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

Overview

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).

Interventions

• Dietary supplement N-Acetyl cysteine
  NAC capsules
• Drug Dexamethasone Oral
  Dexamethasone tablets
• Dietary supplement N-Acetyl cysteine Placebo
  Matching placebo for NAC capsules
• Drug Dexamethasone Placebo
  Matching placebo for dexamethasone tablets
• Radiation Radiation Therapy
  All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.

Primary outcome measures

• Rate of Grade 2-5 Dyspnea within 6 Months Post Radiation Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5 [Time frame: Up to 6 months post radiation therapy]

Secondary outcome measures (11)

• Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS) [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy]
• Local Control as Determined by Radiographic Evidence [Time frame: 9 years]
• Progression Free Survival [Time frame: 9 years]
• Overall Survival [Time frame: 9 years]
• Cancer Specific Survival [Time frame: 9 years]
• Rates of Radiation Treatment Completion [Time frame: 50 months]
• Rates of Study Drug Completion Rates [Time frame: 50 months]
• Rates of Participant Unblinding Related to Adverse Events Development [Time frame: 50 months]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Double blind

Primary purpose

Treatment

Study locations

Canada · 3 centers

• BC-Cancer Agency - Vancouver — Vancouver
• Verspeeten Family Cancer Centre, London Health Sciences Centre — London
• Centre Hospitalier de l'Universite de Montreal (CHUM) — Montreal

Publications

• Verstegen NE, Lagerwaard FJ, Hashemi SM, Dahele M, Slotman BJ, Senan S. Patterns of Disease Recurrence after SABR for Early Stage Non-Small-Cell Lung Cancer: Optimizing Follow-Up Schedules for Salvage Therapy. J Thorac Oncol. 2015 Aug;10(8):1195-200. doi: 10.1097/JTO.0000000000000576. PMID 26200274
• Choi YW, Munden RF, Erasmus JJ, Park KJ, Chung WK, Jeon SC, Park CK. Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis. Radiographics. 2004 Jul-Aug;24(4):985-97; discussion 998. doi: 10.1148/rg.244035160. PMID 15256622
• Kainthola A, Haritwal T, Tiwari M, Gupta N, Parvez S, Tiwari M, Prakash H, Agrawala PK. Immunological Aspect of Radiation-Induced Pneumonitis, Current Treatment Strategies, and Future Prospects. Front Immunol. 2017 May 2;8:506. doi: 10.3389/fimmu.2017.00506. eCollection 2017. PMID 28512460
• Tsoutsou PG, Koukourakis MI. Radiation pneumonitis and fibrosis: mechanisms underlying its pathogenesis and implications for future research. Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1281-93. doi: 10.1016/j.ijrobp.2006.08.058. PMID 17126203
• Niska JR, Schild SE, Rule WG, Daniels TB, Jett JR. Fatal Radiation Pneumonitis in Patients With Subclinical Interstitial Lung Disease. Clin Lung Cancer. 2018 Jul;19(4):e417-e420. doi: 10.1016/j.cllc.2018.02.003. Epub 2018 Feb 17. No abstract available. PMID 29526532
• Axelsson GT, Putman RK, Aspelund T, Gudmundsson EF, Hida T, Araki T, Nishino M, Hatabu H, Gudnason V, Hunninghake GM, Gudmundsson G. The associations of interstitial lung abnormalities with cancer diagnoses and mortality. Eur Respir J. 2020 Dec 17;56(6):1902154. doi: 10.1183/13993003.02154-2019. Print 2020 Dec. PMID 32646918
• Ozawa Y, Abe T, Omae M, Matsui T, Kato M, Hasegawa H, Enomoto Y, Ishihara T, Inui N, Yamada K, Yokomura K, Suda T. Impact of Preexisting Interstitial Lung Disease on Acute, Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer. PLoS One. 2015 Oct 13;10(10):e0140437. doi: 10.1371/journal.pone.0140437. eCollection 2015. PMID 26460792
• Sanuki N, Ono A, Komatsu E, Kamei N, Akamine S, Yamazaki T, Mizunoe S, Maeda T. Association of computed tomography-detected pulmonary interstitial changes with severe radiation pneumonitis for patients treated with thoracic radiotherapy. J Radiat Res. 2012;53(1):110-6. doi: 10.1269/jrr.110142. PMID 22302051

Identifiers

NCT: NCT05986318 · RESPIRE-ILD

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗