Bayesian dose-regimen assessment in early phase oncology incorporating pharmacokinetics and pharmacodynamics

TL;DR

This paper introduces a Bayesian method, DRtox, that integrates pharmacokinetics and pharmacodynamics data to accurately identify the optimal dose-regimen in early phase oncology trials, improving safety and efficacy assessment.

Contribution

The novel DRtox approach combines PK/PD modeling with Bayesian toxicity estimation to better determine the maximum tolerated dose-regimen, outperforming traditional methods.

Findings

DRtox achieves higher correct MTD-regimen selection rates.

Inclusion of PK/PD data improves toxicity curve estimates.

Method successfully recommends untested regimens for further trial phases.

Abstract

Phase I dose-finding trials in oncology seek to find the maximum tolerated dose (MTD) of a drug under a specific schedule. Evaluating drug-schedules aims at improving treatment safety while maintaining efficacy. However, while we can reasonably assume that toxicity increases with the dose for cytotoxic drugs, the relationship between toxicity and multiple schedules remains elusive. We proposed a Bayesian dose-regimen assessment method (DRtox) using pharmacokinetics/pharmacodynamics (PK/PD) information to estimate the maximum tolerated dose-regimen (MTD-regimen), at the end of the dose-escalation stage of a trial to be recommended for the next phase. We modeled the binary toxicity via a PD endpoint and estimated the dose-regimen toxicity relationship through the integration of a dose-regimen PD model and a PD toxicity model. For the dose-regimen PD model, we considered nonlinear mixed-effects models, and for the PD toxicity model, we proposed the following two Bayesian approaches: a logistic model and a hierarchical model. We evaluated the operating characteristics of the DRtox through simulation studies under various scenarios. The results showed that our method outperforms traditional model-based designs demonstrating a higher percentage of correctly selecting the MTD-regimen. Moreover, the inclusion of PK/PD information in the DRtox helped provide more precise estimates for the entire dose-regimen toxicity curve; therefore the DRtox may recommend alternative untested regimens for expansion cohorts. The DRtox should be applied at the end of the dose-escalation stage of an ongoing trial for patients with relapsed or refractory acute myeloid leukemia (NCT03594955) once all toxicity and PK/PD data are collected.