Phase I Designs That Allow for Uncertainty in the Attribution of Adverse Events

Iasonos, Alexia; O’Quigley, John

doi:10.1111/rssc.12195

Cited by 4 publications

(6 citation statements)

References 24 publications

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“…Our method relies on clinical judgment regarding DLT attribution. In many phase I trials, such decisions are subject to error classifications and a possible extension is to introduce a parameter to account for errors in toxicity attribution as in Iasonos and O’Quigley (2016) for single agent trials. We also plan to study the performance of this design using other link functions under different copula models, and extend this method to early phase cancer trials with late onset toxicity and by accounting for patient’s baseline characteristic by extending the approaches in Tighiouart et al (2014, 2012) to the drug combination setting.…”

Section: Discussionmentioning

confidence: 99%

“…However, if the DLT occurs after the second drug has been administered, then the DLT could be caused by any of the drugs and therefore is not attributable. Iasonos and O’Quigley (2016) propose a method that reduces the effect of the bias caused by toxicity attribution errors by using personalized scores instead of the traditional binary DLT outcome. Lee and Fan (2012) considered the toxicity attribution problem for ruled-based designs with non-overlapping toxicities.…”

Section: Introductionmentioning

confidence: 99%

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Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents

2018

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Drug combination trials are increasingly common nowadays in clinical research. However, very few methods have been developed to consider toxicity attributions in the dose escalation process. We are motivated by a trial in which the clinician is able to identify certain toxicities that can be attributed to one of the agents. We present a Bayesian adaptive design in which toxicity attributions are modeled via copula regression and the maximum tolerated dose (MTD) curve is estimated as a function of model parameters. The dose escalation algorithm uses cohorts of two patients, following the continual reassessment method (CRM) scheme, where at each stage of the trial, we search for the dose of one agent given the current dose of the other agent. The performance of the design is studied by evaluating its operating characteristics when the underlying model is either correctly specified or misspecified. We show that this method can be extended to accommodate discrete dose combinations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents

2018

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“…Our approach has both theoretical and practical differences from a recent publication on the same topic. 11 Iasonos and O’Quigley jointly model Y (true DLT outcome) and the clinicians’ classification ( Z in their paper), and link them through the error rate of the classification. In contrast, we directly model Y , and in the case that the value of Y cannot be ascertained, we ask clinicians to provide the likelihood that the toxicity is related to the drug, that is, Pr( Y = 1).…”

Section: Discussionmentioning

confidence: 99%

“…Iasonos and O’Quigley published a design for this setting in which clinicians are asked to classify toxicities as treatment related or not and to provide estimates of the conditional probability of DLT given they have classified the toxicity as treatment related. 11 They discuss the two possible types of classification errors and develop a design for the setting where there may be false-positive findings (i.e. clinician calls a toxicity a DLT when it is not) but no errors in the other direction.…”

Section: Introductionmentioning

confidence: 99%

A Bayesian dose-finding design for outcomes evaluated with uncertainty

et al. 2021

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Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

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“…Another advantage for methods that sequentially borrow information across dose levels are their ability to accommodate revisions to data errors. 23 Subsequent allocations can proceed based on estimation from corrected data across all dose levels. This would be more challenging for local methods if the error occurs at a level far from that at which the study is currently experimenting.…”

Section: Discussionmentioning

confidence: 99%

Revisiting isotonic phase I design in the era of model-assisted dose-finding

Wages

Conaway

2018

Clinical Trials

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Background/aims In the conduct of phase I trials, the limited use of innovative model-based designs in practice has led to an introduction of a class of "model-assisted" designs with the aim of effectively balancing the trade-off between design simplicity and performance. Prior to the recent surge of these designs, methods that allocated patients to doses based on isotonic toxicity probability estimates were proposed. Like model-assisted methods, isotonic designs allow investigators to avoid difficulties associated with pre-trial parametric specifications of model-based designs. The aim of this work is to take a fresh look at an isotonic design in light of the current landscape of model-assisted methods. Methods The isotonic phase I method of Conaway, Dunbar, and Peddada was proposed in 2004 and has been regarded primarily as a design for dose-finding in drug combinations. It has largely been overlooked in the single-agent setting. Given its strong simulation performance in application to more complex dose-finding problems, such as drug combinations and patient heterogeneity, as well as the recent development of user-friendly software to accompany the method, we take a fresh look at this design and compare it to a current model-assisted method. We generated operating characteristics of the Conaway-Dunbar-Peddada method using a new web application developed for simulating and implementing the design and compared it to the recently proposed Keyboard design that is based on toxicity probability intervals. Results The Conaway-Dunbar-Peddada method has better performance in terms of accuracy of dose recommendation and safety in patient allocation in 17 of 20 scenarios considered. The Conaway-Dunbar-Peddada method also allocated fewer patients to doses above the maximum tolerated dose than the Keyboard method in many of scenarios studied. Overall, the performance of the Conaway-Dunbar-Peddada method is strong when compared to the Keyboard method, making it a viable simple alternative to the model-assisted methods developed in recent years. Conclusion The Conaway-Dunbar-Peddada method does not rely on the specification and fitting of a parametric model for the entire dose-toxicity curve to estimate toxicity probabilities as other model-based designs do. It relies on a similar set of pre-trial specifications to toxicity probability interval-based methods, yet unlike model-assisted methods, it is able to borrow information across all dose levels, increasing its efficiency. We hope this concise study of the Conaway-Dunbar-Peddada method, and the availability of user-friendly software, will augment its use in practice.

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Phase I Designs That Allow for Uncertainty in the Attribution of Adverse Events

Cited by 4 publications

References 24 publications

Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents

Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents

A Bayesian dose-finding design for outcomes evaluated with uncertainty

Revisiting isotonic phase I design in the era of model-assisted dose-finding

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