Clinical Trials in the Adult Brain Tumor Consortium

ABTC 1603: Phase I Study of Neoadjuvant GMCI + PD-1 Inhibitor Combined with Standard of Care for Newly Diagnosed High-Grade Gliomas
PI: Nino Chiocca, MD, PhD, FAANS

The hypothesis of this study is combining Gene Modified Cytotoxic Immunotherapy (GMCI) with a PD-1 inhibitor will be safe and improve the clinical outcome of patients with high grade glioma (Gr III-IV glioma), compared to standard of care (surgery + radiochemotherapy). GMCI is comprised of a replication-defective adenoviral vector (AdV-TK) expressing the herpes simplex virus thymidine kinase gene combined with valacylovir, an anti-Herpse prodrug. In this trial, GMCI is combined with nivolumab, an anti-PD-1 checkpoint inhibitor. The rationale for the trial is the AdV-TK infects a small number of tumor cells, which then die when valacyclovir is administered releasing multiple autologous tumor-derived antigens and creating a local immunostimulotory mileau, facilitating a local immune response at the site of the tumor with recruitment of immune effector cells and upregulation of immune cytokines. The PD-1 should mitigate the immunosuppressive cells that are also recruited to HGGs.

All patients will undergo surgical resection with an injection of GMCI into the tumor bed, followed by radiotherapy and nivolumab. The patients will then be divided into two cohorts, depending on MGMT promotor methylation:

Cohort 1: patients with HGGs with MGMT unmethylated, who will not receive concurrent or adjuvant TMZ.

Cohort 2: patients with HGGs withmethylated MGMT, who will be treated with concurrent and adjuvant TMZ.

The primary goal of the study is to assess the safety and toxicity of combining GMCI and nivolumab and identify the maximal toderated dose (MTD) of this combination. Secondary goals include estimation of PFS, OS and assessment of various immune biomarkers and their correlation with clinical response.