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
Phase: PHASE2
Conditions: 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
Sponsor: Roswell Park Cancer Institute

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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
Roswell Park Number:
I 257814
Initial Date:
13 October 2014
Amendment 1:
25 February 2015
Amendment 2:
09 April 2015
Amendment 3:
24 July 2015
Amendment 4:
27 July 2016
Amendment 5:
24 January 2017
Amendment 6:
2 April 2019
Principal Investigator:
Grace Dy, MD 
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-3099
Grace.Dy@RoswellPark.org
Sponsor (regulatory):
Roswell Park Cancer Institute
Funding:
National Comprehensive Cancer Network (NCCN)
Industry/Other Supporter:
Boehringer Ingelheim Pharmaceuticals
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above. The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party (ies) above.
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SYNOPSIS
Title / Phase
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
RPCI Study Number
I 257814
Roswell Park Cancer Institute
Investigator
Grace Dy, MD 
Sponsor
Roswell Park Cancer Institute
Funding
National Comprehensive Cancer Network (NCCN)
Industry / Other Supporter
Boehringer Ingelheim Pharmaceuticals
Study Drug(s)
Nintedanib, placebo; durvalumab
Objectives
Primary:
•
Phase 1: To evaluate the safety of the combination of durvalumab with 
nintedanib in patients with unresectable Stage II/III/oligometastatic IV 
NSCLC
•
Phase 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.
Secondary:
•
To compare the quality of life (QOL) in patients who received 
nintedanib versus placebo during active treatment until 6 months after 
completion of treatment.
•
To compare the progression-free survival, overall survival and 1-year 
progression-free survival rate in patients who received nintedanib 
versus placebo.
•
To compare pulmonary function test (PFT) results and RP score in 
patients who received nintedanib versus placebo.
•
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:
•
To investigate blood-based biomarkers in evaluating risk of developing 
radiation pneumonitis as well as the efficacy of nintedanib.
Study Design
A Phase II, randomized, double-blind, placebo-controlled study of nintedanib as 
prophylaxis against radiation pneumonitis in patients with advanced NSCLC.
Addition of Phase I:
With the November 2018 amendment allowing immune checkpoint inhibitor 
such as durvalumab consolidation therapy, a conventional dose-escalation 
design will be explored for patients who will be receiving durvalumab. Patients 
enrolled in the dose-escalation portion must commence nintedanib dosing at the 
same time as durvalumab is started. Dosing with nintedanib will start at 100 mg 
BID (see Table 1). 
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For patients who will be receiving durvalumab as standard of care prior to 
establishment of the recommended phase II dose of this combination, they will 
NOT undergo randomization (i.e. not blinded to treatment) and will receive 
active drug (nintedanib) on the first day of the first dose of durvalumab 10mg/kg 
every 2 weeks for up to 12 months. 
Target Accrual and Study 
Duration
Phase I: A maximum of 18 participants will be enrolled to the non-randomized 
dose escalation portion of this study. The number of participants required is a 
function of the unknown dose-toxicity relationship.
Phase II: A maximum of 99 participants will be enrolled to the randomized 
Phase 2 portion of this study (excluding patients replaced due to ineligibility or 
inability to start therapy).
Participants will be enrolled from up to 4 sites including Roswell Park.
 This study is anticipated to complete accrual within 4 years of study activation. 
Patients will receive either nintedanib or placebo to be administered for 
6 months. Patients will be followed for at least one year for initial primary 
analysis of study outcomes. Patients will be followed for no longer than 
2.5 years.
Study Procedures
Physical Examination: Baseline, Cycle 1 Day 1, Cycle 2 through Cycle 6 
Day 1, anytime when radiation pneumonitis is suspected to have occurred 
(within the first 6 months after completing radiation therapy), end of 
active treatment, between 76 to 97  days after last nintedanib/placebo dose, 
between 166 to 187 days after last nintedanib/placebo dose, long term follow-
up.
Hematology: Baseline, Cycle 1 Day 1, Cycle 2 through Cycle 6 Day 1, anytime 
when radiation pneumonitis is suspected to have occurred (within the first 
6 months after completing radiation therapy), end of active treatment, 
between 166 to 187 days after last nintedanib/placebo dose, long term follow-
up.
Chemistry: Baseline, Cycle 1 Day 1, Cycle 2 through Cycle 6 Day 1, anytime 
when radiation pneumonitis is suspected to have occurred (within the first 
6 months after completing radiation therapy), end of active treatment, 
between 166 to 187 days after last nintedanib/placebo dose, long term follow-
up.
Disease Evaluation: Baseline, Cycle 3 Day 1, Cycle 6 Day 1, anytime when 
radiation pneumonitis is suspected to have occurred (within the first 6 months 
after completing radiation therapy), between 76 to 97 days after last 
nintedanib dose, between 166 to 187 days after last nintedanib/placebo dose, 
and long term follow-up.
Performance Status: Baseline, Cycle 1 Day 1, Cycle 2 through Cycle 6 Day 1, 
anytime when radiation pneumonitis is suspected to have occurred (within the 
first 6 months after completing radiation therapy), end of active treatment, 
between 76 to 97 days after last nintedanib/placebo dose, between 166 to 
187 days after last nintedanib/placebo dose, long term follow-up.
Adverse Events: Baseline, Cycle 1 Day 1, Cycle 2 through Cycle 6 Day 1, 
anytime when radiation pneumonitis is suspected to have occurred (within the 
first 6 months after completing radiation therapy), end of active treatment, 
between 76 to 97 days after last nintedanib/placebo dose, between 166 to 
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187 days after last nintedanib/placebo dose, long term follow-up.
Statistical Analysis
Sample Size Determination: A maximum of 18 participants will be enrolled to 
the non-randomized dose escalation portion of this study. The number of 
participants required is a function of the unknown dose-toxicity relationship.
A maximum of 99 participants will be enrolled to the randomized Phase 2 
portion of this study (excluding patients replaced due to ineligibility or inability 
to start therapy).
Participants will be enrolled from up to 4 sites including Roswell Park.  Accrual 
is expected to take 4 years.
Phase II Randomization: Patients will be randomized to either the placebo or 
nintedanib arm in a 1:2 fashion using a stratified permuted block randomization 
scheme. The randomization lists to be used in this study will be generated by the 
study biostatistician. Patients will be included in data analyses according to their 
randomized treatment assignment irrespective of the treatment actually received 
(intent-to-treat). After randomization, initiation of the study intervention will 
take place once symptoms arise for the patient, this will be left to the patient’s 
discretion. Patient randomization will be done by the Department of 
Biostatistics at Roswell Park.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
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
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age 18 years or greater.
2.
Histologically or cytologically-proven non squamous cell NSCLC. Mixed 
histology with SCLC component not allowed.
3.
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 
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.
4.
Patient must have had a CR/PR/SD, 4-6 weeks after completing last 
fraction of radiation therapy.
5.
ECOG Performance Score 0-2.
6.
ANC ≥ 1,500/μL.
7.
Platelet count ≥ 100,000/μL.
8.
Hemoglobin ≥ 9 g/dL.
9.
Total bilirubin ≤ normal or for patients with Gilbert’s 
syndrome, ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin 
normal (per institute standards).
10. AST ≤ 1.5 x ULN. ALT and AST ≤ 2.5 x ULN is acceptable if there is 
liver metastasis.
11. Fertile patients must use adequate contraception.
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator:___________________________________________________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
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
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
WBRT < 14 days from the anticipated start of nintedanib/placebo 
administration.
2.
Squamous cell NSCLC
3.
Unable to start nintedanib/placebo treatment between 4 - 8 weeks after 
completing the last dose of thoracic radiation.
4.
Active untreated brain or leptomeningeal metastases. In patients with 
treated CNS metastases, eligible if symptoms controlled for at least 
4 weeks. Dexamethasone allowed if total daily dose does not exceed 
2 mg.
5.
Major injuries or surgery (e.g., craniotomy) < 28 days from the start of 
nintedanib/placebo administration. Wound should be healed prior to 
starting therapy.
6.
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-CTLA4 or HER2 
monoclonal antibodies). Hormone-related therapies (e.g., LHRH 
agonists, tamoxifen, etc.) are allowed.
7.
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.
8.
Inability to swallow study medication.
9.
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.
10. Known bleeding or thrombotic diathesis.
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
11. History of arterial or venous thromboembolic event within 12 months 
prior to study participation.
12. 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.
13. CTCAE Grade 2 or higher proteinuria.
14. Investigational agent administered < 28 days prior to treatment with 
nintedanib. Last dose of systemic chemotherapy administered < 14 days 
prior to treatment with nintedanib.
15. Known chronic active hepatitis B or hepatitis C. HIV-positive patients 
receiving or are candidates for antiretroviral therapy are also excluded.
16. Pregnancy or breast feeding. Female patients with child-bearing potential 
must have a negative pregnancy test (β-HCG test in urine or serum) prior 
to commencing study treatment.
17. Creatinine > 1.5 x ULN or CrCL < 45 mL/min. Refer to Appendix D.
18. Centrally located tumors with radiographic evidence (CT or MRI) of 
local invasion of major blood vessels.
19. 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).
20. 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.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature:___________________________________
Date:__________
Printed Name of Investigator:_________________________________________________
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TABLE OF CONTENTS
1
Background.....................................................................................................................12
1.1
Study Disease..................................................................................................................12
1.2
Study Drug......................................................................................................................12
1.3
Preclinical Studies with Nintedanib................................................................................13
1.4
Relevant Clinical Studies with Nintedanib.....................................................................14
1.4.1
Phase I.............................................................................................................................14
1.4.2
NSCLC ...........................................................................................................................15
1.4.3
Ovarian Cancer ...............................................................................................................16
1.4.4
Colorectal Cancer ...........................................................................................................17
1.4.5
Renal Cell Cancer...........................................................................................................17
1.4.6
Hepatocellular Cancer ....................................................................................................17
1.5
Correlative Studies..........................................................................................................17
1.6
Risks and/or Benefits......................................................................................................18
2
Rationale.........................................................................................................................19
3
Objectives .......................................................................................................................20
3.1
Primary Objective...........................................................................................................20
3.2
Secondary Objectives .....................................................................................................20
3.3
Exploratory Objective:....................................................................................................21
4
Methodology...................................................................................................................21
5
Study Design...................................................................................................................21
5.1
Target Accrual and Study Duration................................................................................23
6
Participant Selection .......................................................................................................23
6.1
Inclusion Criteria ............................................................................................................23
6.2
Exclusion Criteria ...........................................................................................................23
6.3
Inclusion of Women and Minorities...............................................................................25
7
Treatment Plan................................................................................................................25
7.1
Dosing and Administration.............................................................................................25
7.1.1
Nintedanib.......................................................................................................................26
7.1.2
Placebo to Nintedanib.....................................................................................................27
7.2
Dose Delays/Modifications ............................................................................................27
7.2.1
Treatment Delay .............................................................................................................27
7.2.2
Treatment Re-Initiation ..................................................................................................28
7.2.3
Dose Reduction...............................................................................................................29
7.2.4
Management of Adverse Events.....................................................................................29
7.3
General Concomitant Medication and Supportive Care.................................................30
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7.3.1
Diarrhea ..........................................................................................................................30
7.3.2
Nausea and Vomiting .....................................................................................................30
7.3.3
Neutropenia and Sepsis...................................................................................................30
7.3.4
Hepatic Function.............................................................................................................30
7.3.5
Other ...............................................................................................................................31
7.4
Duration of Treatment ....................................................................................................31
7.5
Treatment Discontinuation .............................................................................................31
7.6
Compliance.....................................................................................................................32
8
Investigational Product ...................................................................................................32
8.1
Drug Shipment................................................................................................................32
8.2
Pharmaceutical information............................................................................................33
8.2.1
Nintedanib - Study Drug.................................................................................................33
8.2.2
Placebo - Comparator .....................................................................................................33
8.3
Storage and Stability.......................................................................................................33
8.4
Handling and Disposal....................................................................................................34
8.5
Treatment Unblinding.....................................................................................................34
9
Study Procedures ............................................................................................................34
9.1
Participant Randomization and Registration ..................................................................35
9.2
Baseline Evaluations.......................................................................................................35
9.3
Evaluations Performed at Cycle 1 Day 1........................................................................36
9.4
Evaluations Performed on Day 1 of Cycle 2 through Cycle 6 .......................................36
9.5
Evaluations Performed Anytime When Radiation Pneumonitis is Suspected to Have 
Occurred (Within the First 6 Months After Completing Radiation Therapy)................37
9.6
Evaluations Performed at End of Active Treatment.......................................................38
9.7
Evaluations Performed 76 Days – 96 Days After the Last Nintedanib Dose.................38
9.8
Evaluations Performed 166 Days – 187 Days After the Last Nintedanib Dose.............38
9.9
Long Term Follow-Up Evaluations................................................................................39
9.10
Schedule of Procedures and Observations......................................................................40
9.11
Mitochondrial DNA and Cytokine Sampling.................................................................44
9.11.1
Blood Sample Collection and Processing.......................................................................44
9.11.2
Sample Handling and Shipment .....................................................................................44
9.12
miRNA and Vitamin D Sampling...................................................................................45
9.12.1
Blood Sample Collection and Processing.......................................................................45
9.12.2
Sample Handling and Shipment .....................................................................................45
10
Efficacy Evaluations.......................................................................................................46
10.1
Objective Tumor Response.............................................................................................46
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10.2
Target Lesions ................................................................................................................46
10.3
Non-Target Lesions ........................................................................................................47
10.4
Evaluation of Response ..................................................................................................47
10.5
Confirmation Measurement............................................................................................48
10.6
Guidelines for Evaluation of Measurable Disease..........................................................48
10.7
Radiation Pneumonitis Score..........................................................................................50
10.8
Radiation Treatment Field Central Review/Radiation Specifications (adapted from 
NCCN guidelines for NSCLC version 4.2014) ..............................................................51
11
Safety Evaluation............................................................................................................52
11.1
Adverse Events ...............................................................................................................52
11.1.1
Definition........................................................................................................................52
11.1.1.1 Diagnosis Versus Signs and Symptoms .........................................................................52
11.1.1.2 Adverse Events Occurring Secondary to Other Events..................................................52
11.1.1.3 Abnormal Laboratory Values .........................................................................................52
11.1.1.4 Preexisting Medical Conditions (Baseline Conditions)..................................................53
11.1.2
Grading and Relationship to Drug..................................................................................53
11.1.3
Reporting Adverse Events ..............................................................................................54
11.2
Serious Adverse Events ..................................................................................................55
11.2.1
Definition........................................................................................................................55
11.2.2
Reporting Serious Adverse Events .................................................................................55
11.3
Investigator Reporting: Notifying Boehringer Ingelheim ..............................................55
11.4
Follow-Up for Serious Adverse Events..........................................................................57
11.5
Unanticipated Problems..................................................................................................57
11.5.1
Definition........................................................................................................................57
11.5.2
Reporting Unanticipated Problems.................................................................................57
11.6
FDA Reporting ...............................................................................................................58
12
Data and Safety Monitoring............................................................................................59
13
Statistical Methodology..................................................................................................59
13.1
Sample Size Determination ............................................................................................60
13.2
Stratification ...................................................................................................................60
13.3
Randomization................................................................................................................61
13.4
Demographics and Baseline Characteristics...................................................................61
13.5
Primary Analysis ............................................................................................................61
13.6
Safety Analysis ...............................................................................................................62
13.7
Secondary Analyses........................................................................................................62
14
Correlative Studies..........................................................................................................64
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14.1
Mitochondrial DNA and Cytokine Analysis ..................................................................64
14.2
miRNA Analysis.............................................................................................................64
15
Ethical and Regulatory Standards...................................................................................64
15.1
Ethical Principles............................................................................................................64
15.2
Informed Consent ...........................................................................................................64
16
Study Responsibilities ....................................................................................................65
16.1
Data Collection ...............................................................................................................65
16.2
Maintenance of Study Documents..................................................................................65
17
Administrative Rules ......................................................................................................66
17.1
Revisions to the Protocol................................................................................................66
17.2
Termination of the Study................................................................................................66
17.3
Confidentiality ................................................................................................................66
18
Appendices .....................................................................................................................67
19
References.......................................................................................................................80
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IN-TEXT TABLES
Table 1
Dose escalation scheme for the combination of nintedanib with durvalumab............26
Table 2
Management of Nintedanib Adverse Events...............................................................28
Table 3
Nintedanib/Placebo Dose Reduction...........................................................................29
Table 4
Recommended Dose Adjustments for Nintedanib ......................................................29
Table 5
Schedule of Procedures and Observations ..................................................................41
Table 6
Time Point Response Criteria (+/- non-target disease) ...............................................47
Table 7
Time Point Response Criteria (non-target disease only).............................................48
Table 8
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies (Regardless of 
Expectedness) ................................................................................................................................54
Table 9
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness) ................................................................................................................................54
APPENDICES
Appendix A.
Instructions for Network Sites .............................................................................68
Appendix B.
Procedures for the Follow-Up of a Potential Drug-Induced Liver Injury Case 
(Hy`s Law Case)............................................................................................................................72
Appendix C.
ECOG Performance Status Scores.......................................................................75
Appendix D.
Calculation for Creatinine Clearance...................................................................76
Appendix E.
Patient Diary ........................................................................................................77
Appendix F.
Quality-of-Life-Questionnaires............................................................................79
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1
BACKGROUND
1.1
Study Disease
Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide 
(1). Majority of patients present with an advanced unresectable stage of disease. Concurrent 
chemoradiation therapy is the standard of care in patients with Stage III locally advanced non-
small cell lung cancer (NSCLC) (2). Symptomatic radiation pneumonitis occurs in 15 - 40% of 
NSCLC patients receiving concurrent chemoradiation (3,4). This treatment complication 
adversely affects quality of life and may rarely be fatal (3,4).
Various treatment-related risk factors have been identified that can predict the development of 
symptomatic radiation pneumonitis (4,5). These include V20 (lung volume receiving > 20 Gy), 
chemotherapy regimen and mean lung dose (MLD). For example, to limit the frequency of 
symptomatic radiation pneumonitis to < 30%, the V20 and MLD thresholds as calculated from 
the dose-volume histogram minus the gross tumor volume were 41.5% and 22.4 Gy, respectively 
(5). The use of carboplatin and paclitaxel regimen was associated with the highest risk in patients 
greater than 65 years (4).
The pathophysiology of radiation pneumonitis and the eventual pulmonary fibrosis that ensues is 
thought to be secondary to inflammatory and/or profibrotic cytokines such as IL-1α, IL-6, IL-10 
and TGF-β that are activated by volatile reactive oxygen and nitrogen species which are 
generated in response to the oxidative stress caused by the tissue damage incurred from radiation 
(6-10). A TH2-like immune response with elevated mRNA levels of the transcription factor 
GATA-3 has been implicated as well in this process (11). Pharmacologic inhibition of 
CC chemokine receptor 1 (CCR1) prevented lung inflammation and fibrosis induced by radiation 
(12). More recently, murine models of radiation-pneumonitis reveals early accumulation of 
CD4+FoxP3+Treg cells 21 days post-radiation. However, the role of these Treg cells in 
dampening or worsening radiation-induced inflammatory tissue damage is speculative at this 
time and not clearly defined (13).
Preclinical studies suggest that antioxidants can be effective radioprotectors in mice models (10, 
13-14), but optimal dose and method of administration maybe challenging (15,16). Amifostine, a 
widely studied radioprotective agent metabolized to an active form which binds to free radicals, 
did not appear to reduce the incidence of pulmonary toxicity in the large RTOG 9801 Phase III 
trial in patients with locally advanced NSCLC receiving hyperfractionated radiation concurrently 
with chemotherapy, with no difference seen in the patient-reported quality of life (QOL) scales 
in terms of dyspnea, cough and chest pain between the amifostine versus no-amifostine groups 
(17,18).
1.2
Study Drug
Nintedanib is a multikinase inhibitor with potent activity against VEGFR/PDGFR/FGFR. PDGF, 
VEGF and FGF are critical profibrotic mediators, which have been shown to play a role in the 
development of fibrosis (19).
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1.3
Preclinical Studies with Nintedanib
Nintedanib (BIBF1120) is a potent, orally available triple kinase inhibitor targeting VEGFRs, 
PDGFRs and FGFRs.
Nintedanib inhibits the signaling cascade mediating angiogenesis by binding to the adenosine 
triphosphate (ATP) binding pocket of the receptor kinase domain, thus interfering with cross-
activation via auto-phosphorylation of the receptor homodimers.
The specific and simultaneous abrogation of these pathways results in effective growth inhibition 
of both endothelial and, via PDGF- and FGF-receptors of perivascular cells which may be more 
effective than inhibition of endothelial cell growth via the VEGF pathway alone. Furthermore, 
signaling by FGF-receptors has been identified as a possible escape mechanism for tumor 
angiogenesis when the VEGF pathway is disrupted.
Besides inhibition of neo-angiogenesis, it may alter tumor maintenance by inducing apoptosis of 
tumor blood vessel endothelial cells. Inhibition of receptor kinases may also interfere with 
autocrine and paracrine stimulation of tumor angiogenesis via activation loops involving VEGF, 
PDGF, and bFGF utilized by vascular and perivascular cells such as pericytes and vascular 
smooth muscle cells.
In addition, preclinical models show that nintedanib may have a direct anti-tumor effect on those 
malignant cells which overexpress PDGFR and/or FGFR (e.g., H1703 NSCLC cells).
IC50 (nmol/L)
VEGFR (1 / 2 / 3)
34 / 21 / 13
PDGFR (α / β)
59 / 65
FGFR (1 / 2 / 3)
69 / 37 / 108
Flt-3
26
RET
35
Src, Lck, Lyn
156 / 16 / 195
In vitro, the target receptors are all inhibited by nintedanib in low nanomolar concentrations. In 
in vivo nude mouse models, nintedanib showed good anti-tumor efficacy at doses of 
50 - 100 mg/kg, leading to a substantial delay of tumor growth or even complete tumor-stasis in 
xenografts of a broad range of differing human tumor types. Histological examination of treated 
tumors showed a marked reduction of tumor vessel density by approximately 80% (20).
The metabolism of nintedanib was predominantly characterized by the ester cleavage of the 
methyl ester moiety yielding BIBF1202, which was further metabolized by conjugation to 
glucuronic acid yielding the 1-O-acylglucuronide. Data collected in this study show that 
nintedanib has a favorable PK and excretion profile with almost no elimination via the urine, 
only 0.7% of total 14C radioactivity was eliminated via the urine. The metabolic characteristics 
are predominantly independent of cytochrome P450-catalysed metabolic pathways (21).
A soft gelatin capsule formulation of nintedanib is used in man. After oral administration, 
nintedanib is absorbed quickly. Maximum plasma concentrations (Cmax) generally occur 2 to 
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4 hours after administration. So far, no evidence for a deviation from dose proportionality of the 
PK of nintedanib has been observed. Steady state is reached latest after one week of dosing. The 
terminal half-life of nintedanib is in the range of 7 to 19 hours. Nintedanib is mainly eliminated 
via faeces (21). Nintedanib is non-mutagenic, even at high doses.
Two exploratory studies in rats revealed a teratogenic effect of nintedanib with a steep 
dose/effect relationship and an early onset of embryofetal deaths at low dosages. This effect was 
observed at dose levels resulting in plasma drug concentrations comparable to or below those in 
humans. Because the concentration of nintedanib in semen is unknown, males receiving 
nintedanib and having sexual intercourse with females of childbearing potential should use latex 
condoms. Women of childbearing potential should be advised to use adequate contraception 
during and at least 3 months after the last dose of nintedanib.
A detailed discussion of the preclinical pharmacology, pharmacokinetics and toxicology of 
nintedanib can be found in the Investigator’s Brochure.
1.4
Relevant Clinical Studies with Nintedanib
Nintedanib is being evaluated in several cancers. Additionally, nintedanib has been recently 
studied for the non-cancer indication idiopathic pulmonary fibrosis (IPF). A randomized Phase II 
placebo-controlled trial investigating the efficacy and safety of nintedanib in IPF showed that 
even though the primary endpoint was not met (annual rate of forced vital capacity FVC 
decline), there was a significant reduction in the rate of acute exacerbations seen in the 
nintedanib 150 mg BID treatment group compared to placebo (2.4 versus 15.7 per 100 patient-
years, p = 0.02), improved QOL nintedanib 150 mg BID treatment compared to worsening QOL 
scores in the placebo group (p = 0.007), as well as less decline in baseline total lung capacity 
(p < 0.001) and resting oxygen saturations (p = 0.05) over time in the nintedanib 150 mg BID 
treatment compared to placebo (22). Two replicate Phase III trials (INPULSIS-1 and 
INPUSLSIS-2) were then conducted which showed that 52-week treatment with nintedanib 
reduced the decline in FVC compared to placebo. In INPULSIS-2, there was a significant benefit 
with nintedanib versus placebo in the time to first acute exacerbation (p = 0.005) which was not 
significantly different in INPULSIS-1 (23). Multikinase inhibitors similar to nintedanib such as 
sunitinib and sorafenib have demonstrated immunomodulatory effects through reduction of 
cytokines such as IL-10 and TGF-B (24,25).
As of 15 February 2013, 3556 cancer patients, over 1000 patients with IPF, and 140 healthy 
volunteers had been treated with nintedanib or nintedanib matching placebo, in monotherapy or 
in combination with chemotherapy.
1.4.1
Phase I
Phase I dose selection studies revealed that nintedanib is generally well tolerated with mild to 
moderate adverse effects such as gastrointestinal symptoms (i.e., nausea, diarrhoea, vomiting, 
abdominal pain) and reversible elevations of liver enzymes. Initial signs of clinical activity 
including an encouraging rate of patients with stabilization of their tumor of 54% and 68%, 
respectively; have been observed in patients with various solid tumors (26).
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Based on the Phase I dose escalation trials with nintedanib monotherapy, the maximum tolerated 
dose was defined to be 250 mg for twice daily dosing in Caucasians and 200 mg twice daily in 
Japanese patients with a manageable safety profile in advanced cancer patients. Based on the 
overall safety profile, the recommended Phase II dose (RP2D) for nintedanib as monotherapy is 
200 mg bid.
The maximum tolerated dose for combination therapy of nintedanib in combination with 
pemetrexed, docetaxel, paclitaxel/carboplatin and FOLFOX is 200 mg bid. Combination of 
nintedanib with other anti-cancer drugs revealed a similar adverse event profile as compared to 
nintedanib monotherapy except for the chemotherapy related toxicities. There was no change of 
the pharmacokinetic parameters of nintedanib or of the cytotoxic compounds due to the 
combined treatment. Dose limiting toxicity consisted mostly of liver transaminase elevations as 
in the monotherapy Phase I trials with the exception of the combination of nintedanib with 
pemetrexed, where fatigue was the most relevant dose limiting toxicity.
Available pharmacokinetic data indicate that the systemic exposure needed for biological activity 
can be achieved starting with doses of 100 mg nintedanib once daily.
The predominant adverse events were nausea, diarrhoea, vomiting, abdominal pain and fatigue 
of mostly low to moderate severity. Dose limiting toxicities (DLT) were mainly confined to 
reversible hepatic enzyme elevations (AST, ALT, γ-GT) which increased dose-dependently. 
Most cases occurring at doses of 250 mg and above, and a very low incidence at doses below 
200 mg and were reversible after discontinuation of nintedanib treatment. All adverse events 
observed after single administration of single doses of nintedanib to healthy volunteers were only 
of CTCAE Grade 1 severity and fully reversible (21).
1.4.2
NSCLC
In a Phase II trial in NSCLC patients the safety profile of nintedanib observed in Phase I trials 
could be confirmed. Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea 
(47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine 
transaminase (13.7%) and aspartate aminotransferase elevations (9.6%) In conclusion, it was 
generally well tolerated and displayed single agent activity in advanced or recurrent NSCLC 
patients. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group 
(ECOG) 0–1 patients (n = 56) had a median progression free survival (PFS) of 11.6 weeks and a 
median OS of 37.7 weeks. Tumor stabilization was achieved in 46% of patients (ECOG 0–
1 patients: 59%), with one confirmed partial response at 250 mg bid (27).
LUME-Lung 1 was an international, randomized, double-blind, Phase III trial assessing the 
efficacy and safety of docetaxel plus nintedanib as 2nd line therapy for non-small-cell lung cancer 
(NSCLC). In total, 1314 patients with Stage IIIB/IV or recurrent NSCLC (all histologies) who 
had progressed after 1st line chemotherapy were randomized in 1:1 fashion to either receive 
Nintedanib 200 mg BID + Docetaxel (n = 655) or Placebo BID + Docetaxel (n = 659).
LUME-Lung 1 met its primary endpoint by showing a statistically significant improvement of 
PFS for all patients regardless of histology (median PFS 3.4 versus 2.7 months; HR 0.79, 
p = 0.0019) for Nintedanib in combination with docetaxel.
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A significant improvement in OS was demonstrated in patients with adenocarcinoma (HR 0.83, 
p = 0.0359, median 10.3 to 12.6 months).
Patients with a poor prognosis defined as time since start of 1st line therapy < 9 months also 
experienced significant OS improvement from the addition of nintedanib to docetaxel (HR 0.75, 
p = 0.0073, median OS 7.9 to 10.9 months).
The predominant adverse events were nausea, diarrhoea, vomiting, abdominal pain and fatigue 
of mostly low to moderate intensity after monotherapy with nintedanib. Dose limiting toxicities 
were dose dependent hepatic enzyme elevations that were reversible after discontinuation of 
nintedanib treatment. These liver enzyme elevations were only in few cases accompanied by a 
simultaneous increase of bilirubin. In general common terminology criteria for adverse events 
(CTCAE version 3, Grade 3liver enzyme increases were reported in the dose groups of 250 mg 
twice daily or higher. They also were reversible and usually occurred within the first 2 months of 
treatment.
Hypertension or thromboembolic events were rare and did not suggest an increased frequency as 
a consequence of therapy with nintedanib (28).
LUME-Lung 2 was a similar randomized, double-blind, Phase III study of nintedanib plus 
pemetrexed versus placebo plus pemetrexed in patients with advanced non-squamous NSCLC 
after failure of first line chemotherapy.
Based on a preplanned futility analysis of investigator-assessed PFS, enrolment was halted after 
713/1300 planned patients had been enrolled. The analysis (based on conditional power for PFS 
by investigator assessment) suggested that the study was futile and that the primary endpoint of 
centrally assessed PFS would likely not be met. The futility analysis was based on conditional 
power; there was no formal testing of null hypothesis as planned for primary analysis no safety 
issues were identified.
Even though the study was stopped prematurely, the primary endpoint of this Phase III trial was 
met; treatment with nintedanib plus pemetrexed resulted in a significant prolongation of centrally 
reviewed PFS compared with placebo plus pemetrexed (median PFS 4.4 vs. 3.6 months with a 
HR 0.83; p = 0.0435). The disease control rate was also increased significantly in nintedanib-
treated patients. There was no improvement in OS in nintedanib-treated patients. Nintedanib 
200 mg bid in combination with pemetrexed had an acceptable and manageable safety profile, 
with no new or unexpected safety findings. The most frequent AEs were reversible increases in 
liver enzymes and gastrointestinal events (29).
The LUME Columbus is an ongoing randomized Phase III study of docetaxel plus nintedanib or 
placebo as second-line treatment in advanced NSCLC (NCT02231164). Approximately 
800 patients will be recruited to this study with an estimated completion date in March 2018.
1.4.3
Ovarian Cancer
A randomized Phase II maintenance trial in ovarian cancer in which the efficacy and safety of 
nine months of continuous twice daily doses of nintedanib following chemotherapy was 
investigated, has identified the potential activity of nintedanib with a 36-week PFS of 16.3% 
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compared to 5.0% in the control group. The safety profile was consistent with findings 
previously reported for nintedanib administered as monotherapy as mentioned above (30).
Nintedanib was evaluated in a Phase III randomized, placebo-controlled, double-blind, 
multicentre ovarian study with 1366 patients. Patients received nintedanib plus paclitaxel and 
carboplatin or placebo plus paclitaxel and carboplatin for 6 cycles. This was followed by 
monotherapy nintedanib or placebo for up to 120 weeks. The trial met its primary endpoint by 
demonstrating a statistically significant improvement in progression-free survival (HR 0.84; 
95%CI 0.72 - 0.98; p = 0.0239, median PFS 17.3 months for nintedanib and 16.6 months for 
placebo). Overall survival data are immature but currently show no trend in either direction. 
Main adverse events were GI side effects and increased hematological toxicity (31).
1.4.4
Colorectal Cancer
A Phase I/II, open-label, randomized study of nintedanib plus mFOLFOX6 compared to 
bevacizumab plus mFOLFOX6 in 120 patients with metastatic colorectal cancer was performed, 
demonstrating an acceptable safety profile of nintedanib in combination with mFOLFOX6. In 
comparison to bevacizumab, nintedanib showed a similar magnitude of efficacy, a similar 
safety/tolerability profile, a similar exposure and dose intensity of mFOLFOX6 (32).
A Phase III study is going to ongoing to evaluate the efficacy of nintedanib in patients with 
metastatic colorectal cancer (mCRC) after failure of previous treatment with standard 
chemotherapy and biological agents (ClinicalTrials.gov Identifier: NCT02149108).
1.4.5
Renal Cell Cancer
Nintedanib has been studied in a randomized Phase II study in metastatic clear cell RCC with 
sunitinib as the control arm. Similar efficacy was seen in both arms of this study. AEs observed 
more frequent in the nintedanib arm included diarrheal, nausea, fatigue and infection, whereas 
AEs more frequent in the sunitinib arm consisted of bleeding, anaemia, hypertension, hand-foot 
syndrome and stomatitis (33).
1.4.6
Hepatocellular Cancer
The efficacy and safety of nintedanib versus sorafenib in Asian Patients with Advanced 
Hepatocellular Carcinoma was investigated in a randomized Phase II trial. Nintedanib showed 
similar efficacy to sorafenib, with a favorable and manageable AE profile. More patients in the 
sorafenib arm had severe AEs and drug-related AEs compared with patients in the nintedanib 
arm, and more patients in the sorafenib arm required dose reduction compared with the 
nintedanib arm. Nintedanib AEs were manageable; in the nintedanib arm there were fewer 
hypertension, palmar-plantar erythrodysesthesia syndrome, and transaminase elevation events 
(34).
For more details please refer to the investigator drug brochure for nintedanib.
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1.5
Correlative Studies
The pathophysiology of radiation pneumonitis (RP) and the eventual pulmonary fibrosis that 
ensues is thought to be secondary to inflammatory and/or profibrotic cytokines such as IL-1α, 
IL-6, IL-10 and TGF-β that are activated by volatile reactive oxygen and nitrogen species 
generated in response to the oxidative stress caused by the tissue damage incurred from radiation 
(35-39). The 1,25 (OH)2D3-vitamin D receptor (VDR) pathway in turn has been implicated as a 
negative regulator of the profibrotic TGF-B/SMAD signaling (40-42). In fact, one in vivo rat 
model demonstrated that vitamin D3 administration has a protective effect against radiation-
induced pulmonary toxicity(43). Although vitamin D insufficiency is highly prevalent, there is 
no consensus on optimal blood levels. Moreover, there are no well-designed prospective studies 
evaluating vitamin D levels as a modifiable risk factor in association with radiation pneumonitis. 
In addition, new models of acute lung injury implicate mitochondrial damage-associated 
molecular patterns, including mitochondrial DNA, which are proinflammatory in nature by 
increasing endothelial cell permeability and levels of various cytokines such as Il-6 and IL-10 
(44,45). However, the clinical relevance of mitochondrial DNA in radiation-induced lung 
inflammation is not well-characterized to date. We propose that baseline vitamin D and changes 
in levels of cytokine and mitochondrial DNA levels maybe predictive of the development of 
radiation pneumonitis.
MicroRNAs (miRNAs) are crucial biological regulators of gene expression that function through 
suppression of their target genes and are involved in a variety of pathophysiologic processes 
(46,47). A TH2-like immune response with elevated mRNA levels of the transcription factor 
GATA-3 has been implicated in radiation-induced lung injury (48). VEGF appears to facilitate 
TH2-mediated lung inflammatory responses as well by reducing miR-1 expression whereas 
exogenous administration of miR-1 inhibited inflammatory responses and cytokine expression 
(49). Another experimental model shows that expression of miR-127 significantly reduced 
cytokine release by macrophages and attenuated lung inflammation (50). More recently, murine 
models of radiation-pneumonitis reveals early accumulation of CD4+FoxP3+Treg cells 21 days 
post-radiation (51). This also implicates GATA-3 since it transactivates TH2 cytokines, regulates 
FoxP3 expression and Treg function. GATA-3 activity in Tregs in turn is regulated/decreased by 
the transcriptional repressor Bcl6 resulting in downregulation of miR-2(52). Another thoracic 
radiation model reveals changes in endothelial and alveolar cell-specific gene transcripts which 
correlated with mi-RNA expression, such as miR-107 and miR-511 (with TLR4 expression), 
miR-155 (with TGF-B expression) and miR-126 (with VEGF expression).(53). We propose that 
the nanoparticle chip assay maybe a useful tool to measure the expression of selected miRNAs as 
biomarkers that may predict risk of developing radiation pneumonitis and potentially to identify 
patients who may benefit from nintedanib treatment in the prevention of radiation pneumonitis.
Semi-quantitative scores based on computerized tomography (CT) findings have been shown to 
have prognostic implications among patients with idiopathic pulmonary fibrosis or 
hypersensitivity pneumonitis (54,55). This study proposes to evaluate a modified RP score to 
compare the severity of changes in each treatment group as it correlates with QOL and 
pulmonary function changes.
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1.6
Risks and/or Benefits
The risks of therapy with nintedanib in adult patients are primarily related to:
•
the GI tract (i.e., nausea, vomiting, diarrhea, abdominal pain)
•
increases in liver enzymes (i.e., AST, ALT, γ-GT)
•
fatigue, asthenia and anorexia
Liver enzymes must be followed closely during treatment with nintedanib.
Therapy with the trial drugs must be interrupted in the event of relevant hepatic toxicity and 
further treatment is to be withheld until recovery of the abnormal laboratory parameters.
Impairment of immune and of kidney function, thromboembolic events and GI perforations are 
considered possible side effects of treatment with nintedanib as they have been reported for some 
other drugs in the class of angiogenesis inhibitors. Thus far, these side effects have been 
observed in the trials conducted with nintedanib, but not to a relevant degree. Hypertension is 
also supposed to be a possible side effect of VEGFR inhibitors and a slightly increased 
frequency of hypertension has been observed in the trials with nintedanib to a mild to moderate 
degree and only few cases of CTCAE Grade 3 or Grade 4 hypertension have been observed. 
With respect to bleeding as one of the potentially serious side effects of antiangiogenesis agents 
in the LUME–Lung 1 trial involving 1314 patients more bleeding events were reported for 
nintedanib-treated squamous cell carcinoma (SCC) patients (all grades: 17.1% vs. 10.9%; 
Grade ≥ 3: 2.9% vs. 1.3%) than for those with adenocarcinoma (all grades: 10.9% vs. 11.1%; 
Grade ≥ 3: 1.5% vs. 1.3%). Fatal bleeding events, serious skin reactions, thrombosis, and 
perforations occurred at a low frequency and were balanced between both arms regardless of 
histology.
Based upon a non-clinical safety study in vitro, nintedanib may have a potential risk of 
phototoxicity (skin and eyes) in vivo. Few cases of photosensitivity reactions (less than 1%) and 
of CTCAE Grade 1 intensity only have been reported from the clinical studies to date. If 
adequate precautions are taken (avoidance of prolonged ultraviolet (UV) exposure, use of broad 
spectrum sunscreen and sunglasses), treatment with nintedanib is considered safe.
Although considerable progress has occurred in understanding the biological characteristics of 
cancer as well as the development of more effective treatment regimens, most patients with 
locally advanced or metastatic tumors succumb to their disease. Thus, there is a substantial need 
for novel therapeutic strategies to improve the outcome for patients with advanced NSCLC. The 
sequelae of treatment, such as radiation pneumonitis and fibrosis, can also negatively impact 
short-term and long-term QOL.
2
RATIONALE
Nintedanib 200 mg orally twice daily had been evaluated in several Phase III NSCLC studies as 
discussed previously. Based on the data summarized in Section 1.4, the use of nintedanib may 
potentially mitigate both the early phase of inflammatory response and the latter phase of fibrotic 
response. Because the risk of acute radiation pneumonitis is greatest within the first 6 months 
after completion of thoracic radiation, this study will randomize patients to begin treatment 
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between 4 - 8 weeks upon completion of the last fraction of thoracic radiation, with either 
nintedanib or placebo treatment for 6 months.
Antiangiogenic treatment with the orally available triple angiokinase inhibitor nintedanib with 
inhibition of VEGFR, PDGFR and FGFR offers the chance to control both locally recurrent and 
distant metastatic disease on an outpatient basis. Treatment with nintedanib may have the 
potential to provide significant benefit to patients with locally advanced NSCLC by slowing 
tumor progression and metastasis, since its cellular target is expressed on the tumor vasculature 
in most malignancies. Induction of endothelial cell apoptosis may result in subsequent 
degradation of tumor vessels and subsequent tumor necrosis. Additionally, tumor growth may be 
affected by direct anti-tumor effects (e.g., tumor cells that express VEGFR, PDGFR or FGFR). 
Moreover, due to the positive effects of nintedanib therapy in patients with ILD, we hope that 
nintedanib therapy can also ameliorate radiation pneumonitis in locally advanced NSCLC who 
receive chemoradiation therapy.
As the standard of care has changed in mid-2017 with the announcement of the results from the 
PACIFIC trial showing that consolidation treatment with durvalumab, after concurrent 
chemoradiation for unresectable stage III NSCLC, prolonged progression-free survival as well as 
overall survival in an updated analysis (56,57), nintedanib treatment will occur concurrently 
while patients receive durvalumab consolidation treatment as standard of care practice. Notably, 
there is approximately 10% higher frequency of any grade pneumonitis or radiation pneumonitis 
in patients who received durvalumab versus placebo as consolidation in the PACIFIC trial (34% 
versus 25%). Moreover, additional immune checkpoint inhibitors are in various stages of testing, 
either as induction therapy, consolidation therapy or concurrently with radiation. Hence, an 
additional stratification factor of exposure to immunotherapy agents will be introduced in the 
analysis of the study. 
The combination of nintedanib with immune checkpoint inhibitors are ongoing (NCT03377023 
with nivolumab + ipilimumab in NSCLC; NCT02856423 with pembrolizumab in solid tumors, 
PEMBIB). The results of the PEMBIB study were recently reported. A total of 13 patients (12 
evaluable for DLT) were enrolled in the dose-escalation portion (none of which were NSCLC 
patients). Three DLTs of liver enzyme elevation were observed in the 200 mg BID nintedanib 
dose thus for the phase II portion, final recommended dose of nintedanib was 150 mg BID 
nintedanib in combination with pembrolizumab 200mg flat dosing every 21 days (58)
3
OBJECTIVES
3.1
Primary Objectives
•
Phase I: To evaluate the safety of the combination of durvalumab with nintedanib in 
patients with unresectable Stage II/III/oligometastatic IV NSCLC
•
Phase 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.
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3.2
Secondary Objectives
•
To compare the quality of life (QOL) in patients who received nintedanib versus placebo 
during active treatment until 6 months after completion of treatment.
•
To compare the progression-free survival, overall survival and 1-year progression-free 
survival rate in patients who received nintedanib versus placebo.
•
To compare pulmonary function test (PFT) results and RP score in patients who received 
nintedanib versus placebo.
•
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.
3.3
Exploratory Objective:
•
To investigate blood-based biomarkers in evaluating risk of developing radiation 
pneumonitis as well as the efficacy of nintedanib.
4
METHODOLOGY
5
STUDY DESIGN
A maximum of 18 participants will be enrolled to the Phase I non-randomized dose escalation 
portion of this study. See Figure 1 for the Phase 1 dose-escalation study schema.
A maximum of 99 participants will be enrolled to the randomized Phase II, double-blind, 
placebo-controlled portion of the study of nintedanib as prophylaxis against radiation 
pneumonitis in patients with advanced NSCLC. The study schema is depicted below.
All participants will sign an informed consent prior to study related tests. All participants will 
meet the inclusion and exclusion criteria summarized in Section 6.1 and Section 6.2. 
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Figure 1
Phase 1 Dose-escalation Study Schema
Unresectable Stage II/III/oligometastatic 
IV NSCLC
Platinum doublet combination concurrently with 
thoracic radiation (patients must receive at least > 54 
Gy of the total planned radiation dose
CR/PR/SD, 4-8 weeks after completing 
last fraction of radiation therapy
Nintedanib Dose-escalation (n max=18)
3 + 3 design with fixed-dose durvalumab consolidation 
treatment on Cycle 1-Day 1 and Day 15 (subsequent 
durvalumab doses per institutional practice)
MTD determined for Phase II
For patients who will be receiving durvalumab consolidation treatment as standard of care prior 
to establishment of the recommended phase II dose of this combination, they will NOT undergo 
randomization (i.e. not blinded to treatment) and will receive active drug (nintedanib) on the first 
day of the first dose of durvalumab 10mg/kg every 2 weeks for up to 12 months.
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Figure 2.
Phase II Study Schema
Unresectable Stage II/III/oligometastatic 
IV NSCLC
Platinum doublet combination 
concurrently with thoracic radiation 
(patients must receive at least > 54 Gy of 
the total planned radiation dose)
CR/PR/SD, 4-8 weeks after completing 
last fraction of radiation therapy, 2:1 
randomization
Nintedanib200 mg BID (without durvalumab) or 
dose determined from dose-escalation portion in 
combination with durvalumab consolidation
N=66
Nintedanib matching 
Placebo
BID with or without 
durvalumab consolidation
N=33
6 months of therapy (discontinuation only for toxicity 
or patient choice) §§. Upon occurrence of radiation 
pneumonitis, may continue nintedanib/placebo in 
addition to supportive medications
§Patients will be stratified according to chemotherapy regimen (i.e., platinum with etoposide, 
platinum with taxane, platinum with pemetrexed) utilized concurrently with radiation as well as 
exposure to immune checkpoint inhibitor therapy.
§§An interim analysis for futility will be conducted when the first n1=33 patients have completed 
6-months of follow-up post-chemoradiation; that is, when the first n1=33 patients are evaluable 
for the primary end-point (the rate of CTCAE Grade 2 or higher radiation pneumonitis at 6 
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months after completion of chemoradiation). If the estimated common odds ratio (COR) is 
greater than or equal to 0.8, then the study will stop early for futility. Otherwise, the study will 
continue and enroll and additional n2=66 patients. Additionally, at this time the safety profile of 
the treatment arms may be evaluated and considered in the decision for study continuation.
5.1
Target Accrual and Study Duration
A maximum of 18 participants will be enrolled to the non-randomized dose escalation portion of 
this study. The number of participants required is a function of the unknown dose-toxicity 
relationship.
A maximum of 99 participants will be enrolled to the randomized Phase 2 portion of this study 
(excluding patients replaced due to ineligibility or inability to start therapy).
Participants will be enrolled from up to 4 sites including Roswell Park. Accrual is expected to 
take up to 4 years.
6
PARTICIPANT SELECTION
6.1
Inclusion Criteria
1
Age 18 years or greater.
2
Histologically or cytologically-proven non squamous cell NSCLC. Mixed histology with SCLC 
component not allowed.
3
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 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.
4
Patient must have had a CR/PR/SD, 4-6 weeks after completing last fraction of radiation therapy. 
5
ECOG Performance Score 0 - 2 (Appendix C).
6
ANC ≥ 1,500/μL.
7
Platelet count ≥ 100,000/μL.
8
Hemoglobin ≥ 9 g/dL.
9
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).
10 AST ≤ 1.5 x ULN. ALT and AST ≤ 2.5 x ULN is acceptable if there is liver metastasis.
11 Fertile patients must use adequate contraception.
6.2
Exclusion Criteria
1
WBRT < 14 days from the anticipated start of nintedanib/placebo administration.
2
Squamous cell NSCLC
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3
Unable to start nintedanib/placebo treatment between 4 – 8 weeks after completing the last dose of 
thoracic radiation.
4
Active untreated brain or leptomeningeal metastases. In patients with treated CNS metastases, eligible 
if symptoms controlled for at least 4 weeks. Dexamethasone allowed if total daily dose does not 
exceed 2 mg.
5
Major injuries or surgery (e.g., craniotomy) < 28 days from the start of nintedanib/placebo 
administration. Wound should be healed prior to starting therapy.
6
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-CTLA4 
or HER2 monoclonal antibodies). Hormone-related therapies (e.g., LHRH agonists, tamoxifen, etc.) 
are allowed.
7
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.
8
Inability to swallow study medication.
9
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.
10 Known bleeding or thrombotic diathesis.
11 History of arterial or venous thromboembolic event within 12 months prior to study participation.
12 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.
13 CTCAE Grade 2 or higher proteinuria.
14 Investigational agent administered < 28 days prior to treatment with nintedanib. Last dose of systemic 
chemotherapy administered < 14 days prior to treatment with nintedanib. 
15 Known chronic active hepatitis B or hepatitis C. HIV-positive patients receiving or are candidates for 
antiretroviral therapy are also excluded.
16 Pregnancy or breast feeding. Female patients with child-bearing potential must have a negative 
pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment.
17 Creatinine > 1.5 x ULN or CrCL < 45 mL/min. Refer to Appendix D.
18 Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood 
vessels.
19 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/day).
20
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. 
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6.3
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
7
TREATMENT PLAN
7.1
Dosing and Administration
Treatment will be administered on an outpatient basis. Each cycle will be 28 days. Patients will 
be dispensed sufficient supply for at least 28 days or until their next scheduled visit. Reported 
adverse events (AEs) and potential risks are described in Section 1.6. Appropriate dose 
modifications are described in Section Error! Reference source not found..
With the November 2018 amendment allowing immune checkpoint inhibitor such as durvalumab 
consolidation therapy, a conventional dose-escalation design will be explored for patients who 
will be receiving durvalumab. Patients enrolled in the dose-escalation portion must commence 
nintedanib dosing at the same time as durvalumab is started. Dosing with nintedanib will start at 
100 mg BID (see Table 1). 
For patients who will be receiving durvalumab as standard of care prior to establishment of the 
recommended phase II dose of this combination, they will NOT undergo randomization (i.e. not 
blinded to treatment) and will receive active drug (nintedanib) on the first day of the first dose of 
durvalumab 10mg/kg every 2 weeks for up to 12 months. 
All administered doses of the study drugs will be recorded in a pill diary to be provided to the 
patient (Appendix E).
7.1.1
Nintedanib 
During Phase I dose escalation the participant will not be blinded to treatment and will receive 
active nintedanib according to the dose level assigned.
During Phase II, the participant will be randomized to receive either nintedanib or matched 
placebo.
The capsules of the defined dose (or placebo during Phase II) should be swallowed unchewed 
with a glass of water of about 250 mL or 8 oz. The dose interval should be of around 12 hours at 
the same times every day, usually in the morning and the evening after food intake.
In case of a missed dose, patients should proceed with the intake of medication according to the 
predefined schedule and take the next scheduled dose when it is due. Do not replace missed dose. 
All administered doses will be recorded in a pill diary to be provided to the patient (Appendix E).
7.1.2
Durvalumab
During dose escalation, the first two doses of durvalumab (10 mg/kg) will be given intravenously 
(IV) every 2 weeks over 60 minutes. These doses will be administered together with Cycle 1 Day 
1 and day 15 (-1/+7 days) doses of nintedanib. Subsequent doses will be administered according 
to institutional practice.
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During phase II, use of an immune checkpoint inhibitor (durvalumab), in the post-
chemoradiation consolidation period is at the discretion of the treating physician.
7.2
Phase I
Dose escalation will proceed in a 3+3 fashion. Standard 3+3 rules will be followed until the 
maximum tolerated dose (MTD) is found. A total of 3 dose levels will be explored, with the 
MTD defined as the dose level wherein no more than 1 out of 6 patients evaluable for dose 
limiting toxicities (DLTs) experienced treatment-related DLT (Table 1). 
Initially, 3 patients are enrolled at dose level 1. If no dose DLTs are observed, then 3 new 
patients are escalated to dose level 2. If ≥ 2 DLTs are observed at dose level 1, then dose-
escalation stage is completed and study will be terminated. 
If 1 DLT is observed, an additional 3 patients are enrolled at dose level 1. In those 6 patients at 
dose level 1, if ≤ 1 DLTs are observed attributable to the combination or nintedanib alone, we 
will proceed to dose level 2; otherwise, the study will be terminated if > 2 DLTs are observed at 
dose level 1. If ≥ 2 DLTs are observed at dose level 2, the prior dose level (level 1) will be 
expanded to total of 6 patients if it has not been done yet. Otherwise, if 0-1 DLTs are observed at 
dose level 2, we proceed to dose level 3. The same basic principles are followed until the dose 
determined as the MTD is identified to use in Phase II.
Dose-limiting toxicities (DLTs) are as defined in Section 7.2.3. Once the MTD is determined, 
subsequent patients  receiving durvalumab will be randomized to either nintedanib at MTD or 
placebo (Phase II). Nintedanib may also be started for subsequent patients at any time point (i.e. 
one or more durvalumab doses maybe given in the consolidation phase before protocol treatment 
is started) provided other eligibility criteria are met.
Table 1
Dose escalation scheme for the combination of nintedanib with durvalumab 
(Phase I)
Dose Level
Nintedanib Dose
Durvalumab dose
1
100 mg BID
10mg/kg every 2 weeks
2
150 mg BID
10mg/kg every 2 weeks
3
200 mg BID
10mg/kg every 2 weeks
7.2.1
Definition of DLTs for the Combination of Nintedanib with Durvalumab
A DLT is defined by the occurrence of toxicities outlined below attributable to either Nintedanib 
alone or the combination of Nintedanib plus durvalumab. Toxicity will be assessed using the 
NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. DLTs must be 
scored as possibly, probably, or definitely related to either Nintedanib alone or the combination 
of Nintedanib plus durvalumab within the first 28 days of combination treatment. Patients who 
developed significant DLTs deemed possibly, probably or definitely related to Nintedanib (alone 
or in combination) will be taken off study.
•
Nausea of CTCAE Grade ≥ 3, despite maximal supportive care
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•
Vomiting of CTCAE Grade ≥ 3, despite maximal supportive care
•
Diarrhea of CTCAE Grade ≥3 of any duration despite maximal supportive care
•
AST and/or ALT > 5x ULN regardless of total bilirubin level
•
AST and/or ALT > 2.5x ULN together with total bilirubin > 1.5x ULN (or 1.5x baseline 
in patients with Gilbert’s syndrome)
•
Other non-hematological adverse event of CTCAE Grade ≥ 3 considered drug-related 
and clinically significant(except transient electrolyte abnormality, alopecia, untreated 
vomiting or diarrhea, and isolated elevation of gamma glutamyl transpeptidase which will 
not be considered as DLT)
•
CTCAE grade 4 Neutropenia and fever ≥ 38.5°C
•
Neutropenia CTCAE Grade 4 for more than 7 days, without fever > 38.5 C
•
Platelets CTC grade 4 or CTC grade 3 associated with bleeding or requiring transfusion
•
Grade > 2 proteinuria
•
Nintedanib < 50% of prescribed dose for the first cycle or inability to resume nintedanib 
dosing within 14 days of stopping due to treatment-related toxicity
•
Durvalumab < 2 doses received
7.3
Phase II
7.3.1
Dose Delays/Modifications
7.3.1.2. Immune checkpoint inhibitor(s)
Use of immune checkpoint inhibitor(s), such as durvalumab, in the post-chemoradiation 
consolidation period is at the discretion of the treating physician.
7.3.2
Treatment Delay
Treatment delay of immune checkpoint inhibitor will follow standard practice in managing 
toxicities attributed to immune checkpoint inhibitor or for other reasons (scheduling preference, 
etc). No dose reductions are allowed.
Treatment with nintedanib/placebo has to be interrupted in case ANY of the criteria listed below 
is fulfilled.
•
Nausea of CTCAE Grade ≥ 3, despite supportive care
•
Vomiting of CTCAE Grade ≥ 2, despite supportive care
•
Diarrhea of CTCAE Grade ≥ 2 for more than 3 consecutive days, despite supportive care
•
AST and/or ALT of CTCAE Grade ≥ 2 in conjunction with bilirubin of CTCAE 
Grade ≥ 1
•
AST and/or ALT of CTCAE Grade ≥ 3
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•
Other non-hematological adverse event of CTCAE Grade ≥ 3 considered drug-related
•
Neutropenia and fever > 38.5°C
•
Neutropenia CTCAE Grade 4 for more than 7 days, without fever
•
Platelets < 25,000mm³, with or without bleeding
•
Grade > 2 proteinuria
7.3.3
Treatment Re-Initiation
A patient is eligible to restart nintedanib/placebo if all criteria listed below are met.
If a patient has to interrupt intake of nintedanib/placebo due to an adverse event for more than 
30 days, the decision to restart treatment with nintedanib/placebo needs to be discussed and 
agreed upon between the principal investigator and the treating physician.
•
Nausea CTCAE Grade ≤ 2
•
Vomiting CTCAE Grade ≤ 1
•
Diarrhea CTCAE Grade < 2
•
AST and ALT CTCAE Grade < 2 and bilirubin CTCAE Grade ≤ 1
•
No other non-hematological adverse event CTCAE Grade ≥ 3 which is considered drug-
related
•
Neutropenia CTCAE Grade ≤ 1, without fever or equal to the patient’s pre-therapy value 
at study enrollment
•
Platelets CTCAE Grade ≤ 1 or equal to the patient’s pre-therapy value at study 
enrollment
•
Proteinuria CTCAE Grade < 2
Table 2
Management of Nintedanib Adverse Events
Grade of Event
Management / Next Dose
≤ Grade 1
No change in dose.
Grade 2
Hold while maximizing supportive care until ≤ Grade 1. Resume at same dose 
level.
Grade 3
Hold1 until < Grade 2. Resume at 1 dose level lower, if indicated.2
Grade 4
Off protocol therapy.
1
Participants requiring a delay of > 30 days will go off protocol therapy unless permitted to remain in protocol 
treatment after discussion with principal investigator Dr. Grace Dy.
2
Participants requiring > 2 dose reductions will go off protocol therapy.
Recommended management for diarrhea: Loperamide antidiarrheal therapy. Dosage schedule: 4 mg at first onset, 
followed by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum dosage: 16 mg / 24 hours) 
Adjunct antidiarrheal therapy is permitted and should be recorded when used.
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7.3.4
Dose Reduction
As initial measure for the management of side effects, treatment with nintedanib/placebo should 
be temporarily interrupted until the specific adverse reaction has resolved to levels that allow 
continuation of therapy. Nintedanib/placebo treatment may be resumed at a reduced dose. Dose 
adjustments in 100 mg steps per day (i.e., a 50 mg reduction per dosing) based on individual 
safety and tolerability are recommended. In case of further persistence of the adverse reaction(s), 
i.e., if a patient does not tolerate 100 mg twice daily, treatment with nintedanib will be 
discontinued.
The following dose levels will be used in case dose adjustments are required for management of 
undue toxicity:
Table 3
Nintedanib/Placebo Dose Reduction
Dose Level
Dose
-2
100 mg BID
-1
150 mg BID
1 (Starting Dose)
200 mg BID
7.3.5
Management of Adverse Events
Table 4
Recommended Dose Adjustments for Nintedanib
CTCAE Adverse Reaction
Dose Adjustment
Diarrhea ≥ Grade 2 for more than 7 consecutive days, 
despite anti-diarrheal treatment**
OR
Diarrhea ≥ Grade 3, despite anti-diarrheal treatment**
Vomiting ** ≥ Grade 2
AND/OR
Nausea ≥ Grade 3, despite anti-emetic treatment**
AST and/or ALT elevations Grade 2 in conjunction with 
bilirubin of ≥ Grade 1
OR
AST and/or ALT elevations of ≥ Grade 3
Other non-hematological or hematological adverse 
reaction of > Grade 3
1st Episode
Reduce dose from 200 mg BID to 150 mg BID
2nd Episode
Reduce dose from 150 mg BID to 100 mg BID
3rd Episode
Stop treatment
** See Section 7.4 for additional guidelines.
If nintedanib will be combined with compounds that are solely metabolized by the liver and/or 
induce liver enzyme elevations, both molecules should be reduced in case of liver enzyme 
elevations according to the defined dose reductions for nintedanib/placebo as mentioned above 
and for the other compound as mentioned in their prescribing information.
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7.4
General Concomitant Medication and Supportive Care
7.4.1
Diarrhea
Diarrhea was the most frequently reported GI event and appeared in close temporal relationship 
with the administration of docetaxel in the clinical trial LUME-Lung 1. The majority of patients 
had mild to moderate diarrhea, 6.3% of the patients had diarrhea of Grade ≥ 3 in combination 
treatment compared to 3.6% treated with docetaxel alone. Diarrhea should be treated at first 
signs with adequate hydration and anti-diarrheal medicinal products (e.g., loperamide), and may 
require interruption, dose reduction or discontinuation of therapy with nintedanib/placebo.
7.4.2
Nausea and Vomiting
Nausea and vomiting, mostly of mild to moderate severity, were frequently reported 
gastrointestinal adverse events in the clinical trial LUME-Lung 1. Interruption, dose reduction or 
discontinuation of therapy with nintedanib/placebo may be required despite appropriate 
supportive care. Supportive care for nausea and vomiting may include medicinal products with 
anti-emetic properties, e.g., glucocorticoids, anti-histamines or 5-HT3 receptor antagonists and 
adequate hydration.
In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of 
electrolytes should be monitored, if relevant GI adverse events occur. Participants may be 
pretreated for nausea and vomiting with appropriate anti-emetics as clinically indicated.
7.4.3
Neutropenia and Sepsis
A higher frequency of neutropenia of CTCAE Grade > 3 was observed in patients treated with 
nintedanib in combination with docetaxel as compared to treatment with docetaxel alone in the 
clinical trial LUME-Lung 1. Subsequent complications such as sepsis or febrile neutropenia have 
been observed.
7.4.4
Hepatic Function
The safety and efficacy of nintedanib has not been studied in patients with moderate (Child 
Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with nintedanib is 
not recommended in such patients.
Administration of nintedanib was associated with an elevation of liver enzymes (i.e., ALT, AST, 
ALKP (alkaline phosphatase), and bilirubin), with a potentially higher risk for female patients.
These increases were reversible in the majority of cases and not associated with clinically 
manifest liver disorders. Hepatic transaminases, ALKP and bilirubin levels are recommended to 
be closely monitored after start of therapy with nintedanib.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation 
of the therapy with nintedanib/placebo may be required. Refer to Appendix B for guidelines in 
the recognition and approach to drug-induced liver injury.
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7.4.5
Other
Additional chemo-, immuno-, biologic therapies are not allowed during the active treatment 
period of this trial. Hormone-related therapies (e.g., adjuvant aromatase inhibitors, etc) are 
permitted if patients have been on these for more than one month prior to initiation of study 
protocol. Palliative radiotherapy may be permitted for symptomatic control of pain from bone 
metastases in extremities after discussion with the Principle Investigator. Patients who develop 
new/worsening brain metastases within the study treatment period may continue on protocol and 
receive 
palliative 
WBRT 
(or 
gamma-knife 
radiosurgery 
as 
clinically 
indicated). 
Nintedanib/placebo treatment will be temporarily interrupted while undergoing palliative therapy 
for brain metastases. If such patient does not have disease progression elsewhere, development 
of brain metastasis will not be considered a disease-progression event (clarification for purposes 
of secondary objective analysis).
If co-administered with nintedanib strong P-gp inhibitors (e.g., ketoconazole or erythromycin),  
may increase exposure to nintedanib. In such cases, patients should be monitored closely for 
tolerability of nintedanib. Management of side effects may require interruption, dose reduction or 
discontinuation of therapy with nintedanib/placebo.
Strong P-gp inducers (e.g., rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may 
decrease exposure to nintedanib. Co-administration with nintedanib/placebo should be carefully 
considered.
7.5
Duration of Treatment
Participants may remain on study and continue to receive a total of six 28-day cycles of open-
label nintedanib (Phase I) or nintedanib/placebo (Phase II) treatment in the absence of disease 
progression, unacceptable toxicity or withdrawal from study, intercurrent illness that prevents 
further administration of treatment, participant’s inability/refusal to comply with oral medication 
regimen, and participant’s withdrawal from study. For patients who have disease progression 
(exceptions noted previously) before completing 6 months of nintedanib/placebo, patients may 
continue on study only if other systemic therapy is not planned/indicated and only after 
approval/discussion with the principal investigator, Dr. Grace Dy. Patients who require initiation 
of systemic therapy for disease progression should discontinue study treatment but should remain 
on protocol and be followed for analysis of secondary endpoints unless patient elects to 
discontinue protocol follow-up procedures.
7.6
Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the participant’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:
•
Death
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•
Progressive disease warranting either initiation of systemic chemotherapy or hospice care
•
Toxicity; related or unrelated toxicity
•
Investigator judgment
o
The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so.
•
Noncompliance
•
Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain 
information regarding the reason for withdrawal.
•
Sponsor decision.
7.7
Compliance
Patients will be provided a pill diary to record each dose of nintedanib/placebo (date, time, 
number of capsules) taken. A pill count will be performed at each subsequent clinic 
visit/evaluation.
8
INVESTIGATIONAL PRODUCT
8.1
Drug Shipment
Nintedanib/placebo will be provided by Boehringer Ingelheim and shipped to the participating 
sites.
The date of receipt, of the shipment, and the amount of drug received will be documented. Drug 
shipment records will be retained by the investigational pharmacist or designee.
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8.2
Pharmaceutical information
8.2.1
Nintedanib - Study Drug
Substance (INN):
Nintedanib
Pharmaceutical Form:
Soft gelatine capsule
Pharmaceutical Code
BIBF1120
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
100 mg and 150 mg capsules
Daily Dose:
Dose escalation portion: dose according to dose level assigned.  During Phase II 
randomized study: 200 mg orally twice daily (without durvalumab) or dose 
determined from dose escalation portion in combination with durvalumab.  Dose 
reduction according to Section Error! Reference source not found..
Duration of Use:
Continuous daily dosing until progression of disease (see exception regarding 
brain metastases in Section 7.3.5) or until criteria for interruption of treatment is 
met. The maximum time on treatment will be 6 months.
Route of Administration:
Oral
Posology:
Twice daily (to be swallowed whole, with a glass of water of about 250 mL with 
a dose interval of around 12 hours at the same times every day, usually in the 
morning and the evening after food intake)
8.2.2
Placebo - Comparator
Substance (INN):
Not applicable
Pharmaceutical Form:
Soft gelatine capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
Placebo contains 0 mg of nintedanib in capsules matching 100 mg and 150 mg of 
nintedanib
Daily Dose:
Matching  capsules orally twice daily, dose reduction according to 
Section Error! Reference source not found..
Duration of Use:
Continuous daily dosing until progression of disease (see exception regarding 
brain metastases in Section 7.3.5) or until criteria for interruption of treatment is 
met. The maximum time on treatment will be 6 months.
Route of Administration:
Oral
Posology: 
Twice daily (to be swallowed whole, with a glass of liquid of about 250 mL with 
a dose interval of 12 hours at the same times every day, usually in the morning 
and the evening after food intake)
8.3
Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified by Boehringer Ingelheim 
and in accordance with the applicable regulatory requirements.
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The current shelf life for all dosage strengths and formulations is 60 months. The capsules are 
packaged in child resistant high density polyethylene (HDPE) bottles, and have to be stored 
below 30°C.
Refer to the Investigator’s brochure for full details on storage requirements and stability.
Drug storage temperature will be maintained and recorded, as applicable.
8.4
Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Boehringer Ingelheim exercising accepted medical and 
pharmaceutical practices. Study drugs must be handled as cytotoxic agents and appropriate 
precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. This record will 
be reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Unused/expired capsules will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
8.5
Treatment Unblinding
Treatment unblinding may occur only if the knowledge of treatment assignment will materially 
change the planned management of a medical emergency. Envelopes containing treatment arm in 
formation (drug versus placebo) will be stored at the site pharmacy. Given the constitution of the 
drug, unblinding is not anticipated for any circumstance. Any request for unblinding should be 
discussed with the sponsor’s medical monitor, Grace Dy, MD.
8.6
Durvalumab
Durvalumab is commercially available and will be dispensed per standard of care. Durvalumab 
will not be provided by this study and will be paid for by the patient’s insurance carrier as part of 
standard of care treatment post chemo-radiation.
9
STUDY PROCEDURES
Unless otherwise defined in the written protocol text, all procedures/assessments will be 
conducted in accordance with RPCI Clinical Research Services Standard Operating Procedures.
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9.1
Participant Randomization and Registration
Phase I:
Subjects enrolled to the dose escalation portion of the study will NOT undergo randomization 
(i.e. not blinded to treatment) and will receive the active drug nintedanib according to the dose 
level assigned.
Phase II:
Patients will be randomized, by site, at the baseline visit into one of 2 arms, placebo or 
nintedanib, in a 1:2 fashion using a block-permutation design, but this will be masked to the 
investigator and patient. The randomization list will be generated by the study biostatistician.
Patients will be included in data analyses according to their randomized treatment assignment 
irrespective of the treatment actually received (intent-to-treat).
Patients will be assigned a study number in the order of randomization.
No study-specific procedures are to be performed until informed consent is obtained. Eligibility 
of each patient will be established prior to study enrollment.
9.2
Baseline Evaluations
The following will be performed within 4 weeks prior to first dose of study drug:
•
Medical history
•
Smoking History (Type of Tobacco/Nicotine Product [cigarettes, cigars, pipes, chew 
tobacco, nicotine gum, nicotine patch, other], current use, how long ago product use 
stopped.) 
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, body weight, and height)
•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
Pulmonary Function Test
•
ECOG Performance Status (Appendix C)
•
Urinalysis to assess proteinuria
•
Tumor/Disease Assessment
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•
Concomitant Medications: List any ongoing medications with an onset within 1 week of 
first dose of study drug.
•
Adverse Events
9.3
Evaluations Performed at Cycle 1 Day 1
The following will be performed on Cycle 1 Day 1 or within 7 days prior to drug administration:
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
25-OH Vitamin D level (one 3 mL gold-top tube)
•
Mitochondrial DNA Assay (one 10 mL heparinized green-top tube)
•
miRNA Biochip Assay (one 10 mL red-top tube)
•
QOL Questionnaire (Appendix F)
•
Pregnancy Test (Urine or Serum) for females of child-bearing potential
•
ECOG Performance Status (Appendix C)
•
Dispense nintedanib/Placebo
•
Concomitant Medications
•
Adverse Events
9.4
Evaluations Performed on Day 1 of Cycle 2 through Cycle 6
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
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lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
Mitochondrial DNA Assay (Cycle 3 and Cycle 6 only) (one 10 mL heparinized green-top 
tube)
•
QOL Questionnaire (Cycle 3 and Cycle 6 only) (Appendix F)
•
ECOG Performance Status (Appendix C)
•
Tumor/Disease Assessment (Cycle 3 and Cycle 6 only)
•
Dispense nintedanib/Placebo
•
Concomitant Medications
•
Adverse Events
9.5
Evaluations Performed Anytime When Radiation Pneumonitis is Suspected to Have 
Occurred (Within the First 6 Months After Completing Radiation Therapy)
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
Mitochondrial DNA Assay (one 10 mL heparinized green-top tube)
•
QOL Questionnaire (Appendix F)
•
ECOG Performance Status (Appendix C)
•
Tumor/Disease Assessment
•
Concomitant Medications
•
Adverse Events
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9.6
Evaluations Performed at End of Active Treatment
The following evaluations will be performed within 30 days at the end of treatment or at time of 
treatment discontinuation:
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
Pulmonary Function Test
•
QOL Questionnaire (Appendix F)
•
ECOG Performance Status (Appendix C)
•
Concomitant Medications
•
Adverse Events
9.7
Evaluations Performed 76 Days – 97 Days After the Last Nintedanib Dose
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Mitochondrial DNA Assay (one 10 mL heparinized green-top tube)
•
QOL Questionnaire (Appendix F)
•
ECOG Performance Status (Appendix C)
•
Tumor/Disease Assessment
•
Concomitant Medications
•
Adverse Events
9.8
Evaluations Performed 166 Days – 187 Days After the Last Nintedanib Dose
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
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•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
Pulmonary Function Test
•
QOL Questionnaire (Appendix F)
•
ECOG Performance Status (Appendix C)
•
Tumor/Disease Assessment
•
Concomitant Medications
•
Adverse Events
9.9
Long Term Follow-Up Evaluations
Follow-up to 2.5 years after completing nintedanib/placebo treatment to be conducted as part of 
routine/standard care. Information may be conducted by phone only if patient relocated/unable to 
return to treating institution (if patient unable to return, phone call follow-up includes QOL 
Questionnaire (Appendix F) only if possible).
•
Medical history
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the 
physicians’ discretion): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % 
neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, 
absolute eosinophils, % basophils, absolute basophils,), % lymphocyte total, absolute 
lymphocyte total, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated). Note: Participants experiencing Grade 4 
neutropenia should be monitored according to institutional guidelines. As needed at each 
study visit as determined by the Investigator or study physician.
•
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
•
QOL Questionnaire (Appendix F)
•
ECOG Performance Status (Appendix C)
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•
Tumor/Disease Assessment
•
Concomitant Medications
•
Adverse Events
9.10 Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Table 5 below.
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Table 5
Schedule of Procedures and Observations
Active Treatment Stage
Surveillance Stage
Evaluation
Baseline1
Cycle 1 Day 1 (or 
within 7 days 
prior to drug 
administration)
Cycle 2 
through 
Cycle 6 
Day 1
(± 7 days)
Anytime when 
radiation 
pneumonitis is 
suspected to have 
occurred (within 
the first 6 months 
after completing 
radiation therapy)
End of Active 
Treatment 
(within 
30 days of last 
nintedanib 
dose)
Between 
76 to 97 
days after 
last 
nintedanib 
dose
Between 
166 to 187 
days after 
last 
nintedanib 
dose
Long 
Term 
Follow-
Up2
Medical History
X
X
X
X
X
X
X
X
Smoking History
X
Pre-Existing Conditions
X
Physical Examination, 
including vital signs (i.e., 
temperature, heart rate, 
respiratory rate, blood 
pressure, body weight, height)3
X
X
X
X
X
X
X
X
Hematology4
X
X
X
X
X
X
X
Chemistry5
X
X
X
X
X
X
X
25-OH Vitamin D level (Section 
9.12)
X
Mitochondrial DNA and 
Cytokine Assay (Section 9.11)9
X
X7
X
X
miRNA Biochip Assay 
(Section 9.12)
X
Pulmonary Function Test
X
X
X
QOL Questionnaire 
(Appendix F)
X
X7
X
X
X
X
X
Pregnancy Test (Urine or 
Serum)11
X

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Evaluation
Baseline1
Active Treatment Stage
Surveillance Stage
Cycle 1 Day 1 (or 
within 7 days 
prior to drug 
administration)
Cycle 2 
through 
Cycle 6 
Day 1
(± 7 days)
Anytime when 
radiation 
pneumonitis is 
suspected to have 
occurred (within 
the first 6 months 
after completing 
radiation therapy)
End of Active 
Treatment 
(within 
30 days of last 
nintedanib 
dose)
Between 
76 to 97 
days after 
last 
nintedanib 
dose
Between 
166 to 187 
days after 
last 
nintedanib 
dose
Long 
Term 
Follow-
Up2
Urinalysis10
X
ECOG Performance Status 
(Appendix C)
X
X
X
X
X
X
X
X
Tumor/Disease Assessment6
X
X7
X
X
X
X
Study Drug/Placebo
X
X
Durvalumab
X12
Concomitant Medications
X8
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X

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Evaluation
Baseline1
Active Treatment Stage
Surveillance Stage
Cycle 1 Day 1 (or 
within 7 days 
prior to drug 
administration)
Cycle 2 
through 
Cycle 6 
Day 1
(± 7 days)
Anytime when 
radiation 
pneumonitis is 
suspected to have 
occurred (within 
the first 6 months 
after completing 
radiation therapy)
End of Active 
Treatment 
(within 
30 days of last 
nintedanib 
dose)
Between 
76 to 97 
days after 
last 
nintedanib 
dose
Between 
166 to 187 
days after 
last 
nintedanib 
dose
Long 
Term 
Follow-
Up2
1
Performed within 4 weeks prior to initiation of treatment.
2
Follow-up to 2.5 years after completing nintedanib/placebo treatment to be conducted as part of routine/standard care. Information may be 
conducted by phone only if patient relocated/unable to return to treating institution(if patient unable to return, phone call follow-up includes QOL 
Questionnaire (Appendix F) only if possible).
3
Height collected at baseline only.
4
Hematology [(i.e., complete blood count (CBC) with automated differentials)]( or, the physicians’ discretion): WBC, RBC, HGB, HCT, platelet, 
MCV, MCH, MCHC, % neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, absolute eosinophils, % basophils, 
absolute basophils,), % lymphocyte total, absolute lymphocyte total, platelet confirmation (as clinically indicated), and differential confirmation 
(as clinically indicated). Note: Participants experiencing Grade 4 neutropenia should be monitored according to institutional guidelines. As needed 
at each study visit as determined by the Investigator or study physician.
5
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, 
total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
6
For routine tumor assessment, CT abdomen and pelvis with high-resolution CT chest (HRCT) should be obtained. HRCT chest alone will be 
sufficient whenever new onset of dyspnea occurs and radiation pneumonitis is suspected to have occurred (within the first 6 months after 
completing radiation therapy). CT chest obtained/configured at 1.25 mm slice thickness is an acceptable alternative to HRCT. Maximum slice 
thickness allowed for CT chest is 2.5 mm. Use of intravenous contrast for the CT studies is preferred but not mandatory.
7
To be performed prior to drug administration on Day 1 of Cycles 3 and 6 (± 7 days window) only.
8
Medications ongoing within 1 week prior to first dose of study drug.
9
Sample collection will be obtained anytime when radiation pneumonitis is suspected to have occurred (within the first 6 months after completing 
radiation therapy).
10
Urinalysis after baseline will be performed per clinical discretion / judgement.
11
For females of child-bearing potential.
12
Dose Escalation Phase: First two doses of Durvalumab as consolidation therapy will be administered together with cycle 1 day 1 and day 15 (-1/+7 
days) of nintedanib. Subsequent doses will be administered according to institutional practice.  Phase II: use of an immune checkpoint inhibitor, 
such as durvalumab, in the post-chemoradiation consolidation period is at the discretion of the treating physician. 

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9.11 Mitochondrial DNA and Cytokine Sampling
Sample collection will be obtained on:
•
Cycle 1 Day 1
•
Anytime when radiation pneumonitis is suspected to have occurred (within the first 6 
months after completing radiation therapy)
•
Additional assessment for Cycle 3 and Cycle 6 Day 1 (± 7 days)
•
Between 76 to 97 days after last nintedanib dose
9.11.1 Blood Sample Collection and Processing
Whole blood samples for correlative studies will be collected via venipuncture using (1) 10 mL 
heparinized green-top tube and placed on ice for processing same day of collection. Plasma will 
be separated from whole blood within 30 minutes following the collection. Spin at 500 g for 
10 minutes at room temperature then freeze supernatant into 0.5 mL aliquots of plasma at -70ºC 
or below until analyzed. The screw cap polypropylene cryogenic tube will be labeled with the 
participant’s MR number (for RPCI participants), participant’s initials, participant’s study 
number, clinical study number, protocol time point, dose, and protocol day. Samples collected at 
RPCI will be processed and stored at RPCI’s Hematologic Procurement Facility until analysis in 
Dr. Segal’s Laboratory. 
9.11.2 Sample Handling and Shipment
Network sites will store samples until batch shipped to RPCI on a quarterly basis Monday – 
Thursday. Do not ship specimens on Fridays or on day before a holiday. Packaging should be 
clearly labelled as follows with e-mail notification:
Roswell Park Cancer Institute
Hematologic Procurement Facility
Basic Science Bldg. (GBSB) - 538
Attn: Linda Lutgen-Dunckley / Brandon Martens
Elm & Carlton Streets
Buffalo, New York 14263
716-845-8098
Linda.LutgenDunckley@RoswellPark.org / Brandon.Martens@RoswellPark.org
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
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9.12 miRNA and Vitamin D Sampling
9.12.1 Blood Sample Collection and Processing
Serum samples for miRNA will be collected via venipuncture using (1) 10 mL red-top tube. 
25-OH vitamin D serum sample will be collected via venipuncture using (1) 3 mL gold-top tube. 
Both sample collection will be obtained on:
•
Cycle 1 Day 1
The screw cap polypropylene cryogenic tube will be labeled with the participant’s MR 
number,(for RPCI participants) participant’s initials, participant’s study number, clinical study 
number, protocol time point, dose, protocol day, type of assay (miRNA or vitamin D). The 
samples will immediately be frozen at -70ºC or below until analyzed. Samples collected at RPCI 
will be processed and stored at RPCI’s Hematologic Procurement Facility. Network sites may 
batch ship specimen to RPCI on a quarterly basis. 25-OH vitamin D testing will occur in RPCI 
Clinical Lab. Network sites will send 3 mL gold-top blood tube for 25-OH vitamin D samples to 
RPCI’s Hematologic Procurement Facility for processing and storage until analysis. miRNA 
testing will be performed in Dr. Yun Wu’s Laboratory at the end of the study.
9.12.2 Sample Handling and Shipment
Network Sites Processing & Handling Instructions for 25-OH Vitamin D 3 mL Gold Top Blood
•
Mix gently by inverting the tube eight (8) times
•
Allow blood to clot upright at room temperature for 30 minutes
•
Centrifuge for 10 minutes at 1300g or until a complete barrier is formed
•
DO NOT remove the top of the SST
•
Spun Draw tube should be sent for testing – do not send un-centrifuged specimens
•
Ship ambient same day of collection to RPCI
Serum samples collected at RPCI will be sent on ice for processing the same day of collection.
Serum samples collected at participating sites will be separated into 0.5 mL aliquots, frozen and 
stored at -70° or below until batched shipped quarterly Monday - Thursday. Do not ship 
specimens on Fridays or on day before a holiday. Packaging should be clearly labelled as follows 
with e-mail notification:
Roswell Park Cancer Institute
Hematologic Procurement Facility
Basic Science Bldg. (GBSB) - 538
Attn: Linda Lutgen-Dunckley / Brandon Martens
Elm & Carlton Streets
Buffalo, New York 14263
716-845-8098
Linda.LutgenDunckley@RoswellPark.org / Brandon.Martens@RoswellPark.org
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Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
10 EFFICACY EVALUATIONS
10.1 Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. RECIST 1.1 will be used to assess objective tumor response.
10.2 Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline. Target lesions will be selected on the basis of their size. Lesions with the 
longest diameter (short axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph 
nodes, > 20 mm CXR and are for accurate repetitive measurements (either by imaging 
techniques or clinically) will be chosen. A sum of the longest diameter (short axis for lymph 
nodes) of all target lesions will be calculated and reported as the baseline sum diameters. This 
will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease.
•
Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must 
have a reduction in short axis to < 10 mm. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response 
are first met.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. Changes in tumor measurements 
must be confirmed by repeat studies performed no less than 6 weeks after the criteria for 
response are first met.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 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. 
Participants having a documented response with no confirmation of the response will be 
listed with stable disease.
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10.3 Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images 
drawing a regularly-shaped Region of Interest. Measurements of the non-target lesions will not 
be performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.
•
Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm 
short axis).
•
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.
•
Progressive Disease: Appearance of 1 or more new lesions or the unequivocal 
progression of existing non-target lesions. Although a clear progression of non-target 
lesions is exceptional, in such circumstances, the opinion of the treating physician should 
prevail and the progression status should be confirmed at a later time.
10.4 Evaluation of Response
To determine time point response, refer to Table 6, and Table 7 below.
Table 6
Time Point Response Criteria (+/- non-target disease)
Target Lesions
Non-Target Lesions1
New Lesions1
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD1
Any
PD1
Yes or No
PD1
Any
Any
Yes
PD1
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Table 7
Time Point Response Criteria (non-target disease only)
Non-Target Lesions1
New Lesions1
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD1
Any
Yes
PD1
1
If new or worsening lesions are found in the brain only, these are not considered disease progression for the 
purposes of this study. Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint 
for assessment of efficacy in trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until the 
tumor assessment obtained upon completion of nintedanib/placebo treatment taking into account 
any requirement for confirmation. In general, the participant’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria and will be 
determined by combining the participant’s status of target lesions, non-target lesions, and new 
lesions.
•
Residual Disease: Provide the appropriate information that pertains to this study.
•
Symptomatic Deterioration: Participants with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease progression 
at that time, and not related to study treatment or other medical conditions should be 
reported as progressive disease due to “symptomatic deterioration.” Every effort should 
be made to document objective progression even after discontinuation of treatment due to 
symptomatic deterioration. Symptomatic deterioration that may lead to discontinuation of 
treatment include, but is not limited to, symptoms such as:
•
Weight loss > 10% of body weight.
•
Worsening 
of 
disease-related 
symptoms 
(e.g., worsening 
dyspnea, 
increasing 
pain/increasing requirement for narcotic analgesics).
•
Decline in performance status of > 1 level on ECOG scale.
10.5 Confirmation Measurement
To be obtained as clinically warranted in cases of suspected tumor progression.
10.6 Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
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preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
•
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.
•
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
•
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
•
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.
•
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances.
•
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
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pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
•
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.
•
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
•
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG PET imaging can be identified according to the following algorithm:
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
•
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
•
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
10.7 Radiation Pneumonitis Score
Multidetector helical CT images of the chest will be obtained from the supraclavicular region to the 
level of adrenals with the patient in a supine position. A 5 mm slice thickness and appropriate DFOV 
will be applied during a single inspiratory breath hold acquisition. Post processing with a coronal and 
sagittal planes will be performed. IV contrast will be administered.
Images will be sent to PACS (Picture Archiving and Communications System) and viewed and 
analyzed on a workstation. For cases performed outside of RPCI, DICOM (Digital Imaging and 
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Communications in Medicine) archived images on CD disk will be sent to RPCI Radiology 
Department for central review.
Visual analysis will be performed by two thoracic radiologists who will independently record the 
pulmonary fibrosis score. The lungs will be divided into three zones. Upper zone is from the 
level of apex to the carina. Lower zone being inferior to the pulmonary veins. Middle zone is 
anywhere in between the two. 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%).A highest severity score for each of the 6 lung 
zones and overall highest volume of disease involvement will be calculated. Baseline, 3 month, 
6 month, 9 month and 1 year follow-up HRCT images after completion of nintedanib/placebo 
treatment will be scored during the trial. The observers will be blinded to the treatment for the 
approximately 100 patients that will be recruited.
10.8 Radiation Treatment Field Central Review/Radiation Specifications (adapted from 
NCCN guidelines for NSCLC version 4.2014)
Central review will be performed and essential parameters such as V20 and MLD will be 
recorded for each patient. For treatment volume consideration for 3D-conformal RT, planning 
target volume should be defined using the ICRU-50 and ICRU-62(international Commission on 
Radiation Units and Measurements Reports 50 and 62) reports, based on gross tumor volume 
(GTV), plus clinical target volume margins for microscopic diseases, internal target volume 
margins for target motion, and margins for daily set-up errors. ICRU Report 83 is used for 
IMRT. 
The 
ACR-ASTRO 
guidelines 
are 
also 
useful 
(http://www.acr.org/~/media/eabb986bc4ff4a78b53b001a059f27b3.pdf). 
Additional 
volume 
considerations are described in the NCCN algorithm. It is essential to evaluate the dose volume 
histogram (DVH) of critical structures and to limit the doses to the spinal cord, lungs, heart, 
esophagus and brachial plexus to minimize normal tissue toxicity (Refer to Table 5 under 
Principles 
of 
Radiation 
Therapy 
for 
NSCLC, 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp ). These limits are empirical.
Treatment planning should be based on CT scans obtained in the treatment position. Intravenous 
contrast CT scans are recommended for better target delineation whenever possible, especially in 
patients with central tumors or with nodal diseases. PET/CT is recommended for select patients 
(i.e., those with significant atelectasis, when IV contrast is contraindicated). PET/CT can 
significantly improve the target accuracy. Whenever feasible, respiratory motion should be 
managed. Acceptable methods of accounting for tumor motion, per the AAPM Task Group 76 
guideline, are described in the Principles of Radiation Therapy of the NCCN NSCLC algorithm. 
The algorithm also provides recommendations for patients receiving chemoradiation, photon 
beams or IMRT.
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11
SAFETY EVALUATION
11.1 Adverse Events
11.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’). To capture binary classifications in the CRF, 
attributions of possible, probable or definite will fall under the “YES” category while attributions 
of unlikely and unrelated will fall under the “NO” category.
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
11.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
11.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
11.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
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If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
11.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
11.1.2 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:
•
Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.
•
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.
•
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.
•
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions or concomitant drugs.
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•
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
11.1.3 Reporting Adverse Events 
Table 8
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies 
(Regardless of Expectedness)
Table 9 Guidelines for 
Routine Adverse Event 
Reporting for Phase 1 
Studies (Regardless of 
Expectedness)Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Table 10
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
AE in the CRF.
Changes in vital signs, physical examination and laboratory test results will be recorded as an AE 
in the CRF, if they are judged clinically relevant by the investigator.
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11.2 Serious Adverse Events
11.2.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or Boehringer Ingelheim results in ANY of the following:
•
Death.
•
A life-threatening adverse event (experience). Any AE that places a participant or 
participant, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
•
A congenital anomaly or birth defect.
•
Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
•
Patients may be hospitalized for administrative or social reasons during the trial 
(e.g., days on which infusion takes place, long distance from home to site). These and 
other hospitalizations planned at the beginning of the trial do not need to be reported as 
an SAE.
11.2.2 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 11.5 for details on reporting Unanticipated Problems.
11.3 Investigator Reporting: Notifying Boehringer Ingelheim
The following events are considered as Protocol-specified events of special interests:
Any gastrointestinal and non-gastrointestinal perforations, leakage, fistula formation, abscess.
In such case the following additional information need to be collected, documented in the 
respective comment field of the BI IIS SAE form and the respective narratives of the SAE. That 
has to be forwarded to Boehringer Ingelheim:
•
Location of perforation, leakage, fistula, abscess
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•
Location/extent of abdominal tumor manifestations,
•
Imaging and reports (CT, ultrasound, endoscopy, pathology, etc.)
•
Prior surgery (location, wound healing complications)
•
Concomitant diseases with GI involvement (e.g., M Crohn, vasculitis, tuberculosis, 
diverticulitis)
•
Thromboembolic events (or predisposition)
Drug-induced liver injury is under constant surveillance by sponsors and regulators and is 
considered a protocol-specified adverse event of special interest (AESI). Timely detection, 
evaluation, and follow-up of laboratory alterations of selected liver laboratory parameters to 
distinguish an effect of the investigational drug from other causes are important for patient safety 
and for the medical and scientific interpretation of the finding.
The following are considered as protocol-specified AESI:
•
An elevation of ALT and / or AST > 5 x ULN without bilirubin elevation measured in the 
same blood draw sample.
•
An elevation of AST and/or ALT > 2.5 fold ULN combined with an elevation of bilirubin 
to > 1.5 fold ULN measured in the same blood draw sample.
Patients showing above laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met and according to Appendix B of this clinical trial 
protocol.
Protocol-specified AESI are to be reported in an expedited manner similar to Serious Adverse 
Events, even if they do not meet any of the seriousness criteria.
11.3.1 SAE reporting to Boehringer Ingelheim (BI)
Upon inclusion into a trial, the patient’s condition is assessed (e.g., documentation of history / 
concomitant diagnoses and diseases), and relevant changes from baseline are noted subsequently.
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through 30 days following cessation of 
treatment) will be collected, documented by the investigator. 
The investigator shall report all SAEs and non-serious AEs which are relevant to a reported 
SAEs and AESIs by fax using BI IIS SAE form to BI Unique Entry Point as detailed below in 
accordance with the following timelines:
•
within five (5) calendar days upon receipt of initial and follow-up SAEs containing at 
least one fatal or immediately life-threatening event
•
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs
Boehringer Ingelheim Pharmaceuticals, Inc
900 Ridgebury Road
Ridgefield, CT 06877
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AND NCCN at ORPReports@nccn.org or 215-358-7699
For each adverse event, the investigator will provide the onset date, end date, intensity, treatment 
required, outcome, seriousness, and action taken with the investigational drug. The investigator 
will determine the relationship and expectedness with the investigational drug to all AEs as 
defined in the listed adverse event section of Boehringer Ingelheim’s (BI’s) Investigator 
Brochure for the Product.
The investigator does not need to actively monitor patients for adverse events once the clinical 
trial has ended. However, if the investigator becomes aware of an SAE(s) that occurred after the 
patient has completed the clinical trial (including any protocol specified follow-up period), it 
should be reported to BI if considered relevant by the investigator.
Investigators MUST report within 5 business days upon becoming aware, to Boehringer 
Ingelheim ANY Serious Adverse Events, whether or not they are considered related to the 
investigational agent(s)/intervention. 
11.4 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible. New information will be reported when it is received.
11.5 Unanticipated Problems
11.5.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
•
Unexpected (in terms of nature, severity, or frequency) given:
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
b) The characteristics of the participant population being studied.
•
Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research).
•
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 11.2.
11.5.2 Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Unanticipated 
Problem Form will be submitted to the RPCI’s Clinical Research Services (CRS) Compliance 
Office within 1 business day of becoming aware of the Unanticipated Problem.
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When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance with an updated Unanticipated Problem Form. The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
11.6 FDA Reporting
When RPCI is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Serious but not fatal or life-threatening;
Or, meets ANY of the following criteria:
•
A previous adverse event that is not initially deemed reportable but is later found to fit 
the criteria for reporting (report within 15 days from when event was deemed reportable).
•
Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.
•
Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or 
reports of significant organ toxicity at or near the expected human exposure.
•
Any clinically important increase in the rate of occurrence of a serious, related or 
possibly related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
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Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
as well as BI fax cover sheet for any event that meets the above criteria. Forms will be submitted 
to the CRS Compliance Office via email to CRSCompliance@RoswellPark.org.
11.7 Criteria for Closing of study (stopping rule):
There was one patient enrolled on this study who developed massive fatal bleeding of unknown 
origin and this patient expired (grade 5). This fatal bleeding (grade 5) occurred prior to starting 
cycle 4. If one more bleeding-related toxicity of grade 3 or greater occurs (as determined by the 
PI or treating physician as - possibly, probable or definite related to study) , the study will be 
stopped and all patients will discontinue drug.
12 DATA AND SAFETY MONITORING
Dose Escalation:
Phase 1 studies will be reviewed at the scheduled Roswell Park Early Phase Clinical Trials 
(EPCT) Program meetings and the minutes are forwarded to the IRB for review.
Phase II:
The Roswell Park Data Safety Monitoring Committee (DSMC) will assess the progress of the 
study, the safety data, and critical efficacy endpoints. The DSMC will review the study annually 
and will make recommendations that include but are not limited to; (a) continuation of the study, 
(b) modifications to the design (c) or termination of the study. Since the AE and SAE reports 
from all study sites will be sent to Roswell Park, the Roswell Park DSMC will be responsible for 
overall monitoring of the study.
13 STATISTICAL METHODOLOGY
The primary endpoint of the study is the rate of CTCAE Grade 2 or higher radiation pneumonitis 
at 6 months after completion of chemoradiation:
•
To compare the rate of symptomatic radiation pneumonitis in patients who received 
nintedanib versus placebo.
13.1 Sample Size Determination
A maximum of 18 participants will be enrolled to the non-randomized dose escalation portion of 
this study. The number of participants required is a function of the unknown dose-toxicity 
relationship.
A maximum of 99 participants will be enrolled to the randomized Phase 2 portion of this study 
(excluding patients replaced due to ineligibility or inability to start therapy). Participants will be 
randomized in a 1:2 fashion, stratified by chemotherapy regimen (i.e., platinum with etoposide, 
platinum with taxane, platinum with pemetrexed) and immune therapy (i.e. durvalumab), into the 
placebo and nintedanib arms. Accrual is expected to take 4 years.
Evaluable patients will be any patient who receives at least one dose of study drug.
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The sample size justification is based on the primary analysis: a comparison of the rate of 
radiation pneumonitis at 6 months after completion of chemoradiation between the placebo and 
nintedanib arms, stratified by chemotherapy regimen (i.e., platinum with etoposide, platinum 
with taxane, platinum with pemetrexed) and immune therapy exposure (i.e. durvalumab ), using 
the one-sided Cochran-Mantel-Haenszel (CMH) exact test at a significance level of 0.05. The 
expected rate of Grade 2 or higher radiation pneumonitis is 30% in the placebo arm, and a 
decrease in this rate to 10% in the nintedanib arm would be considered clinically significant; 
which is equivalent to a common odds ratio (COR) of approximately 0.26. 
Using a simulation based on the proposed study design; if there is no improvement in the rate of 
radiation pneumonitis (COR = 1.0), then there is a 59.0% chance of stopping early for futility. If 
the true COR is 0.26, then there is only a 10.6% chance of stopping early for futility. If the true 
common odds ratio is 0.26, then there is an 80.1% chance of detecting a significant reduction in 
the rate of Grade 2 or higher radiation pneumonitis in the nintedanib arm. If the COR is 1.0, then 
the chance of detecting a significant reduction is 4.2%; which can be considered the effective 
type-I error rate.
As of the November 2018 Amendment (Amendment #6), patients receiving durvalumab will be 
eligible for enrollment in the study. Since the combination of nintedanib and durvalumab has not 
been tested in this setting, an initial non-randomized dose escalation study will be carried out for 
patients treated with immune therapy (i.e. durvalumab). This dose escalation phase will follow a 
standard 3+3 design starting with dose level 1 (Table 1) and continuing until the MTD is 
identified (maximum dose level at which 1 or fewer DLTs are observed in 6 patients).  A total of 
3 dose levels will be explored, hence a maximum of 18 patients will be accrued to this portion of 
the study.
13.2 Stratification
As of the November 2018 Amendment (Amendment #6), patients receiving durvalumab (and in 
the future, other immunotherapy agents) will be eligible for enrollment in the study. Therefore, 
exposure to immunotherapy agents will be added as an additional stratification factor.
The randomization and the significance tests applied in the analyses will be stratified by 
chemotherapy regimen (i.e., platinum with etoposide, platinum with taxane, platinum with 
pemetrexed) and exposure to immunotherapy agents.
13.3 Randomization
Phase II: Patients will be randomized to either the placebo or nintedanib arm in a 1:2 fashion 
using a stratified permuted block randomization scheme. The randomization lists to be used in 
this study will be generated by the study biostatistician. Patients will be included in data analyses 
according to their randomized treatment assignment irrespective of the treatment actually 
received (intent-to-treat). After randomization, initiation of the study intervention will take place 
within the timeframe specified in the eligibility period. Patient randomization will be done 
electronically by the Department of Biostatistics at RPCI.  
The activity of the dose escalation patients receiving durvalumab will not hold enrollment for 
patients not exposed to immunotherapy agents. (i.e. patients can enroll to Phase II ahead of dose 
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escalation if the choice is not to give durvalumab.  If patient is going to receive durvalumab, it is 
required to go through dose escalation first until MTD is determined).
13.4 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize, by treatment group, demographic and baseline characteristics.
13.5 Primary Analysis
Consider a placebo controlled, randomized trial in which patients are stratified by chemotherapy 
regimen (i.e., platinum with etoposide, platinum with taxane, platinum with pemetrexed) and 
randomized (1:2 ratio) to a treatment group (placebo versus nintedanib). The primary objective 
of the study is to evaluate the rate of 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. The primary outcome is 
radiation pneumonitis status (defined as symptomatic CTC Grade 2 or higher radiation 
pneumonitis at 6 months after completion of chemoradiation), which is treated as a dichotomous 
variable.
The primary objective will be assessed using the intent-to-treat principle and a one-sided exact 
test about the CMH COR:
H0: θ ≥ 1
HA: θ < 1
Where θ is the COR for the odds of Grade 2 or higher radiation pneumonitis in the nintedanib 
treated versus placebo treated populations, stratified by chemotherapy regimen (i.e., platinum 
with etoposide, platinum with taxane, platinum with pemetrexed). A one-sided test is performed 
as the rate of radiation pneumonitis is expected to decrease in the nintedanib arm over the 
placebo arm; that is expect to be θ < 1. The critical value and corresponding rejection region for 
the one-sided test will obtained using the exact methods available in SAS v9.4 and maintaining a 
significance level of 0.05 while accounting for the interim analysis. As of the November 2018 
Amendment (Amendment #6), the primary analysis will be conducted excluding the maximum 
of 18 patients in the durvalumab dose escalation. As a sensitivity analysis, the primary analysis 
will be repeated with the 6 patients treated at the MTD level from the  dose-escalation portion.
13.6 Safety Analysis
The frequency of toxicities will be tabulated by grade. All participants who receive any study 
treatment will be considered evaluable for toxicity.
13.7 Secondary Analyses
The OS and PFS will be reported by study arm using standard Kaplan-Meier methods. 
Comparisons of OS and PFS between study arms may utilize the two-sided stratified log-rank 
test. With a sample size of n = 33 in the control and n = 66 in the treatment group, there is an 
80% chance of detecting a hazard ratio of 0.53 or smaller (with two-sided alpha of 0.05). If the 
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median PFS in the placebo arm is approximately 2 months, then this would be equivalent to 
detecting an increase in PFS of at least 1.75 months.
The overall and sub-category QOL and symptom scores (ranging from 0 to 68) will be reported 
by study arm and time using the appropriate descriptive statistics. Changes in the QOL and 
symptom scores may be compared between study arms using the Wilcoxon rank sum or 
independent sample t-tests, as appropriate. No adjustments for multiple testing will be made as 
this is a secondary analysis. With this sample size, there will be an 80% chance of detecting a 
change of at least 0.5 standard deviations. A 0.5 standard deviations is equivalent to 
approximately 9.1 points for the overall QOL and symptoms score; therefore, this study should 
be able to identify clinically relevant changes in QOL (59).
The PFTs will be reported by study arm and time using the appropriate descriptive statistics. 
Changes in PFTs, relative to baseline, will be evaluated within each study arm using the 
Wilcoxon signed rank or paired t-tests, as appropriate. Changes in PFTs may be compared 
between study arms using the Wilcoxon rank sum or independent sample t-tests, as appropriate. 
No adjustments for multiple testing will be made as this is a secondary analysis. With this 
sample sizes, we will have an 80% chance of detecting a change of at least 0.5 standard 
deviations.
The RP scores will be reported by study arm and time using the appropriate descriptive statistics. 
Changes in RP scores, relative to baseline, will be evaluated within each study arm using the 
Wilcoxon signed rank or paired t-tests, as appropriate. Changes in RP scores may be compared 
between study arms using the Wilcoxon rank sum or independent sample t-tests, as appropriate. 
No adjustments for multiple testing will be made as this is a secondary analysis. With our sample 
sizes, we will have an 80% chance of detecting a change of at least 0.5 standard deviations.
The 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 CMH exact test.
The tCLN (tethered cationic lipoplex nanoparticle biochip), mCLN (microfluidic cationic 
lipoplex nanoparticle biochip) and qRT-PCR (real-time quantitative reverse transcription-
polymerase chain reaction) measurements for the expression of miR-1, -21, -127 and -155 will 
be made on sera collected from NSCLC patients with and with no radiation pneumonitis. The 
miR expressions, vitamin D levels, and mitochondrial DNA levels will be treated as continuous 
and reported by radiation pneumonitis status (no versus yes) using the mean, median and 
standard deviation. Comparisons will be made between groups using a two-sided permutation t-
test, as there is no a priori notion of which group will have higher expression.
A pilot model, using the 4 miR expression levels as the biomarker, will be built for classification 
of patients into 1 of 2 patient populations: radiation pneumonitis versus no radiation 
pneumonitis. Two classification models will be considered. The first model will treat the miR 
expressions as dichotomous variables, where the Youden’s index method will be used to identify 
an appropriate threshold. The resulting threshold will maximize the correct classification rate a 
given miR expression alone was used to classify patients. The second model will treat the miR 
expressions as continuous variables. Both classification models will be constructed in a similar 
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fashion using multivariate logistic regression, such that the resulting model predicts the 
probability of radiation pneumonitis. A set of candidate variables will be obtained from miR 
expressions and relevant patient characteristics (demographic and clinical). Standard variable 
reduction techniques will be applied if the number of candidate variables grows large. The 
variables in the final model will be selected from the set of candidate variables, including 
possible two-way interaction terms, using forward selection (alpha entry = 0.05) followed by 
backward elimination (alpha exit = 0.05). Models are fit using Firth’s penalized function and 
model assumptions are verified graphically. Standard bootstrap and cross-validation techniques 
will be used to calibrate model coefficients. Model performance will be evaluated using 
calibration plots, receiver operating characteristic (ROC) curves, area under the ROC curve 
(AUC) and a decision curve. In both models the Youden’s index method can also be used to 
determine the optimal threshold probability for classifying patients, from which standard 
classification measures can be obtained (sensitivity, specificity, positive predictive value and 
negative predictive values). As an alternative modeling strategy, classification and regression 
tree (CART) analysis may also be considered to develop a model using only the miR 
expressions. These analyses will be repeated using vitamin D, cytokine and mitochondrial DNA 
levels, alone and in combination with miR expression, to develop classification models.
All secondary analyses will be conducted in SAS v9.4 (Cary, NC), except for CART analysis 
conducted in R v2.12, at a significance level of 0.05.
13.8 Interim Analysis
An interim analysis for futility when the first n1=33 patients have completed 6-months of follow-
up post-chemoradiation; that is, when the first n1=33 patients are evaluable for the primary end-
point. If the estimated COR is greater than or equal to 0.8, then the study will stop early for 
futility. Otherwise, the study will continue and enroll and additional n2=66 patients. 
Additionally, at this time the safety profile of the treatment arms may be evaluated and 
considered in the decision for study continuation.
If the true COR is = 1.0 (no improvement in the nintedanib arm), then there is a 59.0% chance of 
stopping early for futility. If the true COR is 0.26, then there is only a 10.6% chance of stopping 
early for futility.
14
CORRELATIVE STUDIES
14.1 Mitochondrial DNA and Cytokine Analysis
Extracellular mitochondrial DNA and cytokine analysis will be performed in the Segal 
laboratory at RPCI.
Total DNA will be extracted from plasma using a DNA purification kit. Ct values of 
mitochondrial DNA in plasma samples will be determined by qPCR using cytochrome B 
primers, and the concentrations of mitochondrial DNA will be calculated based on a standard 
curve consisting of known concentrations of purified mitochondrial DNA. All samples will be 
analyzed in triplicate wells and average concentrations per sample will be determined.
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14.2 miRNA Analysis
miRNA biochip analysis will be performed at the Wu laboratory at RPCI.
15
ETHICAL AND REGULATORY STANDARDS
15.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
procedure. It is the responsibility of the investigator to ensure that the participant is made aware 
of the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated, in accordance with the Declaration 
of Helsinki, Good Clinical Practice, and according to the guidelines in this protocol, including 
attached appendices.
15.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from 
each participant or the participant's legally authorized representative in accordance with ICH-
GCP guidelines using the approved informed consent form, before any study specific procedures 
(including screening procedures) are performed. The informed consent form acknowledges all 
information that must be given to the participant according to ICH-GCP, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other institutions as needed for further processing is allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
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16 STUDY RESPONSIBILITIES
16.1 Data Collection
Data entry into the database is to be completed in a timely fashion (within 30 days) after the 
participant’s clinic visit. If an AE is considered serious it is captured on both the Adverse Event 
page and the Serious Adverse Event Source Form, which is handled in an expedited fashion.
Data management activities will be performed using eClinical. eClinical is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
eClinical Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs (via the EXPeRT Module). eClinical is compliant with all relevant 
technical aspects of relevant GCP guidelines.
•
The system can generate accurate copies of stored data and audit trail information in 
human readable form.
•
System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.
•
The system is designed to periodically force users to change their passwords and verifies 
that user ID and password combinations remain unique.
•
The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
16.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI.
17 ADMINISTRATIVE RULES
17.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation. Approval must be obtained of any 
amendments prior to implementation at each participating institution from their respective IRBs.
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17.2 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or NCCN, may terminate 
this study, provided a written notice is submitted within the time period provided for in the 
Clinical Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate 
notice if it believes termination is necessary for the safety of participants enrolled in the study.
17.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
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18 APPENDICES
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Appendix A. Instructions for Network Sites
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 7:00 AM to 4:00 PM EST
716-845-8084
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2.
INFORMED CONSENT
•
Informed consent must be obtained by the site Investigator/designee from any 
participants wishing to participate, prior to any procedures or treatment.
•
An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.
•
All consent changes must be reviewed by RPCI Network Office prior to submission to 
the site IRB.
•
The informed consent must be IRB approved.
•
Always check that the most up to date version of the IRB approved consent is being used.
•
Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 1 Protocol Registration Instructions
Contact the RPCI Network Monitor to verify that a slot is available in the open cohort when a 
participant has been identified. Do not have the participant sign consent prior to verifying an 
open slot.
•
After the participant signs consent, the Subject Screening and Enrollment Log must be faxed 
or emailed to the RPCI Network Monitor within 1 business day. The RPCI Network Monitor 
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will confirm receipt of the Subject Screening and Enrollment Log and email the participant 
ID number.
•
When the participant has met eligibility, a signed eligibility checklist and other requested 
documentation will be faxed or emailed to the RPCI Network Monitor.
•
Within 1 business day of receipt of the eligibility check list, the RPCI Network Monitor will 
fax or email the cohort assignment and dose level.
•
An email must be sent by the site to confirm receipt of the cohort assignment and to provide 
the planned treatment start date.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be faxed or emailed to the RPCI Network 
Office within 1 business day of the date the participant is consented. Once the Investigator has 
determined that eligibility has been met, complete the eligibility check list and fax or email it to 
the RPCI Network Monitor at 716-845-8743.
4.
STUDY DEVIATIONS
•
If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the study.
•
ALL study deviation will be recorded on the Study Deviation Log.
•
Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
5.
STUDY DOCUMENTATION
•
Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.
•
If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.
•
Do NOT use white-out, magic marker, scratch-outs.
•
Do NOT erase entries.
•
Use only black ink for documentation on the accountability form and any other study 
forms.
•
It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
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6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.
•
Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).
•
A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.
•
Study drug supply will only be used in accordance with the IRB approved study.
•
Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.
•
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.
•
Drug accountability forms must be stored with study related documents.
•
Each medication provided for this study and each dosage form and strength must have its 
own DARF.
•
Dispensing the wrong study supply is considered a medication error.
•
NEVER replace investigational agents with commercial product.
•
Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. A preliminary written report must follow within 1 business day of the first 
notification using the following forms:
•
RPCI SAE Source form
•
MedWatch 3500A (modify as required per protocol)
•
Refer to Section 11.3 for details regarding SAE reporting to BI and NCCN.
A complete follow-up report must be sent to the RPCI Network Monitor when new information 
becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
criteria in Section 11.5.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff 
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from each site will notify their local IRB in accordance with their local institutional 
guidelines. The site must also notify the RPCI Network Monitor within 1 business day of being 
made aware of the Unanticipated Problem by completing the RPCI Unanticipated Problem 
Report Form and faxing or emailing it to the RPCI Network Monitor.
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Appendix B. Procedures for the Follow-Up of a Potential Drug-Induced Liver Injury Case 
(Hy`s Law Case)
Introduction
Drug-induced liver injury
Drug-induced liver injury (DILI) has been the most frequent single cause of safety-related drug 
marketing withdrawals for the past 50 years (e.g., iproniazid), continuing to the present 
(e.g., ticrynafen, benoxaprofen, bromfenac, troglitazone, nefazodone). Accordingly, detection of 
drug-induced liver injury of an investigational compound has become an important aspect of 
patient´s safety guarding in drug development.
The US-FDA has published a Guidance for Industry entitled, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation” which outlines the detection, evaluation, follow-up and 
reporting of drug-induced liver injury in clinical trials. Drugs that have the potential for inducing 
severe liver injury may be identified by marked peak aminotransferase elevations (10 - , 
15 x ULN), or the combination of hepatocellular injury (aminotransferase elevation ≥ 3 x ULN) 
and altered liver function (hyperbilirubinemia ≥ 2 x ULN) which is defined as potential “Hy´s 
law case” if not explained by other causes including evidence of biliary obstruction (i.e., significant 
elevation of alkaline phosphatase, ALP > 2 x ULN) or some other explanation of the injury 
(e.g., viral hepatitis, alcohol hepatitis, concomitant use of other known hepatotoxic drugs). This 
constellation predicts a poor outcome and although very rare, these potential cases have to be 
well characterized as soon as being identified as other confounding conditions may be the cause.
In further consideration of this FDA Guidance, any potential “Hy’s Law case” has to be reported 
in an expedited manner to the FDA (i.e., even before all other possible causes of liver injury have 
been excluded) and be followed-up appropriately. The follow-up includes a detailed clinical 
evaluation and identification of possible alternative etiologies for the “Hy´s Law case” 
constellation such as concomitant diseases (e.g., Hepatitis B) and/or other concomitant therapies 
that might potentially be hepatotoxic.
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and follow-
up of laboratory alterations of selected liver laboratory parameters to ensure patients´ safety.
The concept below has been worked out by Boehringer Ingelheim (BI) in order to guard patient´s 
safety and to respond to regulatory requirements. It is the basis for all clinical studies and should 
be applied as appropriate.
Definition
The following changes in the laboratory values are considered to be a protocol-specific 
significant adverse event for all patients with normal values for ALT/AST at baseline:
•
An elevation of ALT and / or AST > 5 x ULN without bilirubin elevation measured in the 
same blood draw sample.
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•
An elevation of AST and/or ALT > 2.5 fold ULN combined with an elevation of bilirubin 
to >1.5 fold ULN measured in the same blood draw sample.
These definitions are in line with the current dose reduction recommendations as outlined in all 
study protocols for nintedanib.
Patients showing these laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met.
For patients with elevated ALT/AST values at baseline special considerations apply, if they are 
eligible for inclusion into the trial, e.g., if liver metastasis are present and do not qualify as 
exclusion criterion. For those special cases the BI contact person should be involved.
Procedures
Protocol-specified significant events are to be reported in an expedited manner similar as Serious 
Adverse Events, even if they do not meet any of the seriousness criteria and documented in the 
eCRF.
Replication of the following laboratory tests for confirmation within 48 hours:
•
AST
•
ALT
•
bilirubin measurement (total and direct bilirubin)
•
Alkaline Phosphatase
•
Haptoglobin
•
Complete blood count and cell morphology
•
Reticulocyte count
•
CK
•
LDH
The results of these repeated laboratory tests must be documented on the eCRF /CRF forms and 
reported immediately via the SAE form to BI.
An evaluation of the patient within 48 hours with respect to but not limited to:
•
Abdominal ultrasound or clinically appropriate other imaging and investigations adequate 
to rule out biliary tract, pancreatic, intra- or extrahepatic pathology, e.g., bile duct stones, 
neoplasm, hepatic tumor involvement, biliary tract, pancreatic or intrahepatic pathology, 
vascular hepatic conditions such as portal vein thrombosis or right heart failure. These 
data need to be collected, documented in the respective field of the eCRF/CRF/additional 
documentation form, and the respective SAE form has to be updated and forwarded to BI.
•
Detailed history of current symptoms and concurrent diagnoses and medical history.
•
Detailed history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations and e.g., steroids as concomitant supportive 
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treatment), alcohol use, recreational drug use, and special diets detailed history of 
exposure to environmental chemical agents.
In case that both imaging and laboratory value did not unequivocally confirm cholestasis as the 
reason of ALT/AST increase, in particular if AP < 2 x ULN, then please complete the following 
laboratory tests:
•
Clinical chemistry (i.e., alkaline phosphatase, cholinesterase (either plasma or red blood 
cell), albumin, PT or INR, CK, CK-MB, ceruloplasmin*, α-1 antitrypsin*, transferrin, 
ferritin, amylase*, lipase*, fasting glucose*, cholesterol, triglycerides)
•
Serology (i.e., hepatitis A (Anti-IgM, Anti-IgG), hepatitis B (HbsAg, anti-HBs, DNA), 
hepatitis C (anti-HCV, RNA if anti-HCV positive), hepatitis D (anti-IgM, Anti-IgG)*, 
hepatitis E (anti-HEV, anti-HEV IgM, RNA if anti-HEV IgM positive)*, anti-smooth 
muscle antibody (titer)*, anti-nuclear antibody (titer)*, anti-LKM (liver-kidney 
microsomes) antibody*, anti-mitochondrial antibody*, Epstein Barr Virus (VCA IgG, 
VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM), varicella 
(IgG, IgM), parvovirus (IgG, IgM))
•
Hormones, tumor marker (i.e., TSH*)
•
Hematology (i.e., thrombocytes*, eosinophils*)
*If 
clinically 
indicated 
and 
in 
case 
that 
additional 
investigations 
are 
needed 
(e.g., immunocompromised patients.)
Initiate close observation of all patients with elevated liver enzyme and bilirubin elevations by 
repeat testing of ALT, AST, bilirubin (with fractionation into total and direct) and AP at least 
weekly until the laboratory values return to normal or to the values as defined in the protocol. 
In case that transaminases and/or bilirubin increase despite cessation of the experimental therapy, 
more frequent intervals will be warranted.
Depending on further laboratory changes, additional parameters identified e.g. by reflex testing 
will be followed up based on medical judgement and Good Clinical Practices
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Appendix C. ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix D. Calculation for Creatinine Clearance
Creatinine clearance will be calculated using the Cockcroft and Gault method as shown below.
Men: CrCL = [(140-YR) × IBW] / (PCr × 72)
Women: CrCL = 0.85 × [(140-YR) × IBW] / (SCr × 72)
Where:
CrCL is creatinine clearance, mL/min;
IBW is ideal body weight, kg;
PCr is plasma creatinine, mg/dL; and
YR is age, y.
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Appendix E. Patient Diary
Study No.: ______________
Subject’s Name: ______________________________
Drug Name: _____________
Cycle: _______________________________________
Medical Record No.: _________________________
Study Medication Calendar
You should swallow your medication, unchewed, with a large glass of water at the same times every day, in the morning and in the 
evening after a meal.
If you miss a dose, you proceed with the next scheduled dose when it is due. Do not replace missed dose.
Please complete this calendar on a daily basis immediately after you take your pills. Fill in the date for each day and write the total 
number of pills you take each day.
Start Date: _________________
Dose: ___________________________
Take _____ capsule (s) each time, about 12 hours apart. 
Cycle Day
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date
Number of pills taken - AM
Number of pills taken - PM
Cycle Day
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Number of pills taken - AM
Number of pills taken - PM
Cycle Day
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Number of pills taken - AM
Number of pills taken - PM
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Number of pills taken - AM
Number of pills taken - PM
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic appointment.
Coordinator’s Use Only
	
 
		  	
	h
    
!!!!!	
  
  

    
Subject’s Signature: __________________________________________
Date: ____________
CRC Signature: ____________________________________________
Date: ____________
Investigator’s Signature: ______________________________________
Date: ____________
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Lung Cancer Symptom Scale (LCSS)
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Appendix F. Quality-of-Life-Questionnaires
Below is a list of statements that other people with your illness have said are important.
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GP1
I have a lack of energy.
0
1
2
3
4
GP4
I have pain.
0
1
2
3
4
C2
I am losing weight.
0
1
2
3
4
B1
I have been short of breath.
0
1
2
3
4
HI7
I feel fatigued.
0
1
2
3
4
L2
I have been coughing.
0
1
2
3
4
BP1
I have bone pain.
0
1
2
3
4
L4
Breathing is easy for me.
0
1
2
3
4
C6
I have a good appetite.
0
1
2
3
4
GF5
I am sleeping well.
0
1
2
3
4
GE6
I worry that my condition will get worse.
0
1
2
3
4
GP2
I have nausea.
0
1
2
3
4
B5
I am bothered by hair loss.
0
1
2
3
4
GP5
I am bothered by side effects of treatment.
0
1
2
3
4
L1
My thinking is clear.
0
1
2
3
4
GF3
I am able to enjoy life.
0
1
2
3
4
GF7
I am content with the quality of my life 
right now.
0
1
2
3
4
FWB
TSE
DRS-P
DRS-E
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