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. 2012 Aug 15;18(16):4225-33.
doi: 10.1158/1078-0432.CCR-12-0686. Epub 2012 Jun 14.

A 2-stage Phase II Design With Direct Assignment Option in Stage II for Initial Marker Validation

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A 2-stage Phase II Design With Direct Assignment Option in Stage II for Initial Marker Validation

Ming-Wen An et al. Clin Cancer Res. .
Free PMC article

Abstract

Biomarkers are critical to targeted therapies, as they may identify patients more likely to benefit from a treatment. Several prospective designs for biomarker-directed therapy have been previously proposed, differing primarily in the study population, randomization scheme, or both. Recognizing the need for randomization, yet acknowledging the possibility of promising but inconclusive results after a stage I cohort of randomized patients, we propose a 2-stage phase II design on marker-positive patients that allows for direct assignment in a stage II cohort. In stage I, marker-positive patients are equally randomized to receive experimental treatment or control. Stage II has the option to adopt "direct assignment" whereby all patients receive experimental treatment. Through simulation, we studied the power and type I error rate of our design compared with a balanced randomized two-stage design, and conducted sensitivity analyses to study the effect of timing of stage I analysis, population shift effects, and unbalanced randomization. Our proposed design has minimal loss in power (<1.8%) and increased type I error rate (<2.1%) compared with a balanced randomized design. The maximum increase in type I error rate in the presence of a population shift was between 3.1% and 5%, and the loss in power across possible timings of stage I analysis was less than 1.2%. Our proposed design has desirable statistical properties with potential appeal in practice. The direct assignment option, if adopted, provides for an "extended confirmation phase" as an alternative to stopping the trial early for evidence of efficacy in stage I.

Conflict of interest statement

CONFLICTS OF INTEREST: None.

Figures

Figure 1
Figure 1
Design schematic (among M+ patients only). Square brackets [] indicate number of patients enrolled at the given stage. R = randomize; N = total number of patients allocated at start of trial; p1 = p-value based on Stage I patient data; c1, c2, and d are O’Brien-Fleming stopping boundaries (d is the boundary for concluding overall trial efficacy, and is also used to decide between adopting the direct assignment option versus continuing with randomization in Stage II).
Figure 2
Figure 2
Type I error rate as a function of shift in response rate for experimental treatment group, only if Direct Assignment is adopted (vertical dotted line at δ=0, i.e. no population shift). Nominal alpha level = 0.10 (solid line, solid circles) and 0.20 (dotted line, open triangles).
Figure 3
Figure 3
Change in power from a Balanced randomized design to a Design with direct assignment option, as a function of timing of Stage I analysis (f=0.33, 0.50, 0.67 accrual; by columns); overall alpha level (α=0.10, 0.20; by rows); and response rate ratio (RRR=2.0, 2.25, 2.5, 3.0; on x-axis).

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