Background

Radiotherapy has proven efficacy in the treatment of a wide range of cancers. There is growing interest in evaluating radiotherapy-novel agent combinations, and a drive to initiate research earlier in clinical development of the novel agent, running in parallel with exploring drug combinations, especially where scientific rationale for a radiotherapy combination approach is high. Optimal design, delivery and interpretation of studies evaluating these combinations is essential. In particular, design of phase I studies to determine safety and dosing combinations is critical to an efficient development strategy. The NCRI Clinical and Translational Radiotherapy Research Working Group (CTRad) takes a leading role in the delivery of UK radiotherapy clinical research. CTRad specifically has an interest in design and delivery of radiotherapy-novel agent combination studies, an area where scrutiny of trial design methodology has significantly increased.

Method

We developed a road map to inform phase I radiotherapy-novel agent combination study development, from consideration of the research question and intervention through to identifying an appropriate statistical design. A literature search of phase I trial design methodology was performed. Data were extracted on key design aspects, and designs grouped according to: maximum tolerated dose (MTD) determination, dose limiting toxicity (DLT) categorisation, interventions to be escalated, subgroup inclusion, software availability and performance evaluation.

Results

29 full text articles describing unique phase I designs were identified. Design characteristics were evaluated to produce a road map of specific points to consider to facilitate design selection, consisting of four components: i)determining DLT assessment format; ii)determining the MTD; iii)practical considerations in design selection; iv)additional points to consider. Applied examples of using the road map to identify novel statistical approaches to phase I radiotherapy-novel agent combination trials will be presented.

Conclusion

The road map enables researchers to make informed decisions relating to the choice of statistical design for phase I radiotherapy-novel agent combination trials. Specifically designed to be practically implemented, this has the potential to enhance design of such trials, optimize potential for trial funding, and promote efficient trial conduct.

Impact statement

The road map has the potential to improve design of phase I radiotherapy-novel agent combination trials, enabling a more efficient development pathway.