An Extended Bayesian Semi-mechanistic Dose-Finding Design for Phase I Oncology Trials Using Pharmacokinetic and Pharmacodynamic Information

Authors

Chao Yang
Yisheng Li

Language

English

Publication Date

2-20-2024

Journal

Statistics in Medicine

DOI

10.1002/sim.9980

PMID

38110304

PMCID

PMC11583997

PubMedCentral® Posted Date

2-20-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

We propose a model-based, semi-mechanistic dose-finding (SDF) design for phase I oncology trials that incorporates pharmacokinetic/pharmacodynamic (PK/PD) information when modeling the dose-toxicity relationship. This design is motivated by a phase Ib/II clinical trial of anti-CD20/CD3 T cell therapy in non-Hodgkin lymphoma patients; it extends a recently proposed SDF model framework by incorporating measurements of a PD biomarker relevant to the primary dose-limiting toxicity (DLT). We propose joint Bayesian modeling of the PK, PD, and DLT outcomes. Our extensive simulation studies show that on average the proposed design outperforms some common phase I trial designs, including modified toxicity probability interval (mTPI) and Bayesian optimal interval (BOIN) designs, the continual reassessment method (CRM), as well as an SDF design assuming a latent PD biomarker (SDF-woPD), in terms of the percentage of correct selection of maximum tolerated dose (MTD) and average number of patients allocated to MTD, under a variety of dose-toxicity scenarios. When the working PK model and the class of link function between the cumulative PD effect and DLT probability is correctly specified, the proposed design also yields better estimated dose-toxicity curves than CRM and SDF-woPD. Our sensitivity analyses suggest that the design's performance is reasonably robust to prior specification for the parameter in the link function, as well as misspecification of the PK model and class of the link function.

Keywords

Humans, Bayes Theorem, Neoplasms, Computer Simulation, Biomarkers, Maximum Tolerated Dose, Dose-Response Relationship, Drug, Research Design, cytokine release syndrome, dose finding, dose-toxicity curve, maximum tolerated dose, pharmacodynamics, pharmacokinetics

Published Open-Access

yes

Recommended Citation

Chao Yang and Yisheng Li, "An Extended Bayesian Semi-mechanistic Dose-Finding Design for Phase I Oncology Trials Using Pharmacokinetic and Pharmacodynamic Information" (2024). Faculty, Staff and Student Publications. 6104.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6104