Mettinger, K.L.

10524 Background: Reolysin is a Dearing strain, naturally occurring, ubiquitous human reovirus. The PKR (double stranded RNA-activated protein kinase) is inhibited and therefore the virus replicates specifically in transformed cells possessing an activated Ras pathway producing lysis. In vitro and in vivo studies with Reolysin in sarcoma cell lines revealed significant antitumor activity. Methods: This phase II open-label, single agent study was designed to characterize the efficacy and safety of Reolysin given IV every 28 days in patients (pts) with bone or soft tissue sarcoma with lung metastasis using a Simon two-stage design. 38 pts were accrued to the first stage. If 1 or more pts experience clinical benefit (prolonged SD > 6 months, partial or complete response) up to 52 pts could be accrued. The agent will be considered active if 3 or more responses or prolonged SD are observed. Results: Since July 2007, 43 pts age 19–76 (median 49) were enrolled (20 female) and received a total of 141 cycles (range 1–18). All pts had performance status 1 (29 pts) or 0 (14 pts). 38 pts received prior chemotherapy, radiotherapy, biological agents or combinations for their metastatic disease, 15 pts received more than 3 chemotherapy regimens. The sarcoma subtypes included: synovial sarcoma (13 pts), osteosarcoma (7 pts), leiomyosarcoma (7 pts), MFH (5 pts), Ewing/PNET (1 pt), chordoma (1 pt), others (9 pts). Side effects were mild to moderate (grade 1–2) and included constitutional symptoms fever, chills, fatigue. Two pts experienced respiratory side effects (cough and dyspnea) and 2 pts had diarrhea. Hematological side effects included grade 2–3 neutropenia (6 pts) and grade 2 thrombocytopenia (2 pts). One patient experienced grade 2 AST elevation. 33 pts are evaluable for response to date: 14 pts (42%) had SD for 2+ months including 5 pts having SD for more than 6 months. Conclusions: Utilization of single agent reovirus for treatment of sarcoma is a novel and unique therapeutic approach to date. Reolysin is well tolerated and shows promise for the treatment of metastatic sarcoma. Primary efficacy goals have been met. Accrual is ongoing to a total of 52 pts. [Table: see text]

Abstract Purpose: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. Experimental Design: Patients received 75 mg/m2 docetaxel (day 1) and escalating doses of reovirus up to 3 × 1010 TCID50 (days 1-5) every 3 weeks. Results: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. Conclusion: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m2, three times weekly) and reovirus (3 × 1010 TCID50, days 1-5, every 3 weeks). Clin Cancer Res; 16(22); 5564–72. ©2010 AACR.