Clinical trial NCT04648033: Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC
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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Locally Advanced Non-Small Cell Lung Cancer
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
name: National Institute for Health Research, United Kingdom
name: NHS Lothian
name: Oxford University Hospitals NHS Trust
name: NHS Research Scotland
name: Guy's and St Thomas' NHS Foundation Trust
First posted: 2020-12-01
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Time-to-Event Continual Reassessment Method to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.
timeFrame: From first dose of atovaquone to 3-month follow up visit (up to 25 weeks)
Secondary outcomes:
measure: Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03
timeFrame: From first dose of atovaquone until last follow up visit at 6 months post completion of CRT (up to 38 weeks)
measure: 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
timeFrame: At baseline (diagnosis)
measure: Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT
timeFrame: At baseline (prior to atovaquone treatment)
measure: Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR
timeFrame: At baseline (prior to atovaquone treatment)
measure: Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment
timeFrame: Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)
measure: Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR
timeFrame: Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)
measure: 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
timeFrame: At 3 months post completion of chemoradiotherapy (up to 25 weeks after first dose of atovaquone)
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: Western General Hospital, NHS Lothian
city: London
country: United Kingdom
facility: Guy's and St Thomas'
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford University Hospitals
Study officials:
affiliation: University of Oxford
name: Geoffrey Higgins
role: PRINCIPAL_INVESTIGATOR
References: