title: A novel Phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer.
abstract: The Cancer Research UK study CR0720-11 is a trial to determine the tolerability and effect on survival of using two agents in combination in patients with advanced pancreatic cancer. In particular, the trial is designed first to identify the most suitable combination of doses of the two agents in terms of the incidence of dose-limiting toxicities. Then, the survival of all patients who have received that dose combination in the study so far, together with additional patients assigned to that dose combination to ensure that the total number is sufficient, will be analysed. If the survival outcomes show promise, then a definitive randomised study of that dose combination will be recommended. The first two patients in the trial will be treated with the lowest doses of each agent in combination. An adaptive Bayesian procedure based only on monotonicity constraints concerning the risks of toxicity at different dose levels will then be used to suggest dose combinations for subsequent patients. The survival analysis will concern only patients who received the chosen dose combination, and will compare observed mortality with that expected from an exponential model based on the known survival rates associated with current treatment. In this paper, the Bayesian dose-finding procedure is described and illustrated, and its properties are evaluated through simulation. Computation of the appropriate sample size for the survival investigation is also discussed.
authors.affiliation: Medical and Pharmaceutical Statistics Research Unit, Lancaster University, U.K. j.whitehead@lancaster.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Whitehead
authors.forename: Helene
authors.initials: H
authors.lastname: Thygesen
authors.forename: Thomas
authors.initials: T
authors.lastname: Jaki
authors.forename: Scot
authors.initials: S
authors.lastname: Davies
authors.forename: Sarah
authors.initials: S
authors.lastname: Halford
authors.forename: Helen
authors.initials: H
authors.lastname: Turner
authors.forename: Natalie
authors.initials: N
authors.lastname: Cook
authors.forename: Duncan
authors.initials: D
authors.lastname: Jodrell
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001499:Bayes Theorem; D001555:Benzene Derivatives / Q000008:administration & dosage; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003198:Computer Simulation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D015233:Models, Statistical; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011422:Propionates / Q000008:administration & dosage; D012107:Research Design; D018401:Sample Size; D013450:Sulfones / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D001555:Benzene Derivatives; D011422:Propionates; D013450:Sulfones; D003841:Deoxycytidine; D000093542:Gemcitabine