55. Translating Preclinical Results into the Clinical Development of PV701, an Oncolytic Virus

PV701 is an attenuated, non-recombinant oncolytic Newcastle disease virus that is naturally tumor selective by exploiting cancer- specific defects in the interferon-response. In vitro cytotoxicity assays demonstrated that PV701 has a broad spectrum of antitumor activity and a high degree of both tumor selectivity and potency. In human tumor xenograft models, PV701 treatment caused tumor regression by a variety of routes including intravenous (IV) administration, which was selected for clinical development. Initial rodent testing was successful at predicting the mechanism of clinical toxicity, the most common patient side effects, and the starting human dose. For optimization of the dose amount, schedule and infusion rate, three phase 1 studies of IV administration of PV701 were conducted with a total of 113 patients with advanced cancer. Three types of adverse events (AEs) were observed: 1) flu-like symptoms, which were the most common AEs; 2) tumor site specific AEs often associated with tumor inflammation; and 3) infusion reactions. The most recent phase 1 study increased dose intensity and improved patient tolerability (e.g., all flu-like symptoms were mild-to-moderate). In this 18 patient study, encouraging signs of efficacy were seen with four major objective responses (2 colorectal, 1 melanoma and 1 cervical) and 2 minor responses (carcinoid). Of 18 advanced, chemo-refractory patients, eleven (5 colorectal, 2 carcinoid, 2 ovarian, 1 melanoma, 1 cervical) had a progression-free survival of |[ge]|4 months and five were alive at 32+ months. Based on encouraging signs of efficacy, particularly in patients with advanced colorectal cancer in all three phase 1 trials, colorectal cancer has been selected as one of the phase 2 targets for PV701. Preclinical experiments were then conducted combining PV701 with chemotherapy approved for that indication. Using two different human tumor xenografts (HT1080 fibrosarcoma and SW620 colorectal carcinoma), evidence for marked antitumor synergy of intravenous PV701 with either irinotecan or 5-fluorouracil (5-FU) was observed, regardless of the order of administration. For example, while suboptimal doses of PV701 (2E+07 plaque forming units, PFU) or irinotecan (10 mg/kg) alone caused no tumor regression, the combination yielded complete regressions (CRs) of HT1080 tumors in 50% of the mice. Similarly, a combination of the same dose of PV701 with 5-FU at its maximum tolerated dose (100 mg/kg) caused CRs in 38% of mice while either agent alone caused no CRs. These preclinical results indicate the potential advantage of combining PV701 with chemotherapy. In conclusion, single agent PV701 displayed an encouraging safety and efficacy profile by the intravenous route in phase 1 clinical testing. Preclinical testing in rodents is currently providing key insights into the design of phase 2 trials of PV701 combined with chemotherapy.