Assessing cognitive toxicity in early phase trials - What are we missing?
Sarah E Stapleton1,2, Anne-Sophie Darlington2, Anna Minchom1,3
1Royal Marsden Hospital Drug Development Unit, Sutton, UK.
Objectives:
Novel therapies, such as, small protein molecule inhibitors and immunotherapies are first tested clinically in Phase I trials. Moving on to later phase trials and ultimately standard practice. A key aim of these early clinical trials is to define a toxicity profile; however, the emphasis is often on safety. The concern is cognitive toxicity is poorly studied in this context and may be under-reported. The aim of this review is to map evidence of cognitive assessment, toxicity, and confounding factors within reports from Phase I trials and consider putative mechanisms of impairment aligned with mechanisms of novel therapies.
Methods:
A scoping review methodology was applied to the search of databases, including Embase, MEDLINE, Clinicaltrials.gov. A [keyword search was conducted, results screened for duplication then inclusion/exclusion criteria applied. Articles were further screened for relevance; data organised into categories and charted in a tabular format]. Evidence was collated and summarised into a narrative synthesis.
Results:
Despite the availability of robust ways to assess cognitive function, these are not routinely included in the conduct of early clinical trials. Reports of cognitive toxicity in early Phase I trials are limited and available evidence on this shows that a proportion of patients experience impaired cognitive function over the course of participating in a Phase I trial. Links are identified between the targeted action of some novel therapies and putative mechanisms of cognitive impairment.
Conclusion:
The review provides rationale for research investigating cognitive function in this context. A study exploring the cognitive function of patients on Phase I trials and the feasibility of formally assessing this within early clinical trials is currently underway at the Royal Marsden.
Insights
Cognitive toxicity in early phase clinical trials is under-reported, despite evidence of impaired cognitive function in patients receiving novel therapies. Further research is needed to assess cognitive function during these crucial early trials.
Area of Science:
- Oncology
- Clinical Pharmacology
- Neuroscience
Background:
- Phase I clinical trials evaluate novel therapies like small molecule inhibitors and immunotherapies.
- A primary goal of Phase I trials is to establish a toxicity profile, with a strong emphasis on safety.
- Cognitive toxicity is a poorly understood and potentially under-reported concern in this trial phase.
Purpose of the Study:
- To review evidence of cognitive assessment and toxicity in Phase I trial reports.
- To identify confounding factors influencing cognitive function in Phase I trial participants.
- To explore potential mechanisms linking novel therapy actions to cognitive impairment.
Main Methods:
- A scoping review methodology was employed.
- Searches were conducted across Embase, MEDLINE, and Clinicaltrials.gov.
- Data were screened, categorized, charted, and synthesized into a narrative.
Main Results:
- Robust cognitive assessment tools are not routinely used in early clinical trials.
- Limited reports indicate a proportion of Phase I trial patients experience cognitive impairment.
- Potential links exist between novel therapy mechanisms and cognitive impairment mechanisms.
Conclusions:
- There is a clear need for research into cognitive function in Phase I trials.
- Current evidence suggests cognitive impairment occurs in a subset of patients.
- Formal cognitive assessment should be considered in early clinical trials.
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