Abstract CT165: Viral-vectored, gene-directed prodrug therapy (Gedeptin) in needle-accessible solid tumors

Abstract Ad/PNP (Gedeptin®) is a non-replicating adenoviral vector expressing E. coli purine nucleoside phosphorylase (PNP) for intratumoral injection (IT) followed by IV administration of fludarabine (Flu) (Parker, Sorscher. Curr Pharm Design. 2017). The resulting metabolite, fluoroadenine (F-Ade), inhibits RNA and protein synthesis, irrespective of mitotic state. This provides an anticancer modality directed at the quiescent cancer cell compartment and tumor microenvironment (TME). F-Ade has activity against human-tumor xenografts when as few as 2.5-10% of cells express PNP. Initial evaluation of single cycle Gedeptin in patients with head & neck cancer (H&N Ca) and melanoma demonstrated safety and efficacy with a response rate of 66.7% in the two highest dose cohorts (Rosenthal, et al. Ann Oncol. 2015). No subject experienced DLT and none discontinued study therapy. There was no evidence for increased treatment-related adverse events or serious adverse events (SAEs) across dose cohorts. The most frequent treatment-emergent adverse events were associated with IT injection, primarily injection site pain. A follow-on trial with repeated cycles of Gedeptin in 8 patients with advanced H&N Ca (6 with squamous cell Ca, 1 with nasopharyngeal Ca, 1 with lymphoepithelial Ca) has now been completed. With each 28-day cycle, subjects received 3 IT injections of 2.0 X 1011 viral particles of Gedeptin over 2 days followed by 3 daily infusions of Flu 25 mg/m2. Patients were heavily pretreated with median time from diagnosis of 46.7 months, four prior lines of systemic therapy (range 2-5), and prior surgery and/or radiotherapy. Patients completed one to five cycles of therapy. Stable disease was observed in three patients (37.5%), and progressive disease in two (25%). Responses were non-evaluable among three patients (37.5%). Median PFS and OS were each 7.0 months. Lower efficacy was thought due to more refractory disease, lower total Gedeptin dose and/or poor transduction efficiency. Toxicity was acceptable with a low rate of treatment-related AEs. Four deaths were reported due to disease progression. Five patients (62.5%) experienced SAEs: dysphagia, vomiting, fever, pneumonia, dehydration, and tumor hemorrhage. These were considered not treatment related, except vomiting (possibly related). Correlative endpoints describe successful tumor transduction, PNP transgene expression, and potential biomarkers corresponding to tumor regression. Enrollment was challenging in these heavily pretreated patients. In preclinical studies, Gedeptin/Flu strongly sensitizes tumors to immune checkpoint inhibition (ICI), presumably by destroying tumor tissue locally and exposing neoantigens, enhancing immune response, and promoting activity of ICI. Accordingly, an upcoming Phase II trial will evaluate Gedeptin/Flu/pembrolizumab as neoadjuvant therapy in patients with primarily relapsed squamous cell H&N squamous cell cancer. Citation Format: A. Dimitrios Colevas, Eric J. Sorscher, William B. Parker, Luis Fernando Ramirez, Jeong S. Hong, Regina Rab, Nicole C. Schmitt, Madison M. Stallings, Kelly T. McKee, Eben Rosenthal, Erica Raiden, Nabil F. Saba, J. Marc Pipas, Joseph M. Curry. Viral-vectored, gene-directed prodrug therapy (Gedeptin) in needle-accessible solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT165.