Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

NCT ID: NCT04648033

Last Updated: 2025-02-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-07
• Study Completion Date: 2023-10-02

Brief 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.

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.

Conditions

Locally Advanced Non-Small Cell Lung Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Atovaquone Oral Suspension

Intervention Type: DRUG

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 chemotherapy

Intervention Type: DRUG

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 radiotherapy

Intervention Type: RADIATION

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.

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.

Group Type: EXPERIMENTAL

Atovaquone Oral Suspension

Intervention Type: DRUG

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 chemotherapy

Intervention Type: DRUG

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 radiotherapy

Intervention Type: RADIATION

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.

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.

Group Type: EXPERIMENTAL

Atovaquone Oral Suspension

Intervention Type: DRUG

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 chemotherapy

Intervention Type: DRUG

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 radiotherapy

Intervention Type: RADIATION

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.

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.

Group Type: EXPERIMENTAL

Atovaquone Oral Suspension

Intervention Type: DRUG

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 chemotherapy

Intervention Type: DRUG

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 radiotherapy

Intervention Type: RADIATION

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.

Interventions

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).

Intervention Type: 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.

Intervention Type: DRUG

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.

Intervention Type: RADIATION

Other Intervention Names

Wellvone; Cisplatin; Vinorelbine

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cancer Research UK

OTHER

Sponsor Role: collaborator

National Institute for Health Research, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

NHS Lothian

OTHER_GOV

Sponsor Role: collaborator

Oxford University Hospitals NHS Trust

OTHER

Sponsor Role: collaborator

NHS Research Scotland

OTHER

Sponsor Role: collaborator

Guy's and St Thomas' NHS Foundation Trust

OTHER

Sponsor Role: collaborator

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Geoffrey Higgins

Role: PRINCIPAL_INVESTIGATOR

University of Oxford

Locations

Western General Hospital, NHS Lothian

Edinburgh, , United Kingdom

Guy's and St Thomas'

London, , United Kingdom

Churchill Hospital, Oxford University Hospitals

Oxford, , United Kingdom

Countries

United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

OCTO_088

Identifier Type: -

Identifier Source: org_study_id