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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Rady Children's Hospital, San Diego
Duke University
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00124657
First received: July 26, 2005
Last updated: August 25, 2014
Last verified: August 2014
  Purpose

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 Intervention Phase
Brain and Central Nervous System Tumors
Drug: Erlotinib hydrochloride
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • Number of Participants With Dose-limiting Toxicity (DLT) [ Time Frame: During the first 8 weeks of therapy ] [ Designated as safety issue: Yes ]
    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.

  • Maximum Tolerated Dose (MTD) of Erlotinib [ Time Frame: During the first 8 weeks of therapy. ] [ Designated as safety issue: Yes ]
    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.

  • Progression Free Survival (PFS) [ Time Frame: 1 and 2 years after end of therapy ] [ Designated as safety issue: No ]

    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:
  • Cmax of Erlotinib and Its Metabolite OSI-420 [ Time Frame: After first dose of therapy, and Day 8 of therapy ] [ Designated as safety issue: No ]
    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.

  • Erlotinib Tmax [ Time Frame: After first dose of therapy ] [ Designated as safety issue: No ]
    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.

  • AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420 [ Time Frame: After first dose of therapy, and Day 8 of therapy ] [ Designated as safety issue: No ]
    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.

  • Number of Positive Mutations of EGFR and Downstream Pathways [ Time Frame: Once at tumor resection and diagnosis ] [ Designated as safety issue: No ]

    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.


  • Ability of Erlotinib to Inhibit EGFR Signaling [ Time Frame: 5 Years ] [ Designated as safety issue: No ]

    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.


  • 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) ] [ Designated as safety issue: No ]

    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.

    This objective became obsolete over the course of the protocol and was not analyzed.


  • 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 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]

    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.

    The analysis became obsolete over the course of the protocol and was not done.


  • Number of Participants Experiencing Grade 3 or 4 Toxicity Events [ Time Frame: From start of therapy through 2 years. ] [ Designated as safety issue: Yes ]
    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).


Enrollment: 62
Study Start Date: March 2005
Estimated Study Completion Date: September 2014
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   3 Years to 21 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00124657

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:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00124657     History of Changes
Other Study ID Numbers: SJHG04
Study First Received: July 26, 2005
Results First Received: September 10, 2013
Last Updated: August 25, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

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
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 01, 2014