title: A pragmatic dose-finding approach using short-term surrogate efficacy outcomes to evaluate binary efficacy and toxicity outcomes in phase I cancer clinical trials.
abstract: There is a growing need for study designs that can evaluate efficacy and toxicity outcomes simultaneously in phase I or phase I/II cancer clinical trials. Many dose-finding approaches have been proposed; however, most of these approaches assume binary efficacy and toxicity outcomes, such as dose-limiting toxicity (DLT), and objective responses. DLTs are often defined for short time periods. In contrast, objective responses are often defined for longer periods because of practical limitations on confirmation and the criteria used to define 'confirmation'. This means that studies have to be carried out for unacceptably long periods of time. Previous studies have not proposed a satisfactory solution to this specific problem. Furthermore, this problem may be a barrier for practitioners who want to implement notable previous dose-finding approaches. To cope with this problem, we propose an approach using unconfirmed early responses as the surrogate efficacy outcome for the confirmed outcome. Because it is reasonable to expect moderate positive correlation between the two outcomes and the method replaces the surrogate outcome with the confirmed outcome once it becomes available, the proposed approach can reduce irrelevant dose selection and accumulation of bias. Moreover, it is also expected that it can significantly shorten study duration. Using simulation studies, we demonstrate the positive utility of the proposed approach and provide three variations of it, all of which can be easily implemented with modified likelihood functions and outcome variable definitions.
authors.affiliation: Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Asakawa
authors.forename: Chikuma
authors.initials: C
authors.lastname: Hamada
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers
keywords: binary outcome; dose-finding; efficacy; phase I; study duration; surrogate