TY - JOUR
T1 - A phase I study of intravenous oncolytic reovirus type 3 dearing in patients with advanced cancer
AU - Vidal, Laura
AU - Pandha, Hardev S.
AU - Yap, Timothy A.
AU - White, Christine L.
AU - Twigger, Katie
AU - Vile, Richard G.
AU - Melcher, Alan
AU - Coffey, Matt
AU - Harrington, Kevin J.
AU - DeBono, Johann S.
PY - 2008/11/1
Y1 - 2008/11/1
N2 - Purpose: To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity. Experimental Design: Patients received escalating doses of reovirus up to 3 × 1010 TCID50 for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication. Results: Thirty-three patients received 76 courses of reovirus from 1 × 10 8 for 1 day up to 3 × 1010 TCID50 for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation. Conclusions: Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 × 1010 TCID50 for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.
AB - Purpose: To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity. Experimental Design: Patients received escalating doses of reovirus up to 3 × 1010 TCID50 for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication. Results: Thirty-three patients received 76 courses of reovirus from 1 × 10 8 for 1 day up to 3 × 1010 TCID50 for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation. Conclusions: Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 × 1010 TCID50 for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.
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U2 - 10.1158/1078-0432.CCR-08-0524
DO - 10.1158/1078-0432.CCR-08-0524
M3 - Article
C2 - 18981012
AN - SCOPUS:58149252477
SN - 1078-0432
VL - 14
SP - 7127
EP - 7137
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -