Project description:The concept of coherence was proposed for single-agent phase I clinical trials to describe the property that a design never escalates the dose when the most recently treated patient has toxicity and never de-escalates the dose when the most recently treated patient has no toxicity. It provides a useful theoretical tool for investigating the properties of phase I trial designs. In this paper, we generalize the concept of coherence to drug combination trials, which are substantially different and more challenging than single-agent trials. For example, in the dose-combination matrix, each dose has up to 8 neighboring doses as candidates for dose escalation and de-escalation, and the toxicity orders of these doses are only partially known. We derive sufficient conditions for a model-based drug combination trial design to be coherent. Our results are more general and relaxed than the existing results and are applicable to both single-agent and drug combination trials. We illustrate the application of our theoretical results with a number of drug combination dose-finding designs in the literature.
Project description:Little is known about the relative performance of competing model-based dose-finding methods for combination phase I trials. In this study, we focused on five model-based dose-finding methods that have been recently developed. We compared the recommendation rates for true maximum-tolerated dose combinations (MTDCs) and over-dose combinations among these methods under 16 scenarios for 3 × 3, 4 × 4, 2 × 4, and 3 × 5 dose combination matrices. We found that performance of the model-based dose-finding methods varied depending on (1) whether the dose combination matrix is square or not; (2) whether the true MTDCs exist within the same group along the diagonals of the dose combination matrix; and (3) the number of true MTDCs. We discuss the details of the operating characteristics and the advantages and disadvantages of the five methods compared.
Project description:BackgroundDose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM).MethodsWe carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation.ResultsWe describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators' preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome.ConclusionsThere is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia.
Project description:We review the rationale behind the statistical design of dose-finding studies as used in phase I and phase I/II clinical trials. We underline what the objectives of such dose-finding studies should be and why the widely used standard design fails to meet any of these objectives. The standard design is a "memoryless" design and we discuss how this impacts on practical behaviour. Designs introduced over the last two decades can be viewed as designs with memory and we discuss how these designs are superior to memoryless designs. By superior we mean that they require less patients overall, less patients to attain the maximum tolerated dose (MTD), and concentrate a higher percentage of patients at and near to the MTD. We reanalyse some recently published studies in order to provide support to our contention that markedly better results could have been achieved had a design with memory been used instead of a memoryless design.
Project description:We derive optimal designs to estimate efficacy and toxicity in active controlled dose-finding trials when the bivariate continuous outcomes are described using nonlinear regression models. We determine upper bounds on the required number of different doses and provide conditions under which the boundary points of the design space are included in the optimal design. We provide an analytical description of minimally supported optimal designs and show that they do not depend on the correlation between the bivariate outcomes.
Project description:Two useful strategies to speed up drug development are to increase the patient accrual rate and use novel adaptive designs. Unfortunately, these two strategies often conflict when the evaluation of the outcome cannot keep pace with the patient accrual rate and thus the interim data cannot be observed in time to make adaptive decisions. A similar logistic difficulty arises when the outcome is late-onset. Based on a novel formulation and approximation of the likelihood of the observed data, we propose a general methodology for model-assisted designs to handle toxicity data that are pending due to fast accrual or late-onset toxicity and facilitate seamless decision making in phase I dose-finding trials. The proposed time-to-event model-assisted designs consider each dose separately and the dose-escalation/de-escalation rules can be tabulated before the trial begins, which greatly simplifies trial conduct in practice compared to that under existing methods. We show that the proposed designs have desirable finite and large-sample properties and yield performance that is comparable to that of more complicated model-based designs. We provide user-friendly software for implementing the designs.
Project description:Molecularly targeted agent (MTA) combination therapy is in the early stages of development. When using a fixed dose of one agent in combinations of MTAs, toxicity and efficacy do not necessarily increase with an increasing dose of the other agent. Thus, in dose-finding trials for combinations of MTAs, interest may lie in identifying the optimal biological dose combinations (OBDCs), defined as the lowest dose combinations (in a certain sense) that are safe and have the highest efficacy level meeting a prespecified target. The limited existing designs for these trials use parametric dose-efficacy and dose-toxicity models. Motivated by a phase I/II clinical trial of a combination of two MTAs in patients with pancreatic, endometrial, or colorectal cancer, we propose Bayesian dose-finding designs to identify the OBDCs without parametric model assumptions. The proposed approach is based only on partial stochastic ordering assumptions for the effects of the combined MTAs and uses isotonic regression to estimate partially stochastically ordered marginal posterior distributions of the efficacy and toxicity probabilities. We demonstrate that our proposed method appropriately accounts for the partial ordering constraints, including potential plateaus on the dose-response surfaces, and is computationally efficient. We develop a dose-combination-finding algorithm to identify the OBDCs. We use simulations to compare the proposed designs with an alternative design based on Bayesian isotonic regression transformation and a design based on parametric change-point dose-toxicity and dose-efficacy models and demonstrate desirable operating characteristics of the proposed designs.
Project description:We propose a flexible design for the identification of optimal dose combinations in dual-agent dose finding clinical trials. The design is called AAA, standing for three adaptations: adaptive model selection, adaptive dose insertion and adaptive cohort division. The adaptations highlight the need and opportunity for innovation for dual-agent dose finding and are supported by the numerical results presented in the proposed simulation studies. To our knowledge, this is the first design that allows for all three adaptations at the same time. We find that AAA enhances the chance of finding the optimal dose combinations and shortens the trial duration. A clinical trial is being planned to apply the AAA design and a Web tool is being developed for both statisticians and non-statisticians.
Project description:A Bayesian design is presented that does precision dose finding based on time to toxicity in a phase I clinical trial with two or more patient subgroups. The design, called Sub-TITE, makes sequentially adaptive subgroup-specific decisions while possibly combining subgroups that have similar estimated dose-toxicity curves. Decisions are based on posterior quantities computed under a logistic regression model for the probability of toxicity within a fixed follow-up period, as a function of dose and subgroup. Similarly to the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell), the Sub-TITE design downweights each patient's likelihood contribution using a function of follow-up time. Spike-and-slab priors are assumed for subgroup parameters, with latent subgroup combination variables included in the logistic model to allow different subgroups to be combined for dose finding if they are homogeneous. This framework can be used in trials where clinicians have identified patient subgroups but are not certain whether they will have different dose-toxicity curves. A simulation study shows that, when the dose-toxicity curves differ between all subgroups, Sub-TITE has superior performance compared with applying the TITE-CRM while ignoring subgroups and has slightly better performance than applying the TITE-CRM separately within subgroups or using the two-group maximum likelihood approach of Salter et al that borrows strength among the two groups. When two or more subgroups are truly homogeneous but differ from other subgroups, the Sub-TITE design is substantially superior to either ignoring subgroups, running separate trials within all subgroups, or the maximum likelihood approach of Salter et al. Practical guidelines and computer software are provided to facilitate application.
Project description:We present a Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) as a curve in the two-dimensional Cartesian plane. We use a logistic model to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of parameters clinicians can easily interpret. Trial design proceeds using univariate escalation with overdose control, where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. At the end of the trial, an estimate of the MTD curve is proposed as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial design and percent of dose recommendation at dose combination neighborhoods around the true MTD curve. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship.