This is a multicenter study evaluating the safety and tolerability of Toca 511 administered intravenously to patients with recurrent or progressive Grade III or Grade IV Gliomas who have elected to undergo surgical removal of their tumor. Patients meeting all of the inclusion and none of the exclusion criteria will receive an initial dose of Toca 511 administered as an intravenous, bolus injection, followed approximately 11 days later by an additional dose injected into the walls of the resection cavity at the time of planned tumor resection. Approximately 6 weeks later, patients will begin treatment with oral Toca FC, an antifungal agent, and repeated every 4 weeks. All patients enrolled in this study will be encouraged to participate in a continuation protocol that enables additional Toca FC administration and the collection of long-term safety and response data.

Inclusion Criteria:

• Has the subject given written informed consent?
• Is the subject between 18 years old and 80 years old inclusive?
• Has the subject 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 HGG 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 either (1) a single, enhancing tumor recurrence/progression that is ≤ 8 cm in greatest dimension, or (2) multiple enhancing tumor recurrences/progressions within the same surgical field where the sum of their greatest dimensions is ≤ 8 cm?
• Based on the pre-operative evaluation, is the tumor recurrence/progression a candidate for ≥ 80% resection?
• Has the subject elected not to undergo treatment with the Gliadel® wafer?
• Does the subject have a Karnofsky performance status ≥ 70?
• Does the subject have an absolute neutrophil count (ANC) ≥ 1500/mm3?
• Does the subject have an absolute lymphocyte count ≥ 500/mm3?
• Does the subject have a platelet count ≥ 100,000/mm3?
• Does the subject have a Hgb ≥ 10 g/dL?
• Does the subject have a coagulation profile that would allow for the safe performance of surgery under general anesthesia?
• Does the subject have an estimated glomerular filtration rate of at least 50 mL/min (inclusive) by the Cockcroft-Gault formula?
• Does the subject have an ALT < 3 times the upper limit of the laboratory reference range and total bilirubin < 1.5 mg/dL?
• If the subject is a female of childbearing potential, has she had a negative serum pregnancy test within the past 21 days?
• Is the subject 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 subject is a fertile female, is she willing to use contraception for at least 12 months?
• Is the subject willing and able to abide by the protocol?
• Does the subject have adequate venous access?

Exclusion Criteria:

• Has the subject received cytotoxic chemotherapy within the past 3 weeks (6 weeks for nitrosoureas) of the planned date of vector injection?
• Does the subject have, or has the subject had, within the past 4 weeks any infection requiring antibiotic, antifungal or antiviral therapy?
• Has the subject received Avastin® (bevacizumab) for this recurrence/progression, or within the 4 weeks prior to planned Visit 1?
• Does the subject have any bleeding diathesis, or must the subject take any anticoagulants, or antiplatelet agents, including NSAIDs that cannot be stopped for surgery?
• Does the subject have a history of allergy or intolerance to flucytosine?
• Is the subject HIV positive?
• Does the subject have any gastrointestinal disease that would prevent him or her from being able to swallow or absorb flucytosine?
• Has the subject received any investigational treatment within the past 30 days?
• Is the subject breastfeeding?
• 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?