BIPSE: A biomarker-based phase I/II design for immunotherapy trials with progression-free survival endpoint

Abstract

A Bayesian biomarker-based phase I/II design (BIPSE) is presented for immunotherapy trials with a progression-free survival (PFS) endpoint. The objective is to identify the subgroup-specific optimal dose, defined as the dose with the best risk-benefit tradeoff in each biomarker subgroup. We jointly model the immune response, toxicity outcome, and PFS with information borrowing across subgroups. A plateau model is used to describe the marginal distribution of the immune response. Conditional on the immune response, we model toxicity using probit regression and model PFS using the mixture cure rate model. During the trial, based on the accumulating data, we continuously update model estimates and adaptively randomize patients to doses with high desirability within each subgroup. Simulation studies show that the BIPSE design has desirable operating characteristics in selecting the subgroup-specific optimal doses and allocating patients to those optimal doses, and outperforms conventional designs.

Keywords: Bayesian adaptive design; biomarker; dose finding; immune response; immunotherapy; phase I/II trial; progression-free survival; risk-benefit tradeoff; subgroups.

Figure 1:

The mean immune response curves for the two subgroups generated from model (2). The parameters are μ_M = 20, ξ = 0.2, α = 2; μ_M = 20, ξ = 0.2, α = 6; and μ_M = 20, ξ = 0.75, α = 3.5 for the three panels from left to right. Dashed and solid lines represent marker-negative (Z=0) and marker-positive (Z=1) subgroups, respectively.

Figure 2:

Dose-response curves for the 10 scenarios in the simulation study. The dashed and solid lines are for subgroups Z = 0 and Z = 1, respectively; and green, red, purple, and black curves are the toxicity probability π_X, survival probabilities Pr(T > 3) and Pr(T > 12), and mean immune response μ_Y curves, respectively. All probabilities are plotted against the left y-axis, and the immune response is plotted against the right y-axis.

Figure 2:

Dose-response curves for the 10 scenarios in the simulation study. The dashed and solid lines are for subgroups Z = 0 and Z = 1, respectively; and green, red, purple, and black curves are the toxicity probability π_X, survival probabilities Pr(T > 3) and Pr(T > 12), and mean immune response μ_Y curves, respectively. All probabilities are plotted against the left y-axis, and the immune response is plotted against the right y-axis.