A novel framework of Bayesian optimal interval design for phase I trials with late-onset toxicities

Probability-of-decision interval 3+3 (POD-i3+3) design for phase I dose finding trials with late-onset toxicity

Statistical Methods in Medical Research ◽

10.1177/09622802211052746 ◽

2021 ◽

pp. 096228022110527

Author(s):

Zichun Xu ◽

Xiaolei Lin

Keyword(s):

Phase I ◽

Late Onset ◽

Dose Finding ◽

Operating Characteristics ◽

Trial Duration ◽

Probability Interval ◽

Optimal Interval ◽

Patient Resources ◽

Safety And Reliability

Late-onset toxicities often occur in phase I trials investigating novel immunotherapy and molecular targeted therapies. For trials with cohort based designs (such as modified toxicity probability interval, Bayesian optimal interval, and i3+3), patients are often turned away since the current cohort are still being followed without definite dose-limiting toxicities, which results in prolonged trial duration and waste of patient resources. In this paper, we incorporate a probability-of-decision framework into the i3+3 design and allow real-time dosing inference when the next patient becomes available. Both follow-up time for the pending patients and time to dose-limiting toxicities for the observed patients are used in calculating the posterior probability of each possible dosing decision. An intensive simulation study is conducted to evaluate the operating characteristics of the newly proposed probability-of-decision-i3+3 design under various dosing scenarios and patient accrual settings. Results show that the probability-of-decision-i3+3 design achieves comparable safety and reliability performances but much shorter trial duration compared to the complete designs.

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Adaptive Dose-Finding Studies: A Review of Model-Guided Phase I Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2013.54.6051 ◽

2014 ◽

Vol 32 (23) ◽

pp. 2505-2511 ◽

Cited By ~ 54

Author(s):

Alexia Iasonos ◽

John O'Quigley

Keyword(s):

Clinical Trials ◽

Phase I ◽

Dose Escalation ◽

Late Onset ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Design Parameters ◽

Phase I Trials ◽

Phase I Clinical Trials ◽

Trial Duration

Purpose We provide a comprehensive review of adaptive phase I clinical trials in oncology that used a statistical model to guide dose escalation to identify the maximum-tolerated dose (MTD). We describe the clinical setting, practical implications, and safety of such applications, with the aim of understanding how these designs work in practice. Methods We identified 53 phase I trials published between January 2003 and September 2013 that used the continual reassessment method (CRM), CRM using escalation with overdose control, or time-to-event CRM for late-onset toxicities. Study characteristics, design parameters, dose-limiting toxicity (DLT) definition, DLT rate, patient-dose allocation, overdose, underdose, sample size, and trial duration were abstracted from each study. In addition, we examined all studies in terms of safety, and we outlined the reasons why escalations occur and under what circumstances. Results On average, trials accrued 25 to 35 patients over a 2-year period and tested five dose levels. The average DLT rate was 18%, which is lower than in previous reports, whereas all levels above the MTD had an average DLT rate of 36%. On average, 39% of patients were treated at the MTD, and 74% were treated at either the MTD or an adjacent level (one level above or below). Conclusion This review of completed phase I studies confirms the safety and generalizability of model-guided, adaptive dose-escalation designs, and it provides an approach for using, interpreting, and understanding such designs to guide dose escalation in phase I trials.

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

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.3844 ◽

2006 ◽

Vol 24 (27) ◽

pp. 4426-4433 ◽

Cited By ~ 61

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.

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