Locally Advanced Non-Small Cell Lung CancerPhase 1ARCADIANNCT04648033
Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC
A Phase 1 study testing Atovaquone Oral Suspension in people with Locally Advanced Non-Small Cell Lung Cancer, run by University of Oxford at 3 sites in United Kingdom.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Locally Advanced Non-Small Cell Lung Cancer
- What is being tested?
- Atovaquone Oral Suspension
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 3 sitesUnited Kingdom
- Study dates
- 7 Dec 2020to 2 Oct 2023
- Phase
- Phase 1
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
- A patient will be eligible for inclusion in this study if all of the following criteria apply:
- Histologically or cytologically confirmed diagnosis of locally advanced NSCLC and selected for treatment with full dose radical concurrent CRT
- 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)
- Male or female, age at least 18 years
- ECOG performance status 0 or 1
- Adequate pulmonary function tests for thoracic radiotherapy (FEV1 and TLCO, greater than 40 percent predicted)
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- 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 109/L; Platelets ≥ 100 x 109/L; Haemoglobin ≥ 90 g/L; INR ≤ 1.5
- 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 and be capable of co-operating with protocol
Who cannot join
- Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used
- Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment
- Treatment with any other investigational agent as part of a clinical trial within 28 days of study enrolment
- Previous thoracic radiotherapy
- Known previous adverse reaction to atovaquone or its excipients
- Active hepatitis, gallbladder disease or pancreatitis
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- Impaired gastrointestinal function that may significantly alter absorption of atovaquone
- Concurrent administration of warfarin in the 14 days prior to starting atovaquone
- 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).
- An additional cancer diagnosis that the treating clinician feels may significantly impact planned CRT treatment tolerability or treatment outcome
- Established diagnosis of pulmonary fibrosis
- Established diagnosis of connective tissue disorder (e.g. scleroderma or systemic lupus erythematosus)
- Cardiac morbidity such as angina, myocardial infarction in the previous six months, unstable angina or uncontrolled hypertension, left ventricular failure or severe valvular disease
Trial locations and contacts
3 sites in 1 country.
United Kingdom3 sites
Western General Hospital, NHS Lothian
Edinburgh, EH4 2XU
Guy's and St Thomas'
London, SE1 9RT
Churchill Hospital, Oxford University Hospitals
Oxford, OX3 7LE
About this study
Official title: 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.
Read the 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.
- Being tested
- Atovaquone Oral Suspension, Standard of care chemotherapy, Standard of care radiotherapy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Atovaquone Oral SuspensionDrug
Also called Wellvone
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).
Standard of care chemotherapyDrug
Also called Cisplatin, Vinorelbine
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.
Standard of care radiotherapyRadiation
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.
| Study group | Role | What they receive |
|---|---|---|
| Dose level 1 - 450 mg BD atovaquone + concurrent CRT | Experimental | 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. Receives: Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy |
| Dose level 2 - 600 mg BD atovaquone + concurrent CRT | Experimental | 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. Receives: Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy |
| Dose level 3 - 675 mg BD atovaquone + concurrent CRT | Experimental | 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. Receives: Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy |
| Dose level 4 - 750 mg BD atovaquone + concurrent CRT | Experimental | 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. Receives: Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: From first dose of atovaquone to 3-month follow up visit (up to 25 weeks)
Secondary outcomes (7)
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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: At 3 months post completion of chemoradiotherapy (up to 25 weeks after first dose of atovaquone)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2020
- Study start7 Dec 2020
- Primary completion2 Oct 2023
- Study completion2 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Locally Advanced Non-Small Cell Lung CancerStudies 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
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Model description
- Time-to-Event Continual Reassessment Method to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Cancer Research UK, National Institute for Health Research, United Kingdom, NHS Lothian, Oxford University Hospitals NHS Trust, NHS Research Scotland, Guy's and St Thomas' NHS Foundation Trust
- Responsible party
- Sponsor
- Investigators
- Geoffrey Higgins, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04648033
- Sponsor's protocol ID
- OCTO_088
- Acronym
- ARCADIAN
- Status last verified
- May 2023
- First submitted
- 8 Oct 2020
- Last updated
- 29 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No