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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

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ClinicalTrials.gov Identifier: NCT01172964
Recruitment Status : Completed
First Posted : July 30, 2010
Last Update Posted : November 9, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:

RATIONALE: Genetically-modified neural stem cells (NSCs) that convert 5-fluorocytosine (5-FC) into the chemotherapy agent 5-FU (fluorouracil) 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 or disease Intervention/treatment Phase
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 Phase 1

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assess the presence of 5-FU in the brain with the use of fluorine (19F)-magnetic resonance spectroscopy (MRS)(no longer in effect as of 5/1/2012).

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.

After biopsy or 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.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : August 2010
Primary Completion Date : February 11, 2015
Study Completion Date : February 11, 2015


Arms and Interventions

Arm Intervention/treatment
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


Outcome Measures

Primary Outcome Measures :
  1. 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 ]
    Measures of feasibility include the incidence of clinically symptomatic intratumoral hemorrhage, CNS infection, seizures, altered mental status, development of focal neurologic deficits, as well as chemotherapy-associated toxicities. All toxicities at each dose level will be summarized using descriptive statistics. Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0


Secondary Outcome Measures :
  1. Relationship between intracerebral and systemic concentrations of 5-FC and 5-FU with increasing NSC dose level [ Time Frame: Up to Day 10 ]
    Summarized by NSC dose cohort using descriptive statistics and graphs. The Macdonald Criteria will be used to assess response. As of 11/30/2012 patients will no longer undergo these tests.

  2. Presence of 5-FU in the brain using 19F-MRS [ Time Frame: Day 60 ]
    As of 5/1/2012, study patients will no longer undergo 19F-MRS.

  3. Assessment of development of immunogenicity against NSCs [ Time Frame: Day 60 ]
    As of 11/30/2012 patients will no longer undergo these tests.

  4. 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 ]
  5. Assessment of the fate of NSCs at autopsy when feasible [ Time Frame: At autopsy ]
  6. Assess the intracerebral distribution of NSCs using iron-labeling as a cellular tracker. [ Time Frame: Up to Day 10 ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
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
  • Patient has recovered from toxicity of prior therapies; an interval of at least 12 weeks must have elapsed since the completion of radiation therapy; at least 6 weeks since the completion of nitrosourea-containing chemotherapy regimen; and at least 4 weeks since the completion of a non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent treatment was with a targeted agent only; and s/he has recovered from any toxicity of this targeted agent, then a waiting period of only 2 weeks is needed from the last dose and the start of study treatment, with the exception of bevacizumab where a wash out period of at least 4 weeks is required before starting study treatment
  • Absolute neutrophil count of >= 1,500 cells/mm^3 and 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

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

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01172964


Locations
United States, California
City of Hope
Duarte, California, United States, 91010
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Jana Portnow City of Hope Medical Center
More Information

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01172964     History of Changes
Other Study ID Numbers: 08002
NCI-2010-01388 ( Registry Identifier: NCI CTRP )
First Posted: July 30, 2010    Key Record Dates
Last Update Posted: November 9, 2017
Last Verified: November 2017

Keywords provided by City of Hope Medical Center:
Los Angeles

Additional relevant MeSH terms:
Glioblastoma
Glioma
Brain Neoplasms
Astrocytoma
Gliosarcoma
Oligodendroglioma
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
Antimetabolites
Molecular Mechanisms of Pharmacological Action