Oncolytic Adenovirus-Mediated Gene Therapy for Lung Cancer

Nine subjects (3 cohorts, 3 subjects/cohort) with medically inoperable stage I/IIA (T1a - T2b) NSCLC with tumors measuring \> 2 to ≤ 5 cm will receive a single intratumoral injection of the oncolytic Ad5-yCD/mutTKSR39rep-ADP adenovirus at one of three dose levels (1 x 1011 vp, 3 x 1011 vp, 1 x 1012 vp). Depending on the location of the target lesion, the adenovirus will be injected either transbronchially (central tumors) or percutaneously under computed tomography (CT)-guidance (peripheral tumors). Two days later, subjects will be administered (orally) a 10 day course of 5-fluorocytosine (5-FC) and valganciclovir (vGCV) prodrug therapy along with 48 Gy (4 fractions of 12 Gy) of SBRT. Prior to and following the adenovirus injection, subjects will be administered \[18F\]-FHBG, a HSV-1 TK substrate, and will undergo PET imaging to quantify HSV-1 TK gene expression. Toxicity assessments will occur twice a week for the first 2 weeks and then at scheduled follow-up visits through 60 months. The primary endpoint is toxicity. Secondary endpoints include 1) tumor (radiological) response, 2) local, regional, and distal tumor control, 3) progression-free and overall survival, and 4) quality of life. Exploratory endpoints include 1) intensity, persistence, and biodistribution of HSV-1 TK gene expression, and 2) association of select serum biomarkers with toxicity and tumor response.