Dose‐finding methods for Phase I clinical trials using pharmacokinetics in small populations

Abstract

The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studies, dose‐finding and PK analysis are done separately and no attempt is made to combine them during dose allocation. In cases such as rare diseases, paediatrics, and studies in a biomarker‐defined subgroup of a defined population, the available population size will limit the number of possible clinical trials that can be conducted. Combining dose‐finding and PK analyses to allow better estimation of the dose‐toxicity curve should then be considered. In this work, we propose, study, and compare methods to incorporate PK measures in the dose allocation process during a phase I clinical trial. These methods do this in different ways, including using PK observations as a covariate, as the dependent variable or in a hierarchical model. We conducted a large simulation study that showed that adding PK measurements as a covariate only does not improve the efficiency of dose‐finding trials either in terms of the number of observed dose limiting toxicities or the probability of correct dose selection. However, incorporating PK measures does allow better estimation of the dose‐toxicity curve while maintaining the performance in terms of MTD selection compared to dose‐finding designs that do not incorporate PK information. In conclusion, using PK information in the dose allocation process enriches the knowledge of the dose‐toxicity relationship, facilitating better dose recommendation for subsequent trials.

A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer

“…A 3 + 3 design is commonly used in phase I trials due to its simple, intuitive, and pre-specified escalation rules. However, the 3 + 3 method has been criticized for being conservative because the method is dictated by the observed DLT rate without acknowledging the variability arising from a small cohort size [19]. Like the 3 + 3 design, the mTPI method incorporates pre-specified escalation rules.…”

Recent advances in methodology for clinical trials in small populations: the InSPiRe project

“…Incorporation of pharmacokinetics (PK) and pharmacodynamics (PD) data in early-phase dose-finding studies Meta-analysis methods for small trials or small numbers of trials Key publications: [25,[27][28][29][30] Key publications: [33, 34, 36-38, 40, 41] Open-source R software: dfpk [26], dfped [29] Open-source R software: bayesmeta [35], nmaINLA [42] and meta-analysis methods for small trials or small numbers of trials. The work in these four areas is described below.…”

Bayesian dose‐finding phase I trial design incorporating pharmacokinetic assessment in the field of oncology

“…These models utilize both dose and PK assessment. Ursino et al (2017) compared the operating characteristics of the previously mentioned approaches in a simulation study and found that these methods did not improve the effectiveness of dose‐finding trials . These approaches have rarely been used in practice because they do not increase the rate of correct OD selection.…”

“…Ursino et al (2017) compared the operating characteristics of the previously mentioned approaches in a simulation study and found that these methods did not improve the effectiveness of dose-finding trials. 11 These approaches have rarely been used in practice because they do not increase the rate of correct OD selection. Possible reasons are multi-collinearity between dose and PK information, the nonproportional relationship between dose and PK information at higher dose levels, and large inter-individual variability.…”