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

• Sponsor: Roswell Park Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02452463
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 8
• Location: 1
• Arms: 3
• Actual Duration (Months): 47.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Biological: Durvalumab; Drug: Nintedanib; Other: Placebo; Procedure: Quality-of-Life Assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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)
2. 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:

1. To compare the quality of life (QOL) in patients who received nintedanib versus placebo during active treatment until 6 months after completion of treatment.

2. To compare the progression-free survival, overall survival and 1-year progression-free survival rate in patients who received nintedanib versus placebo.

3. To compare pulmonary function test (PFT) results and radiation pneumonitis (RP) score in patients who received nintedanib versus placebo.

4. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: 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
• Actual Study Start Date: Jun 29, 2015
• Actual Primary Completion Date: Jun 10, 2019
• Actual Study Completion Date: Jun 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (nintedanib) 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; Given PO; Other Names: BIBF 1120 BIBF-1120 Intedanib Multitargeted Tyrosine Kinase Inhibitor BIBF 1120 tyrosine kinase inhibitor BIBF 1120 Vargatef ; Procedure: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment
Placebo Comparator: Arm II (placebo) 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; Given PO; Other Names: placebo therapy PLCB sham therapy ; Procedure: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment
Experimental: Arm III (nintedanib, durvalumab) 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; Given IV; Other Names: Imfinzi Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer MEDI-4736 MEDI4736 ; Drug: Nintedanib; Given PO; Other Names: BIBF 1120 BIBF-1120 Intedanib Multitargeted Tyrosine Kinase Inhibitor BIBF 1120 tyrosine kinase inhibitor BIBF 1120 Vargatef ; Procedure: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment

Outcome Measures

Primary Outcome Measures

1. Portion of Common Terminology Criteria for Adverse Events Grade 2 or Higher Radiation Pneumonitis [At 6 months after completion of chemoradiation]

   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.

Secondary Outcome Measures

1. Number of Participants With Adverse Events, Graded According to Common Terminology Criteria for Adverse Events Version 4.0 [Up to 2.5 years post-treatment]

   The frequency of toxicities will be tabulated by grade.

2. Overall Survival [1 year survival, with follow-up assessed up to 2.5 years post-treatment]

   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.

3. Progression-free Survival [1 year progression-free survival, with follow-up assessed up to 2.5 years post-treatment]

   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.

4. Percent Changes in Overall Quality of Life and Symptom Scores [Baseline up to 2.5 years post-treatment]

   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.

5. Percent Change in Pulmonary Function Tests [Baseline up to 2.5 years post-treatment]

   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.

6. Changes in Radiation Pneumonitis Scores [Baseline up to 2.5 years post-treatment]

   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.

7. Responses Rates [Up to 2.5 years post-treatment]

   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.

8. Biomarker Analysis [Up to 97 days post-treatment]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Roswell Park Cancer Institute	Buffalo	New York	United States	14263

Sponsors and Collaborators

• Roswell Park Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Grace K Dy, Roswell Park Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 6, 2019

More Information

Publications

None provided.

• Responsible Party: Roswell Park Cancer Institute
• ClinicalTrials.gov Identifier: NCT02452463
• Other Study ID Numbers: I 257814; NCI-2015-00704; I 257814; P30CA016056
• First Posted: May 22, 2015
• Last Update Posted: Apr 6, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Pneumonia; Carcinoma; Carcinoma, Non-Small-Cell Lung; Radiation Pneumonitis; Durvalumab; Nintedanib; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Pre-assignment Detail	No participants were enrolled in the "Arm III (Nintedanib, Durvalumab)" Arm - study closed prior to any patients being enrolled in this arm.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Period Title: Overall Study
STARTED	5	3	0
COMPLETED	3	1	0
NOT COMPLETED	2	2	0

Baseline Characteristics

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)	Total
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	Total of all reporting groups
Overall Participants	5	3	0	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.40 (5.94)	68.00 (4.58)	65.75 (5.44)
Sex: Female, Male (Count of Participants)
Female	4 80%	1 33.3%	5 Infinity
Male	1 20%	2 66.7%	3 Infinity
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 NaN
Asian	0 0%	0 0%	0 NaN
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 NaN
Black or African American	0 0%	0 0%	0 NaN
White	5 100%	3 100%	8 Infinity
More than one race	0 0%	0 0%	0 NaN
Unknown or Not Reported	0 0%	0 0%	0 NaN
Region of Enrollment (participants) [Number]
United States	5 100%	3 100%	8 Infinity
Body Mass Index (BMI) (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	21.75 (5.47)	32.15 (3.84)	25.65 (7.09)
Chemotherapy (Count of Participants)
CARBOPLATIN + PACLITAXEL (TAXOL)	2 40%	1 33.3%	3 Infinity
CARBOPLATIN + PEMETREXED	1 20%	2 66.7%	3 Infinity
CISPLATIN + ETOPOSIDE (VP-16)	1 20%	0 0%	1 Infinity
CISPLATIN + PEMETREXED	1 20%	0 0%	1 Infinity
Smoking Status (Count of Participants)
Current	2 40%	1 33.3%	3 Infinity
Former	2 40%	2 66.7%	4 Infinity
Unknown	1 20%	0 0%	1 Infinity
Force Expiratory Volume in 1 Second (FEV1) (Percentage of Predicted FEV1) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Predicted FEV1]	66.70 (29.59)	72.67 (6.81)	68.94 (22.87)
Forced Vital Capacity (FVC) (Percentage of Predicted FVC) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Predicted FVC]	91.72 (26.74)	82.93 (5.97)	88.43 (20.96)
Diffusing Capacity for Carbon Monoxide (DLCO) (Percentage of Predicted DLCO) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Predicted DLCO]	60.52 (27.21)	77.93 (10.04)	67.05 (23.09)
peak expiratory flow (PEF) (Percentage of Predicted PEF) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Predicted PEF]	67.22 (33.78)	74.90 (15.89)	70.10 (27.20)
total lung capacity (TLC) (Percentage of Predicted TLC) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Predicted TLC]	110.60 (18.29)	99.17 (8.96)	106.31 (15.78)
Eastern Cooperative Oncology Group Performance Status(ECOG) (Count of Participants)
Fully active	3 60%	0 0%	3 Infinity
Restricted in physically strenuous activity	2 40%	3 100%	5 Infinity

Outcome Measures

1. Primary Outcome

Title	Portion of Common Terminology Criteria for Adverse Events Grade 2 or Higher Radiation Pneumonitis
Description	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.
Time Frame	At 6 months after completion of chemoradiation

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	5	3	0
Number [proportion of participants]	0.00 0%	0.67 22.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.107
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

2. Secondary Outcome

Title	Number of Participants With Adverse Events, Graded According to Common Terminology Criteria for Adverse Events Version 4.0
Description	The frequency of toxicities will be tabulated by grade.
Time Frame	Up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was discontinued prior to subjects being enrolled in Arm III

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	5	3	0
Grade 1 Maximum AE	2 40%	0 0%	0 NaN
Grade 2 Maximum AE	1 20%	1 33.3%	0 NaN
Grade 3 Maximum AE	1 20%	0 0%	0 NaN
No Treatmetn Related AE	1 20%	2 66.7%	0 NaN

3. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	1 year survival, with follow-up assessed up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	5	3	0
Number (95% Confidence Interval) [Percent survival at 1 year]	53.0	100.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments	Null Hypotheses: OS distributions are equal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Progression-free Survival
Description	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.
Time Frame	1 year progression-free survival, with follow-up assessed up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	5	3	0
Number (95% Confidence Interval) [Percent survival at 1 year]	25.0	100.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments	Null Hypotheses: PFS distributions are equal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Percent Changes in Overall Quality of Life and Symptom Scores
Description	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.
Time Frame	Baseline up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3. For Arms 1 and 2, not all follow-up tests were completed.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	2	2	0
Mean (Standard Deviation) [percent change]	110.00 (70.71)	-16.35 (12.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.131
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Percent Change in Pulmonary Function Tests
Description	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.
Time Frame	Baseline up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3. For Arms 1 and 2, not all follow-up tests were completed.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	2	2	0
Mean (Standard Deviation) [percent of change]	-28.29 (13.43)	11.02 (8.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Changes in Radiation Pneumonitis Scores
Description	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.
Time Frame	Baseline up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3. For Arms 1 and 2, not all follow-up tests were completed.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	4	2	0
Mean (Standard Deviation) [score on a scale]	0.50 (0.58)	0.75 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib)
	Comments	Comparing change relative to baseline.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.183
	Comments
	Method	Paired T-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm II (Placebo)
	Comments	Evaluating change relative to baseline.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.203
	Comments
	Method	paired T-test
	Comments

8. Secondary Outcome

Title	Responses Rates
Description	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.
Time Frame	Up to 2.5 years post-treatment

Outcome Measure Data

Analysis Population Description

Study was terminated prior to enrollment in Arm 3.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	5	3	0
SD/PD	5 100%	3 100%
CR/PR	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Nintedanib), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

9. Secondary Outcome

Title	Biomarker Analysis
Description	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.
Time Frame	Up to 97 days post-treatment

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, the biomarker data was never collected and analyzed.

Arm/Group Title	Arm I (Nintedanib)	Arm II (Placebo)	Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies	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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies	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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
Measure Participants	0	0	0

Adverse Events

Time Frame	From start date of intervention until 30 days after the last treatment intervention, up to 2.5 years.
Adverse Event Reporting Description	All treated patients in Arms I and II. No participants were enrolled in the "Arm III (Nintedanib, Durvalumab)" Arm, therefore no adverse events are reported.
Arm/Group Title	Arm I (Nintedanib)		Arm II (Placebo)		Arm III (Nintedanib, Durvalumab)
Arm/Group Description	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. Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies		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. Placebo: Given PO Quality-of-Life Assessment: Ancillary studies		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. Durvalumab: Given IV Nintedanib: Given PO Quality-of-Life Assessment: Ancillary studies
All Cause Mortality
	Arm I (Nintedanib)		Arm II (Placebo)		Arm III (Nintedanib, Durvalumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		1/3 (33.3%)		0/0 (NaN)
Serious Adverse Events
	Arm I (Nintedanib)		Arm II (Placebo)		Arm III (Nintedanib, Durvalumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		0/3 (0%)		0/0 (NaN)
Infections and infestations
Lung infection	1/5 (20%)	2	0/3 (0%)	0	0/0 (NaN)	0
Vascular disorders
Haemorrhage	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Arm I (Nintedanib)		Arm II (Placebo)		Arm III (Nintedanib, Durvalumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		3/3 (100%)		0/0 (NaN)
Blood and lymphatic system disorders
Leukocytosis	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Eye disorders
Dry eye	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Eye disorder	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Ocular hyperaemia	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Gastrointestinal disorders
Abdominal pain	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Abdominal pain upper	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Constipation	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Diarrhoea	5/5 (100%)	7	0/3 (0%)	0	0/0 (NaN)	0
Dyspepsia	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Eructation	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Flatulence	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Nausea	1/5 (20%)	2	0/3 (0%)	0	0/0 (NaN)	0
Vomiting	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
General disorders
Asthenia	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Fatigue	3/5 (60%)	3	1/3 (33.3%)	1	0/0 (NaN)	0
Influenza like illness	1/5 (20%)	1	1/3 (33.3%)	1	0/0 (NaN)	0
Swelling	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Infections and infestations
Pneumonia	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Injury, poisoning and procedural complications
Fall	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Radiation pneumonitis	0/5 (0%)	0	2/3 (66.7%)	2	0/0 (NaN)	0
Investigations
Platelet count decreased	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Back pain	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Nervous system disorders
Dizziness	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Haemoptysis	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Pneumonitis	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Wheezing	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	0/5 (0%)	0	1/3 (33.3%)	1	0/0 (NaN)	0
Vascular disorders
Hypertension	3/5 (60%)	4	2/3 (66.7%)	2	0/0 (NaN)	0
Thrombosis	1/5 (20%)	1	0/3 (0%)	0	0/0 (NaN)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.