BOSTON—Ziopharm Oncology has reported positive Phase 1 trial results in using Controlled interleukin 12 (IL-12) to treat recurrent high-grade glioblastoma. Controlled IL-12, or Ad-RTS-hIL-12 plus veledimex (Ad+V), appears to control the production of human interleukin 12 (hIL-12), which activates the immune system to recruit and sustain cancer-fighting T cells within solid tumors. The Phase 1 trial explored using Ad+V for the treatment of recurrent glioblastoma multiforme (rGBM), both as a monotherapy and in combination with immune checkpoint inhibitors.
“In a Phase 1 trial, we strive to show that a new drug candidate is first and foremost safe for patients and at the same time, aim to demonstrate initial evidence of efficacy,” said lead author Dr. Antonio Chiocca, chairman of neurosurgery and co-director of the Institute for the Neurosciences at Brigham and Women’s Hospital, professor of Neurosurgery at Harvard Medical School, and surgical director of the Center for Neuro-oncology at Dana-Farber Cancer Institute. “We believe these study results show it is now possible to have regulatable immunotherapy via genes. Controlled IL-12 is well tolerated in patients with glioblastoma, with encouraging evidence that the drug is having its intended effect.”
IL-12 is known to effectively actuate the production of T cells to target cancer, but previous attempts to introduce it in a cancer environment through systemic infusion have resulted in levels of toxicity that made it untenable as a long-term therapy. Ziopharm’s study indicates that when treated with AD+V, “a ligand-inducible switch” regulates expression of IL-12 from the central nervous system, bypassing the need for external introduction of the agonist.
“Profiling an expanded number of patients with rGBM shows that Controlled IL-12 engages patients’ immune systems which we previously showed was an indicator of improved overall survival,” reported Dr. Laurence Cooper, CEO of Ziopharm. “Furthermore, we demonstrate that Controlled IL-12 can be combined with a PD-1 inhibitor, and the initial data from this Phase 1 trial are consistent with immune-mediated anti-tumor effects with a favorable safety profile. As the follow-up from these substudies continues, we remain encouraged by the application of Controlled IL-12 as monotherapy, and the combination data support our plans to initiate a Phase 2 trial combining Controlled IL-12 with a second PD-1 inhibitor in the next few weeks.”
The company reported data from 31 initial patients with rGBM, and, according to the press release, found that a 20 mg veledimex dose had superior drug compliance and demonstrated 12.7 months median overall survival (mOS) at a mean follow-up of 13.1 months. Concurrent corticosteroids negatively impacted survival, and patients had further improved mOS of 17.8 months when cumulative amount of dexamethasone was limited to less than 20 mg during active veledimex dosing.
According to Cooper, “This powerful switch technology is the basis for developing IL-12 as a drug for the treatment of recurrent glioblastoma, by advancing Controlled IL-12 as monotherapy and in combination with immune checkpoint inhibitors. In our clinical studies, we have demonstrated an apparent improvement in overall survival, which is likely based on IL-12’s ability to recruit and sustain a T cell response within the tumor. These T cells upregulate PD-1, which provides a compelling rationale to combine our Controlled IL-12 with immune checkpoint inhibitors.”
These positive results prompted the commencement of a Phase 2 trial, which will evaluate the efficacy of combining Ad+V with PD-1 antibody Libtayo as a further treatment for rGBM-impacted adults. This trial will take place at roughly 10 hospitals that specialize in brain cancers and specifically rGBM. In more positive news for the therapy, the FDA has granted the protocol Fast Track designation, while the European Medicines Agency Committee for Orphan Medicinal Products adopted a positive opinion recommending Controlled IL-12 for designation as an orphan medicinal product for the treatment of glioma. These developments are welcome as glioblastoma is an aggressive, largely incurable cancer. Despite aggressive treatment with surgery, radiation and chemotherapy, recurrence occurs in the vast majority of cases, and when it does recur, median overall survival is six to nine months.
Dr. David Mauney, president of Ziopharm, sums up the results’ promise: “The momentum for our Controlled IL-12 program in recurrent glioblastoma has ... increased considerably. To put it in perspective, in the last 13 months, we have dosed 36 patients in the monotherapy group and nine patients in [a] combination cohort. These 45 new patients enrolled are now being followed for overall survival. We will also treat about another 12 patients in [a] maximum dose cohort due to strong clinical interest, and we will treat approximately 30 patients in a Phase 2 study with Libtayo at full dose.”
“Glioblastoma ... is a devastating cancer with few treatment options that have demonstrated success. These updated data show a promising extension of patients’ survival and demonstrate how controlling the powerful cytokine IL-12 can engage the body’s own immune system to generate an anti-tumor response against rGBM,” said co-author Dr. Rimas V. Lukas, an associate professor of neurology (neuro-oncology) at the Northwestern University Feinberg School of Medicine and the Department of Neurology at the University of Chicago.