Related papers: A time-to-event three-outcome design for randomize…
Project Optimus, an initiative by the FDA's Oncology Center of Excellence, seeks to reform the dose-optimization and dose-selection paradigm in oncology. We propose a dose-optimization design that considers plateau efficacy profiles,…
The primary objective of phase I oncology studies is to establish the safety profile of a new treatment and determine the maximum tolerated dose (MTD). This is motivated by the development of cytotoxic agents based on the underlying…
When planning a clinical trial for a time-to-event endpoint, we require an estimated effect size and need to consider the type of effect. Usually, an effect of proportional hazards is assumed with the hazard ratio as the corresponding…
Practical employment of Bayesian trial designs is still rare. Even if accepted in principle, the regulators have commonly required that such designs be calibrated according to an upper bound for the frequentist type I error rate. This…
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.…
We consider two minimal mathematical models for cancer dynamics and self-adaptation. We aim to capture the interplay between the rapid progression of cancer growth and the possibility to leverage and enhance self-adaptive defense mechanisms…
In clinical trials, patients may discontinue treatments prematurely, breaking the initial randomization and, thus, challenging inference. Stakeholders in drug development are generally interested in going beyond the Intention-To-Treat (ITT)…
I develop a model of a randomized experiment with a binary intervention and a binary outcome. Potential outcomes in the intervention and control groups give rise to four types of participants. Fixing ideas such that the outcome is…
In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of…
Phase I dose-escalation trials must be guided by a safety model in order to avoid exposing patients to unacceptably high risk of toxicities. Traditionally, these trials are based on one type of schedule. In more recent practice, however,…
In this paper, we study a phase-space analysis of a mathematical model of tumor growth with an immune response. Mathematical analysis of the model equations with multipoint initial condition, regarding to dissipativity, boundedness of…
Sequential trial design is an important statistical approach to increase the efficiency of clinical trials. Bayesian sequential trial design relies primarily on conducting a Monte Carlo simulation under the hypotheses of interest and…
In this paper, a methodology is proposed that enables to analyze the sensitivity of the outcome of a therapy to unavoidable high dispersion of the patient specific parameters on one hand and to the choice of the parameters that define the…
Dose-finding trials are a key component of the drug development process and rely on a statistical design to help inform dosing decisions. Triallists wishing to choose a design require knowledge of operating characteristics of competing…
Time-to-event estimands are central to many oncology clinical trials. The estimand framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest…
The I-SPY2 phase 2 clinical trial is a long-running platform trial that evaluates neoadjuvant treatments for locally advanced breast cancer, assigning subjects to novel agents using response-adaptive randomization. Recently, I-SPY2 was…
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…
In this article, we propose a phase I-II design in two stages for the combination of molecularly targeted therapies. The design is motivated by a published case study that combines a MEK and a PIK3CA inhibitors; a setting in which higher…
Under two-phase designs, the outcome and several covariates and confounders are measured in the first phase, and a new predictor of interest, which may be costly to collect, can be measured on a subsample in the second phase, without…
Background. Non-inferiority (NI) trials are increasingly used to evaluate new treatments expected to have secondary advantages over standard of care, but similar efficacy on the primary outcome. When designing a NI trial with a binary…