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Development of target-based antineoplastic agents
1Department of Medicine, University of Chicago, IL 60637, USA.
Abstract:
The elucidation of multiple potential targets in cancer cells and the development of multiple target-based antineoplastic agents provide unique challenges in clinical trial design. Many of these agents are predicted to have cytostatic as opposed to cytotoxic effects and thus the traditional surrogate endpoint of radiologic tumor shrinkage may be inadequate. The ethical and safety issues of obtaining multiple tumor biopsies further complicate the assessment of appropriate target inhibition in patients. We discuss specific issues that need to be addressed during preclinical, phase I, II, and III testing of these agents. We propose clinical trial designs, including a randomized discontinuation design during phase II evaluation, that may be particularly useful for cytostatic antineoplastic agents.
Insights
Designing clinical trials for novel cancer therapies presents challenges. New agents may be cytostatic, requiring innovative trial designs beyond traditional tumor shrinkage assessments.
Area of Science:
- Oncology
- Clinical Trial Design
- Pharmacology
Background:
- Multiple targets in cancer cells necessitate novel antineoplastic agents.
- Many new agents exhibit cytostatic rather than cytotoxic effects.
- Traditional endpoints like tumor shrinkage may be insufficient for cytostatic agents.
Purpose of the Study:
- To address challenges in clinical trial design for multi-target antineoplastic agents.
- To discuss issues in preclinical and clinical testing (Phases I-III) of these agents.
- To propose suitable clinical trial designs for cytostatic antineoplastic agents.
Main Methods:
- Review of challenges in clinical trial design for novel antineoplastic agents.
- Discussion of ethical and safety considerations for tumor biopsies.
- Proposal of specific trial designs, including randomized discontinuation designs.
Main Results:
- Current trial designs and endpoints may not adequately assess cytostatic agents.
- Ethical and safety concerns limit repeated tumor biopsies.
- Randomized discontinuation designs show promise for evaluating cytostatic agents in Phase II.
Conclusions:
- Clinical trial design for multi-target antineoplastic agents requires adaptation.
- Alternative endpoints and designs are crucial for evaluating cytostatic therapies.
- Innovative trial strategies can improve the assessment of novel cancer treatments.