Atovaquone as Tumour HypOxia Modifier (ATOM)

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.

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 Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Atovaquone

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • Churchill Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Suspected NSCLC considered suitable for surgical resection by the lung multidisciplinary team meeting (MDT).
2. 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.
3. Male or female, Age ≥ 18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
5. The patient is willing and able to comply with the protocol, scheduled follow-up visits and examinations for the duration of the study.
6. Written (signed and dated) informed consent.
7. Haematological and biochemical indices within given ranges

Exclusion Criteria:

1. Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment.
2. Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment.
3. Known previous adverse reaction to atovaquone or its excipients.
4. Active hepatitis, gallbladder disease or pancreatitis
5. Patients with impaired gastrointestinal (GI) function or GI disease that may significantly alter absorption of atovaquone.
6. 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).
7. Concurrent administration of warfarin in the 14 days prior to starting atovaquone.
8. Patients taking known inhibitors of the electron transport chain such as Metformin.
9. 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.
10. 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).
11. Pregnant or breast-feeding women or women of childbearing potential unless highly effective methods of contraception are used.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1; Atovaquone suspension, 750mg/5ml bd and 1000mg (6.25ml) bd for 7-17 days. Device: PET-CT, Device: DWI-MRI	Drug: Atovaquone; 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
NO_INTERVENTION: Cohort 2; Device: PET-CT, Device: DWI-MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 0 v Day 7-17, and Day 0 post surgery (tumour sample)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of perfusion by atovaquone	Changes in tumour blood flow measured by perfusion CT, DWI-MRI, DCE-MRI and PET kinetic modelling	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	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	Day 0 v Day 7-17

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of hypoxia modification with PK (pharmacokinetic) levels of atovaquone (plasma and tumour)	HPLC (high pressure liquid chromatography) based measurement of plasma level and tumour level of atovaquone	Day 0 v Day 7-17 for plasma level. Day 0 v Post resection for tumour sample (cohort 1 only)
Correlations between imaging and histology	Comparison of histological hypoxia and vasculature parameters with prior imaging measuring hypoxia, perfusion, and glycolysis	Day 0 v Day 7-17
Correlations between serological hypoxia markers and histology	Comparison of serological hypoxia parameters with immunohistochemistry on pimonidazole staining	Day 0 v Day 7-17
To assess whether atovaquone results in a lower level of hypoxia metagene signature expression	Hypoxia metagene signature expression and Individual tests to measure gene expression/mutation	Day 0 v Day 7-17
Progression-free survival and overall survival	Progression-free survival and overall survival	At 12 and 24 months

Collaborators and Investigators

• Sponsor: University of Oxford
• Investigators: Principal Investigator: Geoff Higgins, MBChB, MRCP, FRCR, University of Oxford

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2016
• Primary Completion (ACTUAL): October 1, 2018
• Study Completion (ACTUAL): December 1, 2018

Study Registration Dates

• First Submitted: September 7, 2015
• First Submitted That Met QC Criteria: December 8, 2015
• First Posted (ESTIMATE): December 11, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 4, 2019
• Last Update Submitted That Met QC Criteria: September 2, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Hypoxia
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Signs and Symptoms, Respiratory; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Hypoxia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Atovaquone
• Other Study ID Numbers: OCTO-073