Protocol Summary

Protocol No.: OCR14652

Sponsor Protocol No.: Tg 511-15-01

Study Title
A Phase 2/3 Randomized, Open-Label Study of Toca 511, A Retroviral Replicating Vector, Combined with Toca FC versus Standard of Care in Subjects Undergoing Planned Resection for Recurrent Glioblastoma or Anaplastic Astrocytoma

Principal Investigator(s)
Tran, David

This is a multicenter, randomized, open-label phase 2/3 study of Toca 511 and Toca FC versus standard of care that comprises Investigator's choice of single agent chemotherapy (lomustine or temozolomide) or bevacizumab administered to subjects undergoing resection for first or second recurrence (including this recurrence) of GBM or AA.

Subjects meeting all of the inclusion and none of the exclusion criteria will be randomized prior to surgery in a 1:1 ratio to receive either Toca 511 and Toca FC (Experimental arm, Arm T) or control treatment with one option of standard of care (Arm SOC). Due to the prognostic influence of molecular subgroups such as isocitrate dehydrogenase mutation, the trial will be stratified based on this determination from the primary pathology or subsequent biopsy known locally or otherwise determined centrally. A second stratification factor is based on the patient's Karnofsky Performance Score (KPS) (70-80 vs 90-100). Further, to account for potential differences in treatment choices for the control arm in regions, the trial will be stratified by geographical region during the randomization process. The study will be conducted in 2 parts; enrollment in the phase 3 will begin after phase 2 results are available.

Phase: Phase II/III

Age Group: Adult

Scope: National

Arm 1: Toca 511/Toca FC
Resection followed by administration of up to 4 mL Toca 511. Toca 511 is administered by injection into the wall of the subject's tumor resection cavity on Day 1.

Toca FC will be administered at 220 mg/kg/day orally for 7-day courses beginning at least 6 weeks after resection and repeated approximately every 6 weeks.

Arm 2: Lomustine, temozolomide, or bevacizumab
Beginning 6 weeks after tumor resection, one these 3 options will be chosen:

A) Bevacizumab will be administered by IV infusion at 10 mg/kg and repeated every 2 weeks.

B) Lomustine will be administered as a single oral dose of 110 mg/m2 and repeated every 6 weeks.

C) Temozolomide will be administered per 1 of 2 options:
1) at a dose of 50 mg/m2 PO once daily continuously, or
2) at an initial dose of 150 mg/m2 IV or PO once daily for 5 consecutive days per 28-day treatment cycle that may be raised to 200 mg/ m2 once daily for 5 consecutive days in the following 28-day treatment cycles

Detailed Eligibility
1. Subject is between 18 years old and 75 years old, inclusive
2. Subject has given written informed consent
3. Subjects must have histologically proven GBM or AA in first or second recurrence (including this recurrence) or progression following initial definitive multimodal therapy with surgery, temozolomide (unless MGMT promoter unmethylated) and radiation (confirmed by diagnostic biopsy with local pathology review or contrast enhanced MRI). 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
4. Subjects must have measurable disease preoperatively, defined as at least 1 contrast enhancing lesion, measuring at least 1 cm in 2 planes (axial, coronal, or sagittal)
5. Subjects must be at least 4 weeks post last dose of temozolomide
6. Prior gamma knife, stereotactic radiosurgery, or other focal high-dose radiotherapy is allowed but the subject must have either histopathologic confirmation of recurrent tumor, or new enhancement on MRI outside of the radiotherapy treatment field
7. Based on the pre operative evaluation by neurosurgeon, the subject is a candidate for >= 80% resection of enhancing region
8. IDH mutation status of the primary tumor must be available or tumor samples must be available for pre randomization testing
9. 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 = - ALT = - Estimated glomerular filtration rate of at least 50 mL/min by the Cockcroft Gault formula below:
10. Women of childbearing potential (>=12 months of non-therapy-induced amenorrhea or surgically sterile) must have had a negative serum pregnancy test within the past 21 days 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 receiving Toca 511 or until there is no evidence of the virus in his/her blood, whichever is longer.
12. The subject has a KPS >= 70
13. The subject is willing and able to abide by the protocol

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 5 years. Adequately treated basal cell carcinoma or squamous cell skin cancer is acceptable regardless of time, as well as localized prostate carcinoma or cervical carcinoma in situ after curative treatment
3. Histological 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 at least 1 cm in 2 planes that are not contiguous on either fluid attenuated inversion 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 antibiotic, antifungal or antiviral therapy within the past 4 weeks

* Contact study for full list of exclusion criteria.

Applicable Disease Sites
Brain and Nervous System

Participating Institutions
UF Gainesville : Sarah Andrews

Sarah Andrews, RN


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