Reducing Respiratory Symptoms of Pulmonary Irradiation in Interstitial Lung Disease (RESPIRE-ILD)

David Palma

Status and phase: Enrolling; Phase 2

Conditions: Lung Cancer; Interstitial Lung Disease

Treatments: Radiation: Radiation Therapy; Drug: Dexamethasone Placebo; Dietary Supplement: N-Acetyl cysteine; Dietary Supplement: N-Acetyl cysteine Placebo; Drug: Dexamethasone Oral

Study type: Interventional

Funder types: Other

Identifiers

NCT05986318

RESPIRE-ILD

Details and patient eligibility

About

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.

Full 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).

Enrollment: 98 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Double Blind

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98 participants in 4 patient groups, including a placebo group

NAC + Corticosteroids

Active Comparator group

Description:

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.

Treatment:

Drug: Dexamethasone Oral

Dietary Supplement: N-Acetyl cysteine

Radiation: Radiation Therapy

Corticosteroids + NAC Placebo

Active Comparator group

Description:

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.

Treatment:

Dietary Supplement: N-Acetyl cysteine Placebo

Drug: Dexamethasone Oral

Radiation: Radiation Therapy

NAC + Dexamethasone Placebo

Active Comparator group

Description:

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.

Treatment:

Dietary Supplement: N-Acetyl cysteine

Radiation: Radiation Therapy

Drug: Dexamethasone Placebo

NAC Placebo + Dexamethasone Placebo

Placebo Comparator group

Description:

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.

Treatment:

Dietary Supplement: N-Acetyl cysteine Placebo

Radiation: Radiation Therapy

Drug: Dexamethasone Placebo