REO-10: A Phase I Study of Intravenous Reovirus and Docetaxel in Patients with Advanced Cancer

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).

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling

“…Indeed, herpes simplex virus type 1 (OncoVEX GM-CSF ), reovirus (Reolysin) and vaccinia virus (JX-594) have all reached late-stage, randomised clinical trials either as single agent therapies or in combination with cytotoxic chemotherapy. In addition, recent studies have highlighted the fact that combining oncolytic virotherapy with ionizing radiation may lead to synergistic anti-tumor efficacy and translational phase I/II clinical trials have been completed (1,2). However, the reported complex effects of radiation on viral infectivity, replication, gene expression and cytotoxicity mean that detailed mechanistic preclinical studies are an essential prerequisite to trials of new oncolytic viral agents in combination with radiation.…”

Evolution of Reovirus in Cancer Therapy

“…Other chemotherapeutic agents that have completed at least Phase I clinical trials in combination with reovirus include docetaxel, [78] and paclitaxel and carboplatin. [69] All aforementioned combinations have gone on to further Phase II or Phase III clinical trials.…”

“…[89,90] Overall, combination therapies have demonstrated that reovirus does not exacerbate known chemotherapy or radiation-associated toxicities or vice versa. [69,71,78] However, the known toxicities of gemcitabine and reovirus were observed in one trial. [73] Lolkema et al concluded that since gemcitabine appears to have an inhibitory effect on the development of neutralizing antireoviral antibodies (NARAs), a chemotherapeutic regimen in combination with reovirusmay exacerbate reovirus toxicity in the liver and further elevate liver enzyme levels.…”

Evolution of Reovirus in Cancer Therapy

“…A Phase II clinical trial is ongoing to further evaluate the interactions between reovirus and gemcitabine in a clinical setting. [75][76][77] Other chemotherapeutic agents that have completed at least Phase I clinical trials in combination with reovirus include docetaxel, [78] and paclitaxel and carboplatin. [69] All aforementioned combinations have gone on to further Phase II or Phase III clinical trials.…”