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Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC (ARCADIAN)

Primary Purpose

Locally Advanced Non-Small Cell Lung Cancer

Status

Completed

Phase

Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

Atovaquone Oral Suspension

Standard of care chemotherapy

Standard of care radiotherapy

About this trial

This is an interventional treatment trial for Locally Advanced Non-Small Cell Lung Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Western General Hospital, NHS Lothian
Guy's and St Thomas'
Churchill Hospital, Oxford University Hospitals

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Atovaquone in Combination with concurrent CRT

Arm Description

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.

Outcomes

Primary Outcome Measures

The dose of atovaquone associated with no more than 48% dose limiting toxicity (DLT) rate (target toxicity 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)

Secondary Outcome Measures

Number of adverse events graded per Common Terminology Criteria for Adverse Events (CTCAE) v4.03

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

Hypoxia metagene signature from diagnostic tissue using 3'RNA-Seq

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

Correlation between tumour hypoxic volume and plasma miR-210 level

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

Correlation between tumour hypoxic volume and tumour hypoxia gene expression

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

Correlation between changes in tumour hypoxic volume and plasma miR-210 level

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

Response to treatment assessed per Response Evaluation Criteria in Solid Tumours (RECIST) V1.1

Assessment of the tumour response rate at three months following treatment

Full Information

NCT ID

NCT04648033

First Posted

October 8, 2020

Last Updated

October 11, 2023

Sponsor

University of Oxford

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

1. Study Identification

Unique Protocol Identification Number

NCT04648033

Brief Title

Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

Acronym

ARCADIAN

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Completed

Study Start Date

December 7, 2020 (Actual)

Primary Completion Date

October 2, 2023 (Actual)

Study Completion Date

October 2, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Oxford

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Locally Advanced Non-Small Cell Lung Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Atovaquone in Combination with concurrent CRT

Arm Type

Other

Arm Description

Intervention Type

Drug

Intervention Name(s)

Atovaquone Oral Suspension

Other Intervention Name(s)

Wellvone

Intervention Description

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

Intervention Name(s)

Standard of care chemotherapy

Other Intervention Name(s)

Cisplatin, Vinorelbine

Intervention Description

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

Radiation

Intervention Name(s)

Standard of care radiotherapy

Intervention Description

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.

Primary Outcome Measure Information:

Title

The dose of atovaquone associated with no more than 48% dose limiting toxicity (DLT) rate (target toxicity level)

Description

Time Frame

From week -2/-3 until three months post-completion of CRT

Secondary Outcome Measure Information:

Title

Number of adverse events graded per Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Description

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

Time Frame

From screening/baseline until six months post completion of CRT

Title

Hypoxia metagene signature from diagnostic tissue using 3'RNA-Seq

Description

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

Time Frame

At baseline

Title

Correlation between tumour hypoxic volume and plasma miR-210 level

Description

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

Time Frame

Week -2/-3 (prior to atovaquone treatment)

Title

Correlation between tumour hypoxic volume and tumour hypoxia gene expression

Description

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

Time Frame

Week -2/-3 (prior to atovaquone treatment)

Title

Correlation between changes in tumour hypoxic volume and plasma miR-210 level

Description

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

Time Frame

Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment

Title

Response to treatment assessed per Response Evaluation Criteria in Solid Tumours (RECIST) V1.1

Description

Assessment of the tumour response rate at three months following treatment

Time Frame

Three months post completion of CRT

Other Pre-specified Outcome Measures:

Title

Correlation between plasma atovaquone levels and hypoxic volume

Description

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

Time Frame

Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment

Title

Correlation between plasma atovaquone levels and plasma miR-210 level

Description

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

Time Frame

Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Geoffrey Higgins

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

Facility Information:

Facility Name

Western General Hospital, NHS Lothian

City

Edinburgh

ZIP/Postal Code

EH4 2XU

Country

United Kingdom

Facility Name

Guy's and St Thomas'

City

London

ZIP/Postal Code

SE1 9RT

Country

United Kingdom

Facility Name

Churchill Hospital, Oxford University Hospitals

City

Oxford

ZIP/Postal Code

OX3 7LE

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

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