Modelling semi‐attributable toxicity in dual‐agent phase I trials with non‐concurrent drug administration

Abstract

In oncology, combinations of drugs are often used to improve treatment efficacy and/or reduce harmful side effects. Dual‐agent phase I clinical trials assess drug safety and aim to discover a maximum tolerated dose combination via dose‐escalation; cohorts of patients are given set doses of both drugs and monitored to see if toxic reactions occur. Dose‐escalation decisions for subsequent cohorts are based on the number and severity of observed toxic reactions, and an escalation rule. In a combination trial, drugs may be administered concurrently or non‐concurrently over a treatment cycle. For two drugs given non‐concurrently with overlapping toxicities, toxicities occurring after administration of the first drug yet before administration of the second may be attributed directly to the first drug, whereas toxicities occurring after both drugs have been given some present ambiguity; toxicities may be attributable to the first drug only, the second drug only or the synergistic combination of both. We call this mixture of attributable and non‐attributable toxicity semi‐attributable toxicity. Most published methods assume drugs are given concurrently, which may not be reflective of trials with non‐concurrent drug administration. We incorporate semi‐attributable toxicity into Bayesian modelling for dual‐agent phase I trials with non‐concurrent drug administration and compare the operating characteristics to an approach where this detail is not considered. Simulations based on a trial for non‐concurrent administration of intravesical Cabazitaxel and Cisplatin in early‐stage bladder cancer patients are presented for several scenarios and show that including semi‐attributable toxicity data reduces the number of patients given overly toxic combinations. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents

“…In the drug combination dose finding literature, designs that recommend a unique MTD (see e.g. Yin & Yuan, , ; Wages, Conaway, & O'Quigley, , ; Shi & Yin, ; Riviere, Yuan, Dubois, & Zohar, ; Wheeler, Sweeting, Mander, Lee, & Cheung, ; Mu & Xu, ) or multiple MTDs (see e.g. Thall, Millikan, Mueller, & Lee, ; Wang & Ivanova, ; Yuan & Yin, ; Braun & Wang, ; Mander & Sweeting, ; Tighiouart, Piantadosi, & Rogatko, ; Tighiouart, Li, Piantadosi, & Rogatko, ; Tighiouart, Li, & Rogatko, ) have been studied extensively.…”

“…In the drug combination dose finding literature, designs that recommend a unique MTD (see e.g. Yin and Yuan (2009a,b); Wages et al (2011a,b); Shi and Yin (2013); Riviere et al (2014); Wheeler et al (2017); Mu and Xu (2017)) or multiple MTDs (see e.g. Thall et al (2003); Wang and Ivanova (2005); Yuan and Yin (2008); Braun and Wang (2010); Mander and Sweeting (2015); Tighiouart et al (2014, 2016, 2017)) have been studied extensively.…”

“…However, they require all toxicities to be attributable, which is rare in practice. Wheeler et al (2017) proposed a semi-attributable toxicity design based on a trial with non-concurrent drug administration. In their design, one drug is administered at the beginning of the treatment cycle and the other drug is administered at a much later time point if and only if the patient did not experience DLT.…”

Phase I Designs That Allow for Uncertainty in the Attribution of Adverse Events

“…Our proposed design that allows patient‐specific scores for AE attribution provides a conceptual link between the clinical challenges of phase I trials and the statistical complexity of recent model‐based dose escalation algorithms. Our work focused on the single‐agent setting but the approach has the potential to be extended to the context of drug combinations (Wages, ; Wheeler et al ., ). For example, there are cases where one of the components of a combination is known to be associated with some particular AEs or type of toxicities such as dermatologic, whereas the other is not.…”

Early phase dose finding methodology

“…This special issue includes some of the work presented at the symposium and provides an idea of the topics covered at the meeting [3][4][5][6][7][8][9][10]. The general feeling was that the objective of the symposiumto share ideas and ongoing work openlywas achieved and the next symposium is planned for April 26-28, 2017, at the University of Virginia, in Charlottesville, Virginia, USA.…”