Genetically Modified Neural Stem Cells, Flucytosine, and Leucovorin Calcium in Treating Patients With Recurrent High-Grade Gliomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT02015819
First received: December 13, 2013
Last updated: October 9, 2014
Last verified: October 2014
  Purpose

This phase I trial studies the side effects and best dose of genetically-modified neural stem cells and flucytosine when given together with leucovorin calcium in treating patients with recurrent high-grade gliomas. Placing the gene for Escherichia coli (E. coli) cytosine deaminase into neural stem cells may improve the body's ability to fight cancer or make the cancer more sensitive to chemotherapy. Drugs used in chemotherapy, such as flucytosine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Leucovorin calcium may help flucytosine kill more tumor cells by making tumor cells more sensitive to the drug. Giving genetically-modified neural stem cells and flucytosine with leucovorin calcium may be an effective treatment for high-grade gliomas.


Condition Intervention Phase
Adult Anaplastic Astrocytoma
Adult Anaplastic Ependymoma
Adult Anaplastic Meningioma
Adult Anaplastic Oligodendroglioma
Adult Ependymoblastoma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Medulloblastoma
Adult Papillary Meningioma
Adult Pineoblastoma
Adult Supratentorial Primitive Neuroectodermal Tumor (PNET)
Recurrent Adult Brain Tumor
Biological: E. coli CD-expressing genetically modified neural stem cells
Drug: flucytosine
Drug: leucovorin calcium
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Cytosine Deaminase-Expressing Neural Stem Cells in Combination With Oral 5-Fluorocytosine and Leucovorin for the 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:
  • Maximum tolerated dose (MTD) and incidence of dose limiting toxicities (DLTs) [ Time Frame: Day 28 of course 1 ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ, severity assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and attribution. Rates and associated 95% confidence limits will be estimated for the DLT rate at the MTD.

  • Incidence of all adverse events and toxicities [ Time Frame: Up to 28 days after the last infusion of NSCs ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ, severity assessed by NCI CTCAE version 4.0.


Secondary Outcome Measures:
  • T cell responses and antibodies against NSCs using T-cell receptor beta chain variable region (TcR Vbeta), CD 107 assays, and flow cytometry [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Development of a T cell response to the NSCs will be evaluated by a combination of TcR Vbeta spectratyping and CD1-7 degranulation assays using established laboratory SOP and protocols. Data from assessing for possible development of NSC immunogenicity with repeat exposure will be presented in an exploratory fashion using descriptive statistics and graphical methods.

  • Pharmacokinetic (PK) parameters (Tmax, Cmax, area under the curve [AUC], t 1/2) [ Time Frame: Baseline and on days 4-8 of course 1 ] [ Designated as safety issue: No ]
    PK data from the patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods. All summaries will be exploratory in spirit.

  • Ratio of the AUC of 5-FU in dialysate to plasma [ Time Frame: Baseline and on days 4-8 of course 1 ] [ Designated as safety issue: No ]
    PK data from the patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods.

  • Ratio of the AUC of flucytosine in dialysate to plasma [ Time Frame: Baseline and on days 4-8 of course 1 ] [ Designated as safety issue: No ]
    PK data from the patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods.

  • NSC biodistribution, specifically the area of NSC coverage [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Data from studying the distribution of NSCs in the brain via iron-labeling of the NSCs will be presented in an exploratory fashion using descriptive statistics and graphical methods.

  • Tumor response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Data from obtaining serial brain MRIs to assess clinical benefit to patients will be presented in an exploratory fashion using descriptive statistics and graphical methods.

  • Fate of NSCs, specifically NSC persistence [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Data from performing autopsies to determine the date of the NSCs will be presented in an exploratory fashion using descriptive statistics and graphical methods.


Estimated Enrollment: 39
Study Start Date: October 2014
Estimated Primary Completion Date: October 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (neural stem cells, flucytosine, leucovorin calcium)
Patients receive E. coli CD-expressing genetically modified neural stem cells IC on days 1 and 15 and flucytosine PO every 6 hours and leucovorin calcium PO every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: E. coli CD-expressing genetically modified neural stem cells
Given IC
Other Name: HB1.F3.CD neural stem cells
Drug: flucytosine
Given PO
Other Names:
  • 5-FC
  • 5-fluorocytosine
  • Ro 2-9915
Drug: leucovorin calcium
Given PO
Other Names:
  • CF
  • CFR
  • LV
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To define the phase II recommended dose of intercerebrally administered cytosine deaminase (CD)-expressing neural stem cells (NSCs) (E. coli CD-expressing genetically modified neural stem cells) in combination with oral 5-fluorocytosine (FC) (flucytosine) and leucovorin.

II. To determine the feasibility of treating study patients with more than 1 dose of NSCs followed by 7-day courses of 5-FC and leucovorin.

SECONDARY OBJECTIVES:

I. To assess for possible development of NSC immunogenicity (anti-NSC T cell and/or antibody response) with repeat doses of NSCs.

II. To characterized the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU at the maximum tolerated dose level.

III. To evaluate the intracerebral distribution of NSCs using iron-labeling as a cellular tracker.

IV. To describe the clinical benefit (defined as stable disease, partial response, or complete response) of this treatment regimen.

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

OUTLINE: This is dose-escalation study of E. coli CD-expressing genetically modified neural stem cells and flucytosine.

Patients receive E. coli CD-expressing genetically modified neural stem cells intracranially (IC) on days 1 and 15 and flucytosine orally (PO) every 6 hours and leucovorin calcium PO every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 months, 6 months, 1 year, and then annually thereafter.

  Eligibility

Ages Eligible for Study:   18 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 IIII or IV glioma (including glioblastoma, anaplastic oligodendroglioma, or 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)
  • Patient's high-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide
  • Patient has a Karnofsky performance status of >= 70%
  • Female patients of childbearing 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 test =< 2 weeks prior to registration
  • 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 judgement, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
  • Absolute neutrophil count (ANC) >= 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
  • There is no limit to the number of prior therapies
  • All subjects must have the ability to understand and the willingness to sign a written informed consent
  • PROCEEDING TO TREATMENT WITH 5-FC:
  • Patient must be tolerating oral intake
  • A patient's daily total dose of dexamethasone must be < 16 mg by day 4

Exclusion Criteria:

  • Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the HB1.F3.CD NSCs
  • Patient has not recovered from any toxicity of prior therapies; an interval of

    • At least 6 weeks must have elapsed since taking a nitrosourea-containing chemotherapy regimen
    • At least 4 weeks since completing a non-nitrosourea-containing cytotoxic chemotherapy regimen
    • At least 2 weeks from taking the last dose of targeted agent
    • At least 4 weeks from the last dose of bevacizumab
  • Patient is unable to under an magnetic resonance imaging (MRI)
  • Patient is allergic to 5-FC, leucovorin, or 5-FU
  • Patient has chronic or active viral infections of the central nervous system (CNS)
  • Patient has a coagulopathy or bleeding disorder
  • Patient has an uncontrolled illness including ongoing or active infection
  • Patient is receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
  • Patient is pregnant or breast feeding
  • Patient has another active malignancy
  • Non-compliance; a patient has a serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the safety monitoring requirements and completion of treatment according to this protocol
  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: NCT02015819

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Jana L. Portnow    800-826-4673    jportnow@coh.org   
Principal Investigator: Jana L. Portnow         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Jana Portnow City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02015819     History of Changes
Other Study ID Numbers: 13401, NCI-2013-02346, 13401, P30CA033572
Study First Received: December 13, 2013
Last Updated: October 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Ependymoma
Gliosarcoma
Oligodendroglioma
Meningioma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Medulloblastoma
Neoplasms
Glioma
Neoplasms, Neuroepithelial
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Calcium, Dietary
Flucytosine
Levoleucovorin
Leucovorin
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antifungal Agents

ClinicalTrials.gov processed this record on October 19, 2014