Mitigation of Radiation Pneumonitis, Fibrosis and Heart Toxicity With Nicorandil in Lung Cancer Patients

Study Overview
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Brief Summary
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This project will test the effect of nicorandil to mitigate the lung damage that can occur as a side effect of radiation therapy for lung cancer. Thousands of veterans develop lung cancer every year, and are treated by radiation therapy. Studies of lung radiation injury in laboratory animals show that with nicorandil, investigators can significantly reduce the severity of lung fibrosis and heart toxicity.1,2 Nicorandil is FDA approved and in common use for treatment of angina. These studies will advance that work to human use. Successful mitigation of lung radiation damage and heart toxicity will improve the quality of life in veterans and non-veterans who are treated for lung cancer by radiation, and may also improve cure rates of radiation therapy for lung cancer.

Official Title
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Mitigation of Radiation Pneumonitis, Fibrosis and Heart Toxicity With Nicorandil in Lung Cancer Patients

Conditions
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Radiation Pneumonitis

Intervention / Treatment
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* Drug: Nicorandil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically-proven NSCLC; mixed histology with small cell lung carcinoma (SCLC) component not allowed Patients with stage II - IV NSCLC who received at least 54 Gy of total planned thoracic radiation dose will be eligible; patients must have received at least one cycle of chemotherapy concurrently during the course of thoracic radiation; regimens allowed are platinum combinations with either etoposide or a taxane regardless of histology subtype; platinum with pemetrexed for patients with nonsquamous NSCLC only; patients with oligometastatic stage IV cancer are eligible if they have received only one line of systemic therapy for their stage IV cancer prior to the concurrent chemoradiation phase Patient must have had a CR/PR/SD, 4-6 weeks after completing last fraction of chemotherapy / radiation therapy. Eastern Cooperative Oncology Group (ECOG) performance score 0-2 at the time of randomization Absolute neutrophil count (ANC) >= 1,500/uL Platelet count >= 100,000/uL Hemoglobin >= 9 g/dL Total bilirubin =< 1.5 times upper limit of normal (ULN) OR direct bilirubin normal (per institute standards) Aspartate aminotransferase (AST) =< 1.5 x ULN; alanine aminotransferase (ALT) and AST =< 3 x ULN is acceptable if there is liver metastasis Fertile patients must use adequate contraception Exclusion Criteria: Whole-brain radiotherapy (WBRT) < 14 days from the anticipated start of nicorandil/placebo administration Unable to start nicorandil/placebo treatment between 4 - 6 weeks after completing the last dose of thoracic radiation Active untreated brain or leptomeningeal metastases; in patients with treated central nervous system (CNS) metastases, eligible if symptoms controlled for at least 4 weeks; dexamethasone allowed if total daily dose does not exceed 2 mg Major injuries or surgery (e.g., craniotomy) < 28 days from the start of nicorandil/placebo administration; wound should be healed prior to starting therapy Second malignancies are allowed as long as the disease does not require active treatment with concomitant systemic cytotoxic chemotherapy, investigational or biologic therapy (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] or human epidermal growth factor receptor 2 [HER2] monoclonal antibodies); hormone-related therapies (e.g., gonadotrophin releasing hormone (LHRH) agonists, tamoxifen, etc.) are allowed Concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would increase the risk associated with study participation and/or limit compliance with study requirements Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher proteinuria Systemic therapy or investigational agent administered < 28 days prior to treatment with nicorandil Pregnancy or breast feeding; female patients with child-bearing potential must have a negative pregnancy test (beta-human chorionic gonadotropin [B-HCG] test in urine or serum) prior to commencing study treatment Creatinine > 1.5 x ULN or creatinine clearance levels (CrCL) < 45 mL/min Centrally located tumors with radiographic evidence (computed tomography [CT] or magnetic resonance imaging [MRI]) of local invasion of major blood vessels acute myocardial infarction within 2 weeks before percutaneous coronary intervention contraindications to treatment with nicorandil (allergy, glaucoma, digestive ulcer, is currently taking phosphodiesterase-5 inhibitor) bypass restenosis PCI history hypotension impaired liver function renal insufficiency requiring hemodialysis pregnancy connective tissue disease life expectancy ≤ 12 months left main coronary artery disease bypass graft lesion and lesions unsuitable for OCT unwillingness or inability to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicorandil<br>Beginning 4-6 weeks during radiation therapy, patients receive nicorandil is given during radiotherapy interval, 5mg each time, 3 times daily oral. Treatment repeats after completion of radiation therapy in the absence of disease progression or unacceptable toxicity. | Drug: Nicorandil<br>* oral intake<br>* Other names: Sigmart;|
| Active Comparator: observation<br>regular radiotherapy as our protocol | Drug: Nicorandil<br>* oral intake<br>* Other names: Sigmart;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of symptomatic radiation pneumonitis in patients with unresectable Stage II/III/ oligometastatic IV non-small cell lung carcinoma (NSCLC) who completed chemoradiation followed by nicorandil or not |  | Up to 2.5 years post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The quality of life (QOL) questionnaire |  | Baseline up to 2.5 years post-treatment | 
| Biomarker analysis such as TGF-β, Serum surfactant proteins-A & -D, MMP1 and MMP7 |  | Up to 97 days post-treatment | 
| The overall survival in patients who received nicorandil versus observation |  | Up to 2.5 years post-treatment | 
| Radiation pneumonitis (RP) score in patients who received nicorandil versus observation |  | Baseline up to 2.5 years post-treatment | 
| The composite index (based on PFT, RP score and QOL) at the end of active treatment and 6 months after completion of treatment between patients who received nicorandil versus observation. |  | Baseline up to 2.5 years post-treatment | 
| Responses rates |  | Up to 2.5 years post-treatment |