tmax [ Time Frame: After first dose 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.
3. 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.
4. Number of Positive Mutations of EGFR and Downstream Pathways [ Time Frame: Once at tumor resection and diagnosis ]

   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.

5. Ability of Erlotinib to Inhibit EGFR Signaling [ Time Frame: 5 Years ]

   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.

6. 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) ]
   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.
7. 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 ]
8. 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) ]
   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.
9. Number of Participants Experiencing Grade 3 or 4 Toxicity Events [ Time Frame: From start of therapy through 2 years. ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

University of California San Diego

San Diego, California, United States, 92123-4282

United States, North Carolina

Duke Children's Hospital and Health Center

Durham, North Carolina, United States, 27710

United States, Tennessee

St. Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

Sponsors and Collaborators

St. Jude Children's Research Hospital

Rady Children's Hospital, San Diego

Duke University

Investigators

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

More Information

Additional Information:

St. Jude Children's Research Hospital  Clinical Trials Open at St. Jude 

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00124657 History of Changes
• Other Study ID Numbers: SJHG04
• First Posted: July 28, 2005
• Results First Posted: April 29, 2014
• Last Update Posted: December 4, 2015
• Last Verified: October 2015

Keywords provided by St. Jude Children's Research Hospital:

adult anaplastic astrocytoma; adult anaplastic oligodendroglioma; adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; adult mixed glioma; childhood mixed glioma; untreated childhood cerebellar astrocytoma; childhood high-grade cerebral astrocytoma; childhood low-grade cerebral astrocytoma; childhood oligodendroglioma; childhood spinal cord neoplasm

Additional relevant MeSH terms:

Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms by Site; Nervous System Diseases; Erlotinib Hydrochloride; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action