Kristian Brock1, Victoria Homer2, Gurjinder Soul3, Claire Potter2, Cody Chiuzan4, Shing Lee4. 1. Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK. k.brock@bham.ac.uk. 2. Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK. 3. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. 4. Mailman School of Public Health, Columbia University, New York, NY, USA.
Abstract
BACKGROUND: The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. METHODS: We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. RESULTS: We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. CONCLUSIONS: Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.
BACKGROUND: The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. METHODS: We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. RESULTS: We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. CONCLUSIONS: Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.
Authors: André Rogatko; David Schoeneck; William Jonas; Mourad Tighiouart; Fadlo R Khuri; Alan Porter Journal: J Clin Oncol Date: 2007-11-01 Impact factor: 44.544
Authors: Cody Chiuzan; Jonathan Shtaynberger; Gulam A Manji; Jimmy K Duong; Gary K Schwartz; Anastasia Ivanova; Shing M Lee Journal: J Biopharm Stat Date: 2017-02-06 Impact factor: 1.051