相关论文: Estimands for Early Phase Dose Optimization Trials…

Chemotherapy is one of the primary modalities of cancer treatment. Chemotherapy drug administration is a complex problem that often requires expensive clinical trials to evaluate potential regimens. One way to alleviate this burden and…

The Project Optimus initiative by the FDA's Oncology Center of Excellence is widely viewed as a groundbreaking effort to change the $\textit{status quo}$ of conventional dose-finding strategies in oncology. Unlike in other therapeutic areas…

In phase I dose escalation studies for dual-agent combinations, at least one drug often has an established monotherapy dose. Consequently, substantial prior clinical safety data often exist for one or more monotherapies, allowing the study…

Dose optimization is a hallmark of Project Optimus for oncology drug development. The number of doses to include in a dose optimization study depends on the totality of evidence, which is often unclear in early-phase development. With equal…

A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend…

The ICH E9 (R1) Estimands Guidance1 terminology does not completely address the conceptual needs of time-to-event estimands in the complex oncology context. We previously described how censoring and censoring mechanisms for time-to-event…

Cohort-based enrollment can slow down dose-finding trials since the outcomes of the previous cohort must be fully evaluated before the next cohort can be enrolled. This results in frequent suspension of patient enrollment. The issue is…

FDA's Project Optimus initiative for oncology drug development emphasizes selecting a dose that optimizes both efficacy and safety. When an inferentially adaptive Phase 2/3 design with dose selection is implemented to comply with the…

In oncology dose-finding trials, due to staggered enrollment, it might be desirable to make dose-assignment decisions in real-time in the presence of pending toxicity outcomes, for example, when the dose-limiting toxicity is late-onset.…

Optimal design of a Phase I cancer trial can be formulated as a stochastic optimization problem. By making use of recent advances in approximate dynamic programming to tackle the problem, we develop an approximation of the Bayesian optimal…

One common approach for dose optimization is a two-stage design, which initially conducts dose escalation to identify the maximum tolerated dose (MTD), followed by a randomization stage where patients are assigned to two or more doses to…

The US Food and Drug Administration (FDA) launched Project Optimus and issued guidance to reform dose-finding and selection trials, shifting the paradigm from identifying the maximum tolerable dose (MTD) to determining the optimal…

We consider estimation of an optimal individualized treatment rule from observational and randomized studies when a high-dimensional vector of baseline variables is available. Our optimality criterion is with respect to delaying expected…

Phase I clinical trials are designed to test the safety (non-toxicity) of drugs and find the maximum tolerated dose (MTD). This task becomes significantly more challenging when multiple-drug dose-combinations (DC) are involved, due to the…

Dual agent dose-finding trials study the effect of a combination of more than one agent, where the objective is to find the Maximum Tolerated Dose Combination (MTC), the combination of doses of the two agents that is associated with a…

We consider the effects of parameter uncertainty on the optimal radiation schedule in the context of the linear-quadratic model. Our interest arises from the observation that if inter-patient variations in OAR and tumor sensitivities to…

In causal inference, the correct formulation of the scientific question of interest is a crucial step. Here we apply the estimand framework to a comparison of the outcomes of patient-level clinical trials and observational data to help…

We propose an adaptive design for early phase drug combination cancer trials with the goal of estimating the maximum tolerated dose (MTD). A nonparametric Bayesian model, using beta priors truncated to the set of partially ordered dose…

It is increasingly common for therapies in oncology to be given in combination. In some cases, patients can benefit from the interaction between two drugs, although often at the risk of higher toxicity. A large number of designs to conduct…

In Oncology, trials evaluating drug combinations are becoming more common. While combination therapies bring the potential for greater efficacy, they also create unique challenges for ensuring drug safety. In Phase-I dose escalation trials…