Final Results Of A Phase I Study Of Wild-Type Oncolytic Reovirus Administered Intravenously To Patients With Advanced Cancer

3572 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras, which inactivates the anti-viral effects of double stranded RNA-activated protein kinase. Wild-type reovirus serotype 3 Dearing has selective antitumor activity in pre-clinical models. Methods: Wild-type reovirus serotype 3 Dearing was administered as a 1-hr IV infusion every 4 weeks, initially for 1 day, then for 3 and then 5 days every 4 weeks. The starting dose was 1 x 10^8 tissue culture infectious dose (TCID50), increasing in successive cohorts until the observation of grade 2 toxicity. Endpoints were safety, detection of viral replication, viral shedding, immune response and antitumor activity. Results: A total of 33 patients (25 males, median age 61; ECOG performance status 0/1/2 = 15/17/1) were treated. 8 cohorts were treated at dose levels of 1x10^8 TCID50 for 1 day, 1x10^8 for 3 days, and 1x10^8, 3x10^8, 1x10^9, 3x10^9, 1x10^10 and 3x10^10 for 5 days. Maximum tolerated dose (MTD) was not reached and toxicities were mild (grade 1 or 2), including chills, fever, headache, rhinorrhea, fatigue and myelosuppression. Reverse transcription polymerase chain reaction (RT-PCR) studies of blood, urine, stool and sputum post reovirus administration and every week thereafter were negative for viral shedding for all treated patients. Anti-reovirus antibodies were present at baseline in most patients, and titres increased after cycle 1 by between 1- and 4-log. Intratumoral reovirus replication was detected by electron microscopy in tumor biopsies. PSA decreased by 50% in a patient with metastatic prostate cancer treated at 3x10^9 TCID50, with evidence of tumor necrosis on CT scanning. 2 patients with metastatic colorectal cancer treated at 3x10^8 and 3x10^9 TCID50 had CEA reductions of 60% and 27%, and received 6 and 3 cycles respectively. 1 patient with metastatic bladder cancer treated at 1x10^9 TCID50 had a minor response and received 4 cycles. Conclusions: Wild-type reovirus serotype 3 Dearing is well tolerated, with minimal toxicity, and MTD has not been reached. Despite a vigorous host response to virus, tumor necrosis associated with intratumoral viral replication was observed. Clinical indications of anticancer activity were seen and phase II studies are planned. [Table: see text]