First Patient Dosed in Phase I/II Trial of Novel Immunotherapy Combination in Newly Diagnosed Glioblastoma

David Reardon, MD

David Reardon, MD

The first patient has been dosed in a phase I/II open-label, multicenter trial investigating a novel immunotherapy combination in patients with newly diagnosed glioblastoma (GBM). Fifty patients have been accrued in the trial, as of May 31, 2018, which will be conducted at 25 sites across the nation.

This study aims to investigate the efficacy of INO-5401, a T-cell activating immunotherapy agent encoding multiple antigens in GBM, and INO-9012, an immune activator encoding IL-12, in combination with the PD-1 inhibitor cemiplimab (REGN2810).

INO-5401 is an optimized synthetic DNA immunotherapy targeting WT1, hTERT, and PSMA antigens, which are all frequently overexpressed in many cancers but not in healthy tissue, creating killer T cells specific to these antigens. INO-9012 in turn helps to trigger the activation of immune T cells and cemiplimab would augment T-cell activity.

"The Inovio vaccine platform is highly innovative and uniquely designed with the potential to generate robust antitumor immune responses,” said David Reardon, MD, the lead investigator of the trial and clinical director for the Center of Neuro-Oncology, Medical Oncology, at Dana-Farber Cancer Institute. “We are very hopeful that this novel vaccine technology will translate into meaningful therapeutic benefit when integrated with standard radiation and temozolomide chemotherapy combined with anti—PD-1 treatment for newly diagnosed GBM patients in our recently initiated trial."

The trial is broken into 2 cohorts. Cohort A will include patients with tumors that have an unmethylated MGMT promoter, while cohort B will include patients with tumors that have MGMT methylated promoters or indeterminate MGMT status.

Patients in both cohorts will receive treatment with the same dosing schedule. INO-5401, a combination of 3 DNA plasmids, will be given at 3 mg of each plasmid via intramuscular injection followed by electroporation every 3 weeks for 4 doses, followed by every 9 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or death. INO-9012 will be given in a dose of 1 mg on the same schedule, while cemiplimab will be given at a dose of 350 mg intravenously every 3 weeks.

Radiation and temozolomide (Temodar) will also be given if clinically indicated. Radiation therapy will begin at most 42 days after surgical intervention and approximately 2 weeks after day 0. Temozolomide will be given during the radiation therapy at a 75 mg/m²dose.

To be included in this study, patients had to have newly diagnosed brain cancer with histopathological diagnosis of GBM, a Karnofsky performance status of

≥70 at baseline, and had to have received dexamethasone dose £2 mg per day prior to day 0. Patients must have been over the age of 18 years old, as well.

The primary endpoints of this study are the safety and tolerability of the drug combination. Secondary endpoints include immunological impact, progression-free survival, and overall survival.

“We are proud to have treated our first patient with a powerful combination of Inovio's T-cell—generating immunotherapy INO-5401 with Regeneron's PD-1 checkpoint inhibitor this week,” J. Joseph Kim, president and CEO at Inovio, the company developing INO-5401 and INO-9012, said in a statement. “In preclinical studies, combination of Inovio's T-cell–generating immunotherapies along with checkpoint inhibitors have shown to shrink tumors and improve overall survival of tumor-bearing animals. In this GBM trial, our goal is to increase the overall survival of patients facing a disease where neither the standard of care, nor clinical outcomes have changed in a clinically significant way in more than a decade."

INO-5401 and INO-9012 are also being studied concurrently in a phase I/IIa trial in combination with atezolizumab (Tecentriq) in patients with locally advanced unresectable or metastatic urothelial carcinoma (NCT03502785).