Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC
Research type
Research Study
Full title
A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination with Radical Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Carcinoma
IRAS ID
266541
Contact name
Geoff Higgins
Contact email
Sponsor organisation
University of Oxford
Eudract number
2019-002097-30
Duration of Study in the UK
2 years, 3 months, 31 days
Research summary
Research Summary
In solid tumours, a combination of high metabolic rate and poor blood supply often results in oxygen demand exceeding oxygen supply, leading to areas of hypoxia. Tumour hypoxia is associated with poor clinical outcomes and is a well-recognised barrier to effective treatment – most notably causing desensitisation to radiation.
Pre-clinical data demonstrates that atovaquone, a commonly prescribed anti-protozoal drug, significantly reduces oxygen consumption rate in a range of cancer cell lines in vitro. Atovaquone also significantly reduces tumour hypoxia and increases tumour radiosensitisation in vivo. Furthermore, we have carried out a proof-of concept, window-of-opportunity trial (ATOM: Atovaquone as a Tumour hypOxia Modifier), investigating the effects of atovaquone on hypoxia in patients with Non-Small Cell Lung Cancer (NSCLC) due to undergo surgical treatment. Fifteen patients were recruited and administered atovaquone for approximately 14 days prior to surgery. In 11/15 patients, tumour hypoxia was reduced. Moreover, no toxicity was observed.
This CRUK-funded phase I study will evaluate the safety of combining atovaquone with radical chemoradiotherapy (CRT) in patients with NSCLC. We plan to recruit 20 NSCLC patients at two NHS cancer centres over 20 months. Each patient will take two doses of oral atovaquone suspension per day for approximately two weeks prior to commencing CRT, and will continue this throughout their CRT treatment. Starting from the lowest dose, a statistical model will recommend a dose of atovaquone for each patient based on toxicity data from all proceeding trial participants. The model will determine the Maximum Tolerated Dose (MTD) of atovaquone in conjunction with CRT and the recommended dose for phase II study. A secondary aim of the study is to identify plasma and tissue hypoxia biomarkers to validate the research techniques and identify patients who may benefit from such approaches in the future.
Summary of Results
Cancer cells inside solid tumours divide and grow quickly, using up oxygen in the process. Tumours also typically develop abnormal blood vessels, which makes it difficult to deliver enough oxygen. Because of these factors, some areas within tumours become very low in oxygen. In cancer cells, this triggers abnormal internal pathways to be activated, which make tumours spread more quickly and become resistant to treatment. Low oxygen is also a problem for patients having radiotherapy, because oxygen is required inside the tumour to create the toxic chemicals that help kill the cancer cells. Therefore, there is a need to find ways to increase the oxygen levels inside tumours in order to improve the impact of cancer treatments.
Previous research has shown that a drug used to treat certain infections, called atovaquone, can increase the amount of oxygen in cancer cells. Therefore, the ARCADIAN clinical trial aimed to find out if atovaquone could be safely given to cancer patients at the same time as radiotherapy. This clinical trial focused on patients with a type of cancer called non-small cell lung cancer (NSCLC) who were being treated with chemotherapy and radiotherapy at the same time (chemoradiotherapy).
To find out whether the combination of atovaquone and chemoradiotherapy is safe, initial patients enrolled in the trial were given a low dose of atovaquone alongside their standard treatment. Data on any side effects experienced was collected, and subsequent patients were only given higher doses if safe to do so. This is called a dose escalation study and allows researchers to find the best dose to give.
The key aims of this study were to find out:
• If it is safe to combine atovaquone with chemoradiotherapy
• The best dose of atovaquone to give with chemoradiotherapy
• The side effects of giving atovaquone with chemoradiotherapyResearchers were also interested in finding out whether there is a way to measure the level of oxygen in patient’s tumours from a blood or tumour sample, rather than via a special scan (which measures tumour oxygen level, but is expensive). This could help to identify patients with low tumour oxygen levels who might benefit most from taking atovaquone alongside their standard cancer treatment in the future.
A total of 21 patients were enrolled on the trial. Each was allocated one of four doses of atovaquone (450, 600, 675 or 750 mg) to take in both the morning and the evening for up to 3 weeks before starting chemoradiotherapy, and then alongside their chemoradiotherapy. All patients stopped taking atovaquone when their course of chemoradiotherapy treatment was complete.
Standard chemoradiotherapy for these patients consisted of the following:
• Radiotherapy (every week day for 6 ½ weeks)
• Cisplatin (in weeks 1 and 4)
• Vinorelbine (in weeks 1, 2, 4 and 5)No severe side effects were identified, therefore the trial showed that it is safe to take atovaquone at the same time as having chemoradiotherapy. The best dose of atovaquone to take was the highest dose investigated (750 mg, twice a day). This dose was taken by 15 participants in the trial and was shown to be safe in combination with chemoradiotherapy.
Over half of the participants completed the two scans required to measure change in low tumour oxygen level, before and after atovaquone. Some patients did not complete both scans, for example because low tumour oxygen level was not detected on the first scan. Overall, these demonstrated an increase in oxygen levels in tumours after taking atovaquone. Of the alternative methods tested, neither represented a reliable substitute for scanning.
In summary, this means that the combination of atovaquone with chemoradiotherapy is safe and warrants further trials to determine whether this combination improves patient outcomes after treatment. Since atovaquone is not lung-cancer specific, it has the potential to improve the impact of therapy for other types of cancers too.
REC name
South Central - Oxford A Research Ethics Committee
REC reference
20/SC/0095
Date of REC Opinion
27 Mar 2020
REC opinion
Favourable Opinion