Extending the Continual Reassessment Method to accommodate step-up dosing in Phase I trials.
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SUBMITTER: Braun TM
PROVIDER: S-EPMC9546169 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Extending the Continual Reassessment Method to accommodate step-up dosing in Phase I trials.
Braun Thomas M TM Mercier Francois F
Statistics in medicine 20220605 20
The Continual Reassessment Method (CRM) was developed for Phase I trials to identify a maximum-tolerated dose of an agent using a design in which each participant is treated with a single administration of the agent. We propose an extension of the CRM in which participants receive multiple administrations of an agent using a so-called step-up dosing procedure in which participants receive one or more administrations of lower doses of the agent before they receive their penultimate dose. We use m ...[more]
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Project description:Much of the statistical methodology underlying the experimental design of phase 1 trials in oncology is intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the maximally tolerated dose, the highest dose that can be administered with an acceptable level of toxicity. A fundamental assumption of these methods is monotonicity of the dose-toxicity curve. This is a reasonable assumption for single-agent trials in which the administration of greater doses of the agent can be expected to produce dose-limiting toxicities in increasing proportions of patients. When studying multiple agents, the assumption may not hold because the ordering of the toxicity probabilities could possibly be unknown for several of the available drug combinations. At the same time, some of the orderings are known and so we describe the whole situation as that of a partial ordering. In this article, we propose a new two-dimensional dose-finding method for multiple-agent trials that simplifies to the continual reassessment method (CRM), introduced by O'Quigley, Pepe, and Fisher (1990,?Biometrics 46, 33-48), when the ordering is fully known. This design enables us to relax the assumption of a monotonic dose-toxicity curve. We compare our approach and some simulation results to a CRM design in which the ordering is known as well as to other suggestions for partial orders.
| S-EPMC3141101 | biostudies-literature
Project description:BackgroundA key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible.MethodsThe STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD.ResultsThe simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric.ConclusionWhen considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario.Trial registrationClinical Trials NCT03307148 (11 October 2017).
| S-EPMC6595589 | biostudies-literature
Project description:Model-based dose-finding designs such as the continual reassessment method (CRM) rely on some basic working model. In the Bayesian setting, these take the form of 'guess estimates' of the probabilities of toxicity at each level. In the likelihood setting, these estimates simply take the form of a model as operational characteristics are unaffected by arbitrary positive power transformations. These initial estimates are often referred to as the model skeleton. The impact of any prior distribution on the model parameter that describes the dose-toxicity curve will itself depend on the skeleton being used. We study the interplay between prior assumptions and skeleton choice in the context of two-stage CRM designs. We consider the behavior of a two-stage design at the point of transition from a 3 + 3 design to CRM. We study how use can be made of stage 1 data to construct a more efficient skeleton in conjunction with any prior information through an example of a clinical trial. We evaluate to what extent stage 1 data might be down weighted when the maximum tolerated dose (MTD) is far from the starting level and stage 1 data is strongly informative. The results show no improvement in accuracy; thus, weighting is not necessary unless the investigators feel strongly about the location of the MTD and wish to accelerate into the vicinity of the MTD. In general, because this information is not available, we recommend that the design of two-stage trials utilize stage 1 data to establish a skeleton.
| S-EPMC3538840 | biostudies-literature
Project description:BackgroundThis article studies the notion of irrational dose assignment in Phase I clinical trials. This property was recently defined by Zhou and colleagues as a dose assignment that fails to de-escalate the dose when two out of three, three out of six, or four out of six patients have experienced a dose-limiting toxicity event at the current dose level. The authors claimed that a drawback of the well-known continual reassessment method is that it can result in irrational dose assignments. The aim of this article is to examine this definition of irrationality more closely within the conduct of the continual reassessment method.MethodsOver a broad range of assumed dose-limiting toxicity probability scenarios for six study dose levels and a variety of target dose-limiting toxicity rates, we simulated 2000 trials of n = 36 patients. For each scenario, we counted the number of irrational dose assignments that were made by the continual reassessment method, according to the definitions of Zhou and colleagues. For each of the irrational decisions made, we classified the dose assignment as an underdose assignment, a target dose assignment, or an overdose assignment based on the true dose-limiting toxicity probability at that dose.ResultsAcross eight dose-toxicity scenarios, there were a total of 181,581 dose assignments made in the simulation study. Of these assignments, 8165 (4.5%) decisions were made when two out of three, three out of six, or four out of six patients had experienced a dose-limiting toxicity at the current dose. Of these 8165 decisions, 1505 (18.4%) recommended staying at the current dose level and would therefore be classified as irrational by Zhou and colleagues. Among the irrational decisions, 41.2% were misclassified, meaning they were made either at the true target dose (17.9%) or at a true underdose (23.3%). The remaining 58.8% were made at a true overdose and therefore truly irrational. Overall, irrational dose assignments comprised <1% of the total dose assignments made during the simulation study. Similar findings are reported in simulations across 100 randomly generated dose-toxicity scenarios from a recently proposed family of curves.ConclusionZhou and colleagues argue that the behavior of the continual reassessment method is disturbing due to its ability to make irrational dose assignments. These definitions are based on rules that mimic the popular 3 + 3 design, which should not be the benchmark used to construct guidelines for trial conduct of modern Phase I methods. Our study illustrates that these dose assignments occur very seldom in the continual reassessment method and that even when they do occur, they can often be considered sensible when accounting for all accumulated data in the study.
| S-EPMC6904537 | biostudies-literature
Project description:BackgroundAwareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples.MethodsThe TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant's dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies.ResultsIn setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians' time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion.ConclusionModel-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.
| S-EPMC7477911 | biostudies-literature
Project description:BackgroundThe continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses.MethodsPost-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches.ResultsAll methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches.ConclusionsPrior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important.Trial registrationNCT01162395 , Trial date of first registration: July 13, 2010.
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Project description:A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual re-assessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The Bayesian data augmentation approach is used to sample both the missing data and model parameters from their posterior full conditional distributions. We evaluate the performance of the DA-CRM through extensive simulation studies, and also compare it with other existing methods. The results show that the proposed design satisfactorily resolves the issues related to late-onset toxicities and possesses desirable operating characteristics: treating patients more safely, and also selecting the maximum tolerated dose with a higher probability. The new DA-CRM is illustrated with two phase I cancer clinical trials.
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Project description:This article considers the problem of designing Phase I-II clinical trials with delayed toxicity and efficacy outcomes. The proposed design is motivated by a Phase I-II study evaluating all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The primary objective of the study is to identify a dose that maximizes efficacy and has an acceptable level of toxicity. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not practical to wait until both outcomes for each patient have been fully observed before sequentially assigning the dose of a newly eligible patient. In order to avoid delays in treatment for newly enrolled patients and to accelerate trial progress, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes. Simulation studies are conducted to evaluate the proposed method, and we found that the proposed design is able to accurately select doses that maximize efficacy and have acceptable toxicity, while using all available information in allocating patients at the time of dose assignment. We compare the proposed methodology to two existing methods in the area.
| S-EPMC6823630 | biostudies-literature
Project description:IntroductionThe continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce.MethodsTo help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM.ResultsAn initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design.ConclusionsThe framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.
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Project description:This article proposes a novel criterion for the allocation of patients in phase I dose-escalation clinical trials, aiming to find the maximum tolerated dose (MTD). Conventionally, using a model-based approach, the next patient is allocated to the dose with the toxicity estimate closest (in terms of the absolute or squared distance) to the maximum acceptable toxicity. This approach, however, ignores the uncertainty in point estimates and ethical concerns of assigning a lot of patients to overly toxic doses. In fact, balancing the trade-off between how accurately the MTD can be estimated and how many patients would experience adverse events is one of the primary challenges in phase I studies. Motivated by recent discussions in the theory of estimation in restricted parameter spaces, we propose a criterion that allows to balance these explicitly. The criterion requires a specification of one additional parameter only that has a simple and intuitive interpretation. We incorporate the proposed criterion into the one-parameter Bayesian continual reassessment method and show, using simulations, that it can result in similar accuracy on average as the original design, but with fewer toxic responses on average. A comparison with other model-based dose-escalation designs, such as escalation with overdose control and its modifications, demonstrates that the proposed design can result in either the same mean accuracy as alternatives but fewer toxic responses or in a higher mean accuracy but the same number of toxic responses. Therefore, the proposed design can provide a better trade-off between the accuracy and the number of patients experiencing adverse events, making the design a more ethical alternative over some of the existing methods for phase I trials.
| S-EPMC7064916 | biostudies-literature