Award Title: ARCADIAN: Phase I study combining the tumour hypoxia modifier atovaquone with radical chemoradiotherapy in locally advanced NSCLC
Funder: Cancer Research UK

Abstract: Background:  Lung cancer is the leading cause of cancer death in the UK with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Radiotherapy treatment (+/- chemotherapy) plays a key role in the management of early and locally advanced disease. Despite significant technical improvements in radiotherapy delivery, clinical outcomes for patients treated with 'curative intent' remain extremely poor.  Tumour hypoxia frequently occurs in tumours due to an imbalance in the 'supply and demand' of oxygen. This is recognised as inducing an aggressive tumour phenotype with profound radiation resistance. An emerging strategy to reduce tumour hypoxia is to decrease the oxygen consumption rate (OCR) of cancer cells. We have previously found that the safe and widely used anti-malarial drug atovaquone reduces OCR in vitro. Clinically relevant concentrations of atovaquone rapidly reduce tumour hypoxia in 3D spheroids and tumour xenografts, causing marked radiosensitisation.  We subsequently conducted a window of opportunity clinical trial in NSCLC patients prior to surgery. Approximately 14 days of atovaquone treatment reduced tumour hypoxia (measured using FMISO PET-CT) in 11 out of 15 patients with no toxicity. This data supports that atovaquone is able to safely and effectively reduce hypoxia in the clinical setting.  Aims:  We aim to undertake this phase I, single-arm, open-label, 2-centre trial using the Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal dose of atovaquone in combination with concurrent chemoradiotherapy (CRT) in patients with NSCLC. Also, as a major reason for the lack of success in previous hypoxia modification trials was a failure to utilise biomarkers to select patients with hypoxic tumours, we aim to further develop such biomarkers specifically for this purpose.  Methods: Atovaquone will commence 2 weeks prior to CRT, and be continued throughout CRT. The duration of treatment is 8.5 weeks while the follow-up period is 12 weeks. DLTs will be assessed over this period. Biomarker data will be collected at baseline and following 2 weeks of atovaquone treatment (prior to CRT) and will consist of FMISO PET-CT imaging and plasma levels of hypoxia markers. Hypoxia metagene analysis will also be conducted on diagnostic tissue.   How results will be used:  This study will identify the dose of atovaquone for a subsequent phase II/III trial. Furthermore, the biomarker element of this study will lead to the development of a clear hypoxia-dependant patient selection strategy for the future study and directly inform trial design.

Lay Abstract: Background:  Lung cancer is the leading cause of cancer death in the UK with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Radiotherapy treatment (+/- chemotherapy) plays a key role in the management of early and locally advanced disease. Despite significant technical improvements in radiotherapy delivery, clinical outcomes for patients treated with 'curative intent' remain extremely poor.  Tumour hypoxia frequently occurs in tumours due to an imbalance in the 'supply and demand' of oxygen. This is recognised as inducing an aggressive tumour phenotype with profound radiation resistance. An emerging strategy to reduce tumour hypoxia is to decrease the oxygen consumption rate (OCR) of cancer cells. We have previously found that the safe and widely used anti-malarial drug atovaquone reduces OCR in vitro. Clinically relevant concentrations of atovaquone rapidly reduce tumour hypoxia in 3D spheroids and tumour xenografts, causing marked radiosensitisation.  We subsequently conducted a window of opportunity clinical trial in NSCLC patients prior to surgery. Approximately 14 days of atovaquone treatment reduced tumour hypoxia (measured using FMISO PET-CT) in 11 out of 15 patients with no toxicity. This data supports that atovaquone is able to safely and effectively reduce hypoxia in the clinical setting.  Aims:  We aim to undertake this phase I, single-arm, open-label, 2-centre trial using the Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal dose of atovaquone in combination with concurrent chemoradiotherapy (CRT) in patients with NSCLC. Also, as a major reason for the lack of success in previous hypoxia modification trials was a failure to utilise biomarkers to select patients with hypoxic tumours, we aim to further develop such biomarkers specifically for this purpose.  Methods: Atovaquone will commence 2 weeks prior to CRT, and be continued throughout CRT. The duration of treatment is 8.5 weeks while the follow-up period is 12 weeks. DLTs will be assessed over this period. Biomarker data will be collected at baseline and following 2 weeks of atovaquone treatment (prior to CRT) and will consist of FMISO PET-CT imaging and plasma levels of hypoxia markers. Hypoxia metagene analysis will also be conducted on diagnostic tissue.   How results will be used:  This study will identify the dose of atovaquone for a subsequent phase II/III trial. Furthermore, the biomarker element of this study will lead to the development of a clear hypoxia-dependant patient selection strategy for the future study and directly inform trial design.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS