AplusB: A Web Application for Investigating A + B Designs for Phase I Cancer Clinical Trials

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities

Example trial pathways for various <i>A</i> + <i>B</i> designs.

<p>Example trial pathways for various <i>A</i> + <i>B</i> designs.</p

Pilea brevicornuta Hayata

原著和名: アリサンミヅ科名: イラクサ科 = Urticaceae採集地: 沖縄県 沖縄本島 本部半島 八重岳 (琉球 沖縄本島 本部半島 八重岳)採集日: 1986/2/24採集者: 萩庭丈壽整理番号: JH037576国立科学博物館整理番号: TNS-VS-98757

Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials

Phase I trials of anti-cancer therapies aim to identify a maximum tolerated dose (MTD), defined as the dose that causes unacceptable toxicity in a target proportion of patients. Both rule-based and model-based methods have been proposed for MTD recommendation. The escalation with overdose control (EWOC) approach is a model-based design where the dose assigned to the next patient is one that, given all available data, has a posterior probability of exceeding the MTD equal to a pre-specified value known as the feasibility bound. The aim is to conservatively dose-escalate and approach the MTD, avoiding severe overdosing early on in a trial. The EWOC approach has been applied in practice with the feasibility bound either fixed or varying throughout a trial, yet some of the methods may recommend incoherent dose-escalation, that is, an increase in dose after observing severe toxicity at the current dose. We present examples where varying feasibility bounds have been used in practice, and propose a toxicity-dependent feasibility bound approach that guarantees coherent dose-escalation and incorporates the desirable features of other EWOC approaches. We show via detailed simulation studies that the toxicity-dependent feasibility bound approach provides improved MTD recommendation properties to the original EWOC approach for both discrete and continuous doses across most dose-toxicity scenarios, with comparable performance to other approaches without recommending incoherent dose escalation

Comparison of experimentation percentages for <i>AplusB</i> and pmtd for Examples I, II, III and IV.

<p>Comparison of experimentation percentages for <i>AplusB</i> and pmtd for Examples I, II, III and IV.</p

AplusB: A Web Application for Investigating A + B Designs for Phase I Cancer Clinical Trials

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities

Design schematic of the <i>A</i> + <i>B</i> design with dose de-escalation.

<p>Design schematic of the <i>A</i> + <i>B</i> design with dose de-escalation.</p

Output tabs for <i>AplusB</i> application.

<p>The <i>Scenario plots</i> tab shows the performance of four operating characteristics. The <i>Scenario operating characteristics</i> tab provides tabular and numerical summaries of key operating characteristics that depend on the DLT probabilities chosen on the left-hand panel. The <i>Design operating characteristics</i> tab shows operating characteristics dependent only upon the design selected, specifically confidence intervals and the <i>tipping point</i>.</p

Graphical user interface (GUI) for scenario and design parameters.

<p>Graphical user interface (GUI) for scenario and design parameters.</p

Design schematic of the <i>A</i> + <i>B</i> design without dose de-escalation.

<p>Design schematic of the <i>A</i> + <i>B</i> design without dose de-escalation.</p