title: Is the "3+3" dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design.
abstract: OBJECTIVE
  Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered.
  
  
  METHODS
  We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-escalation design.
  
  
  RESULTS
  The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose.
  
  
  CONCLUSIONS
  Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development.
authors.affiliation: Vaccine Branch, National Cancer Institute, Bethesda, Maryland. Division of Hematology/Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: Osama E
authors.initials: OE
authors.lastname: Rahma
authors.affiliation: Vaccine Branch, National Cancer Institute, Bethesda, Maryland.
authors.forename: Emily
authors.initials: E
authors.lastname: Gammoh
authors.affiliation: Biometric Research Branch, National Cancer Institute, Rockville, Maryland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Simon
authors.affiliation: Vaccine Branch, National Cancer Institute, Bethesda, Maryland. Georgia Health Sciences Cancer Center, Augusta, Georgia. skhleif@gru.edu.
authors.forename: Samir N
authors.initials: SN
authors.lastname: Khleif
mesh_terms: D019496:Cancer Vaccines / Q000008:administration & dosage*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods* / Q000592:standards*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design / Q000592:standards*
chemical_list: D019496:Cancer Vaccines