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Atovaquone as Tumour HypOxia Modifier (ATOM)

Primary Purpose

Carcinoma, Non-Small-Cell Lung

Status

Completed

Phase

Early Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

Atovaquone

About this trial

This is an interventional treatment trial for Carcinoma, Non-Small-Cell Lung focused on measuring Hypoxia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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).
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.

Sites / Locations

Churchill Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Cohort 1

Cohort 2

Arm Description

Atovaquone suspension, 750mg/5ml bd and 1000mg (6.25ml) bd for 7-17 days. Device: PET-CT, Device: DWI-MRI

Device: PET-CT, Device: DWI-MRI

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Reduction of perfusion by atovaquone

Changes in tumour blood flow measured by perfusion CT, DWI-MRI, DCE-MRI and PET kinetic modelling

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

Reproducibility

Comparison of hypoxia-PET-CT, perfusion CT, serological tests, diffusion-weighted imaging (DWI-MRI) and Dynamic contrast-enhanced MRI (DCE-MRI) derived parameters

Full Information

NCT ID

NCT02628080

First Posted

September 7, 2015

Last Updated

September 2, 2019

Sponsor

University of Oxford

1. Study Identification

Unique Protocol Identification Number

NCT02628080

Brief Title

Atovaquone as Tumour HypOxia Modifier

Acronym

ATOM

Official Title

Pre-operative Window of Opportunity Study of the Effects of Atovaquone on Hypoxia in Non-small Cell Lung Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Completed

Study Start Date

May 2016 (Actual)

Primary Completion Date

October 2018 (Actual)

Study Completion Date

December 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Oxford

4. Oversight

Data Monitoring Committee

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Carcinoma, Non-Small-Cell Lung

Keywords

Hypoxia

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

46 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

Atovaquone suspension, 750mg/5ml bd and 1000mg (6.25ml) bd for 7-17 days. Device: PET-CT, Device: DWI-MRI

Arm Title

Cohort 2

Arm Type

No Intervention

Arm Description

Device: PET-CT, Device: DWI-MRI

Intervention Type

Drug

Intervention Name(s)

Atovaquone

Other Intervention Name(s)

Wellvone

Intervention Description

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.

Primary Outcome Measure Information:

Title

Percentage change in reduction of hypoxia by atovaquone

Description

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, and Day 0 post surgery (tumour sample)

Secondary Outcome Measure Information:

Title

Reduction of perfusion by atovaquone

Description

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

Title

Replacement of hyp-PET-CT imaging with serological markers of hypoxia

Description

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

Title

Reproducibility

Description

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

Other Pre-specified Outcome Measures:

Title

Correlation of hypoxia modification with PK (pharmacokinetic) levels of atovaquone (plasma and tumour)

Description

HPLC (high pressure liquid chromatography) based measurement of plasma level and tumour level of atovaquone

Time Frame

Day 0 v Day 7-17 for plasma level. Day 0 v Post resection for tumour sample (cohort 1 only)

Title

Correlations between imaging and histology

Description

Comparison of histological hypoxia and vasculature parameters with prior imaging measuring hypoxia, perfusion, and glycolysis

Time Frame

Day 0 v Day 7-17

Title

Correlations between serological hypoxia markers and histology

Description

Comparison of serological hypoxia parameters with immunohistochemistry on pimonidazole staining

Time Frame

Day 0 v Day 7-17

Title

To assess whether atovaquone results in a lower level of hypoxia metagene signature expression

Description

Hypoxia metagene signature expression and Individual tests to measure gene expression/mutation

Time Frame

Day 0 v Day 7-17

Title

Progression-free survival and overall survival

Description

Progression-free survival and overall survival

Time Frame

At 12 and 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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). 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Geoff Higgins, MBChB, MRCP, FRCR

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

Facility Information:

Facility Name

Churchill Hospital

City

Oxford

State/Province

Oxfordshire

ZIP/Postal Code

OX3 7LE

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

34964932

Citation

Bourigault 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.

Results Reference

derived

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