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Methodology of clinical trials with new molecular-targeted agents: where do we stand?
A Morabito1, M Di Maio, E De Maio
1Clinical Trials Unit, National Cancer Institute, Napoli, Italy.
Abstract:
In recent years, we have witnessed growing interest in the methodology of clinical trials with molecular-targeted agents. In phase I studies, alternative end points to toxicity have been proposed to define the optimal biological dose: the identification of a 'target effect', the measurement of 'surrogates' for biological activity and the assessment of drug plasma levels. However, these end points are not routinely incorporated into the study design and have rarely formed the primary basis for dose selection. In phase II studies, response rate remains the preferred end point in the early evaluation of new drugs. However, this approach might lead to rejection of potentially useful drugs when significant tumor shrinkage cannot be demonstrated. Therefore, a number of alternative end points have been proposed for agents that are not expected to cause a major tumor regression: time to progression, progression-free survival, overall survival, early progression rate and growth modulation index. In phase III trials, where efficacy in terms of survival remains the most important goal of the research, the major issues are the adequate selection of patients and the optimal clinical setting of evaluation of drugs. In conclusion, many important questions regarding the methodology of clinical research with target-based agents remain open and need to be defined by research in the near future.
Insights
Clinical trials for molecular-targeted agents need better methods. Researchers propose alternative endpoints beyond toxicity and response rates to accurately assess drug efficacy and guide dose selection for improved patient outcomes.
Area of Science:
- Oncology
- Clinical Pharmacology
- Biostatistics
Background:
- Growing interest in clinical trials for molecular-targeted agents.
- Current methodologies often rely on traditional endpoints like toxicity and response rates, which may not be optimal for targeted therapies.
Purpose of the Study:
- To review and discuss alternative endpoints for evaluating molecular-targeted agents in clinical trials.
- To highlight the limitations of current endpoints and propose improvements for dose selection and efficacy assessment.
Main Methods:
- Review of existing literature on clinical trial methodology for targeted agents.
- Discussion of proposed alternative endpoints for Phase I, II, and III trials.
- Analysis of the suitability of various endpoints for different phases of drug development.
Main Results:
- Phase I studies: Alternative endpoints like target effect, surrogate markers, and drug plasma levels are proposed but not routinely used for dose selection.
- Phase II studies: Response rate may lead to rejection of useful drugs; alternative endpoints like time to progression and progression-free survival are suggested.
- Phase III studies: Patient selection and optimal clinical setting are key issues for survival-based efficacy.
Conclusions:
- Significant questions remain regarding the optimal methodology for clinical research with target-based agents.
- Further research is needed to define and validate new endpoints for more accurate drug evaluation.
- Adoption of novel endpoints is crucial for advancing targeted cancer therapy development.
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