Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease

Study Overview
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Brief Summary
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In this double-blind phase II randomized controlled trial, patients with lung cancer or ≤2 oligometastatic pulmonary lesions and a concomitant diagnosis of ILD who are planned for radical Radiation Therapy (RT) will be randomized using a 2 x 2 factorial design to oral N-acetylcysteine (NAC) versus placebo, and also to short course corticosteroids versus placebo.

Detailed Description
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Radiation pneumonitis (RP) is the most common and main dose-limiting toxicity after thoracic RT. RP is characterized histologically by diffuse alveolar damage and acute vascular permeability induced by direct cytotoxic effect and oxidative stress, leading to the production of proinflammatory, profibrogenic and proangiogenic cytokines. Patients with Interstitial Lung Disease (ILD) are at increased risk of developing lung cancer compared to the general population. Management of patients with lung cancer in the setting of a concomitant ILD is complex, as these patients are usually not good candidates for surgery or immunotherapy. In addition, patients with ILD, particularly fibrotic ILD, are also reportedly at increased risk of treatment-related toxicity from RT. In the present study, investigators will test the following hypotheses: The use of NAC with RT in patients with underlying ILD will lead to a clinically meaningful reduction in grade 2-5 dyspnea (as per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0). The use of corticosteroids with RT in patients with underlying ILD will lead to a clinically meaningful reduction in grade 2-5 dyspnea (as per CTCAE version 5.0).

Official Title
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Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease: A 2x2 Factorial Randomized Phase II Trial Testing N-Acetyl Cysteine and Dexamethasone

Conditions
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Lung Cancer, Interstitial Lung Disease

Intervention / Treatment
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* Dietary Supplement: N-Acetyl cysteine
* Drug: Dexamethasone Oral
* Dietary Supplement: N-Acetyl cysteine Placebo
* Drug: Dexamethasone Placebo
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Lung cancer or 1-2 oligometastatic pulmonary lesions planned for radical intent radiotherapy [minimal Biologically Effective Does (BED) of 48 Gy10 (Gray) or biological equivalent]. Pathologically (histologically or cytologically) proven diagnosis of cancer is not required, but strongly recommended. If the risk of biopsy is unacceptable, pathologic confirmation is not required providing there is growth over time on Computed Tomography (CT) imaging and/or Fluorodeoxyglucose (FDG) avidity that is strongly suggestive of malignancy. Fibrotic Interstitial Lung Disease (ILD) of any subtype, as diagnosed by a respirologist and confirmed by central review Eastern Cooperative Oncology Group (ECOG) performance status 0-3 Age ≥ 18 Life expectancy > 6 months Patients are allowed to receive anti-fibrotic agents used in the treatment of Idiopathic Pulmonary Fibrosis (IPF) or non-IPF fibrotic ILD (e.g. nintedanib, pirfenidone) and/or corticosteroids, if those are part of their current ILD treatment regimen. Other immunosuppressive drugs such as mycophenolate, azathioprine, cyclophosphamide, and rituximab must be stopped for 2 weeks prior and 2 weeks after Radiation Therapy (RT). Concurrent standard chemotherapy is allowed where indicated. All other systemic therapies, including biologic targeted agents or immunotherapy, or any drugs with known radiosensitive effects, must be stopped for 2 weeks prior and 2 weeks after treatment. Exclusion Criteria: Prior lung radiotherapy Plans for the patient to receive other local therapy to the target lesion(s) while on this study, except at disease progression Any medical condition that could, in the opinion of the investigator, preclude radiotherapy or prevent follow-up after radiotherapy Pregnancy Contraindications to dexamethasone or N-Acetyl Cysteine (NAC). These include: Previous intolerance or allergy to dexamethasone or NAC Scleroderma Active infection Glaucoma Psychiatric disorder that could be exacerbated by dexamethasone Any other condition that the treating physician believes to be a contraindication to dexamethasone or NAC

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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NAC + Corticosteroids<br>Participants will take 600 mg of active NAC orally, three times daily, for 60 days. Participants will also take 4 mg of active dexamethasone, orally, once daily for 10 days, then 2 mg, orally, once daily for 5 days, then 1 mg, orally, once daily for 5 days. All participants will be treated with radical pulmonary radiation therapy. | Dietary Supplement: N-Acetyl cysteine<br>* NAC capsules<br>* Other names: NAC;Drug: Dexamethasone Oral<br>* Dexamethasone tablets<br>* Other names: Corticosteroid;Radiation: Radiation Therapy<br>* All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.<br>|
| Active Comparator: Corticosteroids + NAC Placebo<br>Participants will take 4 mg of active dexamethasone, orally, once daily for 10 days, then 2 mg, orally, once daily for 5 days, then 1 mg, orally, once daily for 5 days. Participants will also take matching NAC placebo orally, three times daily, for 60 days. All participants will be treated with radical pulmonary radiation therapy. | Drug: Dexamethasone Oral<br>* Dexamethasone tablets<br>* Other names: Corticosteroid;Dietary Supplement: N-Acetyl cysteine Placebo<br>* Matching placebo for NAC capsules<br>* Other names: NAC Placebo;Radiation: Radiation Therapy<br>* All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.<br>|
| Active Comparator: NAC + Dexamethasone Placebo<br>Participants will take 600 mg of active NAC orally, three times daily, for 60 days. Participants will also take matching dexamethasone placebo (4 mg for 10 days, then 2 mg for 5 days, then 1 mg for 5 days), orally, once daily. All participants will be treated with radical pulmonary radiation therapy. | Dietary Supplement: N-Acetyl cysteine<br>* NAC capsules<br>* Other names: NAC;Drug: Dexamethasone Placebo<br>* Matching placebo for dexamethasone tablets<br>* Other names: Corticosteroid Placebo;Radiation: Radiation Therapy<br>* All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.<br>|
| Placebo Comparator: NAC Placebo + Dexamethasone Placebo<br>Participants will take matching NAC placebo orally, three times daily, for 60 days. Participants will also take matching dexamethasone placebo (4 mg for 10 days, then 2 mg for 5 days, then 1 mg for 5 days), orally, once daily. All participants will be treated with radical pulmonary radiation therapy. | Dietary Supplement: N-Acetyl cysteine Placebo<br>* Matching placebo for NAC capsules<br>* Other names: NAC Placebo;Drug: Dexamethasone Placebo<br>* Matching placebo for dexamethasone tablets<br>* Other names: Corticosteroid Placebo;Radiation: Radiation Therapy<br>* All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Grade 2-5 Dyspnea within 6 Months Post Radiation Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5 |  | Up to 6 months post radiation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS) | Dyspnea (shortness of breath) severity will be reported by participants via a scale, where a score of 100 is no shortness of breath and a score of 0 is the worst shortness of breath ever. | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | 
| Patient Scored Cough Measured by Visual Analogue Scale (VAS) | Cough severity will be reported by participants via a scale, where a score of 100 is no cough and a score of 0 is the worst cough ever. | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | 
| Quality of Life Measured by FACIT.org Functional Assessment of Cancer Therapy - Lung (FACT-L) Questionnaire | The Functional Assessment of Cancer Therapy - Lung (FACT-L ) is a standardized questionnaire used to measure quality of life. The questionnaire consists of 5 scales measuring 37 items in total. Categories of the 5 scales are: physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns related to symptoms, cognitive function, and regret of smoking. The score for each item in the scale ranges from 0 to 4, where 0 is not at all and 4 is very much. The scores from each scale are added up, and can be combined to provide a total score. | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | 
| Quality of Life Measured by EuroQOL Group EQ-5D-5L Questionnaire | The EQ-5D-5L is a standardized questionnaire used to measure quality of life and health. The first section includes 5 categories: mobility, self-care, usual activities (e.g. work, family), pain/discomfort, and anxiety/depression. Each category contains 5 statements ranging from no problems to extreme problems, where no problems is assigned a code of 1 and extreme problems is assigned a code of 5. Participants are asked to select the statement that best describes their health that day. No score is generated, rather a 5 digit code is generated based on the response provided, which can then be combined into a data set and interpreted in a variety of ways. The second section includes a 20 cm analogue scale from 0 to 100, where 100 is the best health ever imagined and 0 is the worst health imagined. The participant will mark a score on the scale representing the state of their health on that day. | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | 
| Local Control as Determined by Radiographic Evidence | Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 will be used to measure tumors in the lung (by size), on imaging, to determine how tumors are responding to treatment. | 9 years | 
| Progression Free Survival | Time from enrollment to death from any cause or any progression of disease (local, regional, or distant). | 9 years | 
| Overall Survival | Time from enrollment to death from any cause . | 9 years | 
| Cancer Specific Survival | Time from enrollment to death from lung cancer, censored at last follow-up or death from other causes. | 9 years | 
| Rates of Radiation Treatment Completion |  | 50 months | 
| Rates of Study Drug Completion Rates |  | 50 months | 
| Rates of Participant Unblinding Related to Adverse Events Development |  | 50 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Irradiation, Radiation Therapy, N-Acetyl Cysteine, Dexamethasone, Radiation Pneumonitis