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Disease Attributes

Neoplasms, Neuroepithelial

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Neuroectodermal Tumors, Primitive

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Neoplasms by Histologic Type

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Flucytosine

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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.

flucytosine

polymerase chain reaction

immunohistochemistry staining method

Injected at the time of the surgery to resect the tumor

gene therapy

pharmacological study

3-Tesla magnetic resonance imaging

laboratory biomarker analysis

therapeutic conventional surgery

E. coli CD-expressing genetically modified neural stem cells

Jana Portnow

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.

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assess the presence of 5-FU in the brain with the use of fluorine (19F)-magnetic resonance spectroscopy (MRS)(no longer in effect as of 5/1/2012).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

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

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

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.

As of 5/1/2012, study patients will no longer undergo 19F-MRS.

As of 11/30/2012 patients will no longer undergo these tests.

City of Hope Medical Center

Micronutrients

Bone Density Conservation Agents

Hematinics

Vitamins

Leucovorin

Levoleucovorin

Calcium

Calcium, Dietary

Hormones

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dose escalation used the following dose levels:

Dose Level 1 (NSC 5x10\^7 and 5-FC 37.5 mg/kg)

Dose Level 2 (NSC 1x10\^8 and 5-FC 37.5 mg/kg)

Dose Level 3 (NSC 1.5x10\^8 and 5-FC 37.5 mg/kg)

Dose Level 4 (NSC 1.5x10\^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis

leucovorin calcium

This phase I trial studies the side effects and determines the best dose of genetically modified neural stem cells and flucytosine when given together with leucovorin for treating patients with recurrent high-grade gliomas. Neural stem cells can travel to sites of tumor in the brain. The neural stem cells that are being used in this study were genetically modified express the enzyme cytosine deaminase (CD), which converts the prodrug flucytosine (5-FC) into the chemotherapy agent 5-fluorouracil (5-FU). Leucovorin may help 5-FU kill more tumor cells. The CD-expressing neural stem cells are administered directly into the brain. After giving the neural stem cells a few days to spread out and migrate to tumor cells, research participants take a 7 day course of oral 5-FC. (Depending on when a research participant enters the study, they may also be given leucovorin to take with the 5-FC.) When the 5-FC crosses into brain, the neural stem cells convert it into 5-FU, which diffuses out of the neural stem cells to preferentially kill rapidly dividing tumor cells while minimizing toxicity to healthy tissues. A Rickham catheter, placed at the time of surgery, will be used to administer additional doses of NSCs every two weeks, followed each time by a 7 day course of oral 5-FC (and possibly leucovorin). This neural stem cell-based anti-cancer strategy may be an effective treatment for high-grade gliomas.

Funding Source - FDA OOPD

PRIMARY OBJECTIVES:

I. To define the phase II recommended dose of intracerebrally administered cytosine deaminase (CD)-expressing neural stem cells (NSCs) 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 characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU at the maximum tolerated dose/maximum feasible dose level.

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

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

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

Patients receive CD-expressing neural stem cells intracranially (IC) on days 1 and 15 and flucytosine orally (PO) every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally 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 at 30 days, 3 months, 6 months, 1 year, and then annually thereafter.

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

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

Number of DLTs per dose level and the MTD/MFD.

Number of participants with mechanical issues with repeat administrations of NSCs via Rickham.

Development of a antibody response to the NSCs will be evaluated by flow cytometry. Data from assessing for possible development of NSC immunogenicity with repeat exposure will be presented in an exploratory fashion using descriptive statistics.

Pharmacokinetic (PK) data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using descriptive statistics. All summaries will be exploratory in spirit.

PK data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using descriptive statistics.

PK data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using the mean ratio of average brain interstitial 5-FC concentrations to the average steady-state plasma levels.

Per RANO criteria:

Complete Response (CR): Complete disappearance of all enhancing disease that is sustained for at least 4 weeks, stable or improved non-enhancing FLAIR/T2 lesions, no new lesions, off corticosteroids, and neurologically stable or improved.

Partial Response (PR): \>= 50% decrease of all measurable enhancing lesions, sustained or at least 4 weeks, no progression of non-measurable disease, stable or improved non-enhancing FLAIR/T2 lesions, non new lesions, corticosteroid dose stable or reduced, and neurologically stable or improved.

Stable Disease (SD): Dose not qualify for CR, PR, or PD, stable non-enhancing FLAIR/T2 lesions, stable or reduced corticosteroids, clinically stable.

Progressive Disease (PD): \>=25% increase in enhancing lesion despite stable or increasing steroid dose, increase (significant) in non-enhancing T2/FLAIR lesions that is not attributable to other non-tumor causes, any new lesions, clinical deterioration

National Cancer Institute (NCI)

Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)

Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)

Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)

Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. They will also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis

Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Jana Portnow

MFD was determined to be 1.5x10\^8 in combination with oral 5-FC 37.5 mg/kg and leucovorin 25 mg every 6 hours for 7 days.

Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg)

Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg)

Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis

1 participant in dose level 4 was unevaluable and had to be replaced after receiving the first dose of CD-NSCs due to the tip of the Rickham catheter migrating into the lateral ventricle.

Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)

Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham

2 participants in dose level 4 were not assessed in this analysis because one participant only received one dose of CD-NSCs and the other we were unable to obtain post second CD-NSC dose serum sample to analyze.

Number of Participants Developing Antibodies Against NSCs

average steady state levels of 5-FC in the brain

average steady state levels of 5-FU in the brain

Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis

Average Steady State Levels of 5-FC and 5-FU in the Brain

Average Steady State Levels of 5-FC Concentrations in Plasma

Comparison of 5-FC in the Brain to 5-FC in the Plasma

Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria

Overall Study

The investigational drug in the amount of 1x10\^7, 3x10\^7cells per dose into the tumor or the tumor removal site using a syringe during surgery

Administration period: Single dose Route of administration: Intratumoral administration Dose: 1x10\^7, 3x10\^7cells/dose Summary: Administer the investigational drug in the amount of 1x107, 3x107cells per dose into the tumor or the tumor removal site using a syringe during surgery.

Concomitant drug: 5-Flucytosine (prodrug) Dose: 150mg/kg/day

Directions:

Administration period and directions: Administer 150m of 5-Flucytosine per kilogram of body weight every 6 hours for a total of 4 times a day (QID) for a duration of 7 days after surgery.

Route of administration: Oral administration

MSC11FCD

Kyunggi Cho, MD,PhD

This is a phase I trial evaluating the maximum tolerated dose, safety and efficiency of Mesenchymal stem cells into which the suicide gene, cytosine deaminase (CD), injected into the resection cavity of patients with recurrent glioblastoma.

Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients

Investigator-initiated and Open-labeled Clinical Trial for Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients

Assessment of the maximum tolerated dose based on the 3+3 method

* Blood concentrations of 5-FC and 5-FU(Day 1, Day 3, Day 7)
* MSC11FCD concentrations (MSCCD detection) (Day 0, 3months, 6months, 12months)

Evaluate the number of adverse event related to the treatment according to CTCAE V4.0 during the trial (including clinically significant changes in physical examination, radiographic images, safety lab tests, vital signs)

OS is defined as the time from the date of MSC injection to the date of death due to any cause.

The progress-free survival analysis shall be based on the RANO criteria.

Assess the treatment groups participating in this clinical trial based on the RANO criteria.

Compare and present the disease control rates by calculating the ratio of the number of subjects responding to treatment (complete response: CR, partial response: PR, stable disease: SD) among the treatment groups and control group assessed based on the RANO criteria.

Karnofsky performance status (KPS) assessment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	Adult Anaplasti... Recurrent Grade... Recurrent Grade... Adult Anaplasti... Adult Brain Tum... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Mixed Gli... Recurrent Adult... Adult Anaplasti... Recurrent High ...	flucytosine polymerase chai... immunohistochem... gene therapy pharmacological... 3-Tesla magneti... laboratory biom... therapeutic con... E. coli CD-expr...	13 Years -	City of Hope Medical Center
Genetically Modified Neural Stem Cells, Flucytosine, and Leucovorin for Treating Patients With Recurrent High-Grade Gliomas	NCT02015819	Adult Anaplasti... Adult Anaplasti... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Recurrent Adult... Anaplastic Olig...	E. coli CD-expr... flucytosine leucovorin calc... pharmacological... laboratory biom...	18 Years -	City of Hope Medical Center
Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients	NCT04657315	Glioblastoma Adult Gliosarco... Neoplasms, Brai... Neoplasms, Germ... Recurrent Gliob...	MSC11FCD	19 Years - 70 Years	CHA University
Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients	NCT04657315	Glioblastoma Adult Gliosarco... Neoplasms, Brai... Neoplasms, Germ... Recurrent Gliob...	MSC11FCD	19 Years - 70 Years	CHA University
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	Adult Anaplasti... Recurrent Grade... Recurrent Grade... Adult Anaplasti... Adult Brain Tum... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Mixed Gli... Recurrent Adult... Adult Anaplasti... Recurrent High ...	flucytosine polymerase chai... immunohistochem... gene therapy pharmacological... 3-Tesla magneti... laboratory biom... therapeutic con... E. coli CD-expr...	13 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for flucytosine

Every month we try and update this database with for flucytosine cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for flucytosine

Every month we try and update this database with for flucytosine cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for flucytosine cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.