Retroviral Replicating Vector That Delivers Cytosine Deaminase to Cancer Cells Active in Recurrent Glioblastoma


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A phase I study by Timothy F. Cloughesy, MD, Director of the Neuro-Oncology Program at the UCLA Jonsson Comprehensive Cancer Center, and colleagues published in Science Translational Medicine investigated the effectiveness of vocimagene amiretrorepvec (Toca 511), an experimental nonlytic, retroviral replicating vector that delivers cytosine deaminase to cancer cells, and an investigational extended-release version of 5-fluorocytosine (Toca FC) in patients with recurrent glioblastoma. They found that the treatment increased overall survival to 13.6 months vs 7.1 months for an external control.

According to the investigators, standard treatments for recurrent glioblastoma are associated with an overall survival of 7.1 to 9.8 months. For some study participants, survival was extended to more than 2 years. The therapy was associated with few side effects as well as a molecular signature that may correlate with treatment-related survival.

Based on these study results, a phase II/III international clinical trial (Toca5) in recurrent glioblastoma and anaplastic astrocytoma is underway.

Study Methodology

Between 2012 and 2015, 43 patients, the majority diagnosed with glioblastoma (82.2%), were treated first with vocimagene amiretrorepvec and then extended-release 5-fluorocytosine. The median age of the patients was 56 years, with first (51.1%), second (22.3%), or more than two (26.6%) recurrences and a Karnofsky performance status of 70 to 80 (24.5%) or 90 to 100 (75.5%). All patients had previously received radiotherapy and chemotherapy with temozolomide. The majority of the recurrent high-grade gliomas were located in the cerebral hemispheres, including the frontal, temporal, parietal, or occipital lobes.

Study Findings

In the efficacy evaluable population, overall survival for patients with recurrent high-grade glioblastoma (n = 43) was 13.6 months (95% confidence interval [CI] = 10.8–20.0) and for patients with high-grade glioblastoma at first or second recurrence was 14.4 months (95% CI = 11.3–32.3). Overall survival was 11.6 months (95% CI = 9.2–14.6) for glioblastoma patients and 13.6 months (95% CI = 11.1–20.0) for glioblastoma patients at first or second recurrence.

In the efficacy evaluable population, landmark survival data included overall survival at 6 months (87.9%), 9 months (72.4%), 12 months (52.5%), and 24 months (29.1%). In an analysis comparing the higher-dose cohorts with the lower-dose cohorts, there was a trend for dose response in survival (hazard ratio [HR] = 0.56; 95% CI = 0.26–1.20), with median survival of 14.4 months (95% CI =10.8 to not reached) for the higher doses vs the lower doses, with a median survival of 11.8 months (95% CI = 6.7–16.8).

Progression-free survival was 3.2 months (95% CI = 3.0–3.4), progression-free survival at 6 months was 16.3%, and evidence of potential pseudoprogression in resected tumors after vocimagene amiretrorepvec and extended-release 5-fluorocytosine treatment was observed.

Potential Applications in Other Cancers

“For the first time, this clinical data shows that this treatment, used in combination with an antifungal drug, kills cancer cells and appears to activate the immune system against them while sparing healthy cells,” said lead author of the study Dr. Cloughesy, in a statement. “This approach also has potential in additional types of the disease, such as metastatic colorectal and breast cancers.”

Dr. Cloughesy is a consultant for Tocagen, the trial sponsor and manufacturer of vocimagene amiretrorepvec and extended-release 5-fluorocytosine. ■

Cloughesy TF, et al: Sci Transl Med 8:341ra75, 2016.


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