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

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.

Bayesian modeling of a bivariate toxicity outcome for early phase oncology trials evaluating dose regimens.

Most phase I trials in oncology aim to find the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT). Evaluating the schedule of administration in addition to the dose may improve drug tolerance. Moreover, for some molecules, a bivariate toxicity endpoint may be more appropriate than a single endpoint. However, standard dose-finding designs do not account for multiple dose regimens and bivariate toxicity endpoint within the same design. In this context, following a phase I motivating trial, we proposed modeling the first type of DLT, cytokine release syndrome, with the entire dose regimen using pharmacokinetics and pharmacodynamics (PK/PD), whereas the other DLT (DLTo ) was modeled with the cumulative dose. We developed three approaches to model the joint distribution of DLT, defining it as a bivariate binary outcome from the two toxicity types, under various assumptions about the correlation between toxicities: an independent model, a copula model and a conditional model. Our Bayesian approaches were developed to be applied at the end of the dose-allocation stage of the trial, once all data, including PK/PD measurements, were available. The approaches were evaluated through an extensive simulation study that showed that they can improve the performance of selecting the true MTD-regimen compared to the recommendation of the dose-allocation method implemented. Our joint approaches can also predict the DLT probabilities of new dose regimens that were not tested in the study and could be investigated in further stages of the trial.

Bayesian methods for the analysis of early-phase oncology basket trials with information borrowing across cancer types.

Research in oncology has changed the focus from histological properties of tumors in a specific organ to a specific genomic aberration potentially shared by multiple cancer types. This motivates the basket trial, which assesses the efficacy of treatment simultaneously on multiple cancer types that have a common aberration. Although the assumption of homogeneous treatment effects seems reasonable given the shared aberration, in reality, the treatment effect may vary by cancer type, and potentially only a subgroup of the cancer types respond to the treatment. Various approaches have been proposed to increase the trial power by borrowing information across cancer types, which, however, tend to inflate the type I error rate. In this article, we review some representative Bayesian information borrowing methods for the analysis of early-phase basket trials. We then propose a novel method called the Bayesian hierarchical model with a correlated prior (CBHM), which conducts more flexible borrowing across cancer types according to sample similarity. We did simulation studies to compare CBHM with independent analysis and three information borrowing approaches: the conventional Bayesian hierarchical model, the EXNEX approach, and Liu's two-stage approach. Simulation results show that all information borrowing approaches substantially improve the power of independent analysis if a large proportion of the cancer types truly respond to the treatment. Our proposed CBHM approach shows an advantage over the existing information borrowing approaches, with a power similar to that of EXNEX or Liu's approach, but the potential to provide substantially better control of type I error rate.

Robust designs in longitudinal studies accounting for parameter and model uncertainties - application to count data.

Nonlinear mixed effect models (NLMEMs) are widely used for the analysis of longitudinal data. To design these studies, optimal designs based on the expected Fisher information matrix (FIM) can be used. A method evaluating the FIM using Monte-Carlo Hamiltonian Monte-Carlo (MC-HMC) has been proposed and implemented in the R package MIXFIM using Stan. This approach, however, requires a priori knowledge of models and parameters, which leads to locally optimal designs. The objective of this work was to extend this MC-HMC-based method to evaluate the FIM in NLMEMs accounting for uncertainty in parameters and in models. When introducing uncertainty in the population parameters, we evaluated the robust FIM as the expectation of the FIM computed by MC-HMC over the distribution of these parameters. Then, the compound D-optimality criterion (CD optimality), corresponding to a weighted product of the D-optimality criteria of several candidate models, was used to find a common CD-optimal design for the set of candidate models. Finally, a compound DE-criterion (CDE optimality), corresponding to a weighted product of the normalized determinants of the robust FIMs of all the candidate models accounting for uncertainty in parameters, was calculated to find the CDE-optimal design which was robust on both parameters and model. These methods were applied in a longitudinal Poisson count model. We assumed prior distributions on the population parameters, as well as several candidate models describing the relationship between the logarithm of the event rate parameter and the dose. We found that assuming uncertainty in parameters could lead to different optimal designs, and misspecification of models could induce designs with low efficiencies. The CD- or CDE-optimal designs therefore provided a good compromise for different candidate models. Finally, the proposed approach allows for the first time optimization of designs for repeated discrete data accounting for parameter and model uncertainties.

An MCMC method for the evaluation of the Fisher information matrix for non-linear mixed effect models.

Non-linear mixed effect models (NLMEMs) are widely used for the analysis of longitudinal data. To design these studies, optimal design based on the expected Fisher information matrix (FIM) can be used instead of performing time-consuming clinical trial simulations. In recent years, estimation algorithms for NLMEMs have transitioned from linearization toward more exact higher-order methods. Optimal design, on the other hand, has mainly relied on first-order (FO) linearization to calculate the FIM. Although efficient in general, FO cannot be applied to complex non-linear models and with difficulty in studies with discrete data. We propose an approach to evaluate the expected FIM in NLMEMs for both discrete and continuous outcomes. We used Markov Chain Monte Carlo (MCMC) to integrate the derivatives of the log-likelihood over the random effects, and Monte Carlo to evaluate its expectation w.r.t. the observations. Our method was implemented in R using Stan, which efficiently draws MCMC samples and calculates partial derivatives of the log-likelihood. Evaluated on several examples, our approach showed good performance with relative standard errors (RSEs) close to those obtained by simulations. We studied the influence of the number of MC and MCMC samples and computed the uncertainty of the FIM evaluation. We also compared our approach to Adaptive Gaussian Quadrature, Laplace approximation, and FO. Our method is available in R-package MIXFIM and can be used to evaluate the FIM, its determinant with confidence intervals (CIs), and RSEs with CIs.

A Bayesian dose-finding design for drug combination clinical trials based on the logistic model.

In early phase dose-finding cancer studies, the objective is to determine the maximum tolerated dose, defined as the highest dose with an acceptable dose-limiting toxicity rate. Finding this dose for drug-combination trials is complicated because of drug-drug interactions, and many trial designs have been proposed to address this issue. These designs rely on complicated statistical models that typically are not familiar to clinicians, and are rarely used in practice. The aim of this paper is to propose a Bayesian dose-finding design for drug combination trials based on standard logistic regression. Under the proposed design, we continuously update the posterior estimates of the model parameters to make the decisions of dose assignment and early stopping. Simulation studies show that the proposed design is competitive and outperforms some existing designs. We also extend our design to handle delayed toxicities.

Effect of medical staff training on vaccination coverage in outpatients with cancer: An interventional multicenter before-and-after study.

Purpose: Despite widely disseminated guidelines, pneumococcal and influenza vaccination coverage (VC) remains insufficient in patients with cancer receiving cancer treatment. We performed an interventional study to evaluate VC in patients with cancer treated at the medical oncology departments of three North-of-France hospitals and to assess the effect of medical staff training on VC in these patients. Methods: A standardized questionnaire assessed VC in adult patients with cancer receiving anticancer treatment at three day hospitals during December 2-7, 2019. Subsequently (January 2020), we organized educational training sessions for medical staff from each hospital to discuss the current vaccination guidelines. To assess the impact of training on pneumococcal and influenza VC, we re-administered the same questionnaire in March 2020. Because there are no specific guidelines on Diphtheria-Tetanus-Pertussis (DTP) vaccination and no improvement was expected, DTP VC acted as an internal control. Results: In total, 272 patients from all three hospitals were enrolled in the "before study"; 156 patients from only two hospitals were enrolled in the "after study" as medical training and data collection at the third were impossible because of administrative reasons and COVID-19 pandemic. The predictors were age for DTP VC; treatment center for pneumococcal VC; and age, sex, and tumor histology (adenocarcinoma vs. others) for influenza VC. Neither influenza VC (42.6% vs. 55.1%, p = 0.08), nor pneumococcal VC were significantly improved post-intervention (11.8% vs. 15.4%, p = 1). There seems to be a small effect in the most fragile for influenza VC. Conclusion: As expected, VC was very low in patients with cancer, consistent with the literature. There was no impact of the intervention for pneumococcal and influenza VC.

Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization.

Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose-efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.

dfcomb: An R-package for phase I/II trials of drug combinations.

In this paper, we present the dfcomb R package for the implementation of a single prospective clinical trial or simulation studies of phase I combination trials in oncology. The aim is to present the features of the package and to illustrate how to use it in practice though different examples. The use of combination clinical trials is growing, but the implementation of existing model-based methods is complex, so this package should promote the use of innovative adaptive designs for early phases combination trials.