A Study of a Retroviral Replicating Vector Combined With a Prodrug Administered to Patients With Recurrent Malignant Glioma

Study Overview
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Brief Summary
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This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of increasing doses of Toca 511, a Retroviral Replicating Vector (RRV), administered to patients with recurrent high grade glioma (rHGG) who have undergone surgery followed by adjuvant radiation therapy and chemotherapy. Patients will receive Toca 511 either via stereotactic, transcranial injection into their tumor or as an intravenous injection given daily for 3 & 5 days, depending on cohort. Approximately 3-4 weeks following injection of the RRV, treatment with Toca FC, an antifungal agent, will commence and will be repeated approximately every 6 weeks until study completion. 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.

Official Title
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A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma

Conditions
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Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma

Intervention / Treatment
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* Biological: Toca 511 vector
* Drug: Toca FC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: at least 18 years of age for intratumoral cohorts, supratentorial HGG (WHO grade III or IV) technically unresectable HGG initial definitive therapy such as surgery with or without adjuvant radiation subject elected not to undergo treatment with Gliadel wafer if receiving corticosteroids, dose is stable or decreasing for past 7 days KPS: at least 70 absolute neutrophil count > 1500/mm^3 absolute lymphocyte count > 500/mm^3 platelet count > 100,000/mm^3 hemoglobin > 10 g/dL for intratumoral cohort, coagulation profile favorable to surgery estimated glomerular filtration rate > 50 mL/min ALT < 3 times ULN and bilirubin < 1.5 mg/dL negative serum pregnancy test Exclusion Criteria: cytotoxic therapy within the past 4 weeks (6 weeks for BCNU/CCNU) more than 2 recurrences including present recurrence Gliadel wafer or wafers implanted within the past 8 weeks taking more than 8 mg of dexamethasone per day for intratumoral cohorts, injection of tumor would require violation of ventricular system any infection requiring antibiotic, anticoagulant, or antiplatelet agents within the past 4 weeks for intratumoral cohort, bleeding diathesis or use of anticoagulants/antiplatelet agents that cannot be stopped allergy or intolerance to 5-FC HIV positive g.i. condition that would prevent ingestion or absorption of 5-FC any investigational treatment within the past 30 days pregnant or breast feeding received Avastin history of prior malignancy, excluding basal or squamous cell carcinoma of the skin, with an expected survival of less than 5 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Toca 511 vector/ Toca FC prodrug | Biological: Toca 511 vector<br>* Single, stereotactic, transcranial, intratumoral injection or intravenous injection<br>* Other names: Gene Transfer;Drug: Toca FC<br>* 4-6 week cycles of Toca FC. Doses evaluated from 120 mg/kg/day or 300 mg/kg/day. Duration of dosing evaluated: 6 days, 7 days or 14 days.<br>* Other names: flucytosine, 5-FC, 5-FC XR, Toca FC (extended release flucytosine);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Feasible, Safe and Well Tolerated Dose of Toca 511 |  | 8-10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of repeated treatment with Toca FC following administration of Toca 511 | Review of adverse events including laboratory safety data (specifically any Grade 3 or higher non-hematologic toxicity or any Grade 4 or higher hematologic toxicity, felt to be related to Toca 511 or the Toca 511/Toca FC combination) | 6 months | 
| Overall survival of Subjects |  | Overall survivial, Overall survivial at 6 months (OS6), 9 months (OS9), and 12 months (OS12) | 
| Evaluate progression free survival (PFS) at 6 months |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioma, glioblastoma, glioblastoma multiforme, Grade IV astrocytoma, brain cancer, recurrent glioblastoma, GBM, AA, AOD, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, malignant glioma, high grade glioma