Genetically Modified Neural Stem Cells, Flucytosine, and Leucovorin for Treating Patients With Recurrent High-Grade Gliomas
Condition: Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor; Anaplastic Oligoastrocytoma
MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Recurrence
Intervention: E. coli CD-expressing genetically modified neural stem cells; flucytosine; leucovorin calcium; pharmacological study; laboratory biomarker analysis
Intervention description: Given intracranially; Given orally; Given orally; Correlative studies; Correlative studies
Intervention MeSH terms: Leucovorin; Flucytosine; Calcium; Levoleucovorin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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

          -  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