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

Emma Gerard, Sarah Zohar, Hoai-Thu Thai, Christelle Lorenzato, Marie-Karelle Riviere, Moreno Ursino, Emma Gerard, Sarah Zohar, Hoai-Thu Thai, Christelle Lorenzato, Marie-Karelle Riviere, Moreno Ursino

Abstract

Phase I dose-finding trials in oncology seek to find the maximum tolerated dose 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) to estimate the maximum tolerated dose regimen (MTD-regimen) at the end of the dose-escalation stage of a trial. 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 first model, we considered nonlinear mixed-effects models, and for the second one, we proposed the following two Bayesian approaches: a logistic model and a hierarchical model. In an extensive simulation study, the DRtox outperformed traditional designs in terms of proportion of correctly selecting the MTD-regimen. Moreover, the inclusion of PK/PD information 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 was developed to 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.

Keywords: Bayesian inference; dose regimen; early phase oncology; hierarchical model; pharmacokinetics/pharmacodynamics; toxicity.

© 2021 The Authors. Biometrics published by Wiley Periodicals LLC on behalf of International Biometric Society.

Figures

FIGURE 1
FIGURE 1
Trial scheme: the DRtox method is applied at the end of the dose‐escalation stage of a phase I trial
FIGURE 2
FIGURE 2
Concentration (up) and cytokine (down) profiles of two patients, one receiving a dose regimen with intrapatient escalation in solid line and the other receiving a dose regimen without intrapatient escalation in dashed line, administered on days 1, 5, 9, 13, 17, 21, and 25. Horizontal lines represent the maximum peak of cytokine observed after each dose regimen
FIGURE 3
FIGURE 3
The first three subplots represent the panel of dose regimens from S1 in spaced dashed line to S6 in solid line, for the three main scenarios, where the type of points is specific to each scenario. In the last subplot in the lower right corner, the dose regimen toxicity relationship is represented for each scenario, where the MTD‐regimen is the dose regimen having the toxicity probability the closest to the target δT, plotted in dashed line
FIGURE 4
FIGURE 4
Violin plots of the estimated toxicity probabilities in an additional scenario in which the dose regimen panel missed the true MTD‐regimen and in Scenario 3 on 1000 trials implemented with the CRM including 30 patients. The predicted toxicity probability of a new regimen Snew is framed in dotted line. Horizontal lines on the density estimates represent the median and first and third quantiles of the distributions and the plus sign represents the mean. The dashed line represents the toxicity target and the solid line represents the true toxicity probabilities

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Source: PubMed

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