title: Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma.
abstract: Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Noonan
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Farren
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Geyer
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Sanaa
authors.initials: S
authors.lastname: Tahiri
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Sameh
authors.initials: S
authors.lastname: Mikhail
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ciombor
authors.affiliation: Department of Medicine, Hematology/Oncology, Oklahoma University Cancer Institute, Oklahoma City, Oklahoma, USA.
authors.forename: Shubham
authors.initials: S
authors.lastname: Pant
authors.affiliation: Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Aparo
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sexton
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
authors.forename: Bassel
authors.initials: B
authors.lastname: El-Rayes
authors.affiliation: Solid Tumor Translational Science Shared Resource, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Timmers
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland, USA.
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA. Electronic address: Bekaii-Saab.tanios@mayo.edu.
authors.forename: Tanios S
authors.initials: TS
authors.lastname: Bekaii-Saab
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016190:Carboplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000235:genetics; D008875:Middle Aged; D009362:Neoplasm Metastasis; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D016190:Carboplatin; D017239:Paclitaxel