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Updated: Jun 16, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Using circulating tumor DNA as a novel biomarker of efficacy for dose-finding designs in oncology
Xijin Chen1, Pavel Mozgunov1, Richard D Baird2
1MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
Abstract:
Dose-finding trials are designed to identify a safe and potentially effective drug dose and schedule during the early phase of clinical trials. Historically, Bayesian adaptive dose-escalation methods in Phase I trials in cancer have mainly focussed on toxicity endpoints rather than efficacy endpoints. This is partly because efficacy readouts are often not available soon enough for dose escalation decisions. In the last decade, 'liquid biopsy' technologies have been developed, which may provide a readout of treatment response much earlier than conventional endpoints. This paper develops a novel design that uses a biomarker, circulating tumour DNA (ctDNA), with toxicity and activity outcomes in dose-finding studies. We compare the proposed approach based on repeated ctDNA measurement with existing Bayesian adaptive approaches under various scenarios of dose-toxicity, dose-efficacy relationship, and trajectories of regular ctDNA values over time. Simulation results show that the proposed approach can yield significantly shorter trial duration and may improve identification of the target dose. In addition, this approach has the potential to minimise the time individual patients spend on potentially inactive trial therapies. Using two different dose-finding designs, we demonstrate that the way we incorporate biomarker information is broadly applicable across different dose-finding designs and yields notable benefit in both cases.
Insights
This study introduces a new method for early-phase cancer trials, using circulating tumor DNA (ctDNA) biomarkers alongside toxicity data. This approach aims to shorten trial duration and better identify effective drug doses, improving patient outcomes.
Area of Science:
- Oncology
- Biostatistics
- Clinical Trial Design
Background:
- Traditional early-phase cancer trials often prioritize toxicity over efficacy due to delayed response data.
- Bayesian adaptive methods are common but typically rely on late-emerging efficacy signals.
- Emerging liquid biopsy technologies, like ctDNA analysis, offer earlier insights into treatment response.
Purpose of the Study:
- To develop and evaluate a novel Bayesian adaptive dose-finding design incorporating circulating tumor DNA (ctDNA) biomarkers.
- To assess the performance of this new design against existing methods using simulations.
- To demonstrate the potential for earlier identification of optimal drug doses and improved trial efficiency.
Main Methods:
- Development of a novel dose-finding design integrating toxicity, activity, and serial ctDNA measurements.
- Simulation studies comparing the proposed ctDNA-based design with traditional Bayesian adaptive approaches.
- Evaluation across diverse scenarios of dose-toxicity, dose-efficacy relationships, and ctDNA dynamics.
Main Results:
- The proposed ctDNA-guided approach significantly reduces trial duration compared to conventional methods.
- The method shows improved accuracy in identifying the optimal therapeutic dose.
- Simulation results indicate a potential to minimize patient exposure to ineffective treatments.
Conclusions:
- Incorporating ctDNA biomarkers into dose-finding designs offers a significant advantage in early-phase oncology trials.
- This novel approach enhances efficiency and patient-centricity by enabling earlier and more accurate dose selection.
- The framework is adaptable and demonstrates benefits across different dose-finding methodologies.
