title: A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer.
abstract: CG7870 is a replication-selective oncolytic adenovirus genetically engineered to replicate preferentially in prostate tissue. In a previous phase I/II clinical trial of intraprostatic delivery of CG7870 for locally recurrent prostate cancer this virus was well tolerated. In this phase I study CG7870 was administered as a single intravenous infusion in a group-sequential dose escalation design (1 x 10(10) to 6 x 10(12) viral particles (vp)) to 23 patients with hormone-refractory metastatic prostate cancer. Flulike symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common adverse events. Three therapy-related grade 3 adverse events were reported, one of which (fatigue) was serious. At doses greater than 10(12) vp all five patients experienced asymptomatic grade 1 to 2 transaminitis and/or isolated d-dimer elevations starting on day 2 through 8; dose escalation was therefore halted at 6 x 10(12) vp. All tested patients had CG7870 genomes present in the peripheral blood for at least 90 minutes after infusion; patients in the highest dose group had persistence of genomes through 29 days. A "secondary" or "delayed" peak in plasma CG7870 genome copies (defined as a >10-fold increase in CG7870 genomes from nadir concentration) suggestive of active viral replication and shedding into the bloodstream was detected in 16/23 (70%) patients. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in interleukins 6 and 10 (IL-6, IL-10) blood levels were detected. The peak IL-6 concentration after CG7870 treatment was associated with a transient, asymptomatic decrease in blood pressure. No partial or complete prostate-specific antigen (PSA) responses were observed; however, 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment, including 3 of 8 patients at the highest dose levels.
authors.affiliation: University of California, Comprehensive Cancer Center San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: James M
authors.initials: JM
authors.lastname: Burke
authors.forename: Ron
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.forename: Lynn
authors.initials: L
authors.lastname: van Ummersen
authors.forename: D C
authors.initials: DC
authors.lastname: Yu
authors.forename: Junko
authors.initials: J
authors.lastname: Aimi
authors.forename: Dale
authors.initials: D
authors.lastname: Ando
authors.forename: Peter
authors.initials: P
authors.lastname: Working
authors.forename: David
authors.initials: D
authors.lastname: Kirn
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004261:DNA Replication / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000628:therapy*; D012463:Saliva / Q000378:metabolism; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D015850:Interleukin-6; D016753:Interleukin-10; D017430:Prostate-Specific Antigen