Phase I - II Study of Ad/PNP(IND14271,1/19/10)for HNSCC(OrphanDrugDes,14-4438,6/8/15)

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Abstract Over the past 15 years, our laboratories have pursued a mechanism for solid tumor sensitization using the E. coli PNP gene. The approach involves gene transfer with an adenoviral construct, Ad/PNP, and Gene Directed Enzyme Prodrug Treatment or GDEPT. Unique aspects of the strategy include intratumoral generation of fluoroadenine, a purine base that markedly disrupts the non-cycling tumor cell compartment, including tumor progenitor cells. We believe the robust destruction of tumor parenchyma in this manner may also favorably impact checkpoint blockade and immunologic tumor cell clearance. The basic work underlying the strategy has been funded previously by approximately $10 million in NCI support. Preclinical safety and efficacy have been confirmed by many laboratories worldwide, and the strategy is supported by an extensive preclinical database. Our group has obtained an IND and conducted the first clinical trial of the approach in end-stage head and neck squamous cell carcinoma (HNSCC), with directed intratumoral inoculation to deliver Ad/PNP. The study focused on individuals with no other therapeutic options, and received orphan drug designation from FDA (Approval #14-4438). Our Phase 1 trial was completed and published in late 2015, included 12 patients, and demonstrated excellent safety and efficacy. In our end-of-phase-1 meeting with FDA, we discussed the serious unmet clinical need in the setting of end-stage head and neck cancer, the poor response to conventional therapy, and evidence of strong anti-tumor activity using Ad/PNP. We were informed that the FDA would be willing to discuss BLA based on an endpoint of overall response rate, if we can show significant improvement over standard of care. Our Phase 1 data indicates significant improvement over all standard therapeutic modalities in this setting. The purpose of the current application is to conduct a Phase 1/2 trial at Stanford University of repeat administration using Ad/PNP followed by systemic fludarabine, as a way to gain additional information prior to expansion towards a larger patient trial. Through this RO1, we will treat 10 patients, and incorporate a number of new mechanistic and biometric endpoints carried out by experienced laboratories at Emory University. IND approval and orphan drug status for the approach are in place, and GMP-grade adenovirus is available for the study. The work will furnish a means to advance a novel and very potent anticancer agent (fluoroadenine) that confers durable tumor regression.