Doctors at Abbott Northwestern Hospital have begun a new, international Phase 2/3 clinical trial called Toca 5 for patients with recurrent high grade glioma, namely glioblastoma or anaplastic astrocytoma. Patients in the Toca 5 clinical trial will receive the investigational therapy, Toca 511 & Toca FC, or standard-of-care treatment for this type of brain cancer: chemotherapy (lomustine or temozolomide) or antiangiogenic therapy (bevacizumab).
“Given the current lack of effective treatment options for high grade gliomas and the strong clinical data reported on Toca 511 & Toca FC, we are pleased to offer this new trial to our patients,” said John Trusheim, M.D., neurologist and principal investigator. “The potential of this virus-based treatment approach to directly kill cancer cells but also activate the immune system against tumors is very exciting."
About 14,000 people in the U.S. and 160,000 worldwide are diagnosed with high grade glioma each year. The two most common forms of high grade glioma are anaplastic astrocytoma and glioblastoma. Patients with newly diagnosed glioblastoma who receive maximal therapy have a median survival of approximately 14 to 16 months. Median survival in recurrent high grade glioma is reported to be about seven to nine months.
Tocagen, the company developing this investigational treatment, reported recently that it had enrolled 128 recurrent high grade glioma patients in its ongoing Phase 1 trials. In these studies, potential benefits were found, including extended overall survival and a favorable safety profile.
In particularly promising results, recurrent high grade glioma patients who received the treatment at the time of tumor removal (N=43) had a median survival of 13.6 months and probability of survival at two years of 31.6 percent. In the higher dose groups, median survival was 14.4 months and two-year survival probability was 40 percent. These data were reported in the June 1st, 2016 issue of Science Translational Medicine, a leading medical journal.
The investigation treatment involves two discrete steps with Toca 511, a modified virus, given first followed by treatment with Toca FC. During the first step, the patient receives Toca 511 by injection into the bed of the surgical cavity right after the tumor has been removed. Toca 511 is a replicating retrovirus that selectively infects cancer cells and delivers a therapeutic gene for an enzyme called cytosine deaminase, or CD for short.
As it spreads through the tumor, Toca 511 programs cancer cells to make CD. These cancer cells are now primed for the second step during which patients take a pill called Toca FC.
Based on preclinical experiments, CD converts Toca FC into a potent, FDA-approved anticancer drug called 5-FU within infected cancer cells. 5-FU also helps reduce the brakes that tumors use to avoid destruction by the immune system. The immune system is further activated by tumor-associated antigens and viral proteins released from dying cancer cells.
As a result, immune cells are activated selectively against cancer cells. This approach selectively destroys cancer cells, while leaving healthy cells unharmed. Patients take multiple cycles of Toca FC, repeating this sequence of events.
See animation of this process at https://www.youtube.com/watch?v=9HmQj74Z5Xk
Neurosurgeons Mahmoud Nagib, MD, Michael McCue, MD, and Kyle Uittenbogaard, MD, are participating in the study. People who would like to inquire about inclusion in this or any other trials at the Givens Brain Tumor Center at Abbott Northwestern Hospital may call the Neuroscience Research Department at 612-863-3452 or email Nilanjana.Banerji@allina.com.