Abstract
The introduction of new Molecularly Targeted Agents (MTA) has changed the landscape in Early Drug Development (EDD) over the last two decades, leading to an improvement in clinical trial design. Previous Phase 1 (Ph1) studies with cytotoxics focused on safety objectives, only recruiting heavily pre-treated cancer patients, have been left behind. In this review, we will illustrate the slow although unstoppable change that has increasingly been observed in those populations candidate to participate in EDD trials with the advent of MTA. As more evidence regarding oncogene addiction becomes available, molecular-biomarker driven selection has been implemented among Molecularly-Selected Population (MSP) studies. New Window-Of-Opportunity (WOO) and Phase 0 (Ph0) studies have been developed in order to assess whether a MTA produces the hypothetical proposed biological effect. The rising need of getting early pharmacokinetics and pharmacodynamics data has led to the conduction of Healthy Volunteer (HV) studies, in part favoured for the particular and different toxicity profile of these MTA. However, several challenges will need to be addressed in order to boost the implementation of these new clinical trial designs in the forthcoming years. Among the problems to overcome, we would highlight a better coordination effort between centers for ensuring adequate patient accrual among small patient populations and a deepening into the ethics implied in enrolling patients in studies with no therapeutic intent. However, these tribulations will be certainly compensated by the possibility of opening a new horizon of treatment for diseases with dismal prognosis.
Highlights
Over the past two decades, with the advent of new Molecularly Targeted Agents (MTA), cancer research has shifted from standard chemotherapies to the selective inhibition of signaling pathways
The advent of new MTA has broadened the Early Drug Development (EDD) landscape, in terms of expanding the portfolio of drugs, and in changing the candidates exposed to these experimental therapies
It is clear that many different patient populations other than advanced cancer patients are currently exposed to MTA in their early development
Summary
Over the past two decades, with the advent of new Molecularly Targeted Agents (MTA), cancer research has shifted from standard chemotherapies to the selective inhibition of signaling pathways. Considering risks and limited efficacy, only heavily pre-treated cancer patients with no standard effective therapies were considered candidates This dose-toxicity model, though, has shown to be not so effective for testing MTA. Several new trial designs can be successfully implemented in the EDD process further to the classical 3+3 design, such as the accelerated titration design (ATD) and continual reassessment method (CRM) [4]. This new designs take advantage of incorporating supplementary endpoints that help to further characterize the MTA in terms of efficacy
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call