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

NCT02015819 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 13401NCI-2013-02346FD-R-004816
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor; Anaplastic Oligoastrocytoma

Outcome Measures

Primary Outcomes (2)

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

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

  Day 28 of course 1

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

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

  28 days after last infusion of NSCs, up to 6 months total

Secondary Outcomes (5)

• Number of Participants Developing Antibodies Against NSCs

  While receiving treatment, up to 6 months.

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

  Following the first dose of 5-FC, samples were collected every hour for 24 hours and then every 3 hours thereafter until the end of the 7-day course of 5-FC or until the microdialysis catheter stopped functioning.

• Average Steady State Levels of 5-FC Concentrations in Plasma

  Samples were obtained prior to the first dose of 5-FC then every 30 minutes for 3 hours, additional samples at 4 and 6 hours after the morning doses on days 4, 5. On days 6, 7, 8 blood samples were collected just before morning dose and 90 minutes later

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

  The ratio of average brain interstitial 5-FC and 5-FU concentrations to average plasma steady-state levels was calculated using all measured data.

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

  Up to 3 years post NSC infusion

Study Arms (1)

Treatment (neural stem cells, flucytosine, leucovorin)

EXPERIMENTAL

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

Biological: E. coli CD-expressing genetically modified neural stem cells; Drug: flucytosine; Drug: leucovorin calcium; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

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

Given intracranially

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

Treatment (neural stem cells, flucytosine, leucovorin)

flucytosine DRUG

Given orally

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

Treatment (neural stem cells, flucytosine, leucovorin)

leucovorin calcium DRUG

Given orally

Also known as: CF, CFR, LV

Treatment (neural stem cells, flucytosine, leucovorin)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (neural stem cells, flucytosine, leucovorin)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (neural stem cells, flucytosine, leucovorin)

Eligibility Criteria

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

You may qualify if:

• Patient has had a prior, histologically-confirmed, diagnosis of a grade III 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). The presence of infratentorial tumor is allowed as long as the patient also has supratentorial disease that is amenable to resection or biopsy.
• 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%
• Patient has a life expectancy of \>= 3 months
• 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

You may not qualify if:

• Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the 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 (except temozolomide: only an interval of 23 days is required from the last dose administered when patient has been recently treated with the standard temozolomide regimen of daily for 5 days, repeated every 28 days)
• 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 undergo a 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 has had prior therapy with neural stem cells
• Patient is pregnant or breast feeding; pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is participating in this study
• Patient has another active malignancy

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Astrocytoma; Oligodendroglioma; Glioblastoma; Gliosarcoma; Brain Neoplasms

Interventions

Flucytosine; Leucovorin

Condition Hierarchy (Ancestors)

Glioma; 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; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Results Point of Contact

• Title: Dr. Jana Portnow
• Organization: City of Hope Medical Center

jportnow@coh.org

6262189200

Study Officials

• Jana Portnow

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: December 13, 2013
• First Posted: December 19, 2013
• Study Start: October 7, 2014
• Primary Completion: October 7, 2017
• Study Completion: October 7, 2017
• Last Updated: October 20, 2021
• Results First Posted: September 29, 2021

Record last verified: 2021-09

Locations

US (1)