The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma

Inclusion Criteria:

1. Subject has given written informed consent

2. Subject is between 18 years old and 75 years old, inclusive

3. Subjects must have histologically proven GBM or AA and:

4. Must have received first-line multimodal therapy with surgery followed bytemozolomide (unless MGMT promoter unmethylated) and radiation (subjects with GBMmust have received temozolomide and radiation concurrently)

5. Must be in first or second recurrence (including this recurrence)

6. Recurrence must be confirmed by diagnostic biopsy with local pathology review orcontrast-enhanced MRI. If first recurrence of GBM is documented by MRI, aninterval of at least 12 weeks after the end of prior radiation therapy isrequired unless there is either: i) histopathologic confirmation of recurrenttumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field

7. Subjects must have measurable disease preoperatively, defined as at least 1contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as perRANO criteria

8. Subjects must be at least 4 weeks post last dose of temozolomide

9. Prior gamma knife, stereotactic radiosurgery, or other focal high-dose radiotherapy isallowed but the subject must have either histopathologic confirmation of recurrenttumor, or new enhancement on MRI outside of the radiotherapy treatment field

10. Based on the pre-operative evaluation by neurosurgeon, the subject is a candidate for ≥ 80% resection of enhancing region

11. IDH mutation status of the primary tumor must be available or tumor samples must beavailable for pre randomization testing

12. Laboratory values adequate for patient to undergo surgery, including:

• Platelet count ≥ 60,000/mm3

• Hgb ≥ 10 g/dL

• Absolute neutrophil count (ANC) ≥ 1,500/mm3

• Absolute lymphocyte count (ALC) ≥ 500/mm3

• Adequate liver function, including:

• Total bilirubin ≤ 1.5 x ULN (unless has Gilbert's syndrome)

• ALT ≤ 2.5 x ULN f. Estimated glomerular filtration rate of at least 50mL/min by the Cockcroft Gault formula

10. Women of childbearing potential (≥12 months of non-therapy-induced amenorrhea orsurgically sterile) must have had a negative serum pregnancy test within the past 21days and must use a birth control method in addition to barrier methods (condoms).

11. Subject or subject's partner is willing to use condoms for 12 months after receivingToca 511 or until there is no evidence of the virus in his/her blood, whichever islonger.

12. The subject has a KPS ≥ 70

13. The subject is willing and able to abide by the protocol

Exclusion Criteria:

1. History of more than 2 prior recurrences (including this recurrence) of GBM or AA

2. History of other malignancy, unless the patient has been disease free for at least 5years. Adequately treated basal cell carcinoma or squamous cell skin cancer isacceptable regardless of time, as well as localized prostate carcinoma or cervicalcarcinoma in situ after curative treatment

3. Histologically confirmed oligodendroglioma or mixed glioma

4. Known 1p/19q co deletion

5. A contrast enhancing brain tumor that is any of the following:

• Multi focal (defined as 2 separate areas of contrast enhancement measuring atleast 1 cm in 2 planes that are not contiguous on either fluid attenuatedinversion recovery (FLAIR) or T2 sequences);

• Associated with either diffuse subependymal or leptomeningeal dissemination; or

• > 5 cm in any dimension

6. The subject has or had any active infection requiring systemic antibiotic, antifungalor antiviral therapy within the past 4 weeks

7. The subject has any bleeding diathesis, or must take anticoagulants, or antiplateletagents, including nonsteroidal anti inflammatory drugs (NSAIDs), at the time of thescheduled resection that cannot be stopped for surgery

8. The subject is human immunodeficiency virus (HIV) positive

9. The subject has a history of allergy or intolerance to flucytosine

10. The subject has a gastrointestinal disease that would prevent him or her from beingable to swallow or absorb flucytosine

11. The subject received cytotoxic chemotherapy within the past 4 weeks (6 weeks fornitrosoureas) of the planned surgery date

12. The subject received any investigational treatment within the past 30 days or priorimmunotherapy or antibody therapy within the past 45 days.

13. The subject is pregnant or breast feeding

14. The subject intends to undergo treatment with the Gliadel® wafer at the time of thissurgery or has received the Gliadel® wafer < 30 days from W1D1 (surgery)

15. The subject has received bevacizumab for their disease unless in the context ofprimary therapy for newly diagnosed glioma

16. For subjects planned to potentially receive bevacizumab, they have no evidence ofuncontrolled hypertension (defined as a blood pressure of ≥ 150 mm Hg systolic and/or ≥ 100 mm Hg diastolic on medication) or active GI perforation

17. The subject has received systemic dexamethasone continuously at a dose > 8 mg/day for 8 weeks prior to the date of the screening assessment

18. Severe pulmonary, cardiac or other systemic disease, specifically:

• New York Heart Association > Grade 2 congestive heart failure within 6 monthsprior to study entry, unless asymptomatic and well controlled with medication

• Uncontrolled or significant cardiovascular disease, clinically significantventricular arrhythmia (such as ventricular tachycardia, ventricularfibrillation, or Torsades des pointes), clinically significant pulmonary disease (such as ≥ Grade 2 dyspnea, according to CTCAE 4.03)

• Subjects who have any other disease, either metabolic or psychological, which asper Investigator assessment may affect the subject's compliance or place thesubject at higher risk of potential treatment complications