First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma

• First time in Human study in patients with recurrent glioblastoma expressing EGFR.
• Novel and innovative nanocell technology.
• Nanocells contain doxorubicin and target EGFR through Vectibix®.
• Treatment was well tolerated with no dose limiting toxicity.
• A recommended phase two dose was identified.

There are limited treatment options for patients with recurrent glioblastoma (GBM). The EnGeneIC delivery vehicle (EDV) is a novel nanocellular (minicell) compound which packages theoretically effective concentrations of chemotherapeutic drugs that are designed to target tumors via minicell-surface attached bispecific proteins (EnGeneIC, Lane Cove West, NSW, Australia). Epidermal growth factor receptor (EGFR) is overexpressed in 40–50% of patients with GBM and is a promising target for new therapeutics. VEDVDox contains doxorubicin (Dox) within the minicells and targets EGFR through Vectibix (V; Amgen Biologicals, Thousand Oaks, CA, USA). We conducted a first in human Phase I study of VEDVDox in adults with recurrent GBM expressing EGFR on immunohistochemistry, following standard therapy including radiation and temozolomide, to establish a safe maximum tolerated dose and determine a recommended Phase II dose (RPTD). VEDVDox was administered weekly in an 8 week cycle, with dose escalation in successive cohorts of patients using a standard 3 + 3 design. In total, 14 patients were treated at three dose levels, and the RPTD was identified as 5 × 109 VEDVDox. Overall VEDVDox was well tolerated, with no dose limiting toxicity and no withdrawals from the study due to adverse events. The most common adverse events were nausea, fever, and chills or rigors, experienced in seven, five and five patients, respectively. Transient uncomplicated hypophosphatemia was seen in seven patients and was not dose-related. Our results demonstrate that VEDVDox, up to a dose of 5 × 109 VEDVDox weekly, is well tolerated in patients with recurrent GBM.