products: Dose-Escalation Trial Design with ExpDesign Studio

Dose-Escalation Trial Studio is one of the components in ExpDesign Studio. It can also be used as stand-alone software.

Input Features	Output Features
One-Stage or two-stage Escalation Designs Different toxicity models Traditional escalation rules, restricted escalation rules, Up-down schemes, Customized Escalation Rules De-escalation control Fibonacci, modified Fibonacci series, constant increment, and the customized dose interval series And much more...	Aggregate safety: Number of DLTs Individual safety: Number of overtreats Accuracy: Expected MTD Precision: Dispersion of MTDs Efficiency: Expected number of patients Maximum cost: Maximum sample size Robustness: Number of overshoots And much more...

Example:

A Phase-I clinical trial is to be designed. The primary objective is to determine the maximum tolerated dose (MTD) for new test drug ABC. Based on the animal studies, it is estimated that the toxicity (DLT rate) is 1% for the starting dose of 30 mg/m² (1/10 of the lethal dose). The DLT rate at MTD is defined as 0.17 and the MTD is estimated to be 300 mg/m².

Single-Stage Simulations
In the ExpDesign Studio window, click Dose-escalation Trial Design. Choose One Stage Design m+n Escalation Rules in the window and specify the parameters (See Figure 1 below). Click Compute to generate the simulations and click the Report icon to review the results.

Figure 1: Simulations of single-stage dose escalation design

Two-Stage Design Simulations
In the Dose-Escalation window, choose Two Stage Design: Single Patient Escalation Followed by m+n Escalations and give the sample specifications for the design parameters as for the single stage design (See Figure 2 below).

Figure 2: Simulations of two-stage dose escalation design

Selection of Final Model and Presentation of Simulation Results
The evaluations of the escalation designs are based on following criteria: Safety, Accuracy & Precision, Efficiency, Simplicity as summarized in Table 1.

Table 1: Evaluation Criteria for Dose-Escalation Designs

Simulation results for the one- and two-stage designs that we just simulated can be summarized as shown in Table 2.

Table 2: Summary of Sumulation Results for the Single- and Two-Stage Designs

Based on 20,000 simulations in each scenario, both methods underestimate the true MTD (14% lower), the dispersion or the true MTD and the average distance between the MTD generated by simulation is about 70 and 66 mg/m², respectively for the single-stage design and the two-stage design. The expected sample size for the two-stage design is 17 which is much less than the single-stage design with 26 patients. The maximum sample size is 42 (7 dose levels times 6 patients per dose level) which virtually never happens.

Summarizing the results using criteria in Table 1, we have the final comparisons of the two designs (Table 3).

Table 3: Comparison of Single- and Two-Stage Trial Simulations

Based on results in Table 3, the two-stage is chosen for the oncology trial. The simulation also gives the following results for the two-stage design.

Table 4: Summary of Two-Stage Design Simulations

Safety	Accuracy & Precision	Efficiency	Simplicity
Number of DLTs	Bias of predicted MTD	Expected sample size	Ability to enroll multiple patients at one time
Number of patients treated above MTD	Dispersion of predicted MTDs	Maximum sample size	Simplicity in logistic

Method	True MTD (mg/m²)	Mean Predicted MTD (mg/m²)	Dispersion of Predicted MTDs	Expected Number of Patients	Average Number of DLTs	Number of overtreats
3+3 TER	300	257	70	26	2	5
Two-stage	300	258	66	17	2	5

Method	Safety Measures	Accuracy & Precision	Efficiency	Simplicity
3+3 TER	++++	++	++	++++
Two-stage	++++	+++	+++++	++++

Dose level	1	2	3	4	5	6	7
Dose (mg/m²)	30	45	48	101	152	228	342
Expected number of patients	1.1	1.1	1.2	1.3	1.5	5.9	5.2
Probability of MTD	0.000	0.000	0.001	0.004	0.019	0.688	0.287

Customization of Dose-Escalation Rules

The Dose-Escalation Studio has many other features such as Customization of Escalation Rules (See Figure 3 below).

Figure 3: Customization of Dose-Escalation Rules

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