A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas
This study is currently recruiting participants.
Verified July 2012 by City of Hope Medical Center

First Received on July 28, 2010.  
Last Updated on July 17, 2012  
History of Changes
Sponsor: City of Hope Medical Center
Information provided by (Responsible Party): City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01172964
  Purpose

RATIONALE: Genetically-modified neural stem cells (NSCs) that convert 5-fluorocytosine (5-FC) into the chemotherapy agent 5-FU at sites of tumor in the brain may be an effective treatment for glioma.

PURPOSE: This clinical trial studies genetically-modified NSCs and 5-FC in patients undergoing surgery for recurrent high-grade gliomas.

Condition Intervention
Adult Anaplastic Astrocytoma
Recurrent Grade III Glioma
Recurrent Grade IV Glioma
Adult Anaplastic Oligodendroglioma
Adult Brain Tumor
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Mixed Glioma
Recurrent Adult Brain Tumor
Adult Anaplastic Oligoastrocytoma
Recurrent High Grade Glioma
Drug: flucytosine
Other: polymerase chain reaction
Other: immunohistochemistry staining method
Biological: gene therapy
Other: pharmacological study
Other: 3-Tesla magnetic resonance imaging
Other: laboratory biomarker analysis
Procedure: therapeutic conventional surgery
Biological: E. coli CD-expressing genetically modified neural stem cells

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

Resource links provided by NLM:

Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:

  • Determination of the safety and feasibility of intracerebral administration of genetically-modified neural stem cells (NSCs) in combination with oral 5-fluorocytosine. [ Time Frame: Day 60 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

  • Relationship between intracerebral and systemic concentrations of 5-FC and 5-FU with increasing NSC dose level [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • Presence of 5-FU in the brain using 19F-MRS [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • Assessment of development of immunogenicity against NSCs [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • Obtain preliminary imaging data regarding perfusion permeability parameters and imaging characteristics as shown on magnetic resonance imaging (MRI) studies due to the presence of NSCs in the brain. [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • Assessment of the fate of NSCs at autopsy when feasible [ Time Frame: At autopsy ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: August 2010
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Arms

Assigned Interventions
Experimental: Arm I

Patients undergo debulking craniotomy and receive injections of HB1.F3.CD neural stem cells directly into brain tissue on day 0. Patients then receive oral 5-fluorocytosine every 6 hours on days 4-10 in the absence of disease progression or unacceptable toxicity.
Drug: flucytosine

Given orally
Other Names:
  • 5-FC
  • 5-fluorocytosine
  • Alcobon
  • Ancobon
  • Ancotil
  • Ro 2-9915

Other: polymerase chain reaction

Correlative studies
Other Name: PCR

Other: immunohistochemistry staining method

Correlative studies
Other Name: immunohistochemistry

Biological: gene therapy

Injected at the time of the surgery to resect the tumor
Other Name: therapy, gene

Other: pharmacological study

Correlative studies
Other Name: pharmacological studies

Other: 3-Tesla magnetic resonance imaging

Correlative studies
Other Names:
  • 3-Tesla MRI
  • 3T MRI

Other: laboratory biomarker analysis

Correlative studies

Procedure: therapeutic conventional surgery

Surgery to resect the tumor

Biological: E. coli CD-expressing genetically modified neural stem cells

Injected at the time of the surgery to resect the tumor
Other Name: HB1.F3.CD neural stem cells

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and feasibility of intracerebral administration of NSCs in combination with oral 5-FC in patients with recurrent high-grade gliomas.

SECONDARY OBJECTIVES:

I. To characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU with increasing NSC dose level.

II. To non-invasively assess the presence of 5-FU in the brain with the use of (19F)-magnetic resonance spectroscopy (MRS).

III. To assess for the possible development of immunogenicity against the NSCs. IV. To assess the intracerebral distribution of NSCs using iron-labeling as a cellular tracker.

V. To gather preliminary imaging data regarding perfusion permeability parameters and imaging characteristics as shown on magnetic resonance imaging (MRI) studies due to the presence of NSCs in the brain.

VI. To determine, at time of autopsy, the fate of the NSCs.

OUTLINE:

This is a dose-escalation study.

At the time of surgery to resect tumor, study patients receive injections of genetically modified NSCs directly into brain tissue on day 0. Patients then take oral 5-FC every 6 hours during days 4-10 which is converted to 5-FU in the brain by the NSCs.

Follow-up MRIs of the brain are performed on days 32, 60, and every 2 months thereafter to assess for response and side effects.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient has had a prior, histologically-confirmed, diagnosis of a grade III or grade IV glioma (including glioblastoma, anaplastic astrocytoma, gliosarcoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma), or has a prior, histologically-confirmed, diagnosis of a grade II glioma and now has radiographic findings consistent with a high-grade glioma (grade III or IV)
  • Imaging studies show evidence of recurrent supratentorial tumor(s)
  • The patient must be in need of a craniotomy for tumor resection or a stereotactic brain biopsy for the purpose of diagnosis or differentiating between tumor progression versus treatment-induced effects following radiation therapy +/- chemotherapy
  • Based on the neurosurgeon’s judgment, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
  • Patient’s high-grade glioma has recurred or progressed after chemoradiation
  • Patient has a Karnofsky Performance Status of >= 70%
  • Patient has a life expectancy of >=3 months
  • If patient requires corticosteroids for the control of cerebral edema, s/he must be on a stable dose for at least 1 week prior to enrollment
  • Absolute neutrophil count >= 1500 cells/mm^3
  • Platelet count >= 100,000 cells/mm^3
  • Total bilirubin =< 2.0 mg/dl
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times the institutional upper limit of normal
  • Serum creatinine =< the institutional upper limit of normal
  • Patients must be able to swallow pills
  • Patients must be able to understand and be willing to sign a written informed consent document
  • Female patients of child-bearing potential and sexually active male patients must agree to use an effective method of contraception while participating in this study
  • Women of childbearing potential must have a negative pregnancy =< 2 weeks prior to registration

Exclusion Criteria:

  • Patients who are currently receiving chemotherapy, radiotherapy, or are enrolled in another treatment clinical trial
  • Patients who have anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the HB1.F3.CD NSCs
  • Patients who are unable to undergo an MRI
  • Patients with chronic or active viral infections of the central nervous system (CNS)
  • Patients who are allergic to 5-FC or 5-FU
  • Patients who have a serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
  • Female patients who are pregnant or breast-feeding
  • Patients who have not recovered from the toxicities of prior chemotherapy or radiotherapy
  • Patients who require anti-seizure medication but are not on a stable dose of anti-seizure medication for at least 1 week prior to enrollment

INCLUSION CRITERIA FOR PROCEEDING TO TREATMENT WITH 5-FC:

  • Patients must be tolerating oral intake
  • Patients’ daily total dose of dexamethasone must be < 12 mg by Day 4
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01172964

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Jana L. Portnow     800-826-4673     jportnow@coh.org    
Contact: Dept. of Neurosurgery     626-471-9393     neurosurgery@coh.org    
Principal Investigator: Jana L. Portnow            
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Jana Portnow Beckman Research Institute
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01172964    
History of Changes
Other Study ID Numbers: 08002, NCI-2010-01388
Study First Received: July 28, 2010
Last Updated: July 17, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by City of Hope Medical Center:

Los Angeles

Additional relevant MeSH terms:

Astrocytoma
Brain Neoplasms
Glioblastoma
Glioma
Oligodendroglioma
Gliosarcoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Flucytosine
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2012

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