title: Dose-escalation models for combination phase I trials in oncology.
abstract: Designing combination drug phase I trials has become increasingly complex, due to the increasing diversity in classes of agents, mechanisms of action, safety profiles and drug-administration schedules. With approximately 850 agents currently in development for cancer treatment, it is evident that combination development must be prioritised, as based on a specific hypothesis, as well as a projected development path for the involved combination. In this manuscript the most relevant issues and pitfalls for combination drug phase I trial design are discussed. Several phase I study designs that incorporate controls to circumvent bias due to imbalances in observed background toxicity are discussed.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. a.hamberg@erasmusmc.nl
authors.forename: Paul
authors.initials: P
authors.lastname: Hamberg
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lesaffre
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015195:Drug Design; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008954:Models, Biological; D012107:Research Design; D018675:Toxicity Tests