Abstract 75P
Background
The determination of a Maximum Tolerated Dose (MTD) remains the main objective for most dose-finding oncology trials. Whilst many dose-finding trials rely on clinicians to identify dose-limiting toxicities (DLTs), research has suggested that clinicians may under-report patient's adverse events. Current practice may be vulnerable to recommending intolerable doses to patients for further investigation in subsequent trials. There is increasing interest in patients self-assessing their own symptoms using Patient-reported Outcomes (PROs) in dose-finding trials. However currently, only two trial designs incorporate PROs formally in dose-escalation decision making: PRO-CRM and TiTE-PRO-CRM.
Methods
We detail the novel trial design, Utility-PRO-Continual Reassessment Method (U-PRO-CRM). This design simultaneously utilises both clinician and patient assessed DLTs to make dose escalation and de-escalation decisions and to recommend a MTD that optimises the clinician-patient DLT trade-off. U-PRO-CRM also contains PRO-CRM as a special case. We present a simulation study evaluating the performance of the U-PRO-CRM design.
Results
The U-PRO-CRM outperforms PRO-CRM in the simulation study; both when we emulate the PRO-CRM decision rule, and when we look to tailor the balance between the DLT rates reported by clinicians and those reported directly by patients. For instance, U-PRO-CRM is superior in scenarios where we look to compromise the optimal P-DLT rate given a dose’s corresponding C-DLT rate. Compared to PRO-CRM, in the majority of scenarios, U-PRO-CRM recommends the MTD more often and allocates a greater mean proportion of patients to the MTD whilst still maintaining a similar level of overdosing.
Conclusions
U-PRO-CRM generalises PRO-CRM, offering additional flexibility to define a trade-off between the risk of patient and clinician DLTs when we look to find an optimal dose. Continued patient engagement efforts can assist trialists in refining this trade-off. Patient-centric dose-finding approaches which incorporate PROs are likely to play an increasingly pivotal role in advancing our understanding of treatment tolerability, holding substantial implications for the future of early phase trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Institute of Cancer Research.
Disclosure
All authors have declared no conflicts of interest.