A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

Generalized phase I-II designs to increase long term therapeutic success rate

Designs for early phase dose finding clinical trials typically are either phase I based on toxicity, or phase I-II based on toxicity and efficacy. These designs rely on the implicit assumption that the dose of an experimental agent chosen using these short-term outcomes will maximize the agent's long-term therapeutic success rate. In many clinical settings, this assumption is not true. A dose selected in an early phase oncology trial may give suboptimal progression-free survival or overall survival time, often due to a high rate of relapse following response. To address this problem, a new family of Bayesian generalized phase I-II designs is proposed. First, a conventional phase I-II design based on short-term outcomes is used to identify a set of candidate doses, rather than selecting one dose. Additional patients then are randomized among the candidates, patients are followed for a predefined longer time period, and a final dose is selected to maximize the long-term therapeutic success rate, defined in terms of duration of response. Dose-specific sample sizes in the randomization are determined adaptively to obtain a desired level of selection reliability. The design was motivated by a phase I-II trial to find an optimal dose of natural killer cells as targeted immunotherapy for recurrent or treatment-resistant B-cell hematologic malignancies. A simulation study shows that, under a range of scenarios in the context of this trial, the proposed design has much better performance than two conventional phase I-II designs.     

A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity

The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial.     

A Bayesian piecewise exponential phase II design for monitoring a time-to-event endpoint

A robust Bayesian design is presented for a single-arm phase II trial with an early stopping rule to monitor a time to event endpoint. The assumed model is a piecewise exponential distribution with non-informative gamma priors on the hazard parameters in subintervals of a fixed follow up interval. As an additional comparator, we also define and evaluate a version of the design based on an assumed Weibull distribution. Except for the assumed models, the piecewise exponential and Weibull model based designs are identical to an established design that assumes an exponential event time distribution with an inverse gamma prior on the mean event time. The three designs are compared by simulation under several log-logistic and Weibull distributions having different shape parameters, and for different monitoring schedules. The simulations show that, compared to the exponential inverse gamma model based design, the piecewise exponential design has substantially better performance, with much higher probabilities of correctly stopping the trial early, and shorter and less variable trial duration, when the assumed median event time is unacceptably low. Compared to the Weibull model based design, the piecewise exponential design does a much better job of maintaining small incorrect stopping probabilities in cases where the true median survival time is desirably large.     

A Bayesian hierarchical mixture model for platelet-derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancer

Summary.  Advances in understanding the biological underpinnings of many cancers have led increasingly to the use of molecularly targeted anticancer therapies. Because the platelet-derived growth factor receptor (PDGFR) has been implicated in the progression of prostate cancer bone metastases, it is of great interest to examine possible relationships between PDGFR inhibition and therapeutic outcomes. We analyse the association between change in activated PDGFR (phosphorylated PDGFR) and progression-free survival time based on large within-patient samples of cell-specific phosphorylated PDGFR values taken before and after treatment from each of 88 prostate cancer patients. To utilize these paired samples as covariate data in a regression model for progression-free survival time, and be cause the phosphorylated PDGFR distributions are bimodal, we first employ a Bayesian hierarchical mixture model to obtain a deconvolution of the pretreatment and post-treatment within-patient phosphorylated PDGFR distributions. We evaluate fits of the mixture model and a non-mixture model that ignores the bimodality by using a supnorm metric to compare the empirical distribution of each phosphorylated PDGFR data set with the corresponding fitted distribution under each model. Our results show that first using the mixture model to account for the bimodality of the within-patient phosphorylated PDGFR distributions, and then using the posterior within-patient component mean changes in phosphorylated PDGFR so obtained as covariates in the regression model for progression-free survival time, provides an improved estimation.     

Some Geometric Methods for Constructing Decision Criteria Based On Two-Dimensional Parameters

This paper reviews two types of geometric methods proposed in recent years for defining statistical decision rules based on 2-dimensional parameters that characterize treatment effect in a medical setting. A common example is that of making decisions, such as comparing treatments or selecting a best dose, based on both the probability of efficacy and the probability toxicity. In most applications, the 2-dimensional parameter is defined in terms of a model parameter of higher dimension including effects of treatment and possibly covariates. Each method uses a geometric construct in the 2-dimensional parameter space based on a set of elicited parameter pairs as a basis for defining decision rules. The first construct is a family of contours that partitions the parameter space, with the contours constructed so that all parameter pairs on a given contour are equally desirable. The partition is used to define statistical decision rules that discriminate between parameter pairs in term of their desirabilities. The second construct is a convex 2-dimensional set of desirable parameter pairs, with decisions based on posterior probabilities of this set for given combinations of treatments and covariates under a Bayesian formulation. A general framework for all of these methods is provided, and each method is illustrated by one or more applications.     

An explanation of generalized profile likelihoods

Let X, T, Y be random vectors such that the distribution of Y conditional on covariates partitioned into the vectors X = x and T = t is given by f(y; x, ), where = (, (t)). Here is a parameter vector and (t) is a smooth, real–valued function of t. The joint distribution of X and T is assumed to be independent of and . This semiparametric model is called conditionally parametric because the conditional distribution f(y; x, ) of Y given X = x, T = t is parameterized by a finite dimensional parameter = (, (t)). Severini and Wong (1992. Annals of Statistics 20: 1768–1802) show how to estimate and (·) using generalized profile likelihoods, and they also provide a review of the literature on generalized profile likelihoods. Under specified regularity conditions, they derive an asymptotically efficient estimator of and a uniformly consistent estimator of (·). The purpose of this paper is to provide a short tutorial for this method of estimation under a likelihood–based model, reviewing results from Stein (1956. Proceedings of the Third Berkeley Symposium on Mathematical Statistics and Probability, vol. 1, University of California Press, Berkeley, pp. 187–196), Severini (1987. Ph.D Thesis, The University of Chicago, Department of Statistics, Chicago, Illinois), and Severini and Wong (op. cit.).     

Bayesian nonparametric statistics: A new toolkit for discovery in cancer research

Many commonly used statistical methods for data analysis or clinical trial design rely on incorrect assumptions or assume an over‐simplified framework that ignores important information. Such statistical practices may lead to incorrect conclusions about treatment effects or clinical trial designs that are impractical or that do not accurately reflect the investigator's goals. Bayesian nonparametric (BNP) models and methods are a very flexible new class of statistical tools that can overcome such limitations. This is because BNP models can accurately approximate any distribution or function and can accommodate a broad range of statistical problems, including density estimation, regression, survival analysis, graphical modeling, neural networks, classification, clustering, population models, forecasting and prediction, spatiotemporal models, and causal inference. This paper describes 3 illustrative applications of BNP methods, including a randomized clinical trial to compare treatments for intraoperative air leaks after pulmonary resection, estimating survival time with different multi‐stage chemotherapy regimes for acute leukemia, and evaluating joint effects of targeted treatment and an intermediate biological outcome on progression‐free survival time in prostate cancer.     

Evaluation of Viable Dynamic Treatment Regimes in a Sequentially Randomized Trial of Advanced Prostate Cancer

We present new statistical analyses of data arising from a clinical trial designed to compare two-stage dynamic treatment regimes (DTRs) for advanced prostate cancer. The trial protocol mandated that patients were to be initially randomized among four chemotherapies, and that those who responded poorly were to be rerandomized to one of the remaining candidate therapies. The primary aim was to compare the DTRs' overall success rates, with success defined by the occurrence of successful responses in each of two consecutive courses of the patient's therapy. Of the one hundred and fifty study participants, forty seven did not complete their therapy per the algorithm. However, thirty five of them did so for reasons that precluded further chemotherapy; i.e. toxicity and/or progressive disease. Consequently, rather than comparing the overall success rates of the DTRs in the unrealistic event that these patients had remained on their assigned chemotherapies, we conducted an analysis that compared viable switch rules defined by the per-protocol rules but with the additional provision that patients who developed toxicity or progressive disease switch to a non-prespecified therapeutic or palliative strategy. This modification involved consideration of bivariate per-course outcomes encoding both efficacy and toxicity. We used numerical scores elicited from the trial's Principal Investigator to quantify the clinical desirability of each bivariate per-course outcome, and defined one endpoint as their average over all courses of treatment. Two other simpler sets of scores as well as log survival time also were used as endpoints. Estimation of each DTR-specific mean score was conducted using inverse probability weighted methods that assumed that missingness in the twelve remaining drop-outs was informative but explainable in that it only depended on past recorded data. We conducted additional worst-best case analyses to evaluate sensitivity of our findings to extreme departures from the explainable drop-out assumption.