title: Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization.
abstract: Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose-efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.
authors.affiliation: 1 INSERM, U1138, Team 22, Centre de Recherche des Cordeliers, Université Paris 5, Université Paris 6, France.|2 IRIS (Institut de Recherches Internationales Servier), Suresnes, France.
authors.forename: Marie-Karelle
authors.initials: MK
authors.lastname: Riviere
authors.affiliation: 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: 4 INRIA Paris-Rocquencourt, Rocquencourt, France.
authors.forename: Jacques-Henri
authors.initials: JH
authors.lastname: Jourdan
authors.affiliation: 2 IRIS (Institut de Recherches Internationales Servier), Suresnes, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dubois
authors.affiliation: 1 INSERM, U1138, Team 22, Centre de Recherche des Cordeliers, Université Paris 5, Université Paris 6, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Zohar
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D001499:Bayes Theorem; D056808:Biostatistics; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016013:Likelihood Functions; D020714:Maximum Tolerated Dose; D015233:Models, Statistical; D058990:Molecular Targeted Therapy / Q000706:statistics & numerical data*; D009369:Neoplasms / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*
chemical_list: D000970:Antineoplastic Agents
keywords: Dose-finding; molecularly targeted agents; oncology; phase I; phase II