Clinical trial NCT05986318: Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease
Official title: Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease: a 2x2 Factorial Randomized Phase II Trial Testing N-Acetyl Cysteine and Dexamethasone
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Lung Cancer
Interstitial Lung Disease
Keywords: Pulmonary Irradiation
Radiation Therapy
N-Acetyl Cysteine
Dexamethasone
Radiation Pneumonitis
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
Collaborators: name: London Health Sciences Centre
name: Centre Hospitalier de l'Universite de Montreal (CHUM)
First posted: 2023-08-14
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. 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).
2. 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).

Eligibility criteria: 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
* Current use of oral or intravenous corticosteroids
* 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

  * If not pregnant, use of effective contraception methods for women of childbearing age is required which can include:

    * hormonal methods (e.g. oral, injected, implanted),
    * placement of an intrauterine device,
    * barrier methods (i.e. condoms),
    * sterilization of the partner (e.g. previous vasectomy)
    * abstinence
  * Women who become pregnant should stop taking NAC and/or dexamethasone and inform their study doctor.
  * Male participants should use adequate forms of birth control with their partners.
* Currently breastfeeding
* Current or recent use of NAC
* 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
  * Cystinuria
  * Any other condition that the treating physician believes to be a contraindication to dexamethasone or NAC

Primary outcomes:
measure: Rate of Grade 2-5 Dyspnea within 6 Months Post Radiation Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5
timeFrame: Up to 6 months post radiation therapy
Secondary outcomes:
measure: Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS)
timeFrame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
measure: Patient Scored Cough Measured by Visual Analogue Scale (VAS)
timeFrame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
measure: Quality of Life Measured by FACIT.org Functional Assessment of Cancer Therapy - Lung (FACT-L) Questionnaire
timeFrame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
measure: Quality of Life Measured by EuroQOL Group EQ-5D-5L Questionnaire
timeFrame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy
measure: Local Control as Determined by Radiographic Evidence
timeFrame: 9 years
measure: Progression Free Survival
timeFrame: 9 years
measure: Overall Survival
timeFrame: 9 years
measure: Cancer Specific Survival
timeFrame: 9 years
measure: Rates of Radiation Treatment Completion
timeFrame: 50 months
measure: Rates of Study Drug Completion Rates
timeFrame: 50 months
measure: Rates of Participant Unblinding Related to Adverse Events Development
timeFrame: 50 months
Other outcomes:
Locations:
city: London
country: Canada
facility: London Regional Cancer Program, London Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal (CHUM)
state: Quebec
Study officials:
affiliation: London Health Sciences Centre, Lawson Health Research Institute
name: David Palma, MD
role: STUDY_CHAIR
affiliation: Centre Hospitalier de l'Universite de Montreal
name: Houda Bahig, MD
role: STUDY_CHAIR
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