title: The performance of model-based versus rule-based phase I clinical trials in oncology : A quantitative comparison of the performance of model-based versus rule-based phase I trials with molecularly targeted anticancer drugs over the last 2 years.
abstract: Phase I studies with anticancer drugs are used to evaluate safety and tolerability and to choose a recommended phase II dose (RP2D). Traditionally, phase I trial designs are rule-based, but for several years there is a trend towards model-based designs. Simulations have shown that model-based designs perform better, faster and are safer to establish the RP2D than rule-based designs. However, the superiority of model-based designs has never been confirmed based on true trial performance in practice. To aid evidence-based decisions for designing phase I trials, we compared publications of model-based and rule-based phase I trials in oncology. We reviewed 172 trials that have been published in the last 2 years and assessed the following operating characteristics: efficiency (trial duration, population size, dose-levels), patient safety (dose-limiting toxicities (DLTs)) and treatment optimality (percentage of patients treated below and at or above the recommended phase 2 dose). Our results showed a non-significant but clinically relevant difference in trial duration. Model-based trials needed 10 months less than rule-based trials (26 versus 36 months; p = 0.25). Additionally, fewer patients were treated at dose-levels below the RP2D (31 % versus 40 %; p = 0.73) while safety was preserved (13 % DLTs versus 14 % DLTs). In this review, we provide evidence to encourage the use of model-based designs for future phase I studies, based on a median of 10 months of time gain, acceptable toxicity rates and minimization of suboptimal treatment.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: E M J
authors.initials: EM
authors.lastname: van Brummelen
authors.affiliation: Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: van Werkhoven
authors.affiliation: Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. j.schellens@nki.nl.|Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. j.schellens@nki.nl.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents
keywords: Clinical trial design; Dose-escalation trials; Model-based trials; Rule-based trials; Trial duration; Trial performance