Background: Targeted EDV nanocells loaded with doxorubicin and microRNA16a have shown excellent safety profiles in Phase I trials in recurrent glioma and mesothelioma. This planned safety analysis of an ongoing first-in-human, open label Phase I/IIa study in patients with treatment-refractory metastatic pancreatic cancer, assesses safety, biologic and clinical activity of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682, designed to overcome drug resistance, combined with EDV nanocells carrying immunomodulatory adjuvant α-galactosyl ceramide, designed to stimulate anti-tumour immune response. Methods: 9 patients with advanced pancreatic cancer enrolled in the dose escalation phase to evaluate safety of the EDV combination. Doses gradually escalated from 2 x 10⁹ EDVs/dose to a maximum of 7 x 10⁹ EDVs/dose in Week 7, with subsequent dosing at the maximum dose achieved in Cycle 1. iRECIST criteria was used to assess tumour response after each cycle, and blood was collected each cycle for cytokine and PBMC analysis. Results: Combination EDVs were well tolerated with no DLTs, and no drug related SAEs. A minority of patients experienced G1 infusion reactions, which responded promptly to supportive treatment. PR or SD was achieved at 8 weeks in 8/9 patients (CBR 89%), with responses confirmed at 4 months in 4/5 evaluable patients (80%), with 2 durable responses seen beyond 6 months. Exploratory analyses have revealed elevation of IFN-α and IFN-γ in almost all evaluable patients (6/8). In addition, we observed elevated CD8+ T cells (2/8), iNKT, dendritic and NK cells (3/8), and a reduction in exhausted CD8+ T cells (3/8), suggesting activation of both innate and adaptive immune responses. Conclusions: EDVs carrying the cytotoxic drug and immune adjuvant are safe and well tolerated. Early signals point to durable responses, possibly related to the development of an innate and adaptive immune response along with cytotoxic effects on drug resistant tumour cells. The Phase IIa study plans to enrol an additional 35 patients to further evaluate safety and anti-tumour efficacy. Clinical trial information: ACTRN12619000385145.