Promising Subgroup Data Leads to Phase III Immunotherapy Study for GBM

Patrick Y. Wen, MD

Findings from a subgroup of patients enrolled in a phase II study assessing the dendritic vaccine ICT-107 for patients with HLA-A2+ glioblastoma multiforme (GBM) merit further exploration in a phase III study, based on the substantial improvement in overall survival (OS) with the immunotherapy, according to lead investigator Patrick Y. Wen, MD, at the 2015 Society for Neuro-Oncology Annual Meeting.

In a group of patients with HLA-A2+ newly diagnosed GBM, which is the population selected for the phase III study, an immune response to ICT-107 by enzyme-linked immunospot (ELISPOT) corresponded to a prolongation in OS. These findings help predict potential results from the larger study for ICT-107, which is composed of autologous dendritic cells incubated with 6 synthetic peptide CTL epitopes that target the GBM/stem cell-associated antigens MAGE-1, HER2, AIM-2, TRP-2, gp100, and IL-13Rα2.

In the HLA-A2 group of responders from the phase II study, the median OS was 23.1 months compared with 13.7 months in non-responders (P = .0674). For responders, OS was extended by 52% compared with 29% in non-responders (P = .0615). Additionally, progression-free survival (PFS) was extended by 41% versus 15% in non-responders (P = .0259).

“ICT 107 is a dendritic cell peptide vaccine that has shown promising results in a randomized phase II study in patients with newly-diagnosed glioblastomas and was very well-tolerated,” Wen, director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, told OncLive. “If the recently launched phase III study confirms these findings, it will bring a much-needed treatment to our patients.”

In the phase II study, 124 patients were randomized in a 2:1 ratio to receive ICT-107 or matching control (unincubated dendritic cells). Seventy-seven patients were HLA-A2-positive. Patients in the treatment arm (n = 81) received four induction doses of ICT-107 after chemoradiation, and then maintenance doses until progression. All patients in the trial received temozolomide as standard-of-care. The primary endpoint of the trial was OS. Secondary endpoints included PFS along with other measures.

For the full population of the trial, the median OS with ICT-107 was 18.3 versus 16.7 months for control (HR, 0.89, P = .643). Median PFS was 11.2 months with ICT-107 compared with 9.0 months in the control arm (HR, 0.57, P = .011).

When censored to 7.5 months post-treatment in the HLA-A2-positive group, a response to ICT-107 as measured using immune criteria was found to significantly correlate with improvements in OS. At this time point, the median OS with ICT-107 was 17.6 versus 13.7 months (P = .0018). Sixty percent of ICT-107-treated patients demonstrated a statistically significant immune response compared with 36% of patients in the control arm (P = 0.0084).

Furthermore, levels of IL-12 production were linked with survival. In the censored group, high IL-12 producers had a median OS of 20.6 months compared with 15.4 months for low producers (P = .0515). In the full population of HLA-A2+ responders, those who produced high levels of IL-12 had an extension in OS of 54% versus 31% in IL-12 low producers (P = .0426). In the high group, PFS was extended by 43% versus 19% in the low group (P = .0293).

“The final data from the phase II trial continue to demonstrate the therapeutic value of ICT-107 as a potential treatment for patients with newly diagnosed glioblastoma, and strongly support advancing to phase III testing,” John S. Yu, MD, founder of ImmunoCellular Therapeutics, the manufacturer of ICT-107, said in a statement.

The phase III registration trial will enroll more than 400 HLA-A2+ patients with GBM in approximately 120 sites in the United States, Canada, and the European Union. Patients will be randomized to received temozolomide plus control or ICT-107. The primary endpoint of the trial will be OS and secondary endpoints will be PFS and safety, as well as OS in the two pre-specified MGMT subgroups. The phase III study will employ a different control comprised of the patients’ own monocytes, which are less immunologically active than dendritic cells.

The phase III trial was formed under a special protocol assessment with the FDA, which was granted in August 2015. The study hopes to begin enrolling patients soon. Special protocol assessment is a written agreement between the sponsor company, ImmunoCellular Therapeutics, and the FDA on the design, clinical endpoints, size, and statistical design of a clinical trial. The agreement is intended support findings submitted to the FDA for regulatory filings.

Wen P, Reardon D, Phuphanich S, et al. Association of survival and progression-free survival with immune response in HLA-A2+ newly-diagnosed GBM patients in randomized double-blind placebo-controlled phase 2 trial of dendritic cell (DC) immunotherapy with ICT-107. Presented at: 2015 Annual Meeting of the Society for Neuro-Oncology; November 19-22, 2015; San Antonio, TX. Abstract IMCT-20.

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