This is a multicenter study evaluating the safety and tolerability of increasing doses of Toca 511, a retroviral replicating vector, injected into the resection cavity of patients with Grade III or Grade IV Gliomas who have elected to undergo surgical removal of their tumor. Approximately 6 weeks after injection of Toca 511, patients will begin an oral courses of Toca FC, an antifungal agent. These one week courses of Toca FC will be repeated during the approximately 30 week study. Two separate cohorts of patients treated with Toca 511 and Toca FC will also be evaluated with either of the following standard treatments for glioma: lomustine or bevacizumab. After completion of this study, all patients will be eligible for enrollment and encouraged to enter a long-term continuation protocol that enables additional Toca FC treatment cycles to be given, as well as permits the collection of long-term safety and survival data.

Inclusion Criteria (must all be answered "Yes"):

• Has the patient given written informed consent?
• Is the patient between 18 years old and 80 years old inclusive?
• Has the patient had histologically proven HGG with recurrence or progression following initial definitive therapy(s) such as surgery with or without adjuvant radiation therapy and/or chemotherapy (confirmed by diagnostic biopsy or contrast-enhanced MRI and evaluable by Macdonald criteria)? Note if first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field.
• Does the patient have a single, HGG tumor recurrence/progression that is ≤ 5 cm in its greatest dimension?
• Based on the pre-operative evaluation, is the tumor recurrence/progression a candidate for ≥ 80% resection?
• Has the patient elected not to undergo treatment with the Gliadel® wafer?
• Does the patient have a Karnofsky performance status ≥ 70?
• Does the patient have an absolute neutrophil count (ANC) ≥ 1500/mm3?
• Does the patient have an absolute lymphocyte count ≥ 500/mm3?
• Does the patient have a platelet count ≥ 100,000/mm3?
• Does the patient have a Hgb ≥ 10 g/dL?
• Does the patient have a normal PT/PTT? (subnormal PT/PTT acceptable)
• Does the patient have an estimated glomerular filtration rate of at least 50 mL/min (inclusive) by the Cockcroft-Gault formula?
• Does the patient have an ALT < 3 times the upper limit of the laboratory reference range and total bilirubin < 1.5 mg/dL?
• If the patient is a female of childbearing potential, has she had a negative serum pregnancy test within the past 21 days?
• Is the patient willing to use condoms for contraception for 6 months after receiving Toca 511 or until there is no evidence of the virus in his/her blood, whichever is longer. If the patient is a fertile female, is she willing to use contraception for at least 12 months?
• Is the patient willing and able to abide by the protocol?

Exclusion Criteria (must all be answered "No"):

• Has the patient received cytotoxic chemotherapy within the past 3 weeks (6 weeks for nitrosoureas) of the planned surgery date?
• Does the patient have, or has the subject had, within the past 4 weeks any infection requiring antibiotic, antifungal or antiviral therapy?
• Has the patient had a surgical procedure in the last 28 days or a surgical wound that is not healed?
• Does the patient have any bleeding diathesis, or must the subject take any anticoagulants, or antiplatelet agents, including NSAIDs that cannot be stopped for surgery?
• Does the patient have a history of allergy or intolerance to flucytosine?
• Is the patient HIV positive?
• Does the patient have any gastrointestinal disease that would prevent him or her from being able to ingest or absorb flucytosine?
• Has the patient received any investigational treatment within the past 30 days?
• Is the patient breast feeding?
• Has the patient received Avastin® (bevacizumab) for this recurrence/progression, or within the past 5 weeks?
• Does the patient have a history of prior malignancy, excluding basal or squamous cell carcinoma of the skin, with an expected survival of less than five years?