title: A phase I study of the combination of intravenous reovirus type 3 Dearing and gemcitabine in patients with advanced cancer.
abstract: OBJECTIVE
  This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response.
  
  
  METHODS
  Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 10(10) TCID(50). Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay.
  
  
  RESULTS
  Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response.
  
  
  CONCLUSIONS
  Reovirus at the dose of 1 × 10(10) TCID(50) can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule.
authors.affiliation: Phase I Unit, Royal Marsden NHS Foundation Trust, Surrey & London, United Kingdom.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.forename: Patricia
authors.initials: P
authors.lastname: Roxburgh
authors.forename: Rosemary
authors.initials: R
authors.lastname: Morrison
authors.forename: Victoria
authors.initials: V
authors.lastname: Roulstone
authors.forename: Katie
authors.initials: K
authors.lastname: Twigger
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.forename: Karl
authors.initials: K
authors.lastname: Mettinger
authors.forename: George
authors.initials: G
authors.lastname: Gill
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D012089:Mammalian orthoreovirus 3; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine