'SOURCE - LUNG' Stereotactic Ablative Radiation Therapy Of UltRaCEntral LUNG Tumours (SOURCE Lung)

Study Overview
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Brief Summary
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This is a phase II, non-randomised study examining the safety of treating high risk centrally located non-small cell lung cancer (NSCLC) tumours and single pulmonary oligometastatic lesions using radiation therapy (RT), for patients whose disease is inoperable. The method of delivering the RT in this study is image guided stereotactic ablative radiation therapy (IG-SABR). This method involves using imaging to ensure the radiation is being delivered to the correct location within the body and using higher than normal doses per treatment (fraction) to treat the lung cancer (NSCLC)/oligometastatic lung lesion. This study aims to determine its safety by looking at the number and severity of side effects. This study will deliver 8 treatments/fractions of RT with 7.5 Gy delivered in each fraction. To be eligible for this study the initial treatment plan for the patient must be shown to not fulfil certain criteria relating to doses to the tumour and surrounding normal tissue. This study has its own study specific criteria which must be adhered to. Translational sub-studies (optional) are open to patients in participating centres only. Patients will have the option to consent to participating in both translational studies or to neither.

Detailed Description
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This study is a phase II non-randomised, multi-centre, single arm trial of image-guided (IG)-SABR for high-risk centrally located T1-T4 lung tumours (NSCLC) and single pulmonary oligometastatic lesions. Treatment will consist of IG-SABR using a total of 8 fractions of 7.5 Gy per fraction adhering to organ at risk dose-volume histogram constraints allowing a minimum dose coverage of 75% to 95% of the planning target volume (PTV) coverage, and a minimum dose of 87% to 99% of the gross tumour volume (GTV), using dose intensity modulation. The primary aim of the study is to determine the safety of the 8 x 7.5 Gy treatment regimen on the basis of the rate of ≥ Grade 3 treatment related toxicity using NCI CTCAE V5, in patients with medically inoperable early stage, ultracentrally located lung tumours. This is defined by central tumours which are not fulfilling the conservative hybrid DVCs of the LungTech (Adebahr et al., 2015), RTOG 0813 (Bezjak et al., 2015) studies and UK consortium guidelines (v6.1 2019) with full dose coverage, but which subsequently meet SOURCE DVC's with potentially reduced dose coverage. Toxicities occurring between start of treatment and one-year from the end of treatment, which are possibly, probably or definitely related to radiotherapy will be assessed. A total of 60 evaluable patients will be required for the study. The sample size was calculated using continuous monitoring for toxicity, up to one year post RT, using a Pocock-type boundary. Accrual will be halted if excessive numbers of ≥ Grade 3 TxR-AEs are seen. The regime will not be considered to be safe if >25% of evaluable patients experience a ≥ Grade 3 treatment-related adverse event (TxR-AE) by the end of 1-year post-RT. This study will be considered adequately safe if ≤ 25% of evaluable patients experience ≥ Grade 3 TxR-AE by the end of 1 year post-RT. The enrolment period is expected to be 3-3.5 years. Toxicity assessments will be carried out weekly during radiotherapy (RT), at 2, 4 and 8-weeks post-treatment and at 3, 6, 9, 12, 18, 24 months post treatment and annually thereafter to 5 years post treatment. Translational Sub-Study 1 (Raman spectroscopic analysis) - Primary aim is to undertake biomarker discovery using label-free Raman spectroscopy coupled with multivariate statistical methods to identify spectral biomarkers that could: Predict response based on individual radiation sensitivity Monitor response based on individual radiation sensitivity Translational Sub-Study 2 (Proteomic analysis) - Primary aim is to use proteomic analysis of sequential blood samples before, during and after treatment to detect changes in protein expression profiles that may predict outcome and identify prognostic biochemical markers of early toxicity.

Official Title
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'SOURCE - LUNG' Stereotactic Ablative Radiation Therapy Of UltRaCEntral LUNG Tumours

Conditions
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NSCLC/Oligometastatic Cancer (Single Lung Lesion)

Intervention / Treatment
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* Radiation: Image-Guided Stereotactic Ablative Radiotherapy (IG-SABR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained prior to any study-specific procedures ≥ 18 years of age Life expectancy >6 months ECOG (Eastern Cooperative Oncology Group) performance status 0-2 Histological diagnosis (biopsy or cytology) or radiological diagnosis (PET-positive FDG-avid tumour which requires local ablative therapy per Multi-Disciplinary Team (MDT) recommendations) of either: (i) Primary NSCLC (Squamous Cell Carcinoma (SCC), Adenocarcinoma, Large Cell) OR (ii) Single pulmonary oligometastatic lesion Patients with central lung tumours whose radiotherapy plan meets the following criteria: (i) OAR eligibility constraints are initially exceeded when full PTV coverage is met; (ii) subsequently meets the CTRIAL-IE 18-33 SOURCE OAR Lung constraints and meets CTRIAL-IE 18-33 SOURCE Lung minimum constraints Inoperable (as per MDT) or patient refuses surgery, Females of childbearing potential must not be pregnant or lactating, must be prepared to take adequate contraception methods during treatment. Males whose female partners are of childbearing potential must be prepared to take adequate contraception methods during treatment. Examples of effective contraception methods are a condom or a diaphragm with spermicidal jelly, or oral, injectable or implanted birth control Absence of psychological, familial, sociological or geographical condition, or psychiatric illness/social situation potentially hampering compliance with the study protocol and follow-up schedule Exclusion Criteria: Known co-existing or prior malignancy within the last 5 years (except for adequately treated basal cell carcinoma (BCC) or Squamous Cell Carcinoma (SCC) of the skin)) which is likely to interfere with treatment or assessment of outcomes Tumour/oligometastatic lesion that is abutting the oesophagus Evidence of regional (nodal) or distant metastases or metastatic pleural effusion Spinal canal involvement Patients with syndromes or conditions associated with increased radiosensitivity Idiopathic pulmonary fibrosis / usual interstitial pneumonia Chemotherapy and/or other targeted treatment administered within 3 months prior to study registration or planned for <6 weeks following radiotherapy Any previous radiotherapy to the thorax or mediastinum (excluding previous breast or chest wall radiotherapy) which is likely to interfere with treatment or assessment of outcomes Any tumour not clinically definable on the treatment planning CT scan (e.g. surrounding consolidation or atelectasis) Patients unable to undergo 4D-CT scan Uncontrolled intercurrent illness that is likely to interfere with treatment or assessment of outcomes Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study, or if it is felt by the research / medical team that the patient may not be able to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a phase II non-randomised, multi-centre, single arm trial assessing the safety of patients receiving image guided SABR in 8 fractions of 7.5Gy. The treatment will adhere to organ at risk dose-volume histogram constraints allowing a minimum dose coverage of 75% to 95% of the planning target volume (PTV) coverage, and a minimum dose of 75% to 99% of the gross tumour volume (GTV), using dose intensity modulation. These minimums are chosen to represent at least an equivalent BED to the RT standard fractionation of 55 Gy in 20 fractions based on actual treatment dose of 7.5 Gy in 8 fractions. The safety of the regimen will be based on the rate of ≥ Grade 3 treatment related toxicities per CTCAE V5 occurring between start of treatment and one-year from the end of treatment, which are possibly, probably or definitely related to radiotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation<br>Treatment will be delivered via image-guided (IG)-SABR in 8 fractions of 7.5Gy. OAR constraints must be respected but minimum dose coverage of 75% to 95% of the PTV will be allowed and minimum dose of 75% to 99% of the GTV will be allowed. The minimums are chosen to represent at least an equivalent BED to the RT standard fractionation of 55 Gy in 20 fractions based on actual treatment dose of 7.5Gy in 8 fractions. A total of 60 evaluable patients will be required for the study. The sample size was calculated using continuous monitoring for toxicity, up to one year post RT, using a Pocock-type boundary. Accrual will be halted if excessive numbers of ≥ Grade 3 TxR-AEs are seen. The regime will not be considered to be safe if >25% of evaluable patients experience a ≥ Grade 3 treatment-related adverse event (TxR-AE) by the end of 1-year post-RT. This study will be considered adequately safe if ≤ 25% of evaluable patients experience ≥ Grade 3 TxR-AE by the end of 1 year post-RT. | Radiation: Image-Guided Stereotactic Ablative Radiotherapy (IG-SABR)<br>* Image-Guided Stereotactic Ablative Radiotherapy (IG-SABR) delivered in 8 fractions of 7.5 Gy. OAR constraints must be respected but a minimum dose coverage to 95% of the PTV will be allowed down to 75% and a minimum dose to 99% of the GTV allowed at 75%. Respiratory monitoring/active respiratory management will be used. Plans will be created and delivered using photon beams with energies between 6-10 MV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of ≥ Grade 3 treatment-related toxicities occurring between start of treatment and one-year from the end of treatment using NCI CTCAE V5 | The rates of ≥ Grade 3 treatment-related adverse events (TxR-AEs) will be calculated as the proportion of evaluable patients (along with the 95% CI) who have any >= Grade 3 treatment-related adverse event occurring between the start of RT and one year post-RT, among the total evaluable patients. These rates will be reported (for applicable patients) by T stage (T1 versus T2 versus T3 versus T4 or combined T stages). The NCI Common Terminology Criteria for Adverse Events (CTCAE Version 5.0) for scoring the treatment-related adverse events will be used. The following will be reported at the time of primary endpoint analysis Tabulation of all cases entered, and any patients excluded from the analysis with reasons for exclusion; Distribution of important prognostic baseline and other pre-treatment variables; Frequency and severity of adverse events; Compliance rates of treatment delivery with respect to the protocol prescription | From start of treatment to 1 year post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimates of time to locoregional recurrence, 1-year, 3-year and 5-year locoregional recurrence free survival (LRFS), disease-free survival (DFS) and (further) metastasis-free survival using CT/PET imaging/biopsy. | The Kaplan-Meier method will be used to estimate time to locoregional recurrence; the cumulative proportion surviving without local recurrence at 1- year, 3-years and 5-years; DFS; metastasis-free survival for patients with primary NSCLC; further metastasis-free survival for patients with an oligometastatic lesion. These efficacy endpoints will be expressed as median survival with 95% confidence interval. The failure event for disease free survival is defined as death due to any cause, local recurrence, marginal progression, involved node progression, regional progression, distant metastasis, or second primary. Subgroup anal | Up to 5 years post treatment | 
| Estimates of 1-year, 3-year and 5-year overall survival rates | The Kaplan-Meier method will be used to estimate time the cumulative proportion surviving (overall survival) at 1-year, 3-years and 5-years. Overall survival will be measured from date of registration/ enrolment. Patients alive and free of event at the time of analysis and patients lost to follow-up will be censored at the last available assessment. The event for overall survival is a death due to any cause. The primary time-point of interest is 12 months. | Up to 5 years post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, Non-small cell lung cancer, Ultracentral, Stereotactic ablative radiation therapy, Oligometastatic cancer, Single lung lesion