Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

Study Overview
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Brief Summary
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This trial studies the side effects and how well nintedanib works compared to a placebo in treating against radiation-induced pneumonitis (inflammation of the lungs) in patients with non-small cell lung cancer that cannot be removed by surgery and are undergoing chemoradiation therapy. Nintedanib may help shrink or slow the growth of radiation-induced pneumonitis by blocking some of the enzymes needed for cells to grow and may prevent the growth of new blood vessels. It may also help reduce the recurrence of non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety of the combination of durvalumab with nintedanib in patients with unresectable Stage II/III/oligometastatic IV non-small cell lung carcinoma (NSCLC). (Phase I) II. To compare the rate of symptomatic radiation pneumonitis at 6 months after completion of chemoradiation in patients with unresectable stage II/III/ oligometastatic IV NSCLC who completed chemoradiation followed by nintedanib versus placebo. (Phase II) SECONDARY OBJECTIVES: I. To compare the quality of life (QOL) in patients who received nintedanib versus placebo during active treatment until 6 months after completion of treatment. II. To compare the progression-free survival, overall survival and 1-year progression-free survival rate in patients who received nintedanib versus placebo. III. To compare pulmonary function test (PFT) results and radiation pneumonitis (RP) score in patients who received nintedanib versus placebo. IV. To compare 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 nintedanib versus placebo. EXPLORATORY OBJECTIVES: I. To investigate blood-based biomarkers in evaluating risk of developing radiation pneumonitis as well as the efficacy of nintedanib. OUTLINE: This is a phase I, dose-escalation study of nintedanib followed by a phase II study. Patients who are not receiving durvalumab as standard of care prior to establishment of the recommended phase II dose are randomized to 1 of 2 arms. Patients receiving durvalumab are assigned to Arm III. ARM I: Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Beginning 4-8 weeks after completion of radiation therapy, patients receive placebo capsules PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. ARM III: Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib PO BID on days 1-28 and standard of care durvalumab intravenously (IV) over 60 minutes on days 1 and 15. Treatment with nintedanib repeats every 28 days for up to 6 cycles and treatment with durvalumab repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, between 76-97 days, between 166-187 days, and then between 2.5 years.

Official Title
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A Phase II Randomized, Double-Blind, Placebo-Controlled Study Evaluating Nintedanib Versus Placebo as Prophylaxis Against Radiation Pneumonitis in Patients With Unresectable NSCLC Undergoing Chemoradiation Therapy

Conditions
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Lung Non-Squamous Non-Small Cell Carcinoma, Radiation-Induced Pneumonitis, Stage II Lung Non-Small Cell Cancer AJCC v7, Stage IIA Lung Non-Small Cell Carcinoma AJCC v7, Stage IIB Lung Non-Small Cell Carcinoma AJCC v7, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage IV Lung Non-Small Cell Cancer AJCC v7

Intervention / Treatment
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* Biological: Durvalumab
* Drug: Nintedanib
* Other: Placebo
* Procedure: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically-proven non squamous cell NSCLC; mixed histology with small cell lung carcinoma (SCLC) component not allowed Patients with stage II ? IV non squamous cell 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 non-squamous 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 complete response (CR)/partial response (PR)/stable disease (SD), 4-6 weeks after completing last fraction of radiation therapy Eastern Cooperative Oncology Group (ECOG) performance score 0-2 Absolute neutrophil count (ANC) >= 1,500/uL Platelet count >= 100,000/uL Hemoglobin >= 9 g/dL Total bilirubin =< normal or for those with Gilbert?s syndrome =< 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 =< 2.5 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 nintedanib/placebo administration Squamous cell NSCLC Unable to start nintedanib/placebo treatment between 4-8 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 nintedanib/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 Inability to swallow study medication Presence of active malabsorption disorder (e.g., flare episodes documented within the preceding 3 months, presence of symptoms requiring daily medications for control) or history of extensive small bowel resection Known bleeding or thrombotic diathesis History of arterial or venous thromboembolic event within 12 months prior to study participation Active hemoptysis or history of clinically relevant hemoptysis as determined by the treating physician; patients who had history of transient minor hemoptysis after bronchoscopic biopsy are eligible unless deemed otherwise by the treating physician Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher proteinuria Investigational agent administered < 28 days prior to treatment with nintedanib. Last dose of systemic chemotherapy administered < 14 days prior to treatment with nintedanib Known chronic active hepatitis B or hepatitis C; human immunodeficiency virus (HIV)-positive patients receiving or are candidates for antiretroviral therapy are also excluded 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 Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day) Active or previous autoimmune disease requiring treatment within the past 2 years will exclude patients from receiving immune checkpoint inhibitor in this study. Exception allowed: endocrine conditions treated with necessary hormone replacement or other supportive medication; vitiligo, alopecia

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (nintedanib)<br>Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Nintedanib<br>* Given PO<br>* Other names: Vargatef;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Placebo Comparator: Arm II (placebo)<br>Beginning 4-8 weeks after completion of radiation therapy, patients receive placebo capsules PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. | Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm III (nintedanib, durvalumab)<br>Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib PO BID on days 1-28 and standard of care durvalumab IV over 60 minutes on days 1 and 15. Treatment with nintedanib repeats every 28 days for up to 6 cycles and treatment with durvalumab repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. | Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Nintedanib<br>* Given PO<br>* Other names: Vargatef;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Portion of Common Terminology Criteria for Adverse Events Grade 2 or Higher Radiation Pneumonitis | Will compare the rate of symptomatic radiation pneumonitis in patients who received nintedanib versus placebo. Assessed using the intent-to-treat principle and a one-sided exact test about the Cochran-Mantel-Haenszel correlation and regression test. The grade 2 or higher radiation penumonitis is identified by the Common Terminology Criteria for Adverse Events. | At 6 months after completion of chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events, Graded According to Common Terminology Criteria for Adverse Events Version 4.0 | The frequency of toxicities will be tabulated by grade. | Up to 2.5 years post-treatment | 
| Overall Survival | Overall survival will be reported using standard Kaplan-Meier methods. Comparisons of overall survival between study arms may utilize the two-sided stratified log-rank test. | 1 year survival, with follow-up assessed up to 2.5 years post-treatment | 
| Progression-free Survival | Progression-free survival will be reported using standard Kaplan-Meier methods. Comparisons of progression-free survival between study arms may utilize the two-sided stratified log-rank test. | 1 year progression-free survival, with follow-up assessed up to 2.5 years post-treatment | 
| Percent Changes in Overall Quality of Life and Symptom Scores | Percent changes in the quality of life and symptom scores may be compared between study arms using the Wilcoxon rank sum or independent sample t-tests, as appropriate. The quality of life scores are obtained using the Lung Cancer Symptom Scale (LCSS) The scores range from 0 to 68, where 0 indicates poor quality of life and 68 indicates good quality of life. The percent change from baseline was calculated as 100*(post treatment - baseline) / baseline. | Baseline up to 2.5 years post-treatment | 
| Percent Change in Pulmonary Function Tests | Percent change in pulmonary function test, relative to baseline, will be evaluated within each study arm using the Wilcoxon signed rank or paired t-tests, as appropriate. Changes in pulmonary function tests may be compared between study arms using the Wilcoxon rank sum or independent sample t-tests, as appropriate. | Baseline up to 2.5 years post-treatment | 
| Changes in Radiation Pneumonitis Scores | Changes in radiation pneumonitis scores, relative to baseline, will be evaluated within each study arm using the Wilcoxon signed rank or paired t-tests, as appropriate. Changes in radiation pneumonitis scores may be compared between study arms using the Wilcoxon rank sum or independent sample t-tests, as appropriate. The radiation pneumonitis scores were obtained using semi quantitative analysis will be performed for the presence of ground-glass opacity, consolidation, reticulation, mosaic perfusion, traction bronchiectasis and honeycombing for each lung zone and scored on a four point scale (0 = no involvement, 1 ≤ 25%; 2 = 26 50%; 3 = 51 75% and 4 ≥ 76%). The scores are averaged across two radiologists. | Baseline up to 2.5 years post-treatment | 
| Responses Rates | Complete response and complete/partial response rates will be reported by study arm and chemotherapy regimen using Wilson 95% confidence intervals. The responses rates will be compared between study arms using the Cochran-Mantel-Haenszel exact test. The objective tumor response was assessed using RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must have a reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions. The appearance of one or more new lesions is also considered progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameter while on study. Overall response = CR + PR. | Up to 2.5 years post-treatment | 
| Biomarker Analysis | The tethered cationic lipoplex nanoparticle biochip, microfluidic cationic lipoplex nanoparticle biochip and real-time quantitative reverse transcription-polymerase chain reaction measurements for the expression of micro ribonucleic acid -1, -21, -127 and -155 will be made. The micro ribonucleic acid expressions, vitamin D levels, and mitochondrial deoxyribonucleic acid levels will be treated as continuous and reported by radiation pneumonitis status using the mean, median and standard deviation. Comparisons will be made between groups using a two-sided permutation t-test. | Up to 97 days post-treatment |