Churchill Hospital
Oxford, Oxfordshire, OX3 7LE, United Kingdom
NCT Number: NCT02628080
Solid tumours often have highly disorganised vasculature that results in low oxygenation. This combined with high metabolic rates leads to oxygen demand outstripping supply causing tumour hypoxia. Hypoxia drives multiple cellular processes involved in the hallmarks of cancer. Tumour hypoxia also decreases the effectiveness of anticancer treatments. This is especially true for patients treated with radiotherapy since it has been long recognised that hypoxic tumour cells require 3 times the dose of radiation to cause the same amount of cell death as cells irradiated under normal oxygen conditions.
To date, the majority of attempts at overcoming tumour hypoxia have focused on increasing oxygen supply. However, such techniques have produced modest benefits at best and subsequently have not been adopted into current clinical practice.
An interesting alternative approach to tackling tumour hypoxia is to decrease oxygen 'demand' by reducing tumour oxygen consumption. This strategy has been suggested to be more effective in reducing hypoxia than previous methods aimed at increasing oxygen delivery.
Pre-clinical data demonstrates that the commonly prescribed anti-protozoal drug atovaquone significantly reduces oxygen consumption in a variety of tumour cell lines in vitro. This reduction in oxygen consumption leads to a profound reduction in tumour hypoxia in animal models. It is anticipated that if these effects on tumour hypoxia could be reproduced in humans, that their tumours could be rendered markedly more sensitive to radiotherapy.
This window of opportunity trial will assess whether atovaquone significantly reduces tumour hypoxia in adult patients referred for surgery with suspected non-small cell lung cancer. This will be assessed using a combination of functional imaging and circulating markers of hypoxia. If atovaquone is demonstrated to result in a reduction in tumour hypoxia, larger clinical trials will be conducted to determine whether this well-tolerated and inexpensive agent improves radiotherapy efficacy and clinical outcomes.
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Notify Me18 year and older
All sexes
Interventional
Early Phase 1
Oxford, Oxfordshire, OX3 7LE, United Kingdom
Healthy volunteers accepted: No
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
Exclusion criteria
Atovaquone has an EU marketing authorisation (held by Glaxo Wellcome UK Ltd) and is indicated for acute treatment of mild to moderate Pneumocystis pneumonia (PCP). It is also used in combination with proguanil for malaria prophylaxis.
Other names: Wellvone
Time frame: Day 0 v Day 7-17, and Day 0 post surgery (tumour sample)
Average hypoxic volume reduction (%) in 18F-fluoromisonidazole (18F-MISO)/18F-fluoroazomycin arabinoside (18F-FAZA) uptake as detected by hypoxia-PET(positron emission tomography)-CT scans.
Time frame: Day 0 v Day 7-17
Changes in tumour blood flow measured by perfusion CT, DWI-MRI, DCE-MRI and PET kinetic modelling
Time frame: Day 0 v Day 7-17
Changes in hypoxia-PET-CT derived hypoxic volumes compared with changes in plasma levels of serological markers of hypoxia
Time frame: Day 0 v Day 7-17
Comparison of hypoxia-PET-CT, perfusion CT, serological tests, diffusion-weighted imaging (DWI-MRI) and Dynamic contrast-enhanced MRI (DCE-MRI) derived parameters
Time frame: Day 0 v Day 7-17 for plasma level. Day 0 v Post resection for tumour sample (cohort 1 only)
HPLC (high pressure liquid chromatography) based measurement of plasma level and tumour level of atovaquone
Time frame: Day 0 v Day 7-17
Comparison of histological hypoxia and vasculature parameters with prior imaging measuring hypoxia, perfusion, and glycolysis
Time frame: Day 0 v Day 7-17
Comparison of serological hypoxia parameters with immunohistochemistry on pimonidazole staining
Time frame: Day 0 v Day 7-17
Hypoxia metagene signature expression and Individual tests to measure gene expression/mutation
Time frame: At 12 and 24 months
Progression-free survival and overall survival
University of Oxford
Other
Pre-operative Window of Opportunity Study of the Effects of Atovaquone on Hypoxia in Non-small Cell Lung Carcinoma
Acronym: ATOM
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