Related papers: Random-effects meta-analysis of phase I dose-findi…
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…
Purpose: The early identification of maximum tolerated dose (MTD) in phase I trial leads to faster progression to a phase II trial or an expansion cohort to confirm efficacy. Methods: We propose a novel adaptive design for identifying MTD…
Dose-finding clinical trials in oncology aim to estimate the maximum tolerated dose (MTD), based on safety traditionally obtained from the clinician's perspective. While the collection of patient-reported outcomes (PROs) has been advocated…
The traditional more-is-better dose selection paradigm, developed based on cytotoxic chemotherapeutics, is often problematic When applied to the development of novel molecularly targeted agents (e.g., kinase inhibitors, monoclonal…
The primary objective of Phase I oncology trials is to assess the safety and tolerability of novel therapeutics. Conventional dose escalation methods identify the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). However,…
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…
Randomized discontinuation design (RDD) is an enrichment strategy commonly used to address limitations of traditional placebo-controlled trials, particularly the ethical concern of prolonged placebo exposure. RDD consists of two phases: an…
We consider the problem of estimating a dose-response curve. Continuous treatments arise often in practice, e.g. in the form of time spent on an operation, distance traveled to a location or dosage of a drug. Letting $A$ denote a continuous…
Most conventional risk analysis methods rely on a single best estimate of exposure per person which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the…
Meta-analysis is an important tool for combining results from multiple studies and has been widely used in evidence-based medicine for several decades. This paper reports, for the first time, an interesting and valuable paradox in…
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…
We consider a Bayesian framework based on "probability of decision" for dose-finding trial designs. The proposed PoD-BIN design evaluates the posterior predictive probabilities of up-and-down decisions. In PoD-BIN, multiple grades of…
Understanding whether and how treatment effects vary across subgroups is crucial to inform clinical practice and recommendations. Accordingly, the assessment of heterogeneous treatment effects (HTE) based on pre-specified potential effect…
Objective Bayesian inference procedures are derived for the parameters of the multivariate random effects model generalized to elliptically contoured distributions. The posterior for the overall mean vector and the between-study covariance…
Pharmacokinetic modeling using ordinary differential equations (ODEs) has an important role in dose optimization studies, where dosing must balance sustained therapeutic efficacy with the risk of adverse side effects. Such ODE models…
Successful pharmaceutical drug development requires finding correct doses that provide an optimum balance between efficacy and toxicity. Competing responses to dose such as efficacy and toxicity often will increase with dose, and it is…
Phase 1-2 designs provide a methodological advance over phase 1 designs for dose finding by using both clinical response and toxicity. A phase 1-2 trial still may fail to select a truly optimal dose. because early response is not a perfect…
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…
Purpose. Patients with advanced cancer may undergo multiple lines of treatment, switching therapies as their disease progresses. Motivated by a study of metastatic prostate cancer, we develop a microsimulation framework to study therapy…
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…