scholarly journals A Bayesian time‐to‐event pharmacokinetic model for phase I dose‐escalation trials with multiple schedules

2020 ◽  
Vol 39 (27) ◽  
pp. 3986-4000
Author(s):  
Burak Kürsad Günhan ◽  
Sebastian Weber ◽  
Tim Friede
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Pharmacokinetic Model ◽  
Time To Event ◽  
Multiple Schedules

scholarly journals A Bayesian Time-to-event Pharmacokinetic Model for Sequential Phase I Dose-escalation Trials with Multiple Schedules

2020 ◽  
Author(s):  
Burak Kürsad Günhan ◽  
Sebastian Weber ◽  
Abdelkader Seroutou ◽  
Tim Friede
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Relevant Information ◽  
Treatment Schedule ◽  
Phase I Trials ◽  
Time To Event ◽  
Multiple Schedules ◽  
Number Of Patients ◽  
Bayesian Logistic Regression ◽  
Sequential Phase

Abstract Background: Phase I dose-escalation trials constitute the first step in investigating the safety of potentially promising drugs in humans. Conventional methods for phase I dose-escalation trials are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial.Methods: Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. The aim is to utilize the information from both the completed and the ongoing dose-escalation trial to inform decisions on the dose level for the next dose cohort. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results: In a simulation study, the developed appraoch is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The R and Stan code for the implementation of an illustrative sequential phase I trial example is publicly available (https://github.com/gunhanb/TITEPK sequential).Conclusion: In sequential phase I dose-escalation trials, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.

Designing Dose-Escalation Trials With Late-Onset Toxicities Using the Time-to-Event Continual Reassessment Method

2006 ◽  
Vol 24 (27) ◽  
pp. 4426-4433 ◽  
Author(s):  
Daniel Normolle ◽  
Theodore Lawrence
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Late Onset ◽  
Maximum Tolerated Dose ◽  
Phase I Trials ◽  
Operating Characteristics ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Standard Design ◽  
Continual Reassessment

Purpose The standard design for phase I trials of combined chemotherapy and radiation, which enters either three or six patients per dose level, has little statistical basis and is subject to opening and closing because of delayed toxicities that disrupt patient accrual. We compared the operating characteristics of this standard design and the time-to-event continual reassessment method (TITE-CRM) for dose-escalation trials of combination chemotherapy and radiation. Methods The operating characteristics were determined by Monte Carlo simulation of 60,000 phase I trials. Results Compared with the standard trial design, in studies with delayed toxicity (ie, where four or more patients are expected to enter onto the study during a single previously enrolled patient's observation for toxicity), TITE-CRM trials are significantly shorter when toxicity observation times are long, treat more patients at or above the maximum-tolerated dose, identify the maximum-tolerated dose (MTD) more accurately, and provide phase II information, but do not expose patients to significant additional risk. Estimation precision and overdose control of TITE-CRM increase as the design assumptions more closely resemble the true state of nature, but are reduced if, for instance, the toxicity of treatment has been grossly underestimated. Conclusion Compared with the standard design, if there is any prior knowledge concerning the toxicity profile of a treatment, TITE-CRM can leverage it to produce more accurate estimates of the MTD and does not expose patients to significant excess risk, but requires timely communication between clinical investigators, data managers, and study statisticians.

scholarly journals Phase I dose-escalation oncology trials with sequential multiple schedules

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Burak Kürsad Günhan ◽  
Sebastian Weber ◽  
Abdelkader Seroutou ◽  
Tim Friede
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Relevant Information ◽  
Treatment Schedule ◽  
Phase I Trials ◽  
Multiple Schedules ◽  
Number Of Patients ◽  
Dose Recommendations ◽  
Bayesian Logistic Regression ◽  
Sequential Phase

Abstract Background Conventional methods for phase I dose-escalation trials in oncology are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial. Methods Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. The aim is to utilize the information from both the completed and the ongoing schedules to inform decisions on the dose level for the next dose cohort. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results In a simulation study, the developed approach is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-predictive prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The and code for the implementation of an illustrative sequential phase I trial example in oncology is publicly available (https://github.com/gunhanb/TITEPK_sequential). Conclusion In phase I oncology trials with sequential multiple schedules, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.

594 A Phase I Dose-escalation, Pharmacokinetic (PK) and Pharmacodynamic (PD) Evaluation of LY2940680, an Oral Smo Inhibitor

2012 ◽  
Vol 48 ◽  
pp. 182 ◽  
Author(s):  
J. Bendell ◽  
G. Weiss ◽  
J. Infante ◽  
R. Ramanathan ◽  
S. Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Smo Inhibitor

Phase I–II Vinorelbine (Navelbine®) by Continuous Infusion in Patients with Metastatic Breast Cancer: Cumulative Toxicities Limit Dose Escalation

2001 ◽  
Vol 19 (5) ◽  
pp. 459-466 ◽  
Author(s):  
Nuhad K. Ibrahim ◽  
Vicente Valero ◽  
Zia Rahman ◽  
Richard L. Theriault ◽  
Ronald S. Walters ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Continuous Infusion ◽  
Dose Escalation ◽  
Metastatic Breast
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