Seamless phase I/II design for novel anticancer agents with competing disease progression

Abstract

Molecularly targeted agents and immunotherapies have prolonged administration and complicated toxicity and efficacy profiles requiring longer toxicity observation windows and the inclusion of efficacy information to identify the optimal dose. Methods have been proposed to either jointly model toxicity and efficacy, or for prolonged observation windows. However, it is inappropriate to address these issues individually in the setting of dose‐finding because longer toxicity windows increase the risk of patients experiencing disease progression and discontinuing the trial, with progression defining a competing event to toxicity, and progression‐free survival being a commonly used efficacy endpoint. No method has been proposed to address this issue in a competing risk framework. We propose a seamless phase I/II design, namely the competing risks continual reassessment method (CR‐CRM). Given an observation window, the objective is to recommend doses that minimize the progression probability, among a set of tolerable doses in terms of toxicity risk. In toxicity‐centered stage of the design, doses are assigned based on toxicity alone, and in optimization stage of the design, doses are assigned integrating both toxicity and progression information. Design operating characteristics were examined in a simulation study compared with benchmark performances, including sensitivity to time‐varying hazards and correlated events. The method performs well in selecting doses with acceptable toxicity risk and minimum progression risk across a wide range of scenarios.

Adaptive phase I–II clinical trial designs identifying optimal biological doses for targeted agents and immunotherapies

“…Several phase I-II designs have been proposed, which use the competing risks and semi-competing risks models developed for survival analysis to resolve this issue. [70][71][72][73] Through the integration of phase I and II trials, a phase I-II trial requires a larger sample size than a traditional phase I trial, resulting in increased costs and longer trial durations. As per the FDA guidelines, no general mathematical formulas are available for determining the sample size of phase I-II designs.…”

Dose optimization for cancer treatments with considerations for late-onset toxicities

“…[48][49][50][51][52][53] Proposals are numerous, and this is not an exhaustive list. The proposals differ in their definition of the optimal dose(s) which depend on the design's objective: for example, maximizing the efficacy criterion while satisfying a toxicity constraint [48][49][50][54][55][56] or optimizing an efficacy-toxicity trade-off or utility measure. 52,[57][58][59][60] Given the small sample sizes and short follow-up periods in a dose-finding trial, it is important to continue the evaluation of efficacy and longer-term tolerability in the dose-optimization trial using selection designs and dose ranging designs in the intended patient population.…”

A Bayesian adaptive biomarker stratified phase II randomized clinical trial design for radiotherapies with competing risk survival outcomes

“…41 The differences between the Zhang et al 41 's design and this new design are (a) the previous design is for phase I dose-finding trials whereas the new design is for randomized phase II trials; (b) the previous design treats the competing risk data as an ordinal outcome and develops a Bayesian data augmentation method to impute the late-onset outcomes whereas this new design treats the competing risk data as survival outcome and uses the cause-specific hazard approach to model the competing risk survival data; (c) the previous design assumes population homogeneity whereas this new design incorporates each patient's biomarker information; and (d) the previous design is mainly used for immunotherapies and targeted therapies whereas the new design is developed explicitly for RT. In addition, Biard et al 42 recently proposed another phase I/II design dealing with competing risk outcomes. However, similar to our previous phase I/II design, this design is only for dose-finding trials.…”

“…In addition, Biard et al. 42 recently proposed another phase I/II design dealing with competing risk outcomes. However, similar to our previous phase I/II design, this design is only for dose-finding trials.…”