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Clinical trial designs for cytostatic agents: are new approaches needed?
E L Korn1, S G Arbuck, J M Pluda
1Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA. korne@ctep.nci.nih.gov
Abstract:
Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.
Insights
New anticancer drugs, known as cytostatic agents, may inhibit tumor growth without shrinking tumors. Traditional clinical trial designs may need modification to properly evaluate these novel therapies and their potential benefits.
Area of Science:
- Oncology
- Clinical Trial Design
- Pharmacology
Background:
- Novel anticancer agents can be cytostatic, inhibiting tumor growth rather than causing shrinkage.
- Cytostatic agents may offer clinical benefits even without tumor shrinkage.
- Dose-finding for cytostatic agents may not rely on toxicity as the primary endpoint.
Purpose of the Study:
- To discuss modifications to traditional clinical trial designs for cytostatic agents.
- To explore alternative trial designs that accommodate the unique properties of cytostatic therapies.
- To provide recommendations for selecting appropriate trial designs based on preclinical data and patient population characteristics.
Main Methods:
- Review of existing literature and clinical trial methodologies.
- Analysis of preclinical data suggesting cytostatic effects.
- Examination of ongoing and planned trials utilizing modified designs.
Main Results:
- Traditional cytotoxic trial designs (Phase I, II, III) may be suboptimal for cytostatic agents.
- Modified trial designs are being explored and tested to better evaluate cytostatic therapies.
- Recommendations for trial design selection depend on agent characteristics and patient population data.
Conclusions:
- Clinical trial designs require adaptation for novel cytostatic anticancer agents.
- Successful evaluation of cytostatic agents necessitates flexible and innovative trial approaches.
- Future trials will assess the efficacy of these modified designs in oncological research.