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

November 7, 2017 updated by: City of Hope Medical Center

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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assess the presence of 5-FU in the brain with the use of fluorine (19F)-magnetic resonance spectroscopy (MRS)(no longer in effect as of 5/1/2012).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

Interventional

Enrollment (Actual)

15

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Duarte, California, United States, 91010
        • City of Hope

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

13 years and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / 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.
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Other: immunohistochemistry staining method
Correlative studies
Other Names:
  • immunohistochemistry
Drug: flucytosine
Given orally
Other Names:
  • 5-FC
  • 5-fluorocytosine
  • Ancobon
  • Alcobon
  • Ancotil
  • Ro 2-9915
Other: polymerase chain reaction
Correlative studies
Other Names:
  • PCR
Biological: gene therapy
Injected at the time of the surgery to resect the tumor
Other Names:
  • therapy, gene
Other: 3-Tesla magnetic resonance imaging
Correlative studies
Other Names:
  • 3T MRI
  • 3-Tesla MRI
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 Names:
  • HB1.F3.CD neural stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Day 60

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Up to Day 10
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.
Day 60
Assessment of development of immunogenicity against NSCs
Time Frame: Day 60
As of 11/30/2012 patients will no longer undergo these tests.
Day 60
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
Day 60
Assessment of the fate of NSCs at autopsy when feasible
Time Frame: At autopsy
At autopsy
Assess the intracerebral distribution of NSCs using iron-labeling as a cellular tracker.
Time Frame: Up to Day 10
Up to Day 10

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

City of Hope Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2010

Primary Completion (ACTUAL)

February 11, 2015

Study Completion (ACTUAL)

February 11, 2015

Study Registration Dates

First Submitted

July 28, 2010

First Submitted That Met QC Criteria

July 28, 2010

First Posted (ESTIMATE)

July 30, 2010

Study Record Updates

Last Update Posted (ACTUAL)

November 9, 2017

Last Update Submitted That Met QC Criteria

November 7, 2017

Last Verified

November 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 08002
  • NCI-2010-01388 (REGISTRY: NCI CTRP)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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