A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant Glioma

• Determine Response Rate at MTD [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Determine the PFS-6 at MTD [ Time Frame: 6 months ] [ Designated as safety issue: No ]

This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of increasing, single doses of Toca 511, a Retroviral Replicating Vector (RRV), administered transcranially to subjects with recurrent high grade glioma (rHGG) who have undergone surgery, radiation therapy and chemotherapy with temozolomide. Approximately 3-4 weeks following injection of the RRV, 6-day courses of treatment with oral 5-FC will commence and will be repeated monthly for up to 6 cycles.

There is an ongoing, intensive search for novel therapies to improve the prognosis of patients with the most common and aggressive form of primary brain cancer, glioblastoma multiforme (GBM). Gene transfer is one such approach. Early gene-transfer studies with replication incompetent vectors showed this approach to be generally safe, but ineffective due to limited transduction of the tumor. More recently gene transfer has been attempted with oncolytic, replicating viruses. However these viruses are rapidly cleared by the immune system. To overcome these shortcomings of previous gene transfer protocols, Toca 511 has been developed utilizing a Retroviral Replicating Vector (RRV). This platform has the following potential advantages: 1) The vector only infects dividing cells, 2) The virus stably integrates into the genome of the tumor cells allowing for the potential for long-term control of the tumor, 3) The virus is not intrinsically oncolytic and is not cleared from the tumor by the immune system, and 4) The virus has been engineered to express the prodrug-activator, cytosine deaminase (CD), a gene that catalyzes the intracellular conversion of the antifungal drug, 5-FC (flucytosine) to the cytotoxic drug 5-FU. In both xenograft and syngeneic intracranial mouse tumor models the Toca 511/5-FC combination was able to significantly increase the survival of treated animals. The goal of the current trial is to demonstrate the safety and efficacy of Toca 511 administered intratumorally to patients with recurrent GBM followed by cyclic treatment with the prodrug 5-FC.

This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of increasing, single doses of Toca 511 administered transcranially to subjects with rHGG who have undergone surgery, radiation therapy and chemotherapy with temozolomide. The study will be conducted in 2 parts. Part one will study ascending, single doses of Toca 511 delivered via stereotactic, transcranial injection into the tumor. Approximately 3-4 weeks later subjects will undergo a baseline Gd-MRI exam and then begin treatment with oral 5-FC administered for 6 consecutive days. If tolerated, these 6-day courses of 5-FC will be repeated every 4 weeks for 6 cycles. Subjects will undergo Gd-MRI scanning every 8 weeks. In part 2 of the study, 9 additional subjects will be studied at the highest dose of Toca 511 found in part one to be safe and well tolerated. Each subject will receive a single, transcranial injection of Toca 511. Approximately 3-4 weeks later subjects will undergo a baseline Gd-MRI exam and then begin treatment with oral 5-FC administered for 6 consecutive days. If tolerated, these 6-day courses of 5-FC will be repeated every 4 weeks for 6 cycles. Subjects will undergo Gd-MRI scanning every 8 weeks. Tumor response will be assessed using the Macdonald criteria.

• Glioblastoma
• Anaplastic Astrocytoma
• Anaplastic Oligodendroglioma
• Anaplastic Oligoastrocytoma

• Biological: Toca 511
  Single, stereotactic, transcranial, intratumoral injection
  Other Names:

  • Retroviral Replicating Vector (RRV)
  • Gene Therapy
  • Gene Transfer
• Drug: 5-FC
  130 mg/kg/day for 6 days, repeated every month for 6 months
  Other Name: flucytosine, 5-FC, 5-FC XR, Toca FC (extended release flucytosine)

• Tai CK, Wang WJ, Chen TC, Kasahara N. Single-shot, multicycle suicide gene therapy by replication-competent retrovirus vectors achieves long-term survival benefit in experimental glioma. Mol Ther. 2005 Nov;12(5):842-51.
• Ostertag D, Amundson KK, Lopez Espinoza F, Martin B, Buckley T, Galvão da Silva AP, Lin AH, Valenta DT, Perez OD, Ibañez CE, Chen CI, Pettersson PL, Burnett R, Daublebsky V, Hlavaty J, Gunzburg W, Kasahara N, Gruber HE, Jolly DJ, Robbins JM. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol. 2012 Feb;14(2):145-59. Epub 2011 Nov 9.

Inclusion Criteria:

• at least 18 years of age
• single, supratentorial HGG (WHO grade III or IV) less than or equal to 9 cm^2 in its greatest cross sectional area
• at least one surgical gross-total or subtotal resection
• postoperative radiation with concurrent temozolomide
• at least 2 cycles of maintenance temozolomide
• must have progressive disease and be at least 12 weeks post radiation therapy
• stable or decreasing dose of corticosteroids for past 7 days
• KPS:18-75 years of age, at least 60; > 75 years of age, at least 70
• absolute neutrophil count > 1500/mm^3
• absolute lymphocyte count > 500/mm^3
• hemoglobin > 10 g/dL
• estimated glomerular filtration rate > 50 mL/min
• ALT/AST < 3 times ULN and bilirubin < 1.5 mg/dL
• negative serum pregnancy test
• if being screened for part two of study, must have evaluable disease on Gd-MRI

Exclusion Criteria:

• cytotoxic therapy within the past 4 weeks (6 weeks for BCNU/CCNU)
• implanted Gliadel wafer/wafers within past 8 weeks
• injection of enhancing rim of tumor would require violation of ventricular system
• clinical evidence of increased intracranial pressure
• bleeding diathesis
• use of anticoagulants/antiplatelet agents that cannot be stopped
• poorly controlled seizures
• HIV positive
• Avastin use within 5 weeks of projected vector injection
• allergy or intolerance to 5-FC
• g.i. condition that would prevent ingestion or absorption of 5-FC
• any investigational treatment within the past 30 days
• pregnant or breast feeding