- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04648033
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
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Edinburgh, United Kingdom, EH4 2XU
- Western General Hospital, NHS Lothian
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London, United Kingdom, SE1 9RT
- Guy's and St Thomas'
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Oxford, United Kingdom, OX3 7LE
- Churchill Hospital, Oxford University Hospitals
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
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)
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
- 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
Exclusion Criteria:
- 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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Atovaquone in Combination with concurrent CRT
Atovaquone is taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care CRT. Atovaquone dose level is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). Two 21-day cycles of cisplatin and vinorelbine chemotherapy will be given concurrently during radiotherapy treatment. Patients will receive 80 mg/m2 cisplatin on days 1 & 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 & 29. Thoracic radiotherapy will be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday). The last dose of atovaquone will be on the morning of the last fraction of radiotherapy. Total duration of atovaquone treatment will be 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Patients will be followed up at 1, 3 and 6 months post-CRT. |
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:
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:
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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The dose of atovaquone associated with no more than 48% dose limiting toxicity (DLT) rate (target toxicity level)
Time Frame: From week -2/-3 until three months post-completion of CRT
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Determination of the maximum tolerated dose (MTD), and therefore recommended phase II dose (RPTD), of atovaquone when combined with radical concurrent chemoradiotherapy in patients with non-small cell lung cancer (NSCLC)
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From week -2/-3 until three months post-completion of CRT
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of adverse events graded per Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Time Frame: From screening/baseline until six months post completion of CRT
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Assessment of the safety and toxicity profile of atovaquone in combination with radical concurrent chemotherapy for NSCLC
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From screening/baseline until six months post completion of CRT
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Hypoxia metagene signature from diagnostic tissue using 3'RNA-Seq
Time Frame: At baseline
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Confirmation of feasibility of measuring hypoxia metagene signature using 3'RNA-Seq in diagnostic NSCLC samples
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At baseline
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Correlation between tumour hypoxic volume and plasma miR-210 level
Time Frame: Week -2/-3 (prior to atovaquone treatment)
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To assess agreement of hypoxic volume determined by FMISO PET-CT with plasma miR-210 level pre-treatment with atovaquone
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Week -2/-3 (prior to atovaquone treatment)
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Correlation between tumour hypoxic volume and tumour hypoxia gene expression
Time Frame: Week -2/-3 (prior to atovaquone treatment)
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To assess agreement of hypoxic volume determined by FMISO PET-CT with hypoxia metagene signature from diagnostic tissue pre-treatment with atovaquone
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Week -2/-3 (prior to atovaquone treatment)
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Correlation between changes in tumour hypoxic volume and plasma miR-210 level
Time Frame: Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
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To assess agreement of hypoxic volume determined by FMISO PET-CT with plasma miR-210 level following two weeks (+/- 7 days) of atovaquone
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Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
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Response to treatment assessed per Response Evaluation Criteria in Solid Tumours (RECIST) V1.1
Time Frame: Three months post completion of CRT
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Assessment of the tumour response rate at three months following treatment
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Three months post completion of CRT
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Correlation between plasma atovaquone levels and hypoxic volume
Time Frame: Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
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Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by FMISO PET-CT
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Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
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Correlation between plasma atovaquone levels and plasma miR-210 level
Time Frame: Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
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Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by plasma miR-210 level
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Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Geoffrey Higgins, University of Oxford
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Respiratory Tract Diseases
- Neoplasms
- Lung Diseases
- Neoplasms by Site
- Respiratory Tract Neoplasms
- Thoracic Neoplasms
- Carcinoma, Bronchogenic
- Bronchial Neoplasms
- Lung Neoplasms
- Carcinoma, Non-Small-Cell Lung
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antineoplastic Agents
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Phytogenic
- Antiprotozoal Agents
- Antiparasitic Agents
- Antimalarials
- Cisplatin
- Atovaquone
- Vinorelbine
Other Study ID Numbers
- OCTO_088
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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