A Road Map for Designing Phase I Clinical Trials of Radiotherapy–Novel Agent Combinations

Author:

Brown Sarah R.1ORCID,Hinsley Samantha2ORCID,Hall Emma3ORCID,Hurt Chris4ORCID,Baird Richard D.5ORCID,Forster Martin6,Scarsbrook Andrew F.7ORCID,Adams Richard A.8ORCID

Affiliation:

1. 1Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom.

2. 2Clinical Trials Unit Glasgow, University of Glasgow, Glasgow, United Kingdom.

3. 3Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom.

4. 4Centre for Trials Research, Cardiff University, Cardiff, United Kingdom.

5. 5Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

6. 6University College Hospital, London, United Kingdom.

7. 7Radiotherapy Research Group, Leeds Institute of Medical Research at St James's, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom.

8. 8Centre for Trials Research, Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom.

Abstract

Abstract Radiotherapy has proven efficacy in a wide range of cancers. There is growing interest in evaluating radiotherapy–novel agent combinations and a drive to initiate this earlier in the clinical development of the novel agent, where the scientific rationale and preclinical evidence for a radiotherapy combination approach are high. Optimal design, delivery, and interpretation of studies are essential. In particular, the design of phase I studies to determine safety and dosing is critical to an efficient development strategy. There is significant interest in early-phase research among scientific and clinical communities over recent years, at a time when the scrutiny of the trial methodology has significantly increased. To enhance trial design, optimize safety, and promote efficient trial conduct, this position paper reviews the current phase I trial design landscape. Key design characteristics extracted from 37 methodology papers were used to define a road map and a design selection process for phase I radiotherapy–novel agent trials. Design selection is based on single- or dual-therapy dose escalation, dose-limiting toxicity categorization, maximum tolerated dose determination, subgroup evaluation, software availability, and design performance. Fifteen of the 37 designs were identified as being immediately accessible and relevant to radiotherapy–novel agent phase I trials. Applied examples of using the road map are presented. Developing these studies is intensive, highlighting the need for funding and statistical input early in the trial development to ensure appropriate design and implementation from the outset. The application of this road map will improve the design of phase I radiotherapy–novel agent combination trials, enabling a more efficient development pathway.

Funder

NIHR

Cancer Research UK

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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