Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC (ARCADIAN)

A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination With Radical Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

This is a phase I, open-label trial that will utilise a Time To Event Continual Reassessment Method (TiTE-CRM) to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC. Twenty evaluable participants will be recruited at three centres.

Study Overview

• Status: Completed
• Conditions: Locally Advanced Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy

Detailed Description

Twice daily oral atovaquone will be added to standard concurrent chemoradiotherapy (CRT): 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday), with cisplatin (80 mg/m2 IV on days 1 and 22 of CRT) and vinorelbine (15 mg/m2 IV on days 1, 8, 22 and 29 of CRT). Whilst awaiting CRT to start, patients will receive two weeks (+/- 7 days) of oral atovaquone to ensure steady state is reached (after seven days). Patients will be allocated one of four dose levels: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). Atovaquone dose will be assigned as per the TiTE-CRM statistical model. The first two trial participants will receive 450 mg BD. In the absence of unacceptable toxicity, subsequent patients will be assigned doses up to and including 750 mg BD.

Hypoxia biomarker data will be collected at baseline (start of atovaquone run-in) and following two weeks (+/- 7 days) of atovaquone treatment. Atovaquone will then be continued without break for the duration of CRT, with the CRT schedule remaining constant for all patients at both centres. Assessment for Dose Limiting Toxicities (DLTs) will be from the first scheduled dose of atovaquone until three months after completion of CRT. The CT scan performed at the three-month follow up visit will be reviewed to collect tumour response data.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital, NHS Lothian
  • London, United Kingdom, SE1 9RT
    • Guy's and St Thomas'
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital, Oxford University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

A patient will be eligible for inclusion in this study if all of the following criteria apply:

1. Histologically or cytologically confirmed diagnosis of locally advanced NSCLC and selected for treatment with full dose radical concurrent CRT
2. At least one measurable lesion greater than 2 cm maximal length in any direction on routine imaging (CT or PET-CT scan performed in the 60 days prior to consent)
3. Male or female, age at least 18 years
4. ECOG performance status 0 or 1
5. Adequate pulmonary function tests for thoracic radiotherapy (FEV1 and TLCO, greater than 40 percent predicted)

6. Haematological and biochemical indices within the ranges shown below:

   Bilirubin ≤ 1.5 x upper limit of normal (ULN); ALT and/or AST ≤ 2.5 x ULN; Creatinine clearance ≥ 60 mL/min; Absolute Neutrophil Count ≥ 1.5 x 10*9/L; Platelets ≥ 100 x 10*9/L; Haemoglobin ≥ 90 g/L; INR ≤ 1.5

7. The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for the duration of the study
8. Written (signed and dated) informed consent and be capable of co-operating with protocol

Exclusion Criteria:

1. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used
2. Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment
3. Treatment with any other investigational agent as part of a clinical trial within 28 days of study enrolment
4. Previous thoracic radiotherapy
5. Known previous adverse reaction to atovaquone or its excipients
6. Active hepatitis, gallbladder disease or pancreatitis
7. Impaired gastrointestinal function that may significantly alter absorption of atovaquone
8. Concurrent administration of warfarin in the 14 days prior to starting atovaquone
9. Concurrent administration of known electron transport chain inhibitors (e.g. metformin). A wash-out period prior to administration of atovaquone is required (e.g. 4 days for metformin).
10. An additional cancer diagnosis that the treating clinician feels may significantly impact planned CRT treatment tolerability or treatment outcome
11. Established diagnosis of pulmonary fibrosis
12. Established diagnosis of connective tissue disorder (e.g. scleroderma or systemic lupus erythematosus)
13. Cardiac morbidity such as angina, myocardial infarction in the previous six months, unstable angina or uncontrolled hypertension, left ventricular failure or severe valvular disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level 1 - 450 mg BD atovaquone + concurrent CRT; Atovaquone: Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.; One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.; Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Last dose atovaquone taken on the last day of radiotherapy.; Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: 2 x 21-day cycles.; 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.; 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: 66 Gy in 33 fractions.; Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.	Drug: Atovaquone Oral Suspension; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Other Names: Wellvone; Drug: Standard of care chemotherapy; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 & 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 & 29.; Other Names: Cisplatin; Vinorelbine; Radiation: Standard of care radiotherapy; Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
Experimental: Dose level 2 - 600 mg BD atovaquone + concurrent CRT; Atovaquone: Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.; One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.; Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Last dose atovaquone taken on the last day of radiotherapy.; Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: 2 x 21-day cycles.; 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.; 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: 66 Gy in 33 fractions.; Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.	Drug: Atovaquone Oral Suspension; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Other Names: Wellvone; Drug: Standard of care chemotherapy; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 & 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 & 29.; Other Names: Cisplatin; Vinorelbine; Radiation: Standard of care radiotherapy; Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
Experimental: Dose level 3 - 675 mg BD atovaquone + concurrent CRT; Atovaquone: Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.; One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.; Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Last dose atovaquone taken on the last day of radiotherapy.; Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: 2 x 21-day cycles.; 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.; 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: 66 Gy in 33 fractions.; Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.	Drug: Atovaquone Oral Suspension; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Other Names: Wellvone; Drug: Standard of care chemotherapy; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 & 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 & 29.; Other Names: Cisplatin; Vinorelbine; Radiation: Standard of care radiotherapy; Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
Experimental: Dose level 4 - 750 mg BD atovaquone + concurrent CRT; Atovaquone: Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.; One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.; Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Last dose atovaquone taken on the last day of radiotherapy.; Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: 2 x 21-day cycles.; 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.; 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: 66 Gy in 33 fractions.; Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.	Drug: Atovaquone Oral Suspension; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).; Other Names: Wellvone; Drug: Standard of care chemotherapy; Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 & 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 & 29.; Other Names: Cisplatin; Vinorelbine; Radiation: Standard of care radiotherapy; Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.	To determine the maximum tolerated dose level (and therefore recommended phase II dose) of atovaquone when administered concomitantly with radical concurrent chemoradiotherapy (CRT) in patients with non-small cell lung cancer (NSCLC). This is the dose of atovaquone associated with no more than 48% dose limiting toxicity (DLT) rate (target toxicity level).	From first dose of atovaquone to 3-month follow up visit (up to 25 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03	Toxicity profile when atovaquone administered in combination with radical concurrent chemotherapy for NSCLC. Worst grade adverse event for each patient by dose schedule (according to the Common Terminology Criteria for Adverse Events, Version 4.03). Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant, but not immediately life-threatening); Grade 4 (life-threatening); Grade 5 (death).	From first dose of atovaquone until last follow up visit at 6 months post completion of CRT (up to 38 weeks)
Number of Patients for Whom it Was Possible to Derive a Hypoxia Metagene Signature Score From 3'RNA-Seq of Genetic Material From Archival Tumour Samples	To confirm feasibility of measuring hypoxia metagene signature using 3'RNA-Seq on genetic material extracted from diagnostic non-small cell lung tumour samples. The score method was derived by Buffa et al (Buffa et al. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer. 2010 Jan 19;102(2):428-35. doi: 10.1038/sj.bjc.6605450).	At baseline (diagnosis)
Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT	The level of hypoxia in patient tumours was calculated using the Tumour-to-Blood Ratio volume (TBRvol) assessed from the patient's baseline PET scan. This scan was conducted with 18F-labelled fluoromisonidazole (F18-FMISO) which has been shown to selectively bind to hypoxic cells and can be quantified with PET imaging (Koh, et al. Imaging of hypoxia in human tumours with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys. 1992;22(1)). Tumour outlining of the region of interest on each axial slice was conducted centrally for all patients in consultation with an experienced consultant radiologist and combined to give a volume of interest (VOI). The number of voxels in the VOI with a threshold regional tumor:plasma F18-FMISO ratio of greater than or equal to 1.4 were combined to give the TBRvol (above reference). Patients with a TBRvol at baseline of <1.5mL were regarded as unevaluable for later endpoints, so are excluded from the report.	At baseline (prior to atovaquone treatment)
Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR	MicroRNA-210 (miR-210) has been found to be upregulated in response to hypoxia-inducing factors (Dang and Myers, The Role of Hypoxia-Induced miR-210 in Cancer Progression, Int. J. Mol. Sci., vol 16, 2015). Additionally, elevated serum levels of miR-210 are indicative of poor clinical outcomes in non-small cell lung cancer (He, et al. Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol., vol. 46, 2018). RNA was isolated from blood plasma and miR210 level detected using a two-step TaqMan quantitative PCR, using TaqMan probes for miR-210. An endogenous control miRNA (miR-16), plus an exogenous synthetic miRNA (cel-miR-39) were used for normalisation of miR210 counts. This endpoint was assessed in order to investigate a possible alternative to 18F-FMISO PET-CT scan for assessment of patients' tumour hypoxia level.	At baseline (prior to atovaquone treatment)
Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment	The level of hypoxia (Tumour-to-Blood Ratio volume, TBRvol) in patient tumours was calculated at baseline and following two weeks (+/- 7 days) of atovaquone treatment according to the details given in outcome measure 4. The mean percentage difference in TBRvol between the two timepoints at each dose level of atovaquone was calculated and is reported, below. Patients with a TBRvol at baseline of <1.5mL were regarded as unevaluable as it would not be possible to evaluate a reduction in hypoxic volume between this timepoint and the later timepoint. These patients were excluded from the report.	Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)
Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR	The miR-210 in participant plasma samples was calculated at baseline and following two weeks (+/- 7 days) of atovaquone treatment according to the details given in outcome measure 5. The mean percentage difference in miR210 count between the two timepoints for each dose level of atovaquone was calculated and is reported, below. This endpoint was assessed in order to investigate a possible alternative to 18F-FMISO PET-CT scan for assessment of patients' tumour hypoxia level.	Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)
Objective Tumour Response to Treatment With Atovaquone in Combination With Chemoradiotherapy, as Evaluated by CT or PET-CT Scan and Quantified by RECIST 1.1	Efficacy of the combination (atovaquone and chemoradiotherapy), measured by objective tumour response via RECIST 1.1 (Eisenhauer, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247). Scale of response assessed as Progressive Disease (PD) (worst outcome), Stable Disease (SD), Partial Response (PR), Complete Response (CR) (best outcome).	At 3 months post completion of chemoradiotherapy (up to 25 weeks after first dose of atovaquone)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between plasma atovaquone levels and hypoxic volume	Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by FMISO PET-CT	Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
Correlation between plasma atovaquone levels and plasma miR-210 level	Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by plasma miR-210 level	Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Cancer Research UK; Guy's and St Thomas' NHS Foundation Trust; NHS Lothian; National Institute for Health Research, United Kingdom; Oxford University Hospitals NHS Trust; NHS Research Scotland
• Investigators: Principal Investigator: Geoffrey Higgins, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2020
• Primary Completion (Actual): October 2, 2023
• Study Completion (Actual): October 2, 2023

Study Registration Dates

• First Submitted: October 8, 2020
• First Submitted That Met QC Criteria: November 23, 2020
• First Posted (Actual): December 1, 2020

Study Record Updates

• Last Update Posted (Actual): January 29, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Indoles; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Platinum Compounds; Quinones; Naphthoquinones; Vinorelbine; Cisplatin; Atovaquone
• Other Study ID Numbers: OCTO_088

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No