Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

ARCADIAN: Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC






Full Title

 A Phase I trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

Chief Investigator: Professor Geoff Higgins

Sponsor: University of Oxford


Study Design

ARCADIAN is a phase I, single arm, open-label, dose-finding, study to establish the maximum tolerated dose (MTD) of atovaquone in combination with concurrent chemoradiotherapy (CRT) in locally advanced Non-Small Cell Lung Cancer (NSCLC).


Study Population

Patients with locally advanced NSCLC planned to be treated with concurrent chemoradiotherapy.


Lay Summary

A Lay Summary of this study is available on the CRUK Website:  CLICK HERE


Study Status


Closed to recruitment


Up to 20 evaluable participants


Churchill Hospital – Oxford University Hospital NHS Trust

Western General Hospital – NHS Lothian

Guy’s Hospital - Guy’s and St Thomas’s NHS Foundation Trust

Background and Study Relevance

Many solid tumours, including NSCLC, are typically dependent upon an abnormal, poorly functioning vasculature for oxygen delivery. Coupled with the high metabolic requirements of many tumours, this can lead to an imbalance in oxygen supply and demand. The resulting hypoxic microenvironment is recognised as having a profound radiation resistance which leads to particularly poor outcomes for patients treated with radiotherapy or CRT. Therefore, there is significant interest in developing effective hypoxia modifying therapies which can be safely combined with radiotherapy. 

This phase I study will evaluate the safety of combining atovaquone with radical CRT in patients with locally advanced NSCLC. Clinical outcomes following CRT in NSCLC remains very poor with 3-year overall survival only in the region of 30%. With the correlation between inadequate locoregional control and poor survival well-established in this patient population, developing a clinically useful radiosensitiser is of paramount importance.

The investigational medicinal product used in this study, atovaquone, is indicated for acute treatment of mild to moderate Pneumoystis pneumonia (PCP) and also used in combination with Proguanil for Malaria Prophylaxis. In vitro studies have demonstrated that at clinically relevant concentrations, atovaquone reduces oxygen consumption in a number of tumour cell lines. Subsequent work has confirmed that oral atovaquone can significantly reduce tumour hypoxia in xenograft models. Taken together, this data suggests that atovaquone represents a promising hypoxia modifying, and thus radiosensitising, drug to be used in combination with CRT. 

Despite decades of research, no hypoxia modifiers are currently in widespread clinical use. A major barrier to developing such agents has been a lack of validated hypoxia biomarkers, resulting in an inability to accurately stratify patients in clinical studies. Therefore, ARCADIAN will include important translational endpoints to identify such biomarkers.

Primary Objective

To determine the maximum tolerated dose (MTD), and therefore the recommend phase II dose (RPTD), of atovaquone when combined with radical concurrent chemoradiotherapy in patients with non-small cell lung cancer (NSCLC).

Secondary Objectives

Secondary endpoints will include translational data from plasma and tumour tissue samples with the aim of further establishing the role of atovaquone as a tumour hypoxia modifier, and to identify a hypoxia biomarker for use in a phase II study. 

Study Schema


Funding & Acknowledgements

ARCADIAN is sponsored by the University of Oxford and funded by CRUK (ref C34326/A27515). Statistical support is provided by the Centre for Statistics in Medicine (CSM).

Contact Us

ARCADIAN Trial Office

Tel: +44 (0)1865 617018


On this page