Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

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

Summary: 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 subjects with recurrent high grade glioma (rHGG) who have undergone surgery followed by adjuvant radiation therapy and chemotherapy. Subjects will recieve Toca 511 via stereotactic, transcranial injection into their tumor. Cohort 7 & 9 will receive Toca 511 as an intravenous injection given daily for 3 & 5 days respectively. Approximately 3-4 weeks following injection of the RRV, treatment with Toca FC will commence and will be repeated approximately every 6 weeks until study completion or enrollment in the continuation study.

Detailed description: 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.

Eligibility: 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.

Relevance to patient case: not relevant