## [1] "DADesign"

Design

Dose toxicity model

A logistic log normal model will describe the relationship between dose and toxicity: \[ p(Tox | d) = f(X = 1 | \theta, d) = \frac{e^{\alpha + \beta \cdot log(d/d_{ref})}}{1 + e^{\alpha + \beta \cdot log(d/d_{ref})}} \]where dref denotes a reference dose.

The prior for θ is given by\[ \boldsymbol\theta = \begin{bmatrix}\alpha \\ log(\beta)\end{bmatrix}\sim N \left(\begin{bmatrix}-0.85 \\ 1.00\end{bmatrix} , \begin{bmatrix} 1.00 & -0.50 \\ -0.50 & 1.00\end{bmatrix} \right) \]

The reference dose will be 56.00.

Observed data

No participants are yet evaluable.

The dose grid is 0.1, 0.5, 1, 1.5, 3, 6, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78 and 80.

Safety window

To protect the welfare of individual participants, the rate of enrolment within each cohort will be restricted.

For all cohorts:

  • The gap between the enrolment of the first and the second participants in the cohort should be at least 6 days
  • The gap between all subsequent participants should be at least 2 days

Before the next cohort can open, all participants in the current cohort must have been followed up for at least 7 days and at least one participant must have been followed up for at least 7 days.

Stopping rule

If either of the following rules are TRUE:

  • P(0.2 ≤ prob(DLE | NBD) ≤ 0.35) ≥ 0.5: If the probability of toxicity at the next best dose is in the range [0.20, 0.35] is at least 0.50.

  • ≥ 50 patients dosed: If 50 or more participants have been treated.

Escalation rule

Defined by highest dose administered so far
Dose
Min Max Increment
0 20 1.00
20 Inf 0.33

Use of placebo

Placebo will not be administered in the trial.

Dose recommendation

The dose recommended for the next cohort will be chosen in the following way. First, doses that are ineligible according to the increments rule will be discarded. Next, any dose for which the mean posterior probability of toxicity being in the overdose range - (0.35, 1] - is 0.25 or more will also be discarded. Finally, the dose amongst those remaining which has the highest chance that the mean posterior probability of toxicity is in the target toxicity range of 0.2 to 0.35 (inclusive) will be selected.

Cohort size

The maximum of the cohort sizes defined in the following rules:
Defined by the dose to be used in the next cohort
Dose
Lower Upper Cohort size
0 30 1
30 Inf 3
Defined by the number of toxicities so far observed
No of toxicities
Lower Upper Cohort size
0 1 1
1 Inf 3

Starting dose

The starting dose is 3.