Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Hypoxia

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Vinorelbine

Cisplatin

Atovaquone

Tubulin Modulators

Antimitotic Agents

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

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).

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 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 chemotherapy

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.

Standard of care radiotherapy

Geoffrey Higgins

This is a phase I, single arm, 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.

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.

Time-to-Event Continual Reassessment Method to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC

Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

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

Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by FMISO PET-CT

Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by plasma miR-210 level

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)

Assessment of the safety and toxicity profile of atovaquone in combination with radical concurrent chemotherapy for NSCLC

Confirmation of feasibility of measuring hypoxia metagene signature using 3'RNA-Seq in diagnostic NSCLC samples

To assess agreement of hypoxic volume determined by FMISO PET-CT with plasma miR-210 level pre-treatment with atovaquone

To assess agreement of hypoxic volume determined by FMISO PET-CT with hypoxia metagene signature from diagnostic tissue pre-treatment with atovaquone

To assess agreement of hypoxic volume determined by FMISO PET-CT with plasma miR-210 level following two weeks (+/- 7 days) of atovaquone

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC	NCT04648033	Locally Advance...	Atovaquone Oral... Standard of car... Standard of car...	18 Years -	University of Oxford
Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC	NCT04648033	Locally Advance...	Atovaquone Oral... Standard of car... Standard of car...	18 Years -	University of Oxford

Spots Global Cancer Trial Database for atovaquone oral suspension