Carcinoma, Non-Small-Cell LungEarly Phase 1ATOMNCT02628080
Atovaquone as Tumour HypOxia Modifier
A Early Phase 1 study testing Atovaquone in people with Carcinoma, Non-Small-Cell Lung, run by University of Oxford at 1 site in United Kingdom.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Carcinoma, Non-Small-Cell Lung
- What is being tested?
- Atovaquone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 46 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- May 2016to Dec 2018
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Suspected NSCLC considered suitable for surgical resection by the lung multidisciplinary team meeting (MDT).
- At least one measurable lesion (greater than 2.5cm maximal length in any direction) that the investigators consider on routine imaging (CT or PET-CT scan performed in the 60 days prior to consent (older scans may be accepted at the discretion of the Chief Investigator providing the results remain clinically significant)) likely to contain regions of hypoxia.
- Male or female, Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
- The patient is willing and able to comply with the protocol, scheduled follow-up visits and examinations for the duration of the study.
- Written (signed and dated) informed consent.
- Haematological and biochemical indices within given ranges
Who cannot join
- Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment.
- Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment.
- Known previous adverse reaction to atovaquone or its excipients.
- Active hepatitis, gallbladder disease or pancreatitis
- Patients with impaired gastrointestinal (GI) function or GI disease that may significantly alter absorption of atovaquone.
- Concurrent administration of contraindicated agents in the 14 days prior to starting atovaquone as outlined in section 9.4 and the current atovaquone Summary of Product Characteristics (SmPC).
Show all 11Show fewer
- Concurrent administration of warfarin in the 14 days prior to starting atovaquone.
- Patients taking known inhibitors of the electron transport chain such as Metformin.
- Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
- Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV (Hepatitis and HIV testing specifically for confirming eligibility for this trial are not required).
- Pregnant or breast-feeding women or women of childbearing potential unless highly effective methods of contraception are used.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Pre-operative Window of Opportunity Study of the Effects of Atovaquone on Hypoxia in Non-small Cell Lung Carcinoma
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.
Read more
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.
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Being tested
- Atovaquone
- Keywords
- Hypoxia
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Hypoxia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtovaquoneDrug
Also called Wellvone
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.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | Atovaquone suspension, 750mg/5ml bd and 1000mg (6.25ml) bd for 7-17 days. Device: PET-CT, Device: DWI-MRI Receives: Drug: Atovaquone |
| Cohort 2 | No intervention | Device: PET-CT, Device: DWI-MRI |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage change in reduction of hypoxia by atovaquone
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.
Measured: Day 0 v Day 7-17, and Day 0 post surgery (tumour sample)
Secondary outcomes (3)
Reduction of perfusion by atovaquone
Changes in tumour blood flow measured by perfusion CT, DWI-MRI, DCE-MRI and PET kinetic modelling
Measured: Day 0 v Day 7-17
Replacement of hyp-PET-CT imaging with serological markers of hypoxia
Changes in hypoxia-PET-CT derived hypoxic volumes compared with changes in plasma levels of serological markers of hypoxia
Measured: Day 0 v Day 7-17
Reproducibility
Comparison of hypoxia-PET-CT, perfusion CT, serological tests, diffusion-weighted imaging (DWI-MRI) and Dynamic contrast-enhanced MRI (DCE-MRI) derived parameters
Measured: Day 0 v Day 7-17
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Dec 2015 (estimated)
- Study startMay 2016
- Primary completionOct 2018
- Study completionDec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Carcinoma, Non-Small-Cell LungStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Geoff Higgins, MBChB, MRCP, FRCR, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02628080
- Sponsor's protocol ID
- OCTO-073
- Acronym
- ATOM
- Status last verified
- Jan 2019
- First submitted
- 7 Sep 2015
- Last updated
- 4 Sep 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Bourigault P, Skwarski M, Macpherson RE, Higgins GS, McGowan DR. Timing of hypoxia PET/CT imaging after 18F-fluoromisonidazole injection in non-small cell lung cancer patients. Sci Rep. 2022 Dec 16;12(1):21746. doi: 10.1038/s41598-022-26199-7.
PubMed 36526815Bourigault P, Skwarski M, Macpherson RE, Higgins GS, McGowan DR. Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients. EJNMMI Res. 2021 Dec 29;11(1):130. doi: 10.1186/s13550-021-00871-x.
PubMed 34964932
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pre-operative Window of Opportunity Study of the Effects of Atovaquone on Hypoxia in Non-small Cell Lung Carcinoma
- ClinicalTrials.gov ID
- NCT02628080
- Acronym / sponsor ID
- ATOM / OCTO-073
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Keywords
- Hypoxia
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- May 2016 (actual)
- Primary completion
- Oct 2018 (actual)
- Study completion
- Dec 2018 (actual)
- First posted
- 11 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: AtovaquoneAtovaquone suspension, 750mg/5ml bd and 1000mg (6.25ml) bd for 7-17 days. Device: PET-CT, Device: DWI-MRI |
| Cohort 2 | No intervention | –Device: PET-CT, Device: DWI-MRI |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Suspected NSCLC considered suitable for surgical resection by the lung multidisciplinary team meeting (MDT).
- At least one measurable lesion (greater than 2.5cm maximal length in any direction) that the investigators consider on routine imaging (CT or PET-CT scan performed in the 60 days prior to consent (older scans may be accepted at the discretion of the Chief Investigator providing the results remain clinically significant)) likely to contain regions of hypoxia.
- Male or female, Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
- The patient is willing and able to comply with the protocol, scheduled follow-up visits and examinations for the duration of the study.
Key exclusion criteria (11 listed)
- Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment.
- Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment.
- Known previous adverse reaction to atovaquone or its excipients.
- Active hepatitis, gallbladder disease or pancreatitis
- Patients with impaired gastrointestinal (GI) function or GI disease that may significantly alter absorption of atovaquone.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtovaquoneAlso: WellvoneAtovaquone 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. | Drug | Cohort 1 |
Primary outcome
Percentage change in reduction of hypoxia by atovaquone
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.
3 secondary outcomes
Reduction of perfusion by atovaquone
Time frame: Day 0 v Day 7-17
Replacement of hyp-PET-CT imaging with serological markers of hypoxia
Time frame: Day 0 v Day 7-17
Reproducibility
Time frame: Day 0 v Day 7-17
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2019.
- Derived from this study: PubMed 36526815Bourigault P, Skwarski M, Macpherson RE, Higgins GS, McGowan DR. Timing of hypoxia PET/CT imaging after 18F-fluoromisonidazole injection in non-small cell lung cancer patients. Sci Rep. 2022 Dec 16;12(1):21746. doi: 10.1038/s41598-022-26199-7.
- Derived from this study: PubMed 34964932Bourigault P, Skwarski M, Macpherson RE, Higgins GS, McGowan DR. Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients. EJNMMI Res. 2021 Dec 29;11(1):130. doi: 10.1186/s13550-021-00871-x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Geoff Higgins, MBChB, MRCP, FRCR principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Atovaquone in people with Carcinoma, Non-Small-Cell Lung, run by University of Oxford at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage change in reduction of hypoxia by atovaquone (time frame: Day 0 v Day 7-17, and Day 0 post surgery (tumour sample)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02628080, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2019.