A Pilot Study of Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung, Non-Small Cell Lung Cancer, Nonsmall Cell Lung Cancer
Sponsor: Washington University School of Medicine

 
 
 
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A Pilot Study of Nintedanib in Molecularly Selected Patients with Advanced Non-Small Cell 
Lung Cancer (NSCLC) 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201412116  
Version Date: 02/02/2024 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
Ramaswamy Govindan, M.D. 
(314) 362-5654 
rgovindan@wustl.edu 
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Saiama Waqar, M.D.  
 
Washington University 
Medical Oncology 
Daniel Morgensztern, M.D.  
Washington University 
Medical Oncology 
Feng Gao, Ph.D. 
 
 
Washington University 
Biostatistics 
Ticiana Leal, M.D.                              University of Wisconsin        Medical Oncology 
 
Study Drug(s): 
 
Nintedanib (BIBF1120) 
 
IND #: 
 
 
124976 EXEMPT 
ClinicalTrials.gov #: 
NCT02299141 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them 
 
 

 
 
 
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A Pilot Study of Nintedanib in Molecularly Selected Patients with Advanced Non-Small Cell 
Lung Cancer (NSCLC) 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
12/11/14 
Amendment #1 Version 
 
 
 
 
 
 
02/26/15 
Amendment #2 Version 
 
 
 
 
 
 
06/18/15 
Amendment #3 Version 
 
 
 
 
 
 
11/07/16 
Amendment #4 Version 
 
 
 
 
 
 
04/18/17 
Amendment #5 Version 
 
 
 
 
 
 
02/02/24 
 
 

 
 
 
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A Pilot Study of Nintedanib in Molecularly Selected Patients with Advanced Non-Small Cell 
Lung Cancer (NSCLC) 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United States 
Code of Federal Regulations or local regulations governing the conduct of 
clinical studies. 
 
 

 
 
 
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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
ATP 
Adenosine triphosphate 
BID 
Bis in die (twice a day) 
BW 
Body weight 
CBC 
Complete blood count 
CMP 
Comprehensive metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLTs 
Dose Limiting Toxicities 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin-fixed paraffin-embedded 
GGT 
Gamma glutamyltransferase 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IULN 
Institutional upper limit of normal 
mCRC 
Metastastic colorectal cancer 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 

 
 
 
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PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QD 
Quaque die (each day) 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
SNV 
Single nucleotide variant 
SOC 
Standard of care 
TKI 
Tyrosine kinase inhibitor 
UPN 
Unique patient number 
 
 

 
 
 
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Table of Contents 
1.0 
BACKGROUND AND RATIONALE .................................................................................. 8 
1.1 
Non-Small Cell Lung Cancer ............................................................................................. 8 
1.2 
Angiogenesis ...................................................................................................................... 8 
1.3 
Nintedanib (BIBF1120)...................................................................................................... 9 
1.4 
Next Generation Sequencing ............................................................................................ 15 
1.5 
Rationale........................................................................................................................... 15 
1.6 
Benefit – Risk Assessment ............................................................................................... 15 
2.0 
OBJECTIVES ...................................................................................................................... 16 
2.1 
Primary Objectives ........................................................................................................... 16 
2.2 
Secondary Objectives ....................................................................................................... 16 
3.0 
PATIENT SELECTION ...................................................................................................... 16 
3.1 
Inclusion Criteria .............................................................................................................. 16 
3.2 
Exclusion Criteria ............................................................................................................. 18 
3.3 
Inclusion of Women and Minorities................................................................................. 19 
4.0 
REGISTRATION PROCEDURES ..................................................................................... 19 
4.1 
Confirmation of Patient Eligibility ................................................................................... 20 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ............................. 20 
4.3 
Assignment of UPN ......................................................................................................... 20 
5.0 
TREATMENT PLAN .......................................................................................................... 20 
5.1 
Agent Administration ....................................................................................................... 20 
5.2 
General Concomitant Medication and Supportive Care Guidelines ................................ 21 
5.3 
Women of Childbearing Potential .................................................................................... 21 
5.4 
Duration of Therapy ......................................................................................................... 22 
5.5 
Duration of Follow-up ...................................................................................................... 22 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ...................................................................... 22 
6.1 
Criteria for Interruption of Treatment with Nintedanib ................................................... 22 
6.2 
Criteria to Restart Nintedanib .......................................................................................... 23 
6.3 
Dose Adjustments of Nintedanib ..................................................................................... 23 
6.4 
Management of Adverse Events ...................................................................................... 24 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ................................................. 24 
7.1 
Definitions ........................................................................................................................ 25 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
26 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University ................................................................................................................ 27 
7.4 
Reporting Requirements for Secondary Sites .................................................................. 27 
7.5 
Reporting to Secondary Sites ........................................................................................... 27 
7.6 
Reporting to Boehringer Ingelheim and NCCN ............................................................... 28 
7.7 
Timeframe for Reporting Required Events ...................................................................... 31 
8.0 
PHARMACEUTICAL INFORMATION ............................................................................ 31 
8.1 
Nintedanib (BIBF1120).................................................................................................... 31 
9.0 
CORRELATIVE STUDIES ................................................................................................ 32 
9.1 
Specific Hypothesis .......................................................................................................... 32 
9.2 
Tumor Biopsy Specimens for Research ........................................................................... 32 
10.0 STUDY CALENDAR ......................................................................................................... 33 

 
 
 
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11.0 DATA SUBMISSION SCHEDULE ................................................................................... 33 
12.0 MEASUREMENT OF EFFECT.......................................................................................... 34 
12.1 Antitumor Effect – Solid Tumors..................................................................................... 34 
12.2 Disease Parameters ........................................................................................................... 34 
12.3 Methods for Evaluation of Measurable Disease .............................................................. 35 
12.4 Response Criteria ............................................................................................................. 37 
13.0 DATA AND SAFETY MONITORING .............................................................................. 40 
14.0 AUDITING .......................................................................................................................... 41 
15.0 STATISTICAL CONSIDERATIONS................................................................................. 42 
15.1 Study Objectives and Endpoints ...................................................................................... 42 
15.2 Study Design .................................................................................................................... 42 
15.3 Data Analysis ................................................................................................................... 43 
15.4 Correlative Studies Analysis ............................................................................................ 43 
16.0 MULTICENTER REGULATORY REQUIREMENTS ..................................................... 43 
17.0 REFERENCES .................................................................................................................... 45 
APPENDIX A: ECOG Performance Status Scale .......................................................................... 48 
APPENDIX B: PATIENT’S MEDICATION DIARY ................................................................... 49 
APPENDIX C: Procedures for the follow-up of a potential DILI case (Hy’s Law case) in IIS with 
nintedanib (BIBF 1120) .................................................................................................................. 50 
APPENDIX D: SAE Reporting Form ............................................................................................ 53 
 
 

 
 
 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Non-Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer related death in both men and women in the 
United States.1 Over 200,000 patients are diagnosed with lung cancer every year in the 
United States. More than 80% of these patients have non-small cell lung cancer (NSCLC) 
and over half of them present with advanced stage disease at the time of diagnosis.  Platinum 
based chemotherapy remains the mainstay of first line treatment for patients with advanced 
stage NSCLC. In a prospective randomized study that compared four commonly used 
platinum-based chemotherapy regimens for patients with stage IIIB or stage IV disease: 
cisplatin plus paclitaxel, cisplatin plus gemcitabine, cisplatin plus docetaxel, and carboplatin 
plus paclitaxel, no regimen was found to have a significantly better response rate or survival 
time.2 The response rate for all 1,158 of the eligible patients was 19%, and the median 
survival time was 7.9 months (95% CI, 7.3-8.5 months). The results from this study indicate 
that the combination of platinum with third generation chemotherapeutic agents (paclitaxel, 
docetaxel, vinorelbine, gemcitabine) has limited benefit in the treatment of patients with 
metastatic NSCLC.  Unfortunately treatment benefit from 1st line cytotoxic chemotherapy 
is usually short lived with a median time to progression of 3 to 5 months. Standard second 
line treatment options are few, limited to docetaxel, pemetrexed, and erlotinib for patients 
with good performance status. 3-5 Therefore it is essential to develop effective treatment 
options 
for 
patients 
with 
relapsed/refractory 
NSCLC. 
Many 
patients 
with 
relapsed/refractory NSCLC also have marginal performance status and it is important to 
develop therapies that are tolerable. 
 
1.2 
Angiogenesis 
 
Angiogenesis, an essential step for tumor growth and progression is defined as the growth 
of new blood vessels from existing vasculature.6 Due to its critical role in several tumors 
including NSCLC, its inhibition represents a rational therapeutic strategy. VEGF is key 
ligand and regulator of both physiological and pathological angiogenesis, including from 
tumors, with the signaling occurring mostly through VEGFR2.7 The two main mechanisms 
of VEGF inhibition are the use of monoclonal antibodies against circulating VEGF and 
small molecules that inhibit its tyrosine kinase activity. Several VEGFR TKIs have been 
tested as single agents in patients with NSCLC, and it is not surprising that the response 
rates to these drugs in molecularly unselected patients have been disappointing.8-10 Sunitinib 
is an oral tyrosine kinase inhibitor (TKI) of VEGFR and PDGFR. The phase II study of 
sunitinib in 47 previously treated NSCLC patients showed potential therapeutic benefit 
(median progression-free survival (PFS) 11.9 weeks), and one patient had a confirmed 
partial response.8  
 
Bevacizumab, a humanized monoclonal antibody against circulating VEGF was the first 
antiangiogenic drug to be approved for NSCLC, with its use restricted to patient with non-
squamous histology due to the increased risk of life-threatening bleeding in squamous cell 
carcinoma.11 Two randomized clinical trials, Eastern Cooperative Oncology Group (ECOG) 
4599 and Avastin in Lung (AVAiL), comparing chemotherapy alone or with bevacizumab, 

 
 
 
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showed improved response rate and progression-free survival (PFS) for the combination 
therapy.12,13 However, only the ECOG 4599 study showed a survival benefit. VEGFR 
tyrosine kinase inhibitors (TKIs) compete with adenosine triphosphate (ATP) for the active 
site of the kinase domain. Due to the well-conserved ATP binding site of the kinases, most 
VEGFR TKIs inhibit multiple receptors including PDGFR.14,15 Additionally, recently 
published research shows that expression of VEGF-A correlated with mutations in TP53, 
suggesting that TP53 mutational status may also play a role in response to antiangiogenic 
therapies. 16,17 
 
PDGF promotes tumor cell proliferation, invasion, migration and angiogenesis.18 The 
PDGF pathway plays a significant role in angiogenesis through its effects on pericytes and 
vascular smooth muscle cells, which in turn secrete VEGF.19 This signaling cooperation 
could be explored with a dual inhibitor. One of the major obstacles for further development 
of anti-angiogenesis inhibitors is the lack of reliable predictors for response. We believe that 
with the use of a potent single agent TKI against VEGFR and PDGFR in a molecularly 
selected patient population may lead to a significant benefit in some patients and further 
evaluation of responders with a comprehensive molecular profile both at diagnosis and at 
progression, may provide valuable information predictors for response and mechanisms of 
resistance.  
 
1.3 
Nintedanib (BIBF1120) 
 
Nintedanib is a TKI of VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3.20 In the phase I 
monotherapy study, nintedanib was well tolerated with dose limiting toxicities of elevated 
AST, ALT, and GGT. Other toxicities included nausea, diarrhea, vomiting, abdominal pain, 
and fatigue.  The maximum tolerated dose (MTD) determined at 200 mg bid. When 
nintedanib (at 200mg bid) was used in combination with chemotherapy (FOLFOX, 
pemetrexed, docetaxel, and paclitaxel/carboplatin) it showed no added safety concerns. This 
led to two separate phase III studies in patients with NSCLC in the 2nd line setting comparing 
chemotherapy alone to chemotherapy in combination with nintedanib. Both studies met 
their primary endpoint of PFS with no unexpected toxicities. 21 
 
1.3.1 Preclinical Development and Pharmacokinetics 
 
Nintedanib (BIBF1120) is a potent, orally available triple kinase inhibitor 
targeting VEGFRs, PDGFRs, and FGFRs.  
 
Nintedanib inhibits the signalling 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, signalling by FGF-receptors 

 
 
 
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has been identified as a possible escape mechanism for tumour angiogenesis 
when the VEGF pathway is disrupted.  
 
Besides inhibition of neo-angiogenesis, it may alter tumour maintenance by 
inducing apoptosis of tumour blood vessel endothelial cells. Inhibition of receptor 
kinases may also interfere with autocrine and paracrine stimulation of tumour 
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 (BIBF1120) may have a 
direct anti-tumour 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-
tumour efficacy at doses of 50 – 100 mg/kg, leading to a substantial delay of 
tumour growth or even complete tumour-stasis in xenografts of a broad range of 
differing human tumour types. Histological examination of treated tumours 
showed a marked reduction of tumour vessel density by approximately 80% .20 
 
The metabolism of nintedanib (BIBF1120) was predominantly characterized by 
the ester cleavage of the methyl ester moiety yielding BIBF 1202, which was 
further metabolized by conjugation to glucuronic acid yielding the 1-O-
acylglucuronide.  Data collected in this study show that nintedanib (BIBF1120) 
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.21 The 
metabolic characteristics are predominantly independent of cytochrome P450-
catalysed metabolic pathways.22 
 
A soft gelatine capsule formulation of nintedanib is used in man. After oral 
administration, nintedanib is absorbed quickly. Maximum plasma concentrations 
(Cmax) generally occur 2 to 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 h. Nintedanib is mainly eliminated via 
faeces.22  

 
 
 
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Nintedanib (BIBF1120) is non-mutagenic, even at high doses.  
 
Two exploratory studies in rats revealed a teratogenic effect of nintedanib 
(BIBF1120) 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 (BIBF1120) in semen is unknown, males 
receiving nintedanib (BIBF1120) 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.  
 
1.3.2 Clinical Development of Nintedanib  
 
Nintedanib is being evaluated in several cancers. Additionally, nintedanib is in 
advanced phase III for the non-cancer indication idiopathic pulmonary fibrosis 
(IPF). As of 15 Feb 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.  
 
Phase I 
Phase I dose selection studies revealed that nintedanib (BIBF1120) is generally 
well tolerated with mild to moderate adverse effects such as gastrointestinal 
symptoms (nausea, diarrhoea, vomiting, abdominal pain) and reversible 
elevations of liver enzymes. Initial signs of clinical activity including an 
encouraging rate of patients with stabilisation of their tumour of 54% and 68%, 
respectively, have been observed in patients with various solid tumours.23 
 
Based on the Phase I dose escalation trials with nintedanib (BIBF1120) 
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 RP2D for nintedanib as monotherapy is 200 mg bid  
 
The maximum tolerated dose for combination therapy of nintedanib (BIBF1120) 
in combination with pemetrexed, docetaxel, paclitaxel/carboplatin and FOLFOX 
is 200mg bid. Combination of nintedanib (BIBF1120) with other anti-cancer 
drugs revealed a similar adverse event profile as compared to nintedanib 
(BIBF1120) monotherapy except for the chemotherapy related toxicities. There 
was no change of the pharmacokinetic parameters of nintedanib (BIBF1120) 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 (BIBF1120) with 
pemetrexed, where fatigue was the most relevant dose limiting toxicity.  
 

 
 
 
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Available pharmacokinetic data indicate that the systemic exposure needed for 
biological activity can be achieved starting with doses of 100 mg nintedanib 
(BIBF1120) 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.22 
 
NSCLC 
In a phase II trial in NSCLC patients the safety profile of nintedanib (BIBF1120) 
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 PFS 
of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved 
in 46% of patients (ECOG 0–1 patients: 59%), with one confirmed partial 
response (250 mg bid.).24  
 
LUME-Lung 1 was an international, randomized, double-blind, phase III trial 
assessing the efficacy and safety of docetaxel plus nintedanib as second 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 
200mg 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. 
 
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 

 
 
 
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pain and fatigue of mostly low to moderate intensity after monotherapy with 
nintedanib (BIBF1120). Dose limiting toxicities were dose dependent hepatic 
enzyme elevations that were reversible after discontinuation of nintedanib 
(BIBF1120) 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 three liver 
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 two 
months of treatment.  
 
Hypertension or thromboembolic events were rare and did not suggest an 
increased frequency as a consequence of therapy with nintedanib (BIBF1120).21 
 
LUME-Lung 2 was a similar randomised, double-blind, phase III study of 
nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with 
advanced non-squamous non-small cell lung cancer 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.25 
 
Ovarian Cancer 
A randomised phase II maintenance trial in ovarian cancer in which the efficacy 
and safety of nine months of continuous twice daily doses of nintedanib 
(BIBF1120) following chemotherapy was investigated, has identified the 
potential activity of nintedanib (BIBF1120) with a 36-week PFS of 16.3 % 
compared to 5.0 % in the control group. The safety profile was consistent with 
findings previously reported for nintedanib (BIBF1120) administered as 
monotherapy as mentioned above.26   
 

 
 
 
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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 six 
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.27   
 
Colorectal Cancer 
A Phase I/II, open-label, randomised 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 mFOLFOX 6. In comparison to bevacizumab, 
nintedanib showed a similar magnitude of efficacy, a similar safety/tolerability 
profile, a similar exposure and dose intensity of mFOLFOX6.28  
 
A Phase III study is going to start in late 2014 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). 
 
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.29 
 
Hepatocellular Cancer  
The efficacy and safety of nintedanib versus sorafenib in Asian Patients with 
Advanced Hepatocellular Carcinoma was investigated in a randomised phase II 
trial. Nintedanib showed similar efficacy to sorafenib, with a favourable 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 erythrodysaesthesia syndrome, and transaminase 
elevation events.30  
 
For more details please refer to the investigator drug brochure for nintedanib 
(BIBF1120). 
 

 
 
 
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1.4 
Next Generation Sequencing 
 
It is a standard of care at our institution to perform next-generation sequencing in the tumor 
specimens from patients with metastatic NSCLC and at the time of disease progression 
when feasible following targeted therapies.  Next generation sequencing involves targeted 
exon sequencing of ‘clinically significant’ cancer genes using next-generation sequencing 
technology. 
 
1.5 
Rationale 
 
There has been limited benefit with angiogenesis inhibitor drugs when used with 
molecularly selected patients in NSCLC. We propose that patients who are molecularly 
selected for treatment with nintedanib based on the presence of mutations (VEGFR1-3, 
PDGFR-A, PDGFR-B, RET21,31, and FGFR1-3) will have clinically meaningful benefits in 
terms of RR and PFS. Furthermore we plan to perform exome sequencing of paired tumor 
(pre and post treatment) in order to better define molecular marker predictors for response 
and resistance.  
 
1.6 
Benefit – Risk Assessment  
 
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 or metastatic non-small cell lung cancer.  
 
Antiangiogenic treatment with the orally available triple angiokinase inhibitor nintedanib 
(BIBF1120) with inhibition of VEGFR, PDGFR, RET and FGFR offers the chance to 
control both locally recurrent and distant metastatic disease on an outpatient basis. 
Treatment with nintedanib (BIBF1120) may have the potential to provide significant benefit 
to patients with locally advanced and/or metastatic non-small cell lung cancer 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-tumour effects, e.g. tumor cells that express 
VEGFR, PDGFR, RET, or FGFR.  
 
The risks of therapy with nintedanib (BIBF1120) in adult patients are primarily related to: 
• the gastro-intestinal tract (nausea, vomiting, diarrhea, abdominal pain)  
• increases in liver enzymes (AST, ALT, γ-GT) 
• fatigue, asthenia and anorexia.  
 
Liver enzymes must be followed closely during treatment with nintedanib (BIBF1120). 
 
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.  

 
 
 
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Impairment of immune and of kidney function, thromboembolic events and GI perforations 
are considered possible side effects of treatment with nintedanib (BIBF1120) 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 (BIBF1120), 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 (BIBF1120) to a mild to moderate degree and only few cases of CTCAE 
grade 3 or 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 (BIBF1120) 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 
(BIBF1120) is considered safe.  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
To evaluate the response rates for patients with advanced NSCLC with mutations in the 
target genes for nintedanib. 
 
2.2 
Secondary Objectives 
 
1. To evaluate progression free survival. 
2. To correlate outcomes with specific mutations. 
3. To further evaluate extreme responders with exome and transcriptome sequencing. 
4. To evaluate the mechanisms of secondary resistance. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically confirmed diagnosis of advanced (metastatic or unresectable) NSCLC 
with mutations, rearrangement and fusion involving RET oncogene, or abnormalities 
(non-synonymous SNV or amplification) in the nintedanib target genes VEGFR1-3, 

 
 
 
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TP53, PDGFR-A, PDGFR-B, or FGFR1-3.CLIA certified lab testing for nintedanib 
target genes using cell free DNA from  peripheral blood and/or assays performed on  
tumor tissues are acceptable 
 
2. Patients with EGFR mutations or ALK rearrangements must have disease progression 
on appropriate FDA-approved therapy for these genomic aberrations prior to 
enrollment. 
 
3. Disease progression on platinum-doublet chemotherapy prior to enrollment. 
 
4. At least one measurable lesion or evaluable disease.  Measurable disease is defined as 
lesions that can be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥10 mm with CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with 
calipers by clinical exam. 
 
5. Prior treatment of cancer (chemotherapy, radiation therapy, and surgery) is allowed if 
completed at least 3 weeks prior to start of treatment with nintedanib and if all treatment-
related toxicities are resolved. 
 
6. At least 18 years of age. 
 
7. ECOG performance status 0-1 (see Appendix A). 
 
8. Normal bone marrow and organ function as defined below: 
a. Leukocytes ≥ 3,000/mcL 
b. Absolute neutrophil count ≥ 1,500/mcL 
c. Platelets ≥ 100,000/mcL 
d. Hemoglobin ≥ 9.0 g/dL 
e. INR < 2.0 
f. PT and PTT < 50% of deviation from IULN 
g. Total bilirubin ≤ 1.5 x IULN 
h. AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN for patients without liver metastases and ≤ 
2.5 x IULN for patients with liver metastases 
i. Urine protein < 2+ 
j. Creatinine within normal institutional limits         
OR 
Creatinine clearance > 45 mL/min for patients with creatinine levels above 
institutional normal 
 
9. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry, for the 
duration of study participation, and for 3 months after the end of treatment.  Should a 
woman become pregnant or suspect she is pregnant while participating in this study, she 
must inform her treating physician immediately. 
 

 
 
 
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10. Able to understand and willing to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Prior treatment with VEGFR tyrosine kinase inhibitors. 
 
2. A history of other malignancy ≤ 5 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix. 
 
3. Currently receiving any other investigational agents, or received an investigational agent 
within 3 weeks of the first dose of nintedanib. 
 
4. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging. 
 
5. Symptomatic brain metastases.  Patients with known brain metastases are eligible if the 
metastases are asymptomatic and previously treated. 
 
6. Leptomeningeal disease. 
 
7. Radiographic evidence of cavitary or necrotic tumors. 
 
8. Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of 
major blood vessels. 
 
9. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nintedanib or other agents used in the study. 
 
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure > NYHA II, active coronary artery 
disease, unstable angina pectoris, serious cardiac arrhythmia, uncontrolled hypertension 
(defined as systolic pressures > 150 mmHg or diastolic pressure > 90 mmHg), 
pericardial effusion, uncontrolled seizure disorder, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
11. Major injuries and/or surgery with then past 4 weeks prior to the start of study treatment 
with incomplete wound healing and/or planned surgery during the on-treatment study 
period. 
 
12. History of clinically significant hemorrhagic or thromboembolic event in the past 6 
months. 
 
13. Known inherited predisposition to bleeding or thrombosis. 
 

 
 
 
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14. History of cardiac infarction within the past 12 months prior to the start of study 
treatment. 
 
15. Receiving therapeutic anticoagulation (except low-dose heparin and/or heparin flush as 
needed for maintenance of an in-dwelling intravenous device) or anti-platelet therapy 
(except for low-dose therapy with acetylsalicylic acid < 325 mg QD). 
 
16. Pregnant and/or breastfeeding.  Patients of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
17. Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the 
trial. 
 
18. Known active or chronic hepatitis B or C infection. 
 
19. Active alcohol or drug abuse. 
 
20. Gastrointestinal disorder or abnormality that would interfere with absorption of the 
study drug. 
 
21. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with nintedanib.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
 

 
 
 
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4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Current approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within one business day. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Nintedanib is an oral drug which will be administered on an outpatient basis at a dose of 
200 mg twice daily during each 28-day cycle. Starting with cycle 64, cycles will last 12 
weeks. Patients should take nintedanib approximately 12 hours apart at around the same 
time every day after food intake.  Capsules should not be opened and should be swallowed 
unchewed with approximately 8oz of water.  If a patient misses a dose, the patient should 

 
 
 
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be instructed not to take or make up that dose and to resume dosing with the next scheduled 
dose.  Patients will be instructed to bring all unused capsules and their medication diary to 
each study visit for assessment of compliance.   
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
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. 
 
Supportive care for nausea and vomiting may include medicinal products with anti-emetic 
properties, e.g. glucocorticoids, antihistamines, 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 AEs occur.  Interruption, 
dose reduction, or discontinuation of therapy may be required despite appropriate supportive 
care. 
 
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. 
 
Strong P-gp inducers, e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort, may 
decrease exposure to nintedanib.  Co-administration with nintedanib should be carefully 
considered. 
 
5.3 
Women of Childbearing Potential 
 
Women of childbearing potential are required to have a negative pregnancy test within 14 
days prior to the first dose of nintedanib.  Women will be considered to be of childbearing 
potential 
unless 
surgically 
sterilized 
by 
hysterectomy 
or 
bilateral 
tubal 
ligation/salpingectomy, or post-menopausal for at least two years. 
 
Female and male patients (along with their female partners) are required to use a highly 
effective method of birth control during participation in the study and for 3 months 
following the last dose of nintedanib.  A highly effective method of birth control is defined 
as one which results in a low failure rate (i.e. less than 1% per year) when used consistently 
and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine 
devices (IUDs), sexual abstinence, or vasectomized partner.  
 
If a patient is suspected to be pregnant, nintedanib should be immediately discontinued.  In 
addition, a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 

 
 
 
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If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of nintedanib, the investigator must be notified in order 
to facilitate outcome follow-up. 
 
5.4 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s 
health and/or the patient no longer wishes to continue protocol therapy, the protocol therapy 
should be discontinued and the reason(s) for discontinuation documented in the case report 
forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
• NCCN decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as indicated 
in the study calendar. 
 
5.5 
Duration of Follow-up 
 
There is a 28-day follow-up visit following the last dose of study drug.  Patients will be 
monitored as per routine care thereafter for progression and survival, and that data will be 
captured in the case report forms.  Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Criteria for Interruption of Treatment with Nintedanib 
 
Treatment with nintedanib has to be interrupted in case any of the criteria listed in the table 
below is fulfilled. 

 
 
 
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If one criterion is met, nintedanib has to be interrupted 
• 
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 
• 
other non-hematological adverse event of CTCAE grade ≥ 3 considered drug-
related 
 
6.2 
Criteria to Restart Nintedanib  
 
A patient is eligible to restart nintedanib if all criteria listed in the table below are met.  
 
If a patient has to interrupt intake of nintedanib due to an adverse event for more than 14  
days, the decision to restart treatment with nintedanib needs to be discussed and agreed upon 
between the investigator and the study supporter. 
 
All criteria have to be met in order to restart nintedanib  
• 
nausea CTCAE grade ≤ 2 
• 
vomiting CTCAE grade ≤ 1 
• 
diarrhoea CTCAE grade < 2 
• 
AST and ALT CTCAE grade ≤ 2 and bilirubin CTCAE grade ≤ 1  
• 
no other non-hematological adverse event grade CTCAE ≥ 3 which is considered 
drug-related 
 
6.3 
Dose Adjustments of Nintedanib 
 
As initial measure for the management of side effects, treatment with nintedanib should be 
temporarily interrupted until the specific adverse reaction has resolved to levels that allow 
continuation of therapy. Nintedanib 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 as described in the sections above.  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 should be discontinued. 
  
The following dose levels will be used in case dose adjustments are required for 
management of undue toxicity.   

 
 
 
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Dose-level: 
0 
-1 
-2 
-3 
Dose: 
200 mg BID 
150 mg BID 
100 mg BID 
Discontinue 
 
 
Of note: 
If the dose of nintedanib had to be reduced due to toxicity, it will stay on the lower dose 
level for the entire time of administration. 
 
6.4 
Management of Adverse Events 
 
 CTCAE Adverse reaction 
Dose adjustment 
  Diarrhea ≥ grade 2 for more than 7 consecutive days 
despite anti-diarrheal treatment 
 OR 
 diarrhoea ≥ grade 3 despite anti-diarrheal treatment 
1st episode 
Reduce dose from 200 mg 
twice daily to 150 mg twice 
daily 
 
2nd episode  
Reduce dose from 150 mg 
twice daily to  100 mg twice 
daily 
   
 3rd episode 
 Stop 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 
 
Please note, dose adjustments are only required in adverse events that are drug-related. 
 
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 as mentioned 
above and for the other compound as mentioned in their prescribing information.  
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 

 
 
 
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Boehringer Ingelheim and NCCN require that all events as defined in Section 7.6 be reported as 
outlined. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health and 
Human Services’ Office for Human Research Protections (OHRP).  A copy of this 
guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 

 
 
 
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not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject 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); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 

 
 
 
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• Any unanticipated problems involving risks to participants or others which occur at 
WU, any BJH or SLCH institution, or that impacts participants or the conduct of the 
study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a 
QASMC auditor. 
 
7.4 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 7.6) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report (using either an FDA MedWatch form if required or 
an institutional SAE reporting form if not).  A formal written report must be sent to the 
Washington University PI and research coordinator within 10 working days of the 
occurrence of the event or notification of the secondary site’s PI of the event.  The death of 
a research participant that qualifies as a reportable event should be reported within 1 
working day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.   
 
7.5 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 
site of all reportable events that have occurred at other sites within 10 working days of the 

 
 
 
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occurrence of the event or notification of the PI of the event.  This includes events that take 
place both at Washington University and at other secondary sites, if applicable. 
 
 
7.6 
Reporting to Boehringer Ingelheim and NCCN 
 
7.6.1 Definitions 
 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who 
received a pharmaceutical product. The event does not necessarily have to have a 
causal relationship with this treatment. 
 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is 
immediately life-threatening, results in persistent or significant disability / 
incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / 
birth defect, or is to be deemed serious for any other reason if it is an important 
medical event when based upon appropriate medical judgement which may 
jeopardise the patient and may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definitions. 
 
Patients may be hospitalised 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 hospitalisations planned at the beginning of the trial do not need to be reported 
as an SAE.  
 
Severity of adverse event 
The severity of the AE should be judged based on the following:  
The severity of adverse events should be classified and recorded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) <add version> in the 
(e)CRF. 
 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or 
re-challenge, confounding factors such as concomitant medication, concomitant 
diseases and relevant history. Assessment of causal relationship must be recorded 
for each adverse event.  
 
Causality will be reported as either “Yes” or “No”. 
 
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the AE.  

 
 
 
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No: 
There is no reasonable causal relationship between the investigational 
product administered and the  AE.  
 
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be 
recorded as an AE in the CRF. 
 
Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory test results will 
be recorded as an AE in the CRF , if they are judged clinically relevant by the 
investigator. 
 
7.6.2 Adverse Events of Special Interests (AESI) 
 
The following events are considered as protocol-specified events of special interests: 
 
Any gastrointestinal- and non-gastrointestinal perforation, leakage, fistula 
formation, abscess 
 
In such case the following additional information need to be collected, documented 
in the respective comment field of the CRF page and the respective narratives of the 
SAE. That has to be forwarded to Boehringer Ingelheim: 
• Location of perforation, leakage, fistula, abscess 
• Location/extent of abdominal tumor manifestations, 
• Imaging & 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 > 5x 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 
 

 
 
 
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Patients showing above laboratory abnormalities need to be followed up until the 
protocol specific retreatment criteria have been met and according to Appendix C 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.  
 
7.6.3 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 (Appendix D) 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 
Fax: 1-203-837-4329 
 
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.  

 
 
 
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7.7 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked during study treatment and for 30 days following the last 
day of study treatment.  For the purposes of this protocol, adverse events collected and 
documented on CRFs are grade 3, 4, or 5 adverse events. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Nintedanib (BIBF1120) 
 
8.1.1 Nintedanib Description 
 
Molecular formula: C33H39N5O7S 
Molecular weight: 649.8 
 
8.1.2 Clinical Pharmacology 
 
Ten hours following the first intake of nintedanib, mean plasma levels of VEGF and 
bFGF showed a trend to increase in relation to the baseline level, which could be 
indicative of successful blockade of angiogenesis receptors. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
After oral administration, maximum plasma concentrations generally occurred 
between 2-4 hours after dose.  Steady state was latest reached within one week of 
dosing.  The pharmacokinetics of nintedanib can be considered time-independent. 
 
Nintedanib is mainly metabolized by esterases. 
 
The terminal half-life of nintedanib varied between 7 and 19 hours.  The major route 
of elimination was via fecal/biliary excretion.  The contribution of renal excretion to 
the total clearance was low.  The overall recovery was considered complete within 
4 days after single dosing. 
 
8.1.4 Suppliers 
 
Nintedanib will be provided by Boehringer Ingelheim. 
 
8.1.5 Dosage Form and Preparation 
 
Nintedanib is provided as soft gelatin capsules containing a suspension of milled 
active as the salt.  It is available in two dose strengths corresponding to 100 mg and 
150 mg. 
 

 
 
 
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8.1.6 Storage and Stability 
 
Store below 30°C.  Protect from exposure to high humidity. 
 
8.1.7 Administration 
 
Patients should take nintedanib approximately 12 hours apart at around the same 
time every day after food intake.  Capsules should not be opened and should be 
swallowed unchewed with approximately 8oz of water. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Specific Hypothesis   
 
The genomic landscape of cancer is complex and evolves through the process of clonal 
evolution innately and in response to treatment. Unbiased exome and transcriptome 
sequencing performed on tumor samples at time of diagnosis in responders and non-
responders will help us identify unique variations that confer susceptibility to nintedanib. 
Moreover, genomic analysis at time of progression after treatment with nintedanib (after 
response (CR/PR/SD) lasting for 6 months or longer) will provide some unique insights into 
mechanisms underlying acquired resistance. 
 
9.2 
Tumor Biopsy Specimens for Research 
 
9.2.1 Collection of Specimens 
 
If archival tissue samples are available and/or a biopsy is obtained for clinical 
purposes at the time of disease progression, WUSM may request a tissue samplefor 
research sequencing, including whole exome and transcriptome sequencing.  The 
specimens will be collected in accordance with standard of care practice and will be 
taken to the Washington University Tissue Procurement core for processing and 
storage per institutional practice. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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10.0 
STUDY CALENDAR 
 
All visits have a window of +/- 3 days.  
 
Screening 
Day 1 of 
Each 
Cycle 
End of Every 
Cycle 
End of 
Treatment 
Informed consent 
X 
 
 
 
H&P, ECOG PS 
X 
X 
 
X 
CBC6 
X 
X 
 
X 
CMP7 
X 
X 
 
X 
Coagulation panel8 
X 
 
 
 
Urinalysis9 
X 
 
 
 
Pregnancy test 
X1 
 
 
 
CT scan – chest and 
abdomen with contrast 
X 
 
X 
 
Nintedanib 
 
X2 
 
 
Fresh biopsy for research 
sequencing3 
 
 
 
X4 
Adverse events assessment 
X 
X ------------------------------------ X5 
1. Women of childbearing potential only; serum or urine 
2. Taken twice a day every day of each 28-day cycle.  Starting with cycle 64 cycles will last 12 weeks. 
3. If a biopsy is obtained for clinical purposes at the time of disease progression, a sample may be collected for 
research purposes 
4. To be monitored for 28 days after end of treatment 
5. One follow-up visit at 28 days after end of treatment, then routine follow-up as per standard of care, with data 
collection regarding progression and survival to take place for the study 
6. CBC with differential includes: WBCs, RBCs, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW-CV, 
Platelets, MPV, Absolute Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils   
7. CMP includes: Sodium, Potassium, Carbon Dioxide, BUN, Glucose, Creatinine, Calcium, Chloride, Albumin, 
AST, ALT, Alkaline Phosphatase, Bilirubin, Plasma Protein and Anion Gap 
8. CoAg panel includes PT, PTT, and INR 
9. Urinalysis includes: Color, Clarity, Specific Gravity, pH, Protein, Glucose, Ketones, Bilirubin, Blood, 
Urobilinogen, Nitrites and Leukocyte Esterase 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Tumor Biopsy Form 
Prior to starting treatment 
Treatment Form 
End of every cycle 
Toxicity Form 
Continuous 

 
 
 
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Treatment Summary Form 
Tumor Biopsy Form 
Completion of treatment 
Tumor Measurement Form Baseline, end of every even numbered cycles (after every cycle 
starting with cycle 64), and end of treatment 
Follow-Up Form 
As per routine care 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).32  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 

 
 
 
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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout 
follow-up.  
 
12.3 
Methods 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 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 

 
 
 
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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 
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 patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published.33-35  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer.36 
 

 
 
 
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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. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 

 
 
 
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Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference 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.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
    
 
 

 
 
 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 

 
 
 
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until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
12.4.6 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) 
independent of the study at the study’s completion.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Committee (DSMC) will be specifically convened for this 
trial to review toxicity data at least every 6 months.  A DSMC will consist of no fewer than 3 
members including 2 clinical investigators and a biostatistician.  Like investigators, DSMC 
members are subject to the Washington University School of Medicine policies regarding standards 
of conduct. Individuals invited to serve on the DSMC will disclose any potential conflicts of interest 
to the trial principal investigator and/or appropriate university officials, in accordance with 
institution policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMC 
must also be disclosed.  
 
 
The DSM report will be prepared by the study statistician with assistance from the study team, will 
be reviewed by the DSMC, and will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC).  This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 

 
 
 
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• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities at all participating sites 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
Further DSMC responsibilities are described in the DSMC charter. 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to be 
prepared by the study team will be submitted to the QASM Committee beginning 6 months after 
study activation at Washington University. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf  
 
 
14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 

 
 
 
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Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be asked 
to provide the additional charts within two working days. 
 
Items to be evaluated include: 
• Subject screening and enrollment 
• Reporting of adverse events 
• Maintenance of HIPAA compliance 
• Completeness of regulatory documentation 
• Completeness of participant documentation 
• Acquisition of informed consent 
• IRB documentation 
• Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf  
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Objectives and Endpoints 
 
15.1.1 Primary Endpoint 
 
Response rate (partial response plus complete response) after two cycles of therapy 
 
15.1.2 Secondary Endpoints 
 
• To evaluate progression free survival 
• To correlate outcomes with specific mutations 
• To further evaluate extreme responders with exome and transcriptome 
sequencing. 
• To evaluate the mechanisms of secondary resistance 
 
15.2 
Study Design   
 
This is an open label, single-arm pilot study to obtain preliminary information of the efficacy 
of single agent nintedanib.  A total of 20 patients will be enrolled in this study. The sample 
size is determined primarily based on clinical feasibility rather than statistical power.  
However, the proposed sample size will provide us a reasonable precision to estimate the 
preliminary information. 37If 4 responders are observed out of 20 patients, for example, we 
would have 80% confidence that the “true” rate would fall between 9% and 36%. If the 

 
 
 
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“true” response rate is 20% or higher, there would be 80% chance of observing at least 3 
responders out of 20 patients. Conversely, there would be <10% chance to observe 3 or 
more responders if the true rate is less than 5%.  
 
15.3 
Data Analysis   
 
As a pilot study for proof of principal, the data analysis will be descriptive in nature. 
Demographic and clinical characteristics of the sample, as well as response, toxicity by 
grade and loss to follow up will be summarized using descriptive statistics. Kaplan-Meier 
product limit estimator will be used to describe the distribution of progression free survival. 
The 95% confidence interval (CI) for RR and 6-month PFS will also be calculated.  
 
15.4 
Correlative Studies Analysis 
 
The association between response and specific mutation status will be assessed by 
permutation analysis. Taking the relationship between FGFR1 expression and RR as an 
example, for instance, we first compute the observed test statistics, e.g., the sample mean 
difference between responders versus non-responders.  Then to simulate the null distribution 
of the test statistics, or the distribution of the observed mean differences if there were truly 
no difference, we repeat the following 10,000 times: we randomly shuffle the response 
status, and then calculate the sample difference between the newly designated groups. The 
permutation p-value equals the proportion of simulations from the null distribution that 
exceed the observed test statistics. 
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document to 
be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include 
a statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 

 
 
 
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The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 weeks 
of obtaining Washington University IRB approval.  Activated secondary sites are expected to 
submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call to 
update and inform regarding the progress of the trial. 
 
 
 
 
 

 
 
 
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17.0 
REFERENCES 
1. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for 
clinicians 2014;64:9-29. 
2. 
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens 
for advanced non-small-cell lung cancer. The New England journal of medicine 2002;346:92-8. 
3. 
Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus 
vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated 
with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer 
Study Group. J Clin Oncol 2000;18:2354-62. 
4. 
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed 
versus docetaxel in patients with non-small-cell lung cancer previously treated with 
chemotherapy. J Clin Oncol 2004;22:1589-97. 
5. 
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-
small-cell lung cancer. The New England journal of medicine 2005;353:123-32. 
6. 
Folkman J. Tumor angiogenesis: therapeutic implications. The New England journal of 
medicine 1971;285:1182-6. 
7. 
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature 
medicine 2003;9:669-76. 
8. 
Socinski MA, Novello S, Brahmer JR, et al. Multicenter, phase II trial of sunitinib in 
previously treated, advanced non-small-cell lung cancer. J Clin Oncol 2008;26:650-6. 
9. 
Blumenschein GR, Jr., Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled 
trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell 
lung cancer. J Clin Oncol 2009;27:4274-80. 
10. 
Schiller JH, Larson T, Ou SH, et al. Efficacy and safety of axitinib in patients with 
advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 2009;27:3836-
41. 
11. 
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing 
bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously 
untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184-
91. 
12. 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for 
non-small-cell lung cancer. The New England journal of medicine 2006;355:2542-50. 
13. 
Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and 
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results 
from a randomised phase III trial (AVAiL). Annals of oncology : official journal of the European 
Society for Medical Oncology / ESMO 2010;21:1804-9. 
14. 
Morgensztern D, Herbst RS. Multitargeted tyrosine kinase inhibitors in unselected patients 
with advanced non-small-cell lung cancer (NSCLC): impressions from MONET (the motesanib 
NSCLC efficacy and tolerability study). J Clin Oncol 2012;30:2805-8. 
15. 
Subramanian J, Morgensztern D, Govindan R. Vascular endothelial growth factor receptor 
tyrosine kinase inhibitors in non-small-cell lung cancer. Clinical lung cancer 2010;11:311-9. 
16. 
Said R, Hong DS, Warneke CL, et al. P53 mutations in advanced cancers: clinical 
characteristics, outcomes, and correlation between progression-free survival and bevacizumab-
containing therapy. Oncotarget 2013;4:705-14. 

 
 
 
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17. 
Schwaederle M, Vladimir L, Validire P, et al. VEGF-A Expression Correlates with TP53 
Mutations in Non-Small Cell Lung Cancer: Implications for Anti-Angiogenesis Therapy. Cancer 
research 2015. 
18. 
Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology 
and medicine. Genes & development 2008;22:1276-312. 
19. 
Rogosin S, Sandler AB. Beyond bevacizumab: antiangiogenic agents. Clinical lung cancer 
2012;13:326-33. 
20. 
Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with 
sustained receptor blockade and good antitumor efficacy. Cancer research 2008;68:4774-82. 
21. 
Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus 
placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, 
double-blind, randomised controlled trial. The lancet oncology 2014;15:143-55. 
22. 
Stopfer P, Rathgen K, Bischoff D, et al. Pharmacokinetics and metabolism of BIBF 1120 
after oral dosing to healthy male volunteers. Xenobiotica; the fate of foreign compounds in 
biological systems 2011;41:297-311. 
23. 
Mross K, Stefanic M, Gmehling D, et al. Phase I study of the angiogenesis inhibitor BIBF 
1120 in patients with advanced solid tumors. Clinical cancer research : an official journal of the 
American Association for Cancer Research 2010;16:311-9. 
24. 
Reck M, Kaiser R, Eschbach C, et al. A phase II double-blind study to investigate efficacy 
and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed 
advanced non-small-cell lung cancer. Annals of oncology : official journal of the European 
Society for Medical Oncology / ESMO 2011;22:1374-81. 
25. 
Hanna NH, Kaiser R, Sullivan RN, et al. Lume-lung 2: A multicenter, randomized, 
double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in 
patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-
line chemotherapy. ASCO Meeting Abstracts 2013;31:8034. 
26. 
Ledermann JA, Rustin GJ, Hackshaw A, et al. A randomized phase II placebo-controlled 
trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following 
treatment of relapsed ovarian cancer (OC). ASCO Meeting Abstracts 2009;27:5501. 
27. 
DuBois et al: ESGO 2013  
28. 
van Cutsem et al: ECCO 2011. 
29. 
Eisen T, Shparyk Y, Jones R, et al. Phase II efficacy and safety study of nintedanib versus 
sunitinib in previously untreated renal cell carcinoma (RCC) patients. ASCO Meeting Abstracts 
2013;31:4506. 
30. 
Yen et al: ECCO 2013. 
31. 
Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nature reviews Cancer 
2014;14:173-86. 
32. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47. 
33. 
Rustin GJS, Quinn M, Thigpen T, et al. Re: New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors (Ovarian Cancer). Journal of the National Cancer Institute 
2004;96:487-8. 
34. 
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-
Specific Antigen Working Group. J Clin Oncol 1999;17:3461-7. 

 
 
 
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35. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148-59. 
36. 
Vergote I, Rustin GJS, Eisenhauer EA, et al. Re: New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors [Ovarian Cancer]. Journal of the National Cancer 
Institute 2000;92:1534-5. 
37. 
Piantadosi S. Translational clinical trials: an entropy-based approach to sample size. 
Clinical trials 2005;2:182-92. 
 
 
 

 
 
 
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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  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). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

 
 
 
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APPENDIX B: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
Agent:  nintedanib 
Cycle:    
 
Study ID#:   
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle.  Take _____mg ( ___capsules) of nintedanib twice daily, approximately 12 
hours apart, after a meal and with a glass of water.  Swallow the capsules whole and do not chew them. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take a dose, then just take the next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill count 
can be done.   
Day 
Date 
AM Dose 
PM Dose 
Comments 
Time taken 
# of capsules 
taken 
Time taken 
# of capsules 
taken 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 

 
 
 
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APPENDIX C: Procedures for the follow-up of a potential DILI case (Hy’s Law case) in IIS 
with nintedanib (BIBF 1120) 
_________________________________________________________________________ 
 
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 (10x-, 15xULN), 
or the combination of hepatocellular injury (aminotransferase elevation ≥3xULN) and altered liver 
function (hyperbilirubinemia ≥2xULN) 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, >2X 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. 
 
Defintion 
 
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: 
  

 
 
 
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- 
an elevation of ALT and / or AST > 5x 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.  
 
These definitions are in line with the current dose reduction recommendations as outlined in all 
study protocols for BIBF 1120. 
 
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 
1. 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 
 
2. 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. 
3. 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 tumour 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 
 

 
 
 
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- 
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 eg steroids as 
concomittant suppportive treatment), alcohol use, recreational drug use, and 
special diets detailed history of exposure to environmental chemical agents 
 
4. In case that both imaging and laboratory value did not unequivocally confirm cholestasis as 
the reason of ALT / AST increase, in particular if AP < 2x ULN,  
then please complete the following laboratory tests: 
 
- 
Clinical chemistry 
alkaline phosphatase, cholinesterase (either plasma or red blood cell), albumin, 
PT or INR, CK, CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin, ferritin, 
amylase*, lipase*, fasting glucose*, cholesterol, triglycerides 
- 
Serology 
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, tumormarker 
TSH* 
- 
Haematology 
Thrombocytes*, eosinophils* 
 
*If clinically indicated and in case that additional investigations are needed (e.g 
immunocompromised patients.) 
 
5. 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.  
 
6. 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 D: SAE Reporting Form 
 
 
 

 
 
 
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