Phase I/II Study of Intratumoral Ad/Purine Nucleoside Phosphorylase (Gedeptin) With Fludarabine Phosphate in Patients With Recurrent Head and Neck Cancer

PURPOSE Ad/PNP (Gedeptin) is a nonreplicating adenoviral vector expressing E. coli purine nucleoside phosphorylase (PNP) for intratumoral injection (IT) followed by intravenous (IV) fludarabine. The resulting metabolite, fluoroadenine (F-Ade), inhibits RNA and protein synthesis, irrespective of the mitotic state. A previous trial of single-cycle Gedeptin in solid tumors demonstrated safety and efficacy. The current trial explored repeated cycles of Gedeptin in patients with refractory head and neck cancers (H&N Ca). METHODS Patients with recurrent H&N Ca with no additional treatment options were eligible. The study evaluated repeat administration of up to five 28-day cycles. Each cycle consisted of three IT injections of 2.0 × 10 11 viral particles of Gedeptin over 2 days followed by IV fludarabine 25 mg/m 2 once daily for 3 days. Primary and secondary end points included safety and tumor response. RESULTS Eight patients were enrolled and treated. All patients had undergone extensive previous treatment with a median of four previous lines of systemic therapy in addition to surgery/radiation. Patients received one to five cycles of therapy. Toxicity was acceptable, and severe adverse events were largely unrelated to treatment. Stable disease was observed in three patients (37.5%), and progressive disease was observed in two (25%). Responses were nonevaluable among three others. Correlative end points established successful tumor transduction, PNP transgene expression, and potential biomarkers corresponding to tumor regression. CONCLUSION The safety profile of repeat Gedeptin dosing was favorable in this heavily pretreated patient cohort. The acceptable toxicity and evidence for disease stability encourage further evaluation of Gedeptin in earlier stages of disease. Opportunities for improved efficacy identified by the study include higher-level Gedeptin dosing/improved tumor transduction efficiency, evaluating less heavily pretreated disease, and coadministration with immunologic therapies.