1. Nalley, Catlin

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High-grade gliomas are among the most common and aggressive primary brain cancers. Approximately 160,000 patients worldwide are expected to be diagnosed with this disease in 2017. The two most common forms of high-grade gliomas are glioblastoma and anaplastic astrocytoma. With current standard of care, recurrent high-grade glioma patients have a median survival of approximately 7-9 months.

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A recent study sought to meet the needs of this patient population and improve treatment options. Data of a subset of patients in this phase I clinical trial offers hope for the future. More than a quarter of patients with recurrent high-grade glioma treated with the retroviral vector vocimagene amiretrorepvec (Toca 511) and 5-fluorouracil (Toca FC), were alive more than 3 years after treatment, according to results recently presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 26-30 (Abstract A085).


Therapy Details

Vocimagene amiretrorepvec is an investigational, injectable retroviral replicating vector that encodes a prodrug activator enzyme, cytosine deaminase (CD). Its selective delivery to cancer cells means that the infected cancer cells selectively carry the CD gene and produce CD protein.


"The approach is a novel one," noted Clark Chen, MD, PhD, study author and Lyle French Chair in Neurosurgery and Head of the Neurosurgery Department of the University of Minnesota Medical School in Minneapolis, during a press briefing. "It utilizes a gammaretrovirus that is engineered to express the CD gene."


Toca FC is an investigational, orally administered, extended-release formulation of 5-fluorocytosine (5-FC). Once inside the cancer cell, CD converts Toca FC into the anticancer drug 5-fluorouracil, which kills the cancer cell.


In addition to destroying cancer cells, 5-fluorouracil kills certain immune suppressive myeloid cells, which in turn boosts the patient's immune system to recognize and attack the cancer cells. "This approach is fundamentally not just a gene therapy, but also an immune therapy that combines efficacies of both approaches," Chen explained.


Methodology, Results

Currently, there are three dose-escalation, phase I trials for Toca 511 and Toca FC in patients with recurrent high-grade glioma: resection injection (NCT01470794), intratumoral administration (NCT01156584), and intravenous (NCT01985256).


Fifty-six patients with recurrent high-grade glioma were included in the resection study. Of these patients, 82 percent had a diagnosis of glioblastoma. The rest of the participants were diagnosed with anaplastic astrocytoma (11%), anaplastic oligodendroglioma (2%), and other gliomas (5%).


Approximately half of study participants (50%) were at their first recurrence, 23 percent were facing their second recurrence, and 27 percent began the study at their third or greater recurrence, according to study investigators. Among the enrolled patients, the median age was 56 years (24-75) and 77 percent (43 patients) were male.


Researchers administered Toca 511 into the cavity wall after tumor removal. Patients then received an oral course of 5-FC. These 1-week courses of 5-FC were repeated during the 31-week study.


"The treatment we tested in this trial delivers local chemotherapy specifically to the brain tumor. Toca 511 and Toca FC work together to turn the brain tumor into a factory that produces an anticancer drug while also activating the immune system through a combination of mechanisms, which together work to attack the cancer," Chen explained in a statement.


Of the enrolled patients, 53 were evaluable for efficacy. Researchers assessed for durable response rate (partial response or complete response lasting at least 24 weeks or 6 months) and found 6 patients had complete responses. Closer examination of the IDH status of these patients revealed four were IDH wildtype and two were IDH mutants. Median duration of durable response is 35.1 months and researchers reported a clinical benefit rate of 30 percent. Overall survival at 2 and 3 years was 24.5 percent and 13.4 percent, respectively.


Additionally, investigators identified a subset of patients (n=23) in this study, who received higher doses of Toca 511 and met the entry criteria of an ongoing phase II/III study (NCT02414165). Patients in this group were in their first (83%) or second (17%) recurrence with no prior bevacizumab therapy. The majority of patients in this subset had glioblastoma (83%).


Data from this group showed five (21.7%) complete responders with a median duration of durable response of at least 35.7 months. The clinical benefit rate in this subset of patients was 43.5 percent, according to researchers. Additionally, five patients achieved stable disease, bringing the number of patients who derived benefit from the therapy to 10 (43.4%), noted Chen. Data from this cohort showed overall survival rates at 2 and 3 years were 34.8 percent and 26.1 percent, respectively.


"The median survival in this trial is nearly double compared to historical data," according to Chen. "In the subgroup, median survival was 14.4 months, compared to approximately 8 months for historical controls."


In contrast to the ongoing, durable responses observed in this study, patients treated with lomustine had an overall response rate of about 4.3 percent, which, like bevacizumab, was not durable and typically lasted a few months, according to investigators.


The single-arm design of the trial and lack of a control group are limitations of the research. "The ongoing randomized phase II/III trial will be important to confirm the promising safety and efficacy results reported in this phase I study," Chen noted.


The "significant and striking survival signals" observed in the subset of patients eligible for the phase II/III study support the continued investigation of this treatment regimen, Chen concluded during the press briefing. "Given the deadly nature of this disease, 3-year survival is rarely reported in the recurrent setting. It is notable that the survival benefit was seen across a range of patients and not just limited to patients with specific genetic mutations," he reiterated. "This finding indicates that many patients could benefit from this treatment."


Safety Profile

Across all three phase I studies (n=127), the therapy was associated with a low percentage of treatment-related adverse events (AEs).


Grade 1/2 AEs occurred in 25.2 percent of patients who received Toca 511; 7 percent of patients experienced AEs grade 3 or higher. The most common AE was fatigue (11%). Additionally, researchers reported no deaths related to the treatment regimen.


Investigators found that Toca FC has very limited grade >= 3 treatment-related toxicities. Forty-one percent of patients reported grade 1/2 AEs and grade 3 or greater events were seen in only 3 percent of patients. A review of treatment-related AEs showed the most common ones were fatigue (22%), diarrhea (13%), and nausea (10%).


"This treatment has a very favorable safety profile," Chen reported. "The Toca 511 therapy approach spares the body from exposure to systemic chemotherapy, while creating high concentration of chemotherapy in the tumor cells and their microenvironment.


"The treatment is very well-tolerated," he emphasized during the press conference. "We know that in cancer sometimes the therapy is worse than the disease; this is not one of those cases."


Next Steps

Given the positive results from this trial and the implications for practice, the phase II/III study is an important next step to confirm the validity of this therapy for patients with high-grade gliomas.


The clinical development of Toca 511 and Toca FC has been accelerated and the original two-step trial design has been modified into a seamless, pivotal trial (Toca 5). Under this new design, an additional 193 patients with recurrent high-grade glioma will be enrolled and pooled with 187 already enrolled patients, with a target enrollment of 380 patients. The trial includes planned interim analysis at 50 percent and 75 percent of events, which is estimated to occur in the second half of 2018 and the first half of 2019, respectively.


The primary endpoint of this trial is overall survival. Secondary endpoints include durable response rate, which is being assessed as a novel endpoint in the post-surgical setting of recurrent high-grade glioma.


"Brain cancer is one of the deadliest cancers, giving urgency to finding an effective treatment," Chen concluded. "The 160,000 people diagnosed with high-grade gliomas worldwide each year-and high-profile cases including U.S. Senator John McCain, Senator Edward Kennedy, and Beau Biden-demonstrate the high unmet need of this disease. The data generated in the Toca 511 research provides hope for patients with brain cancer and their families."


Catlin Nalley is associate editor.