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

NCT01172964 | Completed Phase 1 DMC

• 2 other identifiers: 08002NCI-2010-01388
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Los Angeles

Outcome Measures

Primary Outcomes (1)

• Determination of the safety and feasibility of intracerebral administration of genetically-modified neural stem cells (NSCs) in combination with oral 5-fluorocytosine.

  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 Outcomes (6)

• Relationship between intracerebral and systemic concentrations of 5-FC and 5-FU with increasing NSC dose level

  Up to Day 10

• Presence of 5-FU in the brain using 19F-MRS

  Day 60

• Assessment of development of immunogenicity against NSCs

  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.

  Day 60

• Assessment of the fate of NSCs at autopsy when feasible

  At autopsy

Study Arms (1)

Arm I

EXPERIMENTAL

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; 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

Interventions

flucytosine DRUG

Given orally

Also known as: 5-FC, 5-fluorocytosine, Alcobon, Ancobon, Ancotil, Ro 2-9915

Arm I

polymerase chain reaction OTHER

Correlative studies

Also known as: PCR

Arm I

immunohistochemistry staining method OTHER

Correlative studies

Also known as: immunohistochemistry

Arm I

gene therapy BIOLOGICAL

Injected at the time of the surgery to resect the tumor

Also known as: therapy, gene

Arm I

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Arm I

3-Tesla magnetic resonance imaging OTHER

Correlative studies

Also known as: 3-Tesla MRI, 3T MRI

Arm I

laboratory biomarker analysis OTHER

Correlative studies

Arm I

therapeutic conventional surgery PROCEDURE

Surgery to resect the tumor

Arm I

E. coli CD-expressing genetically modified neural stem cells BIOLOGICAL

Injected at the time of the surgery to resect the tumor

Also known as: HB1.F3.CD neural stem cells

Arm I

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• City of Hope Medical Center: lead

Study Sites (1)

City of Hope

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Astrocytoma; Oligodendroglioma; Brain Neoplasms; Glioblastoma; Gliosarcoma; Glioma

Interventions

Flucytosine; Polymerase Chain Reaction; Immunohistochemistry; Genetic Therapy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytosine; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acid Amplification Techniques; Genetic Techniques; Investigative Techniques; Histocytochemistry; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Histological Techniques; Immunologic Techniques; Biological Therapy; Therapeutics; Genetic Engineering

Study Officials

• Jana Portnow

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2010
• First Posted: July 30, 2010
• Study Start: August 1, 2010
• Primary Completion: February 11, 2015
• Study Completion: February 11, 2015
• Last Updated: November 9, 2017

Record last verified: 2017-11

Locations

US (1)