Clinical trial NCT04375904: 'SOURCE - LUNG' Stereotactic Ablative Radiation Therapy Of UltRaCEntral LUNG Tumours (SOURCE Lung)
Official title: 'SOURCE - LUNG' Stereotactic Ablative Radiation Therapy Of UltRaCEntral LUNG Tumours
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: NSCLC/Oligometastatic Cancer (Single Lung Lesion)
Keywords: Lung cancer
Non-small cell lung cancer
Ultracentral
Stereotactic ablative radiation therapy
Oligometastatic cancer
Single lung lesion
Lead sponsor: Cancer Trials Ireland
Sponsor class: NETWORK
Collaborators: name: Technological University Dublin
name: University College Dublin
First posted: 2020-05-06
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: This study is a phase II non-randomised, multi-centre, single arm trial of image-guided (IG)-SABR for patients with high-risk centrally located T1-T4 lung tumours (NSCLC) or a 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 current UK consortium guidelines with full dose coverage, but which subsequently meet SOURCE DVC's with potentially reduced dose coverage. To remain in line with international practice, the SOURCE Lung protocol was amended to reduce near maximum dose constraints to 0.1cc for OARs (Diez et al. 2022). 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 6 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:

1. Predict response based on individual radiation sensitivity
2. 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.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent obtained prior to any study-specific procedures
2. ≥ 18 years of age
3. Life expectancy \>6 months
4. ECOG (Eastern Cooperative Oncology Group) performance status 0-2
5. Histological diagnosis (biopsy or cytology) or radiological diagnosis (PET-positive FDG-avid tumour which has only one lesion to be treated for the purpose of the study / CT-based diagnosis for non 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 to be treated for the purpose of the study
6. Patients with central lung tumours/lesions 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
7. Inoperable (as per MDT) or patient refuses surgery,
8. 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
9. 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:

1. 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
2. Tumour/oligometastatic lesion that is abutting the oesophagus
3. Evidence of regional (nodal) or distant metastases or metastatic pleural effusion for patients with primary NSCLC
4. Spinal canal involvement
5. Patients with syndromes or conditions associated with increased radiosensitivity
6. Idiopathic pulmonary fibrosis / usual interstitial pneumonia
7. Chemotherapy and/or other targeted therapy administered within 3 months prior to study radiotherapy or planned for \<6 weeks following radiotherapy for patients with primary NSCLC, or within 1 week prior to study radiotherapy or planned within 1 week following radiotherapy for patients with an oligometastatic lesion
8. 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
9. Any tumour not clinically definable on the treatment planning CT scan (e.g. surrounding consolidation or atelectasis)
10. Patients unable to undergo 4D-CT scan
11. Uncontrolled intercurrent illness that is likely to interfere with treatment or assessment of outcomes
12. 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.

Primary outcomes:
measure: 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
timeFrame: From start of treatment to 1 year post treatment
Secondary outcomes:
measure: Estimate time to locoregional recurrence/progression, locoregional recurrence-free survival (LRFS), disease-free survival (DFS) and metastasis-free survival rates / further metastasis-free survival rates (for patients with an oligometastatic lesion).
timeFrame: Up to 5 years post treatment
measure: Estimates of 1-year, 3-year and 5-year overall survival rates
timeFrame: Up to 5 years post treatment
Other outcomes:
measure: Post treatment response and outcomes using PET and CT at 3, 6, 9, 12,18, 24, 36, 48 and 60 months post-RT
timeFrame: Up to 60 months (5 years) post treatment
measure: Acute toxicity profiles on treatment to 3 months post treatment
timeFrame: Up to 3 months post treatment
measure: Late toxicity profiles to 5 years post treatment
timeFrame: Up to 5 years post treatment
measure: Time to onset of acute and late ≥ Grade 2 and ≥ Grade 3 toxicities
timeFrame: Up to 5 years post treatment
measure: Changes in domain-specific Quality of Life (QoL) outcomes at 6 months post treatment compared with outcomes at baseline using the EORTC QLQ C30 (and EORTC QLQ LC13)
timeFrame: From baseline up to 6 months post treatment
measure: Changes in symptom-specific Quality of Life (QoL) outcomes at 6 months post treatment compared with outcomes at baseline using the EORTC QLQ C30 (and EORTC QLQ LC13)
timeFrame: From baseline up to 6 months post treatment
measure: Treatment tolerability and feasibility rates based on compliance with prescription and the number of treatment reductions/withdrawals.
timeFrame: Through study treatment, an average of 3 weeks
measure: Pulmonary function changes
timeFrame: Up to 12 months post treatment
measure: Changes in overall Quality of Life (QoL) outcomes at 6 months post treatment compared with outcomes at baseline using the European Organisation for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ) C30 and EORTC QLQ Lung Cancer (LC)13
timeFrame: From baseline up to 6 months post treatment
measure: Develop a platform for prediction and monitoring of treatment response/toxicities using Raman spectra of the cellular and plasma fraction of the patient blood. (Sub-Study 1)
timeFrame: 9 months follow-up
measure: Identify blood biomarkers as indicators for toxicity/relapse and the development of a panel of predictive/prognostic biomarkers. (Sub-Study 2)
timeFrame: 9 months follow up
Locations:
city: Dublin
country: Ireland
facility: Beacon Hospital
city: Dublin
country: Ireland
facility: St Luke's Radiation Oncology Network (SLRON) at St Luke's Hospital and St James's Hospital
Study officials:
affiliation: Cancer Trials Ireland/ St Luke's Radiation Oncology Network
name: Prof. John Armstrong, MD FRCPI DABR FFRRCSI
role: PRINCIPAL_INVESTIGATOR
References: