Related papers: Utility-Based Dose Optimization Approaches for Mul…
Dose optimization in oncology clinical trials has shifted from seeking the maximum tolerated dose to identifying the Optimal Biological Dose (OBD) that balances therapeutic benefits and risks across multiple clinical attributes. Existing…
With the development of novel therapies such as molecularly targeted agents and immunotherapy, the maximum tolerated dose paradigm that "more is better" does not necessarily hold anymore. In this context, doses and schedules of novel…
The FDA's Project Optimus initiative emphasizes patient-centered dose selection in oncology that balances efficacy and safety. We develop a framework for randomized dose optimization studies that uses clinically interpretable utility scores…
Phase I dose escalation trials in oncology generally aim to find the maximum tolerated dose (MTD). However, with the advent of molecular targeted therapies and antibody drug conjugates, dose limiting toxicities are less frequently observed,…
The main objective of dose finding trials is to find an optimal dose amongst a candidate set for further research. The trial design in oncology proceeds in stages with a decision as to how to treat the next group of patients made at every…
Optimizing doses for multiple indications is challenging. The pooled approach of finding a single optimal biological dose (OBD) for all indications ignores that dose-response or dose-toxicity curves may differ between indications, resulting…
The conventional more-is-better dose selection paradigm, which targets the maximum tolerated dose (MTD), is not suitable for the development of targeted therapies and immunotherapies as the efficacy of these novel therapies may not increase…
In Phase I/II dose-finding trials, the objective is to find the Optimal Biological Dose (OBD), a dose that is both safe and efficacious that maximises some optimality criterion based on safety and efficacy. This is further complicated when…
Early phase, personalized dose-finding trials for combination therapies seek to identify patient-specific optimal biological dose (OBD) combinations, which are defined as safe dose combinations which maximize therapeutic benefit for a…
Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated dose (MTD) of the investigational cytotoxic agent based on a single toxicity outcome, assuming a monotone dose-response relationship.…
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…
We consider a dose-optimization design for first-in-human oncology trial that aims to identify a suitable dose for late-phase drug development. The proposed approach, called the Pharmacometrics-Enabled DOse OPtimization (PEDOOP) design,…
Traditional dose selection for oncology registration trials typically employs a one- or two-step single maximum tolerated dose (MTD) approach. However, this approach may not be appropriate for molecularly targeted therapy that tends to have…
An important objective in the development of targeted therapies is to identify the populations where the treatment under consideration has positive benefit risk balance. We consider pivotal clinical trials, where the efficacy of a treatment…
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…
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…
Identification of optimal dose combinations in early phase dose-finding trials is challenging, due to the trade-off between precisely estimating the many parameters required to flexibly model the possibly non-monotonic dose-response…
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…
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…