LAUSR

Background: Advanced urothelial carcinoma (UCa; bladder cancer) remains a deadly disease with patients often failing to respond to, or ineligible for, platinum-based therapy. Checkpoint inhibitors (CPIs) have increased response rates, but a majority of patients remain refractory to such agents or relapse. In this study, a novel antigen-specific T cell-generating therapy, INO-5401, combined with INO-9012, together with a CPI will be given to patients with advanced UCa with the aim of demonstrating tolerability, immunogenicity and efficacy (ORR, DoR, PFS, OS) of the combination. INO-5401 is a mixture of three synthetic plasmids that target Wilms tumor gene-1 (WT-1) antigen, prostate specific membrane antigen (PSMA) and human telomerase reverse transcriptase (hTERT) antigen. INO-9012 is a plasmid encoding human interleukin-12 (IL-12) p35 and p40 subunit proteins. In preclinical studies, targeting WT-1, PSMA and hTERT induced robust cellular immune responses and slowed tumor growth in murine tumor implantation and ALL models. Methods: This is a Phase I/IIA, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical efficacy of INO-5401 + INO-9012 delivered by intramuscular (IM) injection followed by electroporation (EP) in combination with atezolizumab in participants with locally advanced unresectable or metastatic/recurrent UCa. INO-5401 + INO-9012 is administered Q3w for the first 4 doses, Q6w for the next 6 doses and Q12w thereafter until disease progression. Atezolizumab will be delivered Q3w until disease progression. The trial population includes Cohort A patients with confirmed disease progression during or following treatment with anti-Programmed Death receptor-1/Programmed Death receptor Ligand-1 (anti-PD-1/PD-L1) therapy and Cohort B patients who are treatment naive and ineligible for cisplatin-based chemotherapy. All patients must have locally advanced unresectable or metastatic/recurrent UCa, measurable disease without previously treated target lesions (unless progressed following therapy) and ECOG of 0-1. Patients must not have had any approved anti-cancer therapy within 2 weeks of enrollment, nor any investigational therapy within 4 weeks of enrollment, any other malignancies within 3 yrs of enrollment, any autoimmune disease, and any immunostimulatory or immunosuppressive treatments. A safety run-in will be performed with up to six patients from Cohort A. Correlative studies include the assessment of antigen-specific cellular immune responses in peripheral blood and tumor tissue. ClinicalTrials.gov NCT03502785. EudraCT 2018-000309-21. Enrollment: Eighty-five patients are estimated to be enrolled. Enrollment began May 2018 and is continuing to accrue as planned. The safety run-in has been completed (no DLTs were observed in participants dosed to date), and the study is now open to full enrollment. Citation Format: Jeffrey Skolnik, Noah Hahn, Joaquim Bellmunt, Samantha Rosencranz, Malissa Diehl, Matthew Morrow, Kimberly Kraynyak, Trevor McMullan. INO-5401 + INO-9012 in combination with atezolizumab for locally advanced unresectable or metastatic/recurrent urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT177.