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'SOURCE - LUNG' Stereotactic Ablative Radiation Therapy Of UltRacentral Non- Small CEll LUNG Cancer (SOURCE Lung)

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ClinicalTrials.gov Identifier: NCT04375904
Recruitment Status : Recruiting
First Posted : May 6, 2020
Last Update Posted : February 12, 2021
Sponsor:
Collaborators:
Prof Fiona Lyng
Prof Stephen Pennington
Information provided by (Responsible Party):
Cancer Trials Ireland

Brief Summary:
This is a phase II, non-randomised study examining the safety of treating high risk non-small cell lung cancer (NSCLC) located in a central location 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. 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.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Radiation: Image-Guided Stereotactic Ablative Radiotherapy (IG-SABR) Not Applicable

Detailed Description:

This study is a phase II non-randomised, multi-centre, single arm trial of image-guided (IG)-SABR for high-risk centrally located T1, T2 and selected T3 lung tumours. 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 77% 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 NSCLC. This is defined by tumours abutting or immediately adjacent to central mediastinal structures who are not fulfilling the conservative hybrid DVCs of the LungTech (Adebahr et al., 2015) and RTOG 0813 (Bezjak et al., 2015) studies with full 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.

The study is planned to be carried out in 2 stages with 91 patients evaluable patients required for stage 1 and 87 evaluable patients required for stage 2. In the first stage, (91 evaluable patients), if there are 35 or fewer ≥ Grade 3 treatment related adverse events (TxR-AEs) in these 91 evaluable patients, the study will be stopped, and it will be concluded that the regime is not unsafe. If there are 43 or more ≥ Grade 3 TxR-AEs in 91 evaluable patients, the study will be stopped, and the conclusion will be made that the regime is not safe. Otherwise, 87 additional evaluable patients will be accrued for a total of 178 evaluable patients. The conclusion will be made that the regime is not safe if 78 or more TxR-AEs are observed in 178 evaluable patients.

The enrolment period is expected to be 5 years which allows for a 1-year hold on accrual during the analysis of stage 1.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 191 participants
Allocation: N/A
Intervention Model: Single Group Assignment
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 77% 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. These minimums are chosen to represent at least an equivalent BED to the RT standard fractionation of 60 Gy in 30 fractions based on actual treatment dose of 7.5 Gy in 8 fractions. The study is planned to take place over two stages, with the continuation to stage two pending the results of stage one. 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)
Primary Purpose: Treatment
Official Title: 'SOURCE - LUNG' Stereotactic Ablative Radiation Therapy Of UltRacentral Non-Small CEll LUNG Cancer
Actual Study Start Date : December 22, 2020
Estimated Primary Completion Date : September 12, 2026
Estimated Study Completion Date : September 12, 2030

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Radiation
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 77% to 95% of the PTV will be allowed and minimum dose of 87% 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 60Gy in 30 fractions based on actual treatment dose of 7.5Gy in 8 fractions. In stage 1 there will be 91 evaluable patients. If there are 35 or less ≥G3 TxR-AEs in these 91 evaluable patients, the study will be stopped, and concluded that the regime is not unsafe. If there are 43 or more ≥G3 TxR-AEs in these 91 patients, the study will be stopped, and the conclusion will be made that the regime is not safe. Otherwise, the study will proceed to stage 2 and 87 additional evaluable patients will be accrued (178 evaluable patients total). The conclusion will be made that the regime is not safe if 78 or more TxR-AEs are observed in 178 evaluable patients.
Radiation: Image-Guided Stereotactic Ablative Radiotherapy (IG-SABR)
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 77% and a minimum dose to 99% of the GTV allowed at 87%. Respiratory monitoring/active respiratory management will be used. Plans will be created and delivered using photon beams with energies between 6-10 MV.




Primary Outcome Measures :
  1. 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 [ Time Frame: From start of treatment to 1 year post treatment ]

    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 by T stage (T1 versus T2 versus T3 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


Secondary Outcome Measures :
  1. Estimates of 1-year, 3-year and 5-year freedom from local progression, local progression-free survival, disease-free survival (DFS) and metastasis-free survival using CT/PET imaging/biopsy. [ Time Frame: Up to 5 years post treatment ]
    The Kaplan-Meier method will be used to estimate freedom from local progression, local progression free survival, disease-free survival, metastasis-free survival and overall survival at 1- year, 3-years and 5-years. These efficacy endpoints will be expressed as median survival with 95% confidence interval. The event for overall survival is a death due to any cause. The failure event for disease free survival is defined as death due to any cause, local progression, marginal progression, involved node progression, regional progression, distant metastasis, or second primary. Subgroup analyses may be undertaken if the sample sizes involved in each subgroup are adequate to support such analyses.

  2. Estimates of 1-year, 3-year and 5-year overall survival rates [ Time Frame: Up to 5 years post treatment ]
    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 primary time-point of interest is 12 months.


Other Outcome Measures:
  1. Post treatment response and outcomes using PET and CT at 3, 6, 9, 12,18, 24, 36, 48 and 60 months post-RT [ Time Frame: Up to 60 months (5 years) post treatment ]
    Patients who received the prescribed RT dose and who are alive at the specified CT TA/PET timepoints during follow up will be evaluated for tumour response and included in the analysis of tumour response rates. Whole body FDG-PET scan will be done within 14 weeks prior to registration, at 6 months and as clinically indicated post-SABR based on review of CT-TA scans. The peak standard uptake value (SUV), normalised SUV (peak SUV of regions of interest/mean SUV of the aortic arch), and the change of SUV and normalised SUV (subtracting SUV and normalised SUV at reassessment from baseline data respectively) will be used as PET scan data. The distribution of the peak SUV and normalised SUV will be reported for each time point, respectively. The distribution of change of SUV and normalised SUV will be reported.

  2. Acute toxicity profiles on treatment to 3 months post treatment [ Time Frame: Up to 3 months post treatment ]
    Acute toxicity rates will be calculated, summarised and presented in tabular format with proportions plus 95% confidence intervals where appropriate.

  3. Late toxicity profiles to 5 years post treatment [ Time Frame: Up to 5 years post treatment ]
    Late toxicity rates will be calculated, summarised and presented in tabular format with proportions plus 95% confidence intervals where appropriate.

  4. Time to onset of acute and late ≥ Grade 2 and ≥ Grade 3 toxicities [ Time Frame: Up to 5 years post treatment ]
    Time to event will be measured from treatment start date. 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 primary time-point of interest is 12 months.

  5. 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) [ Time Frame: From baseline up to 6 months post treatment ]
    The mean and standard deviation (SD) of the domain-specific EORTC QLQ C30 and EORTC QLQ LC13 scores at baseline and 6 months post treatment will be reported. Scoring will be in line with the published guidelines and will use the QLQ-C30 summary score (excluding financial difficulties and global QOL). The scales are from 1(Not at all) to 4(Very Much) with 1 being the best outcome, and from 1(Very poor) to 7(excellent) with 7 being the best outcome. The proportion of patients who report 'quite a bit' and/or 'very much' for each domain or measure will be reported. Changes in scores over time for each patient will be calculated by subtracting the results at baseline from 6 month results. The mean and SD of the changes will be reported. A Wilcoxon signed rank test will be used to compare differences from baseline. The number of patients who had a clinically meaningful change in QoL as identified by the method recommended by the EORTC QoL Group at the time of analysis will also be reported.

  6. 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) [ Time Frame: From baseline up to 6 months post treatment ]
    The mean and standard deviation (SD) of the symptom-specific EORTC QLQ C30 and EORTC QLQ LC13 scores at baseline and 6 months post treatment will be reported. Scoring will be in line with the published guidelines and will use the QLQ-C30 summary score (excluding financial difficulties and global QOL). The scales are from 1(Not at all) to 4(Very Much) with 1 being the best outcome and from 1(Very poor) to 7(excellent) with 7 being the best outcome. The proportion of patients who report 'quite a bit' and/or 'very much' for each domain or measure will be reported. Changes in scores over time for each patient will be calculated by subtracting the results at baseline from 6 month results. The mean and SD of the changes will be reported. A Wilcoxon signed rank test will be used to compare differences from baseline. The number of patients who had a clinically meaningful change in QoL as identified by the method recommended by the EORTC QoL Group at the time of analysis will also be reported.

  7. Treatment tolerability and feasibility rates based on compliance with prescription and the number of treatment reductions/withdrawals. [ Time Frame: Through study treatment, an average of 3 weeks ]
    Treatment tolerability and feasibility will be measured in terms of the compliance rate for treatment delivery with respect to the protocol prescription and the number of treatment reductions and treatment withdrawals

  8. Pulmonary function changes [ Time Frame: Up to 12 months post treatment ]
    Change in pulmonary function post-treatment will be analysed by calculating the differences in measurements from baseline to the 12-month follow-up. The descriptive statistics of changes of FEV1 and diffusion capacity before and after treatment will be reported (at least mean, standard deviation, median, and range).

  9. 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 [ Time Frame: From baseline up to 6 months post treatment ]
    The mean and standard deviation (SD) of the overall EORTC QLQ C30 and EORTC QLQ LC13 scores at baseline and 6 months post treatment will be reported. Scoring will be in line with the published guidelines and will use the QLQ-C30 summary score (excluding financial difficulties and global QOL). The scales are from 1 (Not at all) to 4 (Very Much) with 1 being the best outcome, and from 1 (Very poor) to 7 (excellent) with 7 being the best outcome. The proportion of patients who report 'quite a bit' and/or 'very much' for each domain or measure will be reported. Changes in scores over time for each patient will be calculated by subtracting the results at baseline from 6month results. The mean and SD of the changes will be reported. A Wilcoxon signed rank test will be used to compare differences from baseline. The number of patients who had a clinically meaningful change in QoL as identified by the method recommended by the EORTC QoL Group at the time of analysis will also be reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 18 years of age
  2. Life expectancy >6 months
  3. ECOG (Eastern Cooperative Oncology Group) performance status 0-2
  4. Histological diagnosis (biopsy or cytology) of NSCLC (Squamous Cell Carcinoma (SCC), Adenocarcinoma, Large Cell)
  5. Centrally located tumour defined as:

    1. tumour within 2 cm of touching the zone of the proximal bronchial tree OR
    2. tumour that is immediately adjacent to the mediastinal or pericardial pleura, with a PTV (5 mm) expected to touch or include the pleura OR
    3. tumour adjacent the spinal cord or brachial plexus.
  6. Patients with centrally located tumours whose radiotherapy plan meets the following criteria:

    (i) OAR safety constraints are initially exceeded when full PTV coverage is met OR (ii) subsequently meets the SOURCE OAR constraints with potentially reduced GTV and/or PTV coverage

  7. Inoperable (as per Multi-Disciplinary Team (MDT)) or patient refuses surgery,
  8. No evidence of distant metastases
  9. Tumour size ≤7 cm in maximum diameter
  10. T3 tumours (AJCC 8th edition) with only one lesion and not abutting the Oesophagus
  11. Positron Emission Tomography (PET) scan and CT Thorax and Abdomen acquired within 14 weeks prior to informed consent. In cases of uncertainty about involvement of hilar/mediastinal lymph nodes, endobronchial ultrasound-transbronchial needle aspiration
  12. Pulmonary function tests recorded within 16 weeks of informed consent
  13. No chemotherapy and/or targeted treatment within 3 months before registration
  14. No recent malignancy except adequately treated basal cell carcinoma (BCC) of the skin or malignancy from which the patient has been disease free for >5 years
  15. Females of childbearing potential must not be pregnant and 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
  16. Absence of psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
  17. Protocol treatment to start within 21 days of registration
  18. Provision of written consent in line with ICH-GCP guidelines.

Exclusion Criteria:

  1. Known co-existing or prior malignancy within the last 5 years (except for adequately treated basal cell carcinoma (BCC)) which is likely to interfere with treatment or assessment of outcomes
  2. Evidence of regional (nodal) or distant metastases or metastatic pleural effusion
  3. Spinal canal involvement
  4. Patients with syndromes or conditions associated with increased radiosensitivity or development of lung fibrosis
  5. Idiopathic pulmonary fibrosis / usual interstitial pneumonia
  6. Chemotherapy administered within 3 months prior to study entry or planned for <6 weeks following radiotherapy
  7. Any previous radiotherapy to the thorax or mediastinum
  8. Any tumour not clinically definable on the treatment planning CT scan (e.g. surrounding consolidation or atelectasis)
  9. Patients unable to undergo 4D-CT scan
  10. Uncontrolled intercurrent illness that is likely to interfere with treatment or assessment of outcomes
  11. Psychiatric illness/social situations that would limit compliance with study requirements
  12. Pregnant or lactating at the time of proposed registration
  13. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04375904


Contacts
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Contact: Cancer Trials Ireland, Innovation House, Glasnevin Dublin 11 +353 1 6677211 info@cancertrials.ie
Contact: Prof. John Armstrong

Locations
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Ireland
Beacon Hospital Recruiting
Dublin, Ireland
Contact: Dr Alina Mihai         
Principal Investigator: Dr Alina Mihai         
St Luke's Radiation Oncology Network (SLRON) at St Luke's Hospital and St James's Hospital Recruiting
Dublin, Ireland
Contact: Prof. John Armstrong         
Principal Investigator: John Armstrong         
Sub-Investigator: Pierre Thirion         
Sponsors and Collaborators
Cancer Trials Ireland
Prof Fiona Lyng
Prof Stephen Pennington
Investigators
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Principal Investigator: Prof. John Armstrong, MD FRCPI DABR FFRRCSI Cancer Trials Ireland/ St Luke's Radiation Oncology Network
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Responsible Party: Cancer Trials Ireland
ClinicalTrials.gov Identifier: NCT04375904    
Other Study ID Numbers: CTRIAL-IE 18-33
First Posted: May 6, 2020    Key Record Dates
Last Update Posted: February 12, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cancer Trials Ireland:
Lung cancer
Non-small cell lung cancer
Ultracentral
Stereotactic ablative radiation therapy
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms