title: Toxicity-evaluation designs for phase I/II cancer immunotherapy trials.
abstract: OBJECTIVE
  To facilitate more efficient Phase I/II cancer immunotherapy trials by incorporating statistically rigorous safety analysis.
  
  
  METHODS
  The standard Phase I oncology trial is designed to find the maximum tolerated dose (MTD) in a setting where serious drug-related toxicity is expected. However, many newer agents hope to show the efficacy without increasing the background rate of adverse events. Formal statistical designs in this setting are needed.
  
  
  RESULTS
  The Phase I/II toxicity-evaluation design is suitable when the therapeutic dose is expected to be well below the MTD. In Phase I, the design enrolls multiple cohorts at the target dose, possibly after an initial dose titration stage, and tests a formal safety hypothesis using a standard 3 + 3 enrollment scheme. Phase I serves as an interim safety analysis before proceeding to Phase II efficacy testing. We give an exact upper confidence limit on the toxicity rate at the therapeutic dose using the combined Phase I/II toxicity data, as well as the maximum likelihood estimate of the toxicity rate. We describe an example where the design has been used for a Phase I/II trial of immunotherapy in leukemia.
  
  
  CONCLUSIONS
  Phase I/II toxicity-evaluation designs are simple to execute and may be suitable for some cancer immunotherapy trials. We show how to compute power, expected sample size, and expected number of dose-limiting toxicities, as well as the maximum likelihood estimator and exact small sample confidence intervals for the toxicity rate at the therapeutic dose. More flexible designs are briefly discussed.
authors.affiliation: Division of Biostatistics, Moores UCSD Cancer Center, University of California, La Jolla, CA 92093-0901, USA. kmesser@ucsd.edu
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.forename: Loki
authors.initials: L
authors.lastname: Natarajan
authors.forename: Edward D
authors.initials: ED
authors.lastname: Ball
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lane
mesh_terms: D056808:Biostatistics; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D015331:Cohort Studies; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects*; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D016013:Likelihood Functions; D020714:Maximum Tolerated Dose; D018401:Sample Size; D013602:T-Lymphocytes, Cytotoxic / Q000637:transplantation
chemical_list: D019496:Cancer Vaccines