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International Biometric Society
MODELLING SEMI-ATTRIBUTABLE TOXICITY IN DUAL-AGENT PHASE I TRIALS WITH NONCONCURRENT DRUG ADMINISTRATION
Graham Wheeler1, Michael Sweeting2, Adrian Mander1 and Ying Kuen Cheung3
1
MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care,
University of Cambridge, UK
2
3
Department of Biostatistics, Mailman School of Public Health, Columbia University,
New York, USA
In oncology, there is increasing interest in studying combinations of drugs to improve
treatment efficacy and/or reduce harmful side-effects. Dual-agent phase I clinical trials are
primarily concerned with drug safety, with the aim to discover a maximum tolerated
combination dose via dose-escalation; small cohorts of patients are given set doses of both
drugs and monitored to see if any particular toxic reactions occur. Whether to escalate, deescalate or maintain the current dose for either drug for subsequent cohorts is based on the
number and severity of observed toxic reactions, and a decision rule.
Combinations of drugs may be administered concurrently or non-concurrently over a cycle of
treatment, depending on disease type, disease severity, the number and type of drugs to be
administered, and pharmacokinetic/pharmacodynamic information. In dual-agent trials with
non-concurrent drug administration, 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 present some ambiguity; toxicities may
be attributable to the first drug only, the second drug only, or the synergistic combination of
both. This mixture of attributable and non-attributable toxicity in a trial may be referred to as
semi-attributable toxicity. By using appropriate methodology for dual-agent phase I trials with
non-concurrent drug administration, it is likely that fewer patients will receive overly toxic
doses during the trial and the probability of recommending the correct dose combination will
be increased. Most published methodology assumes all drugs to be administered are given
concurrently, which may not be reflective of trials with non-concurrent drug administration.
The research presented investigates how the concept of semi-attributable toxicity may be
incorporated into Bayesian modelling for dual-agent phase I trials with non-concurrent drug
administration, and how trial performance compares to a similar modelling approach where
treatments are incorrectly assumed to be given concurrently. Simulation studies based on a
submitted trial protocol for non-concurrent administration of intravesical Cabazitaxel and
Cisplatin in early-stage bladder cancer patients are presented across a wide range of
scenarios. We show that including semi-attributable toxicity data in the dose-escalation
modelling process reduces the number of patients given overly toxic dose combinations.
International Biometric Conference, Florence, ITALY, 6 – 11 July 2014