Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

Study Overview
=================
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.

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

Conditions
-----------------
Locally Advanced Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Atovaquone Oral Suspension
* Drug: Standard of care chemotherapy
* Radiation: Standard of care radiotherapy


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Atovaquone in Combination with concurrent CRT<br>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. | Drug: Atovaquone Oral Suspension<br>* 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).<br>* Other names: Wellvone;Drug: Standard of care chemotherapy<br>* 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.<br>* Other names: Vinorelbine;Radiation: Standard of care radiotherapy<br>* 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.<br>|

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From screening/baseline until six months post completion of CRT | 
| 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 | At baseline | 
| 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 | Week -2/-3 (prior to atovaquone treatment) | 
| 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 | Week -2/-3 (prior to atovaquone treatment) | 
| 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 | Week -2/-3 (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment | 
| 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 | Three months post completion of CRT |