Conditions: Appendix Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this trial is to evaluate the disease control rate of nintedanib in subjects with metastatic appendiceal cancer for whom initial fluoropyrimidine-based chemotherapy has failed. Based on previous studies, the anticancer activity of nintedanib in lung and ovarian cancer trials, along with the similarities between appendiceal and colorectal cancer and potentially ovarian cancer, warrant additional investigation for the optimal treatment of metastatic appendiceal carcinomas.

Detailed description:
The primary study objective is to evaluate the disease control rate. The secondary study objectives are to evaluate safety and toxicity, objective response rate, overall and 6-month progression free survival, and overall survival. Exploratory study objectives include evaluation of serum and ascites VEGF, hypertension, and paracentesis frequency in subjects with ascites at study entry.

Arms:
arm 1: Nintedanib

Interventions: intervention 1: nintedanib
Intervention descriptions: intervention 1: Oral nintedanib, taken twice daily

Protocol document:
Prot_SAP_000.pdf: 
Protocol Number:  LCI-GI-APX-NIN-001 
Version 3: 04/18/2018 
Page 1 of 65 
 
Protocol #:  LCI-GI-APX-NIN-001 
TITLE: NINTEDANIB IN METASTATIC APPENDICEAL CARCINOMA 
LAY TITLE: NINTEDANIB IN APPENDICEAL CANCER THAT HAS SPREAD 
Coordinating Site: 
Levine Cancer Institute – Research and Academic Headquarters  
Carolinas Medical Center 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
 
Jimmy J. Hwang, MD  
1021 Morehead Medical Drive,  
Charlotte, NC 28204 
Telephone: (980) 442-6410 
Email:  Jimmy.Hwang@carolinashealthcare.org 
 
Statistician: 
James T. Symanowski, PhD  
Levine Cancer Institute  
1100 Blythe Boulevard, Office 1164 
Charlotte, NC 28203 
Telephone: (980) 442-2371 
Email:  James.Symanowski@carolinashealthcare.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Investigational drug:  Nintedanib 
______________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH-GCP, and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Sponsor-Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 
 


Protocol Number:  LCI-GI-APX-NIN-001 
Version 3: 04/18/2018 
Page 3 of 65 
 
Original Phase II / Version 3 / Dated 04/18/2018 
PROTOCOL SUMMARY 
A. Study Title 
Nintedanib in Metastatic Appendiceal Carcinoma 
B. Indication 
Metastatic appendiceal cancer after failure on fluoropyrimidine-based therapy 
C. Clinical Phase II 
 
D. Summary of 
Rationale 
 
 
Nintedanib is an oral tyrosine kinase inhibitor of VEGFR.  It has demonstrated 
evidence of anticancer activity in lung and ovarian cancer in clinical trials, and 
is undergoing further investigation in metastatic colorectal cancer.  Given the 
analogies between appendiceal and colorectal cancer and potentially ovarian 
cancer, and the limited information about the optimal treatment of metastatic 
appendiceal carcinomas, further investigation with nintedanib is warranted in 
this disease. 
E. Study 
Objectives 
The primary study objective is to evaluate the disease control rate.  The 
secondary study objectives are to evaluate safety and toxicity, objective 
response rate, 6-month progression free survival and overall survival.  
Exploratory study objective include evaluation of serum VEGF, ascites VEGF, 
hypertension and paracentesis frequency in subjects with ascites at study entry.  
F. Sample 
Up to 39 subjects. Stage I: 28 evaluable subjects.  
If the study continues to Stage II: an additional 11 evaluable subjects 
 
 
G. Inclusion 
Criteria 
 
 
 
• 
Histologically confirmed stage IV appendiceal carcinoma 
• 
Failure of initial fluroropyrimdine-based chemotherapy.  Failure is defined 
as progression on or within 6 months of therapy or intolerance of initial 
fluroropyrimdine-based chemotherapy 
• 
ECOG performance status score 0-2  
• 
Measurable and/or evaluable, non-measurable disease according to RECIST 
1.1 criteria  
H. Dosage/ 
Dosage 
Form, Route, 
And Dose 
Regimen 
Subjects will take oral nintedanib (200mg) twice daily.  Dose reductions   to 
150mg and then 100mg twice daily as needed based on toxicity.  Each cycle is 
28 days. 
I. Statistical 
Analysis 
Disease control will be determined for each subject as a binary variable 
indicating whether or not the subject achieved a best overall response of CR, 
PR, or SD as determined by RECIST 1.1.  Disease control rate will be 
estimated with the corresponding 95% Clopper-Pearson confidence interval. 
Objective response rate and 6-month PFS rate will be estimated with the 
corresponding 95% Clopper-Pearson confidence interval.  Progression-free 
survival and overall survival rates will be estimated using Kaplan-Meier 
techniques.  Multivariable regression models will be used to evaluate the 
impact of baseline subject and disease characteristics on outcomes.  Incident 
rates for adverse events, SAEs, and deaths while on study therapy will be 
summarized.   


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SCHEMA 
• 
Metastatic appendiceal carcinoma
• 
Failure of, progression on (or within 6 months after), or 
intolerance of initial fluoropyrimidine-based 
chemotherapy
Nintedanib 200 mg 
twice daily x 2 
cycles 
Restaging
(CT Imaging)
Response/
Stable
Progression
Continue 
Nintedanib until 
progression; 
Scan every two 
cycles until 
progression
Off Treatment
Endpoints
Primary:  DCR
Secondary:  OS, ORR, overall and 6 month PFS, safety/toxicity
Exploratory:  Serum VEGF, hypertension, ascites VEGF, paracentesis
Statistical Plan
Single arm, two-stage design of 39 patients
 
 


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LIST OF ABBREVIATIONS 
β-HCG 
β-human chorionic gonadotropin 
γ-GT 
γ-Glutamyl Transferase 
5-HT3 
5-Hydroxy-Tryptamin receptor 3 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALKP 
Alkaline phosphatase 
ALT / ALT (SGPT) Alanine aminotransferase /  Alanine aminotransferase (serum glutamic 
pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AP 
Alkaline Phosphatase 
AST / AST (SGOT) Aspartate aminotransferase / Aspartate aminotransferase (serum glutamic-
oxaloacetic transaminase) 
ATP 
Adenosine triphosphate 
bFGF 
Basic fibroblast growth factor 
BI 
Boehringer Ingelheim 
BID 
Twice daily 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CHS 
Carolinas HealthCare System 
CI 
Confidence interval 
CK 
Creatine kinase 
CK-MB 
Creatine kinase-MB 
Cmax 
Maximum measured concentration of the analyte in plasma 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF/eCRF 
Case report form / electronic case report form 
CT 
Computed tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical trial management system 
DBP 
Diastolic blood pressure 
DILI 
Drug-induced liver injury 
DLT 
Dose limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
DNA 
Desoxyribo nucleic acid 
ECG 
Electro cardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FGF 
Fibroblast growth factor 
FGFR 
Fibroblast growth factor receptor 
FGR 
Fibroblast growth factor 
GCP 
Good Clinical Practice 


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G-CSF 
Granulocyte Colony Stimulating Factor 
GI 
gastrointestinal  
GGTP 
Gamma-glutamyltranspeptidase 
GMP 
Good Manufacturing Practice 
HCC 
Hepatocelluar carcinoma 
HR 
Hazard ratio 
ICH 
International Conference on Harmonisation 
IB 
Investigator brochure 
ID 
Identification 
IDS 
Investigational Drug Service 
IIS 
Investigator initiated study 
INR 
International normalized ratio 
IPF 
Idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
L 
Litre 
LCI 
Levine Cancer Institute 
LDH 
Lactate dehydrogenase 
LTF 
Lost to follow-up 
Lck 
Lymphocyte-specific protein-tyrosine kinase, member of the Src family of 
kinases 
Lyn 
Yamaguchi sarcoma viral (v-yes-1) oncogene homolog, cellular protein 
tyrosine kinase member of the Src family of kinases 
mg 
Milligram 
mCRC 
Metastatic colorectal cancer 
min 
Minute 
ml/mL 
Millilitre 
mm 
Millimetre 
MRI 
Magnetic resonance imaging 
MTOR 
Mechanistic target of rapamycin 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OS 
Overall survival 
PD 
Progressive disease 
PDGF 
Platelet derived growth factor 
PDGFR 
Platelet derived growth factor receptor 
PFS 
Progression free survival 
P-GP 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RAH 
Research and Academic Headquarters 
RECIST 
Response Evaluation Criteria in Solid Tumours 
REP 
Residual effect period 
RET 
Ret proto-oncogene 


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RCC 
Renal cell carcinoma 
RP2D 
Recommended Phase 2 Dose 
s 
Second 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SOP 
Standard operating procedure 
Src 
Src tyrosine kinase 
TSH 
Thyroid stimulating hormone 
ULN  
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 


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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ........................................................................................................... 3 
SCHEMA ....................................................................................................................................... 4 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
TABLE OF CONTENTS ............................................................................................................. 8 
1. 
OBJECTIVES .................................................................................................................. 11 
1.1. 
Primary Objective .......................................................................................................... 11 
1.2. 
Secondary Objectives ..................................................................................................... 11 
1.3. 
Exploratory Objectives ................................................................................................... 11 
2. 
BACKGROUND AND RATIONALE ........................................................................... 11 
2.1. 
Background .................................................................................................................... 11 
2.2. 
Experience with Nintedanib ........................................................................................... 13 
2.3. 
Study/Dose Rationale ..................................................................................................... 19 
3. 
BENEFIT/RISK ASSESSMENT .................................................................................... 20 
4. 
SUBJECT SELECTION ................................................................................................. 21 
4.1. 
Accrual ........................................................................................................................... 21 
4.2. 
Eligibility Criteria .......................................................................................................... 21 
4.3. 
Reproductive Risks ........................................................................................................ 24 
5. 
INVESTIGATIONAL PLAN ......................................................................................... 25 
5.1. 
Study Milestones ............................................................................................................ 25 
5.2. 
Overall Study Design ..................................................................................................... 25 
5.3. 
Informed Consent ........................................................................................................... 26 
5.4. 
Registration/Enrollment/Discontinuation....................................................................... 26 
5.5. 
Study Procedures ............................................................................................................ 27 
6. 
STUDY CALENDAR ...................................................................................................... 31 
7. 
TREATMENT PLAN ...................................................................................................... 33 
7.1. 
Nintedanib Dosage and Administration ......................................................................... 33 
7.2. 
Treatment Compliance ................................................................................................... 33 
7.3. 
Duration of Therapy ....................................................................................................... 34 
7.4. 
Drug Accountability ....................................................................................................... 34 


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7.5. 
Destruction ..................................................................................................................... 35 
8. 
NINTEDANIB INTERRUPTION .................................................................................. 35 
8.1. 
Criteria for Interruption of Treatment with Nintedanib ................................................. 35 
8.2. 
Criteria to Restart Treatment with Nintedanib ............................................................... 35 
8.3. 
Dose Adjustments of Nintedanib ................................................................................... 36 
9. 
TREATMENT-RELATED ADVERSE EVENTS ........................................................ 37 
9.1. 
Management of Adverse Events……………………………………………………….37 
9.2. 
Additional Precautions for Nintedanib ........................................................................... 38 
9.3. 
Rescue Medications and Additional Treatments ............................................................ 40 
9.4. 
Restrictions ..................................................................................................................... 40 
10. 
DATA AND SAFETY MONITORING PLAN ............................................................. 41 
10.1. Safety Monitoring .......................................................................................................... 41 
10.2. Data Quality Assurance .................................................................................................. 41 
10.3. Communication Between Investigational Sites.............................................................. 42 
10.4. Clinical Trial Registration .............................................................................................. 42 
11. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING...................... 42 
11.1. Unanticipated Problem (UAP) Definition ...................................................................... 42 
11.2. Adverse Event (AE) Definition ...................................................................................... 43 
11.3. Serious Adverse Event (SAE) Definition....................................................................... 44 
11.4. Adverse Event and Deviation Reporting ........................................................................ 45 
12. 
MEASUREMENT OF EFFECT .................................................................................... 48 
12.1. Anti-tumor Effect – Solid Tumor ................................................................................... 48 
13.      STASTICAL CONSIDERATION ……………………………………………………..50 
13.1  Sample Size .................................................................................................................... 50 
13.2. Analysis Populations ...................................................................................................... 52 
13.3. Analysis Methods ........................................................................................................... 53 
13.4. Interim Analyses ............................................................................................................ 54 
14. 
STUDY COMPLETION ................................................................................................. 55 
14.1. Completion ..................................................................................................................... 55 
14.2. Termination .................................................................................................................... 55 
15. 
RETENTION OF RECORDS ........................................................................................ 55 


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16. 
ETHICAL AND LEGAL ISSUES .................................................................................. 56 
16.1. Ethical and Legal Conduct of the Study......................................................................... 56 
16.2. Confidentiality ................................................................................................................ 57 
REFERENCES ............................................................................................................................ 58 
APPENDICES ............................................................................................................................. 60 
 
 
 


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1. OBJECTIVES 
 
1.1. 
Primary Objective 
 
The primary study objective is to evaluate the disease control rate of nintedanib in 
subjects with Stage IV appendiceal carcinoma versus an inferred clinical historical 
disease control rate in the second line setting of 30%.   
Disease control consists of subjects with measurable disease achieving complete 
response, partial response, or stable disease (as defined by RECIST 1.11) and subjects 
with non-measurable disease with at least one disease assessment indicating non-
progressive disease. 
 
1.2. 
Secondary Objectives 
 
The secondary study objectives are to evaluate:  
• Safety and toxicity,  
• Objective response rate,  
• Overall and 6-month progression free survival, and  
• Overall survival   
 
1.3. 
Exploratory Objectives 
 
Exploratory study objectives include: 
• Evaluation of serum VEGF,  
• Evaluation of ascites VEGF,  
• Hypertension  
• Frequency of paracentesis in subjects with ascites at study entry 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Background 
Appendiceal carcinomas are rare malignancies.  This spectrum of malignant diseases 
is characterized by varying components of mucin production.  The differential 
amounts of mucin that is present in the tumor appear to inversely correspond to 
aggressiveness of the malignancy.  A frequent occurrence in metastatic appendiceal 
carcinomas is peritoneal carcinomatosis and/or malignant ascites or mucin production, 
leading to frequent parallels with ovarian and primary peritoneal cancer2. 
There are limited data regarding the efficacy of systemic therapy in the treatment of 
metastatic appendiceal carcinomas, and most of what has been presented is 


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retrospective in nature with its attendant limitations, such as patient selection and 
publication bias.  Generally, patients have received therapy similar to a standard 
regimen for metastatic colorectal cancer, such as 5-fluorouracil, and leucovorin with or 
without oxaliplatin or irinotecan, and with or without the addition of monoclonal 
antibiodies such as bevacuzimab3.  What has been published suggests that the response 
to chemotherapy, at least in the first line setting, is similar to standard chemotherapy.  
After an extensive review of the literature, we were unable to identify any data, 
beyond case reports, demonstrating consistent activity for any therapy in the second 
line setting in appendiceal carcinoma.   
Over the past decade, there has been an increasing focus on the development of 
therapies that target specific molecular pathways.  Although appendiceal carcinomas 
are relatively uncommon, there have been several reports suggesting that there are 
several potentially druggable targets worthy of further investigation4.  For example, 
high vascular endothelial growth factor receptor (VEGFR)2 expression in appendiceal 
cancer has been correlated with poor survival5.  Similarly, mammalian target of 
rapamycin (mTOR) has been correlated with a poorer progression free survival6.   
Since one downstream impact of mTOR is on angiogenesis, it appears that one 
common pathway in the development and progression of appendiceal cancer may be 
through the VEGF pathway and angiogenesis.   Moreover, malignant ascites has been 
demonstrated to have elevated levels of VEGF7.  In addition, in ovarian cancers, in 
which peritoneal metastases and malignant ascites are frequent, anti-VEGF therapy 
with VEGF targeting therapy including monoclonal antibodies like aflibercept, has 
been demonstrated to decrease the ascites, and can induce objective responses8.  
Angiogenesis is involved in tumour growth and development of metastases. Tumors 
induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. 
VEGF and bFGF). Vascular Endothelial Growth Factor (VEGF) and its high affinity 
receptor VEGFR-2 are crucial for the formation of new tumour vessels. In addition, 
there is preclinical evidence that fibroblast growth factor (FGF) and platelet-derived 
growth factor (PDGF) and their associated receptor tyrosine kinases substantially 
contribute to tumour angiogenesis. The VEGF - VEGFR-2 axis, besides promoting 
angiogenesis, may also be involved in stimulating growth of tumour cells themselves 
via an autocrine growth factor loop. This is suggested by in vitro data and 
immunohistochemical studies, e.g. for non-small cell lung cancer, ovarian carcinoma, 
gastric carcinoma, and malignant mesothelioma. Therefore, suppression of 
neoangiogenesis via inhibition of VEGFR-2 is a promising strategy for the treatment 
of human solid cancers. A substantial number of clinical trials with various inhibitors 
of VEGF or VEGFRs in various types of malignant tumors demonstrated this 
approach can convey clinical benefit, as monotherapy in RCC and HCC as well as in 


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combination therapy with standard chemotherapeutic drugs in NSCLC, CRC, Ovarian 
Cancer and others. 
2.2. 
Experience with Nintedanib 
 
2.2.1. 
Preclinical development and pharmacokinetics 
Nintedanib 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 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 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 
 


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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 tumors showed a marked reduction 
of tumour vessel density by approximately 80%9. 
The metabolism of nintedanib 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 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 urine10.  The metabolic characteristics are predominantly independent of 
cytochrome P450-catalysed metabolic pathways11. 
 
A soft gelatine capsule formulation of nintedanib is used in humans. 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 feces11. 
Nintedanib is non-mutagenic, even at high doses.  
 
Two exploratory studies in rats revealed a teratogenic effect of nintedanib with a 
steep dose/effect relationship and an early onset of embryo fetal deaths at low 
dosages. This effect was observed at dose levels resulting in plasma drug 
concentrations comparable to or below those in humans. Because the concentration 
of nintedanib in semen is unknown, males receiving nintedanib and having sexual 
intercourse with females of childbearing potential should use latex condoms. Women 
of childbearing potential should be advised to use adequate contraception during and 
at least 3 months after the last dose of nintedanib.  
 
2.2.2. 
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.  
 


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Phase I 
Phase I dose selection studies revealed that nintedanib is generally well tolerated with 
mild to moderate adverse effects such as gastrointestinal symptoms (nausea, diarrhea, 
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 tumors12. 
Based on the Phase I dose escalation trials with nintedanib monotherapy, the 
maximum tolerated dose was defined to be 250 mg for twice daily dosing in 
Caucasians and 200 mg twice daily in Japanese patients with a manageable safety 
profile in advanced cancer patients. Based on the overall safety profile, the RP2D for 
nintedanib as monotherapy is 200 mg bid.  
 
The maximum tolerated dose for combination therapy of nintedanib in combination 
with pemetrexed, docetaxel, paclitaxel/carboplatin and FOLFOX is 200mg bid. 
Combination of nintedanib with other anti-cancer drugs revealed a similar adverse 
event profile as compared to nintedanib monotherapy except for the chemotherapy 
related toxicities. There was no change of the pharmacokinetic parameters of 
nintedanib or of the cytotoxic compounds due to the combined treatment. Dose 
limiting toxicity consisted mostly of liver transaminase elevations as in the 
monotherapy phase I trials with the exception of the combination of nintedanib with 
pemetrexed, where fatigue was the most relevant dose limiting toxicity.  
Available pharmacokinetic data indicate that the systemic exposure needed for 
biological activity can be achieved starting with doses of 100 mg nintedanib once 
daily. 
The predominant adverse events were nausea, diarrhea, 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 reversible11. 
 
NSCLC 
In a phase II trial in NSCLC patients the safety profile of nintedanib observed in 
phase I trials could be confirmed. Most commonly reported drug-related AEs were 


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nausea (57.5%), diarrhea (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.)13.  
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 docetaxel10. 
A significant improvement in OS was demonstrated in patients with adenocarcinoma; 
median OS 12.6 months [95% CI 10·6–15·1] vs 10·3 [95% CI 8·6 –12·2] months; 
HR 0·83 [95% CI 0·70 –0·99], p=0·0359); the Kaplan -Meier survival curves separate 
at 6 months, continuing throughout the 36-month study observation period. One year 
overall survival was 52·7% (95% CI 46·8 –57·9) in the docetaxel plus nintedanib 
group compared with 44·7% (38·9 –49·8) in the docetaxel plus placebo group; 2 year 
overall survival was 25·7% (95% CI 20·5 –30·2) in the docetaxel plus nintedanib 
group compared with 19·1% (14·4 –23·2) in the docetaxel plus placebo group10. 
In the predefined population of patients with adenocarcinoma who had progressed 
within 9 months after start of first-line therapy, overall survival was significantly 
longer in the docetaxel plus nintedanib group than in the docetaxel plus placebo 
group (median overall survival 10·9 months [95% CI 8·5–12·6] vs 7·9 months [6·7 –
9·1]; HR 0·75 [95% CI 0·60 –0·92], p=0·0073) 10. 
 
In the total population of patients (all histologies), there was no difference in overall 
survival between the two groups: median overall survival was 10·1 months (95% CI 
8·8–11·2) in the docetaxel plus nintedanib group compared with 9·1 (8·4 –10·4) 
months in the docetaxel plus placebo group (HR 0·94 [95% CI 0·83 –1·05], 
p=0·2720)10. 


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Nintedanib plus docetaxel had a manageable safety profile with no unexpected safety 
findings. The predominant adverse events were nausea, diarrhea, vomiting, 
abdominal pain and fatigue of mostly low to moderate intensity after monotherapy 
with nintedanib. Adverse   events   that   were   more   common (≥5% diﬀerence) in 
the docetaxel plus nintedanib group than the docetaxel plus placebo group were: 
diarrhea (all grades, 276 of 652 [42·3%] vs 143 of 655 patients [21·8%]; grade ≥3, 
43 [6·6%] vs 17 [2·6%]), increases in alanine aminotransferase (all grades, 186 
[28·5%] vs 55 [8·4%]; grade ≥3, 51 [7·8%] vs six [0·9%]), nausea (all grades, 158 
[24·2%] vs 118 [18·0%]; grade ≥3, five [0·8%] vs six [0·9%]), increases in aspartate 
aminotransferase (all grades, 147 [22·5%] vs 43 [6·6%]; grade ≥3, 22 [3·4%] vs three 
[0·5%]), decreased appetite (all grades, 145 [22·2%] vs 102 [15·6%]; grade ≥3, nine 
[1·4%] vs eight [1·2%]), and vomiting (all grades, 110 [16·9%] vs 61 [9·3%]; grade 
≥3, five [0·8%] vs three [0·5%];). Most of these adverse events were manageable 
with supportive treatment or dose reduction10.  
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 chemotherapy14.  
 
Based on a pre-planned 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 events14. 
 
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 following 
chemotherapy was investigated, has identified the potential activity of nintedanib 


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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 administered 
as monotherapy as mentioned above15. 
 
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). The trial 
remains blinded for OS as the data were immature at the time of the primary analysis. 
Main adverse events were GI side effects and increased hematological toxicity16. 
 
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 mFOLFOX617. 
 
A Phase III study was completed after recruiting more than 760 participants 
worldwide 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. 
 
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 


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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 events18.  
 
For more details please refer to the investigator drug brochure for nintedanib. 
2.3. 
Study/Dose Rationale 
 
2.3.1. 
Study Rationale 
 
Nintedanib (BIBF 1120) is an oral tyrosine kinase inhibitor of VEGFR.  It has 
demonstrated evidence of anticancer activity in lung and ovarian cancer in clinical 
trials, and is undergoing further investigation in metastatic colorectal cancer.  Given 
the analogies between appendiceal and colorectal cancer and potentially ovarian 
cancer, and the limited information about the optimal treatment of metastatic 
appendiceal carcinomas, further investigation with nintedanib is warranted in this 
disease. 
 
2.3.2. 
Dose Rationale 
The dose of nintedanib was selected based on doses evaluated in single agent and 
combination studies in patients with cancer, or others with idiopathic fibrosis.  The 
most extensive experience with nintedanib in patients with malignancy is in lung 
cancer.  Nintedanib was evaluated at 150 mg twice daily and 250 mg twice daily in 
patients with stage IIIB and IV non-small cell lung cancer (NSCLC) after first or 
second line platinum based chemotherapy in a randomized phase II study.  They 
reported no clear difference in efficacy, though the only confirmed partial response 
was at the 250 mg BID dose.  It did appear that patients receiving the higher dose did 
experience more frequent grade 3-4 elevations in transaminases and GGTP, diarrhea 
and nausea.  Interestingly, no grade 3 or 4 hypertension was reported13.   Thus, a phase 
3, double-blind, placebo-controlled study was performed in 1314 patients with 
NSCLC in the second line setting, comparing docetaxel   with 200 mg po BID of 
nintedanib with docetaxel and placebo.   This study demonstrated that the addition of 
nintedanib to docetaxel significantly improved the median progression free survival, 
compared to docetaxel and placebo (3.5 months, compared to 2.7 months), meeting the 
study’s primary endpoint.   Even in combination with docetaxel, nintedanib was fairly 
well tolerated, with the most common severe toxicities again being diarrhea, and 
transaminase elevations10.  In two large randomized, double-blind phase 3 studies 
totaling 1066 patients with idiopathic pulmonary fibrosis, nintedanib 150 mg twice 
daily was compared to placebo, and proved to be well tolerated, with the most 
common toxicities being diarrhea and elevations in the liver enzymes, but less than 5% 


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of patients discontinued nintedanib because of toxicities.  However, it should be noted 
that five patients (1.6%) had a myocardial infarction while on nintedanib, compared to 
one (0.5%) who was treated with placebo19.  Taken together, this data suggests that 
nintedanib at doses from 150 to 200 mg, and perhaps 250 mg twice daily is tolerable, 
and should be investigated at a dose of 200 mg twice daily as a single agent in the 
second line setting. 
3. 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 appendiceal carcinoma.  
 
Antiangiogenic treatment with the orally available triple angiokinase inhibitor 
nintedanib with inhibition of VEGFR, PDGFR and FGFR offers the chance to control 
both locally recurrent and distant metastatic disease on an outpatient basis. Treatment 
with nintedanib may have the potential to provide significant benefit to patients with 
locally advanced and/or metastatic appendiceal carcinoma by slowing tumor 
progression and metastasis, since its cellular target is expressed on the tutor vasculature 
in most malignancies. Induction of endothelial cell apoptosis may result in subsequent 
degradation of tumor vessels and subsequent tumor necrosis. Additionally tumor growth 
may be affected by direct anti-tumor effects, e.g. tumor cells that express VEGFR, 
PDGFR, or FGFR.  
 
The main risks of therapy with nintedanib in adult patients are: 
• the gastro-intestinal AEs ( diarrhea nausea, vomiting, abdominal pain)  
• increases in liver enzymes (AST, ALT, ALKP) and bilirubin 
• Perforation (gastrointestinal and non-gastrointestinal) 
• Hypertension 
• Venous thromboembolism 
• Bleeding 
• Neutropenia and sepsis, if combined with myelosuppressive chemotherapy 
• Pancreatitis  
 
Liver enzymes must be followed closely during treatment with nintedanib. 
 
Therapy with the trial drug must be interrupted in the event of relevant elevations of 
liver enzymes and/or of bilirubin and further treatment is to be withheld until 
recovery of the abnormal laboratory parameters.  
 


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Hypertension is a side effect of nintedanib and a slightly increased frequency of 
hypertension has been observed in the trials with nintedanib to a mild to moderate 
degree and only few cases of CTCAE grade 3 or 4 hypertension have been observed. 
With respect to bleeding, in the LUME –Lung 1 trial involving 1314 patients more 
bleeding events were reported for nintedanib-treated squamous cell carcinoma 
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 were balanced between both arms regardless of histology.  
 
Based upon a non-clinical safety study in vitro, nintedanib may have a potential risk 
of phototoxicity (skin and eyes) in vivo. Few cases of photosensitivity reactions (less 
than 1 %) and of CTCAE grade 1 intensity only have been reported from the clinical 
studies to date. If adequate precautions are taken (avoidance of prolonged ultraviolet 
exposure, use of broad spectrum sunscreen and sunglasses), treatment with 
nintedanib is considered safe.  
 
4. SUBJECT SELECTION 
 
4.1. 
 Accrual 
This study will enroll up to 39 subjects in 2 stages with appendiceal carcinoma that 
have failed (defined as progression on or within 6 months or intolerance of) initial 
fluoropyrimidine-based chemotherapy. It is anticipated the duration of accrual will be 
48 months.  Both men and women of all races and ethnic groups are eligible for this 
trial. 
4.2. 
Eligibility Criteria 
4.2.1. Inclusion Criteria 
 
Subjects must meet all of the following criteria:  
a. Age ≥ 18 years old 
b. Histologically confirmed appendiceal carcinoma stage IV 
c. Failure of initial fluoropyrimidine -based chemotherapy.  Failure is defined as 
progression on or within 6 months of last day of therapy or intolerance of 
initial fluroropyrimdine-based chemotherapy. 
d. Life expectancy at least 3 months 
e. ECOG performance status score 0-2  


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f. Presence of measurable and/or evaluable, non-measurable disease according 
to RECIST 1.1 criteria  
g. Written informed consent signed and dated by subject or Legally Authorized 
Representative (LAR) prior to admission to the study in accordance with ICH-
GCP guidelines and to the local legislation. 
 
4.2.2 Exclusion Criteria 
 
Subjects must not meet any of the following criteria.  
a. Prior treatment with nintedanib or any other VEGFR inhibitor  
b. Known hypersensitivity to peanut or soya or to contrast media. History of 
hypersensitivity to contrast media is allowed if the subject is able to tolerate 
contrast media with pre-medication.  
c. Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy 
or therapy with monoclonal antibodies or small tyrosine kinase inhibitors 
withinthe past 4 weeks prior to treatment with the trial drug. 
d. Radiotherapy to any target lesion within the past 3 months prior to baseline 
imaging when that target lesion is the only target lesion identified on baseline 
imaging, unless it has subsequently grown.   
e. Persistence of clinically relevant therapy related toxicity from previous chemo 
and/or radiotherapy as determined by the investigator. 
f. Active brain metastases (e.g. stable for <4 weeks, no adequate previous 
treatment with radiotherapy, symptomatic, requiring treatment with anti-
convulsants; dexamethasone therapy will be allowed if administered as stable 
dose for at least one month) or leptomeningeal disease.  
g. Radiographic evidence of cavitary or necrotic tumors. 
h. Tumors with radiographic evidence (CT or MRI) of local invasion of major 
blood vessels. 
i. Anti-neoplastic treatment for appendiceal cancer, with other investigational 
drugs or treatment in another clinical trial within 30 days before start of study 
treatment. 
j. Therapeutic anticoagulation with drugs requiring INR monitoring (except low-
dose heparin and/or heparin flush as needed for maintenance of an in-dwelling 
intravenous devise) or anti-platelet therapy (except for low-dose therapy with 
acetylsalicylic acid ≤ 325mg per day). 


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k. Major injuries and/or surgery within the past 4 weeks prior to start of study 
treatment, incomplete wound healing or planned surgery during the on-
treatment study period. 
l. History of clinically significant hemorrhagic or thromboembolic event in the 
past 6 months prior to consent. 
m. Known inherited predisposition to bleeding or thrombosis. 
n. Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable 
angina, history of infarction, congestive heart failure > NYHA II, serious 
cardiac arrhythmia, pericardial effusion) within the past 12 months prior to 
start of study treatment. 
o. Proteinuria CTCAE grade 2 or greater. 
p. Creatinine > 1.5x ULN or GFR < 45 ml/min.  
q. Hepatic function: total bilirubin above normal limits; ALT or AST > 1.5x ULN 
in subjects without liver metastasis. For subjects with liver metastasis: total 
bilirubin above normal limits; ALT or AST > 2.5x ULN. 
r. Coagulation parameters: International normalised ratio (INR) > 2x ULN, 
prothrombin time (PT) and partial thromboplastin time (PTT) ≥ 1.5x ULN. 
s.  Absolute neutrophil count (ANC) < 1500/ml, platelets < 100000/ml, 
Hemoglobin   < 9.0 g/dl. 
t. Other malignancies at the time of signing the informed consent other than basal 
cell skin cancer or carcinoma in situ of the cervix. 
u. Active serious infections if requiring systemic antibiotic or antimicrobial 
therapy. 
v.  Active or chronic hepatitis C and/or B infection.  
w.  Gastrointestinal disorders (like chronic diarrhea) or abnormalities that would 
interfere with absorption of the study drug per investigator discretion. Subjects 
with this disorder may be allowed if able to tolerate anti-diarrheal medications 
like loperamide. 
x. Serious illness or concomitant non-oncological disease such as neurologic, 
psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or 
laboratory abnormality that may increase the risk associated with study 
participation or study drug administration and in the judgment of the 
investigator would make the subject inappropriate for entry into the study. 
y. Sexually active women of child-bearing potential and men who are sexually 
active with women of child-bearing potential and unwilling to use at least 2 
medically acceptable method of contraception (e.g. such as implants, 


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injectables, combined oral contraceptives, some intrauterine devices or 
vasectomized partner for participating females, condoms for participating 
males) during the trial and for at least three months after end of active therapy. 
Female subjects will be considered of child-bearing potential unless surgically 
sterilized by hysterectomy or bilateral tubal/salpingectomy, or post-menopausal 
for at least 2 years. 
z. Pregnancy or breast feeding; female participants of child-bearing potential must 
have a negative pregnancy test (β-HCG test in urine or serum) before 
commencing study treatment.  
aa. Psychological, familial, sociological, or geographical factors potentially 
hampering compliance with the study protocol and follow-up schedule per the 
investigator.  
bb. Alcohol or drug abuse which in the determination of the investigator would 
interfere with trial participation.   
cc. Significant weight loss, (> 10% of baseline weight) within past 2 months prior 
to consenting for the trial. Removal of ascites should not be calculated as weight 
loss. For subjects who have had ascites removed within the 2 months prior to 
consent, the S-I should be consulted. 
4.3. 
Reproductive Risks 
 
Nintedanib can cause harm to developing fetus. For this reason, males and females of 
childbearing potential will be counseled on the need to use adequate contraception (eg, 
oral contraceptives, intrauterine devices, barrier methods) for all sexual encounters 
prior to start of study therapy and for at least 3 months following discontinuation of 
study therapy.  
 
Female subjects 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.  
 
Women of childbearing potential who are sexually active and not using at least 2 
medically acceptable method of contraception (e.g. such as implants, injectables, 
combined oral contraceptives, some intrauterine devices or vasectomized partner for 
participating females) during the trial and for at least three months after the end of 
active therapy are not allowed to participate in the trial. 
 
Men will also be counseled on the need to use contraception for all sexual encounters. 
 
 
 


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5. INVESTIGATIONAL PLAN 
 
5.1. 
Study Milestones 
 
Registration date: the date the subject signs informed consent. 
 
Eligibility date:  the date of the last documented criterion that confirmed subject 
eligibility. 
 
Enrollment date:  the date of initiation of nintedanib treatment. 
 
Treatment discontinuation date: the date the Investigator decides to discontinue the 
subject from nintedanib treatment for any reason. 
 
5.2. 
Overall Study Design 
 
This is a single arm, two-stage phase II study designed to evaluate disease control rate 
in subjects with metastatic appendiceal carcinomas who have had failure of initial 
fluroropyrimdine-based chemotherapy.   
 
In the first stage, a total of 28 subjects in the evaluable population will be enrolled. Of 
these, if at least 8 should achieve disease control (Section 13.1.1) the study will 
continue on to the second stage.  In the second stage, 11 participants in the evaluable 
population (total of 39) will be enrolled.  If at least 16 of the 39 total subjects enrolled 
achieve disease control, then we will be able to reject the null hypothesis.  The sample 
size of evaluable population for both Stage 1 and Stage 2 include participants who 
begin nintedanib therapy. 
 
Following informed consent and eligibility check, subjects will be enrolled and treated 
with 200mg of oral nintedanib two times per day and undergo disease evaluation after 
two months. Subjects who progress will be discontinued from study treatment and 
those who do not progress will continue twice daily treatment with nintedanib and will 
continue to undergo disease evaluation every two cycles.   
 
Data from this study will be collected on electronic case report forms (eCRFs) and 
stored in the clinical trials management system (CTMS).  
 
 
 
 


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5.3. 
Informed Consent 
 
Written informed consent will be obtained from each subject prior to undergoing 
protocol-specific evaluations or procedures and prior to receiving treatment. In 
addition, all subjects will provide authorization for the release of their medical records 
for research purposes.   
 
5.4. 
Registration/Enrollment/Discontinuation 
 
5.4.1. 
Subject Registration/Enrollment 
 
Following informed consent, subjects will be registered by the Sponsor and assigned a 
Study ID number. The Study ID will be a four-digit number sequentially assigned, 
where 1001 will be the Study ID number assigned to the first registered subject. 
Following eligibility check per standard operating procedures, eligible subjects will be 
enrolled on the first date of nintedanib dosing. Study ID numbers assigned to 
registered subjects not ultimately enrolled will not be re-assigned. 
 
5.4.2. 
Subject Withdrawal 
 
Subjects are defined as withdrawn from the study if they revoke consent for both 
treatment and study procedures or the Investigator withdraws them from the study. 
Subjects must be withdrawn from the trial for any of the following reasons:  
• Subject withdraws consent from study treatment and study procedures. 
A subject must be removed from the trial at his/her own request. At 
any time during the trial and without giving reasons, a subject may 
decline to participate further. The subject will not suffer any 
disadvantage as a result.  
• Subject is lost to follow-up after three consecutive unsuccessful 
documented attempts at contacting the subject.   
• Development of an intercurrent illness or situation which would, in the 
judgment of the Investigator, significantly affect assessments of 
clinical status and trial endpoints. 
 
Subjects may be completely withdrawn from the study by the Investigator if 
criteria for long-term follow-up described in Section 5.5 are met.  
 
Any subject who withdraws themselves or who is withdrawn from the study by the 
Investigator will remain under medical supervision until discharge or transfer is 
medically acceptable.  


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In all cases, the reason for withdrawal must be documented in the subject's medical 
records and/or research chart and recorded in the CTMS. Withdrawn subjects are 
considered to be off-study. Details for the premature termination of the study as a 
whole are provided in Section 14.2. 
 
5.4.3. 
Screen Failures 
 
A subject who, for any reason (i.e. failure to satisfy the eligibility criteria or withdraws 
consent), terminates his/her study participation before receiving first dose of study 
therapy is regarded as a “screen failure.” All screen failures will be tracked in the 
CTMS. 
 
 
5.5. 
Study Procedures 
 
Demographics and Medical/Treatment History.  Demographics and 
medical/treatment history will be collected during screening. Medical and treatment 
history (oncological and relevant non-oncological) will be collected. Cancer history 
and the following information (including but not limited to) will be obtained: 
 
•  Date of first histological/cytological diagnosis 
•  Prior cancer therapy 
 
All significant medical history findings that occurred prior to the subject signing 
informed consent will be documented. 
 
Pregnancy Test.  A urine or serum pregnancy test will be performed at screening and 
as clinically indicated for women of childbearing potential.  
Women who are pregnant and/or breast-feeding are ineligible for study participation.  
 
Physical Examination. Physical exam by body system, height, weight, body surface 
area (BSA) and ECOG performance status will be documented during screening and 
Week 1 of each cycle per Section 6. Height to be assessed at screening only. 
 
Vital Signs. Vital signs will be recorded at screening and Week 1 of each cycle per 
Section 6 and should include temperature, pulse rate, respiratory rate, blood pressure 
and oxygen saturation. Blood pressure (only) will be assessed on Day 8 and Day 15 
(+/- 2 days) during the first 2 cycles of study treatment. Blood pressure assessment 
may be done at home by the subject or at another clinic (i.e. local pharmacy) and the 


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research staff will be responsible for obtaining these results from the subject. Phone 
contact is acceptable. 
 
Adverse Event Evaluation.  All adverse events and serious adverse events will be 
monitored and documented (regardless of grade or attribution) and reported on an 
ongoing basis per Section 11. Investigators should refer to the Safety Information 
section of the current IB for nintedanib.  As with any agent, there is always the 
potential for unexpected AEs, including hypersensitivity reactions.  
 
Concomitant Medications. All medication that is considered necessary for the 
subject’s welfare, and which is not expected to interfere with the evaluation of the 
study treatment, may be given at the discretion of the Investigator. All medications 
taken within 2 weeks prior to the enrollment date and during the study must be 
recorded.  
 
Permitted concomitant therapies include: 
• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 
• Palliative radiation therapy is allowed if the target lesion(s) are not included 
within the radiation field and no more than 10% of the bone marrow is 
irradiated. 
• Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic 
growth factors may be used in the management of acute toxicity, such as 
febrile neutropenia, when clinically indicated or at the Investigator’s 
discretion. However, they may not be substituted for a required dose 
reduction. Subjects are permitted to take chronic erythropoietin. 
• Treatment with nonconventional therapies (such as acupuncture), and 
vitamin/mineral supplements are permitted provided that they do not interfere 
with the study endpoints, in the opinion of the Investigator. 
• Bisphosphonates. 
• Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine, and digoxin). 
 
Laboratory Tests.  The blood-based clinical laboratory tests at screening will include 
a complete blood count with differential and platelets, a comprehensive metabolic 
panel (including sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
and calcium, albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), total 
bilirubin, direct bilirubin only if total bilirubin is above normal, and total protein), 
PTT, PT/INR and urinalysis (UA). After enrollment, a complete blood count with 


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differential and platelets and a comprehensive metabolic panel (including sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, albumin, alkaline 
phosphatase, ALT (SGPT), AST (SGOT), total bilirubin, direct bilirubin only if total 
bilirubin is above normal and total protein) will be performed according to the Study 
Calendar. 
 
Correlative Studies.  Ascites will be removed from the subject when required as a 
part of standard of care and the entire volume that is removed for clinical purposes and 
remaining after any diagnostic tests will be processed to concentrate any cells and 
create a cell block(s) by CHS Pathology. The ascites cell block will be banked and 
stored at room temperature at the BSR for VEGF levels and for future assays.  
 
Serum (2- 10 ml tubes) specimens from subjects and will be processed within one hour 
of collection, if possible, but may be kept at 4°C for no longer than 4 hours before 
processing. Serum will be processed and stored at -80°C until future testing. 
Specimens will be stored at the CHS Biospecimen Repository. 
Specimens will be collected according to the schedule in Section 6. Specimens will be 
collected after subject eligibility confirmation, but prior to administration of the first 
dose of nintedanib and subsequent cycles. Exploratory biomarker arrays may be used.  
 
Radiology and Tumor Measurements.  A computed tomography (CT) scan with oral 
and intravenous contrast of the chest, abdomen and pelvis will be performed within 28 
days prior to the first dose of nintedanib (screening scan). Scans will then be 
performed within 7 days following anticipated completion of cycle 2 unless clinically 
proven otherwise and within 7 days of anticipated completion of every two cycles 
thereafter (e.g. end of cycles 4, 6). A contrast-enhanced MRI of the abdomen and 
pelvis and a CT scan of the chest without contrast may be substituted if clinically 
necessary; however, subsequent studies must be performed using the same imaging 
modality throughout the study period.  
 
For subjects who discontinue study therapy due to toxicity or reasons other than 
progressive disease, every effort will be made to obtain imaging studies and tumor 
assessments every 8 weeks (+/- 2 weeks) until documented progression or the start of 
subsequent anti-cancer therapy.    
 
Subsequent Therapy and Survival Status.  Once subjects complete their End of 
Treatment visit, they will be followed until all treatment-related toxicities have 
resolved, returned to baseline, stabilized, or are deemed irreversible. Subject’s initial 
anti-cancer therapy following discontinuation of nintedanib treatment and survival 


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status will be documented. 
 
Subjects (or their family members or designees) may be contacted by telephone, in 
writing, or during clinic visits after treatment discontinuation for collection of long-
term follow-up data approximately every 6 months until death or lost to follow-up, or 
until the criteria defined for the final analysis (Section 13.3.1) are reached.  However, 
in the event the criteria for the final analysis are met, and there are subjects who have 
not yet been discontinued from nintedanib treatment, subjects in follow up will 
continue to be followed until all subjects have discontinued study treatment and 
completed the safety monitoring period. Long-term follow-up clinical information 
may also be obtained through chart reviews.   
 


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6. STUDY CALENDAR 
Cycle = 28 days (no visit on Week 4) 
 
Pre-treatment 
Clinical Study Treatment 
Post-treatment 
 
Screening  
Within 28 days 
(prior to Cycle 1) 
Cycle 1 
(+/- 3 days) 
 
Cycle 2 
(+/- 3 days) 
 
Remaining 
Cycles 
(+/- 3 days) 
 
End of 
Treatment 
Follow-up 
Week 
 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
Within 30 
days of last 
drug dose 
Every 6 months until 
death , LTF, or 
completion of long-
term follow-up 
Informed consent and 
HIPAA waiver 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Urine or serum pregnancy 
testa 
X 
 
 
 
 
 
 
 
 
 
Concurrent medicationsm 
X 
X 
 
 
X 
 
 
X 
X 
 
Physical examg,m 
X 
Xe 
 
 
X 
 
 
X 
X 
 
Vitalsh,m 
X 
X 
Xn 
Xn 
X 
Xn 
Xn 
X 
X 
 
ECOG performance statusm  
X 
Xe 
 
 
X 
 
 
X 
X 
 
Adverse event evaluationo 
X 
Ongoing 
X 
 
CBC w/differentialm 
X 
Xe 
 
 
X 
 
 
X 
X 
 
CMPj,m 
X 
Xe 
 
 
X 
 
 
X 
X 
 
PTT 
X 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
Xe 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 


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Serum for correlative 
studiesb,m 
 
X 
 
 
X 
 
 
X 
X 
 
Ascites for correlative 
studiesk 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Radiologic evaluation by 
CT and tumor 
measurements by RECIST 
1.1 
X 
 
 
 
 
 
Xc 
Xd 
X 
Xf 
Survival status 
 
 
 
 
 
 
 
 
 
Xl 
Nintedanib dispensingi 
 
X 
 
 
X 
 
 
X 
 
 
Nintedanib compliance 
assessment 
 
 
 
 
X 
 
 
X 
X 
 
a: In women of child-bearing potential; within 7 days of study drug administration and as clinically indicated throughout participation in the study 
b: Serum sample will be collected and assayed for VEGF levels and stored for future study. At the C1D1 timepoint, collect serum after subject eligibility confirmation but prior to 
first nintedanib dose. At all time-points, serum should be collected prior to  nintedanib dosing. 
c: Within 7 days of anticipated completion of cycle 2   
d: Within 7 days of anticipated completion of every two cycles) (e.g. cycles 4, 6, 8) 
e: Not required if screening procedure done w/in 7 days of C1D1 per section 5.5 
f:  For subjects with disease control and who discontinue study therapy due to toxicity or reasons other than progressive disease, every effort will be made to obtain imaging studies 
and tumor assessments every 8 weeks (+/- 2 weeks) until documented progression or the start of new anti-cancer therapy 
g: Physical exam: includes height (at screening only); Weight; body surface area (BSA).  
h: Vitals: temperature; pulse rate; respiratory rate; blood pressure, oxygen saturation 
i: Nintedanib capsules should be swallowed whole (unopened, uncrushed) with a glass of approximately. 8 oz. /240 mL of water.  Since subjects will be taking oral nintedanib 
twice daily, the dose interval should be every 12 hours at the same time every day, usually in the morning and the evening after food intake. 
j: Direct bilirubin required if total bilirubin above normal 
k: Ascites fluid to be collected and assayed for VEGF levels and stored for future study.  The decision to remove ascites fluid by paracentesis is determined as clinically indicated 
by the investigator based on subject symptoms.  If paracentesis is done as part of standard of care, then every attempt will be made to collect a portion of ascites fluid and store 
for possible future study 
l: Subject’s initial anti-cancer therapy following discontinuation of nintedanib treatment and survival status will be documented. 
m. May be performed within 72 hours of Day 1 of each cycle unless otherwise noted 
n Blood pressure (only) will be assessed on Day 8 and Day 15 (+/- 2 days) during the first 2 cycles of study treatment. Blood pressure assessment may be done at home by the 
subject or at another clinic (i.e. local pharmacy), and the research staff will be responsible for obtaining these results from the subject. Phone contact is acceptable. 
o. AE evaluation should be performed on Day 8 and Day 15 (+/- 2 days) of Cycles 1 and 2 when the research staff is contacting the subject for BP results. 
 


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7. TREATMENT PLAN 
 
7.1. 
Nintedanib Dosage and Administration 
 
Research participants for this study will initiate treatment with 200mg of oral 
nintedanib twice per day.  The capsules should be swallowed whole (unopened, 
uncrushed) with a glass of approximately 8 oz. /240 mL of water.  Since subjects will 
be taking oral nintedanib twice daily, the dose interval should be every 12 hours at the 
same time every day, usually in the morning and the evening after food intake.  
 
In case of a missed dose the subjects should not replace that dose, but proceed to the 
next scheduled dose when it is due. Each study cycle length is 28 days. 
 
In the event of a treatment delay at the scheduled Day 1 of a cycle, Day 1 of that cycle 
will be delayed until study treatment is re-started. This may cause a cycle to extend to 
longer than 28 days. Day 1 will be defined as the day the treatment is re-started. 
 
For dose selection and modifications, see Section 8. 
 
7.1.1 Nintedanib (BIBF 1120) Drug Supply 
Nintedanib capsules for oral administration are formulated as soft gelatin capsules in 
two dose strengths (100 mg or 150 mg) and is provided in 30 count bottle. 100 mg 
capsules are peach, opaque, oblong, soft capsules imprinted in black with the BI 
company symbol and "100".150 mg capsules are brown, opaque, oblong, soft capsules 
imprinted in black with the BI company symbol “150”. Nintedanib will be supplied by 
BI. To request nintedanib from Boehringer Ingelheim, IDS Pharmacy will complete 
the BI-provided Drug Supply Request Form. Drug inventory levels should be able to 
provide subjects with nintedanib for up to 4-8 weeks while waiting for additional 
ordered supplies. The LCI Investigational Drug Services Pharmacy will receive 
nintedanib capsules of 100mg; 150 mg dosage in study drug bottles containing 30 
capsules each. The study drug bottles will have a label affixed containing study 
identification, product identification and quantity of capsules. Once the drug has been 
received, it must be kept in a secure, dry location. Study drug must be stored in study 
drug bottle at room temperature 25°C (77°F). Temperature excursions between 15° to 
30°C (59° to 86°F) is permitted. 
7.2. 
Treatment Compliance 
Nintedanib will be dispensed to subjects with instructions to return study drug pill 
bottles to research staff.  Study drug bottles will be returned to the dispensing 
pharmacy.  Capsules will be counted by pharmacy staff or delegate and reported to the 


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applicable research designee.   The number of capsules taken by the subject per cycle 
will be determined by these capsule counts. 
The subject will be considered to be compliant with treatment if ≥75% of doses were 
taken during any given cycle and overall, unless protocol treatment is withheld for 
toxicity. 
 
Subject compliance with the treatment and protocol includes willingness to comply 
with all aspects of the protocol. At the discretion of the Sponsor-Investigator, a subject 
may be discontinued from protocol for non-compliance with follow-up visits or study 
drug.  
 
7.3. 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment will continue 
until one of the following criteria applies: 
 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject decides to withdraw study consent  
•  General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the Investigator. 
Note: In the event the criteria for the final analysis are met, and there are subjects 
who have not yet been discontinued from study treatment, they will continue to 
receive therapy beyond the date the criteria for the study final analysis are met 
and until one of the above criteria applies. 
 
7.4. 
Drug Accountability 
 
All study drugs will be stored at the investigational site in accordance with product 
labeling, Good Clinical Practice (GCP) and Good Manufacturing Practices (GMP) 
requirements and will be inaccessible to unauthorized personnel. 
 
The study bottles will be returned to the pharmacy from which it was dispensed. 
Pharmacy or a designee will count the number of pills and communicate that to the 
applicable research designee. 
 
An adequate record of receipt, distribution, and return or destruction of all study drugs 
must be kept in the form of a Drug Accountability Form. The Investigator, or 


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responsible party designated by the Investigator, will maintain a careful record of the 
inventory using the Drug Accountability Form.  
 
7.5. 
Destruction  
 
At the end of the study, unused and/or partially used supplies of nintendanib will be 
destroyed according to LCI IDS pharmacy policies.   
 
8. NINTEDANIB INTERRUPTION  
 
8.1. 
Criteria for Interruption of Treatment with Nintedanib  
Treatment with nintedanib will be interrupted according to the criteria listed in Table 
1. 
In the event of a treatment delay at the time of Day 1 of a cycle, Day 1 of that cycle 
will be delayed until study treatment is re-started. This may cause a cycle to extend to 
longer than 28 days. 
Table 1: Criteria for interrupting treatment with nintedanib due to an adverse event 
If at least one criterion is met, nintedanib will 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 elevations of > 2.5 x ULN in conjunction with bilirubin 
of > 1.5 x ULN 
□ AST and/or ALT elevations of > 5x ULN  
□ other non-hematological adverse event of CTCAE grade  3 considered drug-related 
□ Neutropenia  grade 3 or 4 and fever > 38.5°C 
□ Neutropenia  CTCAE grade 4 for more than 7 days without fever 
□ Platelets <50,000mm³ with bleeding 
□ High blood pressure; SBP >170 mm Hg, or DBP >100 mm Hg 
□ Clinically significant bleeding, CTCAE grade 3 or 4, or grade 2 for 3 or more days 
 
 
8.2. 
Criteria to Restart Treatment with Nintedanib  
 
A research participant is eligible to restart nintedanib if all criteria listed in Table 2 are 
met.  
 


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If a subject must 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 sponsor-investigator and the treating physician. 
 
Table 2: Criteria to assess eligibility to restart nintedanib treatment  
All criteria must be met in order to restart nintedanib, meaning AEs have to return to 
Grade 1 or baseline (exception is nausea- see below). 
□ nausea CTCAE grade ≤ 2 
□ vomiting CTCAE grade  1 
□ diarrhea CTCAE grade ≤ 1 
□ AST and ALT < 2.5 x ULN; bilirubin < 1.5 x ULN   
□ no other non-hematological adverse event grade CTCAE  3 which is considered drug-
related 
□ *Neutropenia CTCAE grade  1, without fever or equal to the subject’s pre-therapy 
value at study enrolment 
□ *Platelets CTCAE grade  1 or equal to the subject’s pre-therapy value at study 
enrolment 
□ Blood pressure SBP<150 mm Hg; DBP <90 mm Hg 
□ Bleeding CTCAE grade 1 or less 
 
 
8.3. 
Dose Adjustments of Nintedanib  
 
As initial measure for the management of side effects (see section 9), treatment with 
nintedanib should be temporarily interrupted until the specific adverse reaction has 
resolved to levels that allow continuation of therapy. Nintedanib treatment will be 
resumed at a reduced dose. Dose adjustments in 100 mg increments per day (i.e. a 
50mg reduction per dosing) based on individual safety and tolerability are 
recommended as described in Table 1. In case of further persistence of the adverse 
reaction(s), i.e. if a subject 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 toxicity (see Table 3).   
 
Table 3: Nintedanib dose levels – example for starting dose of 200mg twice daily 
Dose-level: 
0 
-1 
-2 
-3 
Dose: 
2 x 200 
mg/day 
2 x 150 
mg/day 
2 x 100 
mg/day 
discontinue 
treatment  
 
 


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Of note: 
If the dose of nintedanib had to be reduced due to toxicity, the subject will stay on the 
lower dose level for the entire time of administration. 
  
9. TREATMENT-RELATED ADVERSE EVENTS 
9.1. 
Management of Adverse Events 
 
Based on prior clinical studies with nintedanib, the sponsor investigator should 
anticipate that any or all of the following AEs could occur. The occurrence of AEs and 
SAEs should prompt immediate notification to appropriate agencies as outlined in 
Section 11.6-11.8.        
As an initial measure for the management of side effects, treatment with nintedanib 
should be temporarily interrupted as outlined in Table 1 until the specific adverse 
reaction has resolved to levels that allow restarting of therapy. Nintedanib treatment 
may be resumed at a reduced dose as outlined in table 4. 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 Table 4. In case of further persistence of 
the adverse reaction(s), i.e. if a subject does not tolerate 100 mg twice daily, treatment 
with nintedanib should be discontinued. 
  
 
 


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Table 4: Dose adjustments for Nintedanib  
 CTCAE* Adverse reaction 
Dose adjustment 
  Diarrhea > grade 2 for more than 7 
consecutive days despite anti- diarrheal 
treatment**   
 OR 
  diarrhea > grade 3 
 despite anti- diarrheal treatment** 
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 of > 2.5 x ULN 
in      conjunction with bilirubin of > 1.5 x 
ULN  
 OR 
 AST and/or ALT elevations of > 5x ULN 
 Other non-haematological or haematological 
adverse reaction of > grade 3 
 Elevation of AST and/or ALT values to > 3 x 
ULN in conjunction with an increase of total 
bilirubin to ≥ 2 x ULN and ALKP < 2 x ULN 
  Unless there is an alternative cause 
established, nintedanib should be 
permanently discontinued 
  
*CTCAE- v4.03: Common Terminology Criteria for Adverse Events 
  
** see also section 9.2.  
 
9.2. 
Additional Precautions for Nintedanib  
• Diarrhea  
Diarrhea was the most frequently reported gastro-intestinal event and 
appeared in close temporal relationship with the administration of docetaxel in 


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the clinical trial LUME-Lung 110. The majority of subjects had mild to 
moderate diarrhea. 6.3 % had diarrhea of grade ≥3 in combination treatment 
compared to 3.6 % treated with docetaxel alone. Diarrhea should be treated at 
first signs with adequate hydration and anti-diarrheal medicinal products, e.g. 
loperamide, and may require interruption, dose reduction or discontinuation of 
therapy with nintedanib.  
 
• Nausea and vomiting 
Nausea and vomiting, mostly of mild to moderate severity, were frequently 
reported gastrointestinal adverse events in the clinical trial LUME-Lung 1 10. 
Interruption, dose reduction or discontinuation of therapy with nintedanib may 
be required despite appropriate supportive care. Supportive care for nausea 
and vomiting may include medicinal products with anti-emetic properties, e.g. 
glucocorticoids, anti-histamines or 5-HT3 receptor antagonists and adequate 
hydration. 
In the event of dehydration, administration of electrolytes and fluids is 
required. Plasma levels of electrolytes should be monitored, if relevant 
gastrointestinal adverse events occur. 
 
• Neutropenia and Sepsis  
A higher frequency of neutropenia of CTCAE grade > 3 was observed in 
subjects treated with nintedanib in combination with docetaxel as compared to 
treatment with docetaxel alone in the clinical trial LUME-Lung 110. 
Subsequent complications such as sepsis or febrile neutropenia have been 
observed. 
Blood counts should be monitored during therapy, if nintedanib (BIBF 1120) 
is combined with a myelosuppressive agent. 
 
• Hepatic Function 
The safety and efficacy of nintedanib has not been studied in patients with 
moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. 
Therefore, treatment with nintedanib is not recommended in such patients. 
 
Administration of nintedanib was associated with an elevation of liver 
enzymes (ALT, AST, ALKP (alkaline phosphatase), and bilirubin), with a 
potentially higher risk for female patients. 
 
These increases were reversible in the majority of cases and not associated 
with clinically manifest liver disorders. Hepatic transaminases, ALKP and 


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bilirubin levels are recommended to be closely monitored after start of therapy 
with nintedanib.  
 
If relevant liver enzyme elevations are measured, interruption, dose reduction 
or discontinuation of the therapy with nintedanib may be required (Refer to 
Table 4). 
 
Alternative causes of the liver enzyme elevations should be investigated and 
respective action should be taken as necessary. In case of specific changes in 
liver values (AST/ALT > 3 x ULN; total bilirubin ≥ 2 x ULN and ALKP < 2 x 
ULN) treatment with nintedanib should be interrupted. Unless there is an 
alternative cause established, nintedanib should be permanently discontinued.  
 
• Special populations 
Nintedanib exposure increased linearly with patient age, was inversely 
correlated to weight, and was generally higher in patients of Asian race. This 
may result in a higher risk of developing liver enzyme elevations. Close 
monitoring is recommended in patients with several of these risk factors.  
In study 1199.13 (LUME-Lung 1), there was a higher frequency of SAEs in 
patients treated with nintedanib plus docetaxel with a body weight of less than 
50 kg compared to patients with a weight ≥ 50 kg; however, the number of 
patients with a body weight of less than 50 kg was small. Therefore, close 
monitoring is recommended in patients weighing < 50 kg. 
 
9.3. 
Rescue Medications and Additional Treatments 
Rescue medication to reverse the actions of nintedanib is not available. Potential side 
effects of nintedanib should be treated symptomatically. 
9.4. 
Restrictions 
The following are not permitted during study treatment: 
 
• Other anti-neoplastic investigational treatment for appendiceal cancer . 
• Systemic antitumor therapy, including cytotoxic therapy, signal transduction 
inhibitors, immunotherapy, radiotherapy and hormonal therapy . 
• Bone marrow transplant or stem cell rescue. 
• Therapeutic anticoagulation with drugs requiring INR monitoring (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 ≤ 325mg per day). 
 


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The following are permitted during study treatment and will require 
additional/close monitoring:  
• Strong P-gp inhibitors may increase exposure to nintedanib (e.g. ketoconazole 
or erythromycin). In such cases patients should be monitored closely for 
tolerability of nintedanib. Management of side effects may require interruption, 
dose reduction or discontinuation of therapy with nintedanib. 
• Strong CYP3A4 and P-gp inducers, including but not limited to rifampicin, 
carbamazepine, phenytoin, and St. John’s Wort (please see Appendix B), may 
decrease exposure to nintedanib. Co-administration with nintedanib should be 
carefully considered and closely monitored. Use of herbal remedies is 
discouraged, and is permitted only with the specific assent of the Investigator. 
All herbal and vitamin supplement use must be carefully documented. 
• Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine, and digoxin). 
 
10. DATA AND SAFETY MONITORING PLAN 
 
10.1. Safety Monitoring 
 
This protocol will be monitored according to the processes in effect for all Levine 
Cancer Institute investigator- initiated studies and the protocol-specific monitoring 
plan, and will abide by standard operating procedures set forth by both the Carolinas 
HealthCare System Office of Clinical and Translational Research and the Levine 
Cancer Institute Clinical Trials Office.  It is the responsibility of the Sponsor-
Investigator to monitor the safety data for this study.  The Sponsor-Investigator, 
Statistician, and other team members as needed will meet regularly to monitor subject 
consents, enrollment and retention, safety data for all subjects [including adverse 
events (AE’s) for all grades and attributions, serious adverse events (SAE’s)], study 
drug administration, and validity/integrity of the data. Documentation of these 
meetings will be kept with study records. SAEs will be reported to the IRB per their 
requirements.  Major protocol deviations that in the Investigator’s judgment 
potentially caused harm to participants or others or indicate that the participants or 
others are at an increased risk of harm, or has adversely impacted data integrity will be 
reported to the IRB per their requirements. The Sponsor-Investigator will submit data 
to the LCI Data and Safety Monitoring Committee according to the overarching LCI 
Data and Safety Monitoring Plan. 
 
10.2. Data Quality Assurance 


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This study will be organized, performed, and reported in compliance with the study 
protocol, standard operating procedures (SOPs) of the Levine Cancer Institute and 
Carolinas HealthCare System Office of Clinical and Translational Research, and other 
applicable regulations and guidelines (e.g. GCP).  
 
Data will be collected on electronic Case Report Forms (eCRFs).  
 
Subjects will be monitored by Levine Cancer Institute Research Monitors routinely for 
data quality. This monitoring will be done by comparing source documentation to the 
eCRFs. The study database will be reviewed and checked for omissions, apparent 
errors, and values requiring further clarification using computerized and manual 
procedures. Data queries requiring clarification will be generated and addressed by the 
appropriate research personnel. Only authorized personnel will make corrections to the 
study database and all corrections will be documented in an electronic audit trail.  
 
10.3. Communication Between Investigational Sites 
 
Investigational sites will be required to report problems with study drug 
administration or any other problem that could affect the validity/integrity of the 
study data to the Sponsor-Investigator by email as soon as possible but within 2 
business days of the Investigator learning of the event.  All investigational sites will 
record AEs using the eCRFs and SAEs using the SAE reporting function in the 
CTMS to the Sponsor. SAEs will be reported to the Sponsor-Investigator within 24 
hours of the Investigator learning of the event.  
 
10.4. Clinical Trial Registration 
This study will be registered on the National Library of Medicine/National Institutes 
of Health ClinicalTrials.gov website.  This trial will be initially registered prior to 
enrollment of the first subject.  Trial’s progress and results will be updated as 
necessary, but at least once every 6 months.  Summary results of the trial will be 
submitted to the ClinicalTrials.gov website within 12 months of final data collected of 
the primary endpoint. 
 
11. SAFETY DATA COLLECTION, RECORDING AND REPORTING 
 
11.1. Unanticipated Problem (UAP) Definition 
An unanticipated problem (UAP) is any incidence, experience or outcome that is 
unexpected, given the information provided in research-related documentation (e.g 
Investigator’s brochure, informed consent) and the study population characteristics 


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that is related or possibly related to participation in the research study and places the 
participant at an increased risk.   
 
11.2. Adverse Event (AE) Definition  
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a subject in a clinical investigation who 
received a pharmaceutical product. The event does not necessarily have to have a 
causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of the study drug, whether or not considered related to the study drug.  Pre-existing 
conditions that increase in frequency or severity or change in nature during or as a 
consequence of use of a drug in human clinical trials are also considered adverse 
events.  Adverse events may also include pre- or post-treatment complications that 
occur as a result of protocol mandated procedures. 
 
Any continuing medical condition or clinically significant laboratory abnormality with 
an onset date before the date of informed consent should be documented in the 
subject’s medical records and/or research chart.  
 
Examples of events not meeting the definition of an adverse event include: 
 
• medical or surgical procedures 
• pregnancy (unless this is associated with an SAE) 
• relapse or progression of the underlying malignant disease 
 
The relationship to study drug should be assessed using the following definitions: 
 
Not Related:  Evidence exists that the AE has an etiology other than the study drug 
(eg, pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  This includes events that are considered remotely or unlikely related to 
study drug. 
 
Related:  A temporal relationship exists between the event onset and administration of 
the study drug.  It cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies.  In the case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge.  It should be 
emphasized that ineffective study drug treatment should not be considered as causally 
related in the context of AE reporting.  This includes events that are considered 
possibly, probably, or definitely related to study drug. 
 


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All adverse events (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and/or research chart and on the case report form for 
this protocol. 
 
Adverse Events of Special Interest (AESI) Definition   
The following will be considered an AESI: 
 
o an elevation of ALT and / or AST > 5x ULN without bilirubin elevation 
measured in the same blood draw sample. 
o an elevation of AST and/or ALT >2.5x ULN combined with an 
elevation of bilirubin to >1.5x ULN measured in the same blood draw 
sample. 
o any gastrointestinal- and non-gastrointestinal perforation, leakage, 
fistula formation, abscess. 
 
In such case the following additional information is recommended to be collected, 
documented in the respective comment field and narratives of the BI SAE Report 
Form, and forwarded to BI: 
• location of perforation, leakage, fistula, abscess 
• location/extent of abdominal tumour manifestations,  
• imaging & reports (CT, ultrasound, endoscopy, pathology, etc) 
• prior surgery (location, wound healing complications) 
• concomitant diseases with GI involvement (eg, M Crohn, vasculitis, 
tuberculosis, 
• diverticulitis) 
• thromboembolic events (or predisposition) 
 
Please refer to Appendix A for recommended procedures for drug induced liver injury. 
 
11.3. AESIs 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. Serious Adverse Event (SAE) Definition 
An AE is to be considered serious if the Investigator (in consultation with the Sponsor-
Investigator if needed) deems it as such and the event results in any of the following 
outcomes: 
• Death (fatal); 
• Life-threatening situation (subject is at immediate risk of death); 
• Persistent or significant disability/incapacity; 
• Requires or prolongs inpatient hospitalization (excluding those for study drug 
administration, protocol-related procedures, palliative or hospice care, or 
placement of an indwelling catheter, unless associated with other serious events;  


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• A congenital anomaly/birth defect in the offspring of a subject who received study 
drug;  
• Or based upon appropriate medical judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the afore listed 
outcomes from occurring (e.g. intensive treatment in an emergency room without 
hospitalization, blood dyscrasias or convulsions that do not result in 
hospitalization, development of drug dependency or drug abuse). 
 
The following events do not meet the criteria for seriousness per ICH definition, but must be 
reported in the same manner as SAEs. Therefore, these events are considered serious for 
collection purposes: 
• 
Drug exposure during pregnancy  
 
Subjects may be hospitalized for administrative or social reasons during the trial. 
These and other hospitalizations planned at the beginning of the trial do not need to be 
reported as an SAE.  
  
The severity of adverse events should be classified and recorded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the 
eCRF. 
 
An increase in grade to a pre-existing CTC toxicity after study treatment initiation will 
be recorded as an AE.  
 
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an AE if they are judged clinically significant by the investigator. 
 
11.4. Adverse Event and Deviation Reporting 
11.4.1. Reporting to the Sponsor (LCI) 
 
All adverse events from the time of study treatment initiation until 30 days after last 
dose of study drug (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and/or research chart and recorded on the case 
report form for this protocol. 
 
The investigator is responsible for verifying and providing source documentation for 
all adverse events and assigning the attribution for each event for all subjects enrolled 
on the trial. 
 


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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. 
 
SAEs and AESIs must be reported to the Sponsor-Investigator within 24 hours of 
awareness via the CTMS.    
 
Information not available at the time of the initial report which is received after the 
initial report must be documented on a follow-up SAE utilizing the same process 
described above for reporting the initial SAE/AESI. For expedited reporting involving 
drug exposure during pregnancy, a follow-up report to describe the outcome of the pregnancy 
is required within 24 hours of investigator awareness. 
 
SAEs will be captured from the time of signing of the informed consent through 30 
days after the date of the last study drug administration. SAEs and AESIs will be 
followed until clinical recovery is complete, laboratory tests have returned to baseline, 
or until there has been acceptable resolution of the event. This may at times cause the 
follow-up period for SAEs and AESIs to be greater than 30 days. The above 
referenced 30-day time period applies even if the subject is taken off treatment and 
initiates subsequent anti-cancer treatment during this time period. Similarly, the 
treating investigator is responsible for following the subject during the required 
follow-up period even if the subject lives elsewhere or has been released from his or 
her care. 
 
Deviations from the investigational plan must be reported to the sponsor via entry into 
the CTMS as soon as they occur, but within no more than 10 business days of 
becoming aware of the event (as soon as possible for deviations reportable to the IRB).   
 
11.4.2. Safety Reporting to the IRB 
 
All events occurring during the conduct of a protocol and meeting the definition of an 
UAP or related and unexpected SAE will be reported to the IRB per their reporting 
requirements. 
 
Protocol deviations that are determined by the Investigator to potentially cause harm to 
participants or others or indicate that the participants or others are at an increased risk 
of harm, or have adversely impacted data integrity will be reported promptly to the 
IRB per their reporting requirements.  
 
11.4.3. Safety Reporting to Funding Company (Boehringer Ingelheim 
Pharmaceuticals Inc.) 


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During the conduct of the study the Sponsor-Investigator shall report all  
i. 
SAEs,  
ii. 
AESIs independent of their seriousness,  
iii. 
and non-serious AEs which are relevant to a reported SAE or AESI 
iv. 
Pregnancies  
by fax or other secure method using BI IIS SAE form providing as much detail as 
possible (pregnancies using Pregnancy Monitoring Form) to the BI Unique Entry Point 
in accordance with the timelines specified below as per the Pharmacovigilance 
agreement.  
• within five (5) calendar days of the Sponsor-Investigator’s knowledge of 
initial and follow-up SAEs containing at least one (1) fatal or immediately 
life-threatening event;  
• within ten (10) calendar days of the Sponsor-Investigator’s knowledge of any 
other initial and follow-up SAEs 
• Pregnancy Monitoring Forms shall be forwarded within seven (7) days of 
Sponsor-Investigator awareness of the pregnancy 
 
 
BI Unique Entry Point: 
 
Boehringer Ingelheim Pharmaceuticals, Inc 
 
900 Ridgebury Road 
 
Ridgefield, CT  06877 
 
Fax: 1-203-837-4329 
E-mail: PV_global_casemanagement@boehringer-ingelheim.com.  
   
With receipt of follow-up information, all remaining fields on the SAE form are to be 
completed or updated.  
 
The investigator does not need to actively monitor the study subjects for adverse 
events once the clinical trial has ended. However, if the investigator becomes aware of 
an SAE(s) or AESI(s) that occurred after the adverse event reporting period as defined 
in Section 11.4.1  (including any protocol specified follow-up period/Residual effect 
period), it should be reported to BI if the investigator considers it as relevant to the BI 
study drug. 
 
11.4.4 Other Reporting 
The IRB and Boehringer Ingelheim Pharmaceuticals (BI) will be notified in 
writing of other events according to the following schedule: 
 
 
 


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Table 5: Reporting to IRB and BI 
Event 
Agency 
Timeframe for Reporting 
Minor changes to the 
investigational plan 
IRB 
Within 90 days of SI 
becoming aware of change 
BI 
Prior approval needed 
 
 
 
Major changes to the 
investigational plan (also 
known as amendments) 
IRB 
Prior approval needed 
BI 
Prior approval needed 
 
 
 
Annual Report 
IRB 
Annually at time of IRB 
approval 
BI 
Annual IRB approval letter 
to be provided to BI. 
 
 
 
Final Report 
IRB 
Part of study termination 
submission 
BI 
Within 60 days after study 
completion 
 
12. MEASUREMENT OF EFFECT 
 
12.1. Anti-tumor Effect – Solid Tumor 
Response and progression will be evaluated in this study using the revised response 
evaluation criteria in solid tumors (RECIST) guideline version 1.11. 
 
12.1.1. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers.  All screening 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 screening, during treatment 
and follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the anti-tumor 
effect of a treatment.   
12.1.2. Response Criteria 
 
Response will be evaluated using RECIST 1.1 Criteria. 
 Complete Response: 


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• Target lesion: Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to  
 
 
<10 mm. 
• Non-target lesion: Disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
 
Partial Response: 
• Target lesion: At least a 30% decrease in the sum of diameters of target, 
 
taking as reference the baseline sum diameters. 
• Non-target lesion: Not applicable 
 
Stable Disease: 
• Target lesion: Neither sufficient shrinkage to qualify for a partial response, 
nor sufficient increase to qualify for progressive disease, taking as 
reference the smallest sum diameters while on study. 
• Non-target lesion: Not applicable. 
 
Progressive Disease: 
• Target lesion: At least a 20% increase in the sum of 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 progression). 
• Non-target lesion: Unequivocal progression (as described in RECIST 
version 1.1) of existing non-target lesions. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
Non-Complete Response / Non-Progressive Disease: 
• Target lesion: Not applicable 
• Non-target lesion: Persistence of one or more non-target lesion(s) 
 
Table 6: Summary of RECIST 


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Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
 4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
 4 weeks from baseline 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once 
 4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
N/A 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and  
NE = inevaluable 
 
 
 
Table 7: Overall Response for Subjects with Non-measurable disease only 
Non-target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
No 
CR 
Non-CR/ 
Non-PD 
No 
Non-CR/ 
Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
 
13. STATISTICAL CONSIDERATION 
 
13.1 Sample Size  
 
This study is a Simon (minimax) two-stage design that will enroll up to a total of 39 
subjects.  The primary endpoint is overall disease control.  In the first stage, a total of 
28 subjects in the evaluable population will be enrolled.  Of these, if at least 8 should 


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achieve disease control (Section 13.1.1)  the study will continue on to the second 
stage.  In the second stage, 11 participants in the evaluable population (total of 39) will 
be enrolled.  If at least 16 of the 39 total subjects enrolled achieve disease control  then 
we will be able to reject the null hypothesis.  The sample size of evaluable population 
for both Stage 1 and Stage 2 include participants who begin nintedanib therapy. 
 
Given the lack of information of clear benefit of any therapy in the second line setting 
of subjects with appendiceal carcinoma, a disease control rate of 30% would be 
considered an inferred clinical historical rate.  Alternatively, a 50% disease control rate 
which, if achieved, would be worthy of further investigation.   Assuming a one-sided 
alpha = 0.10 significance level, this design will provide at least 90% power to reject 
the null hypothesis, assuming the true disease control rate is 50%. 
 
Endpoint Definitions  
 
13.1.1. Disease Control 
 
Disease control will be determined for each subject as a binary variable indicating 
whether or not subjects with measurable disease achieve a best overall response of CR, 
PR, or SD as determined by RECIST 1.1 and subjects with non-measurable disease 
have at least one evaluable disease assessment indicating non-progressive disease. 
 
13.1.2. Objective Response 
 
Objective response will be determined for each subject as a binary variable 
indicating whether or not the subject achieved a best overall response of CR 
or PR as determined by RECIST 1.1. 
 
13.1.3. Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from the 
start of nintedanib treatment to first occurrence of either progressive disease 
or death. Disease progression can be objectively determined as per Section 12 
(RECIST 1.1) or progression can be subjective as determined by the 
investigator. Evidence for subjective progression must be documented in the 
medical records. For objective disease progression, the date of PD is the date 
of the radiologic assessment that identified RECIST-defined progressive 
disease. For subjective disease progression, the date of PD is the date that the 
clinician makes the determination of disease progression. If the subject died 
without documented disease progression, the date of progression will be the 


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date of death. For surviving subjects who do not have documented disease 
progression, PFS will be censored at the date of last radiologic assessment. 
For subjects who receive subsequent anti-cancer therapy prior to documented 
disease progression, PFS will be censored at the date of last radiologic 
assessment prior to the commencement of subsequent therapy. Subjects who 
have an initial PFS event immediately following 2 or more consecutive 
missed assessments will be censored at the date of the last assessment prior to 
those missed assessments. For subjects with only one missed assessment, the 
documented progressive disease status and assessment date will be used.   
 
13.1.4. Six-Month Progression-Free Survival 
 
Six-month progression-free survival will be determined for each subject as a 
binary variable indicating whether or not the subject is alive and progression 
free at 6 months.  The criteria for a PFS event are defined in Section 13.1.3. 
 
13.1.5. Overall Survival 
 
Overall survival is defined as the duration from the start of nintedanib 
treatment to the date of death from any cause.  Subjects who are alive or lost 
to follow-up at the time of the analysis will be censored at the last known date 
they were alive. 
 
13.1.6. Safety Endpoints 
 
Safety endpoints will include treatment administration, AEs, SAEs, deaths 
while on study therapy, and blood pressure.  Treatment administration will be 
determined for each subject in terms of cumulative and average daily dose of 
nintedanib administration (adjusting for dose delays and reductions).  
Additionally, the relative dose intensity will be calculated for each subject in 
terms of the actual daily dose administered as a percent of the intended daily 
dose.   
 
13.2. Analysis Populations 
 
The response-evaluable population for the analysis of objective response will include 
enrolled subjects with measurable disease at baseline. The evaluable population for the 
analysis of disease control, all other secondary endpoints, and safety endpoints  will 
include subjects who begin nintedanib treatment. The sample size requirements for 


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Stage 1 and 2 described above pertain to the evaluable population for the analysis of 
disease control.   
 
13.3. Analysis Methods 
 
13.3.1. Timing of Analysis 
 
The Stage 1 analysis will be conducted after the best overall response for all 
Stage 1 evaluable subjects has been determined.  The primary analysis of 
Stage 2 will be conducted after the best overall response of all evaluable 
subjects has been determined. An updated analysis will be conducted after all 
enrolled participants have been on study for at least one year.  The final 
analysis will be conducted after the PFS censoring rate reduces to 20% or 
after all subjects have been on study for at least 3 years, whichever occurs 
first. 
 
13.3.2. Subject Disposition 
 
An accounting of all consenting subjects will be provided at the end of the 
study. This will include a breakdown of subjects who consented, were treated, 
discontinued treatment, died, and were lost to follow-up or withdrew consent. 
 
13.3.3. Baseline Subject and Disease Characteristics 
 
A summary of subject demographics and disease-related characteristics will 
be completed and assessed. 
 
13.3.4. Efficacy Analyses 
 
13.3.4.1. Primary Analysis 
 
Disease control rate will be estimated with the corresponding 95% 
Clopper-Pearson confidence interval.  Evaluation of the primary 
objective will be made based on the rejection regions described in 
Section 13.1.   
 
13.3.4.2. Secondary Analyses 
 
Objective response rate and 6-month PFS rate will be estimated 
with the corresponding 95% Clopper-Pearson confidence interval.  


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Progression-free survival and overall survival rates will be 
estimated using Kaplan-Meier techniques.   
 
Multivariable regression models (logistic regression for binary 
variables and Cox proportional hazards models for time to event 
variables) will be used to evaluate the impact of correlative 
biomarkers, and baseline subject and disease characteristics on 
outcomes.  Additionally, nintedanib exposure will be considered as 
a covariate. 
 
13.3.5. Safety Analyses 
 
Treatment administration will be summarized descriptively in terms of 
cumulative and average daily dose of nintedanib administration (adjusting for 
dose delays and reductions).  Additionally, the relative dose intensity will be 
calculated in terms of the actual daily dose administered as a percent of the 
intended daily dose.  Incident rates for treatment-emergent adverse events, 
SAEs, and deaths while on study therapy will be summarized.  
Treatment-emergent adverse events are defined as follows: 
• An adverse event that occurs after treatment start that was not present 
at the time of treatment start; or 
• An adverse event that increases in severity after treatment start if the 
event was present at the time of treatment start 
 
13.3.6. Exploratory Analyses 
 
An evaluation of serum VEGF, ascites VEGF, hypertension and paracentesis 
frequency will be made.   This will include summaries of expression levels, 
baseline prevalence, and correlations between these biomarkers and response 
to therapy.  Additional exploratory analysis will be conducted as deemed 
necessary. 
 
 
13.4. Interim Analyses 
 
An analysis of disease control will be conducted after the best overall response of the 
first 28 evaluable participants has been determined.   
 
 
 


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14. STUDY COMPLETION 
 
14.1. Completion 
 
The study will be considered complete when one or more of the following conditions 
is met: 
• All subjects have died and/or withdrawn from the study. 
• All subjects have discontinued from the study. 
• The IRB, LCI DSMC, or Sponsor-Investigator discontinues the study because 
of safety considerations. 
• The Sponsor-Investigator defines an administrative or clinical cut-off date. 
 
14.2. Termination 
 
The study will be terminated when one or more of the following conditions occur: 
If risk-benefit ratio becomes unacceptable owing to, for example, 
• Safety findings from this study (e.g. SAEs) 
• Results of any interim analysis 
• Results of parallel clinical studies 
• Results of parallel animal studies (e.g. toxicity, teratogenicity,  
       carcinogenicity or reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a 
reasonable time frame. 
The Sponsor-Investigator has the right to close the trial at any site and at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local     
law.   
• In case of a partial study closure, ongoing subjects, including those in follow- 
up, must be taken care of in an ethical manner. 
 
Details for individual subject's withdrawal can be found in Section 5.4.2. 
 
15. RETENTION OF RECORDS 
 
Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), 
including all IRB correspondence, will be retained for at least 2 years after the investigation 
is completed.  Documentation will be readily available upon request. 
 
 


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16. ETHICAL AND LEGAL ISSUES 
 
16.1. Ethical and Legal Conduct of the Study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and  
documentation of this study, are designed to ensure that the Investigator abide by 
Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in 
the Declaration of Helsinki.  The study will also be carried out in keeping with 
applicable local law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g. IRB) will be obtained for all 
participating centers before start of the study, according to GCP, local laws, 
regulations and organizations.  Any extension or review of any amendment of protocol 
and annual renewal of IRB approval must be obtained and forwarded to Boehringer 
Ingelheim. 
 
Strict adherence to all specifications laid down in this protocol is required for all 
aspects of study conduct; the Investigators may not modify or alter the procedures 
described in this protocol.   
 
Modifications to the study protocol will not be implemented by the Sponsor-
Investigator without discussion and agreement by Boehringer Ingelheim.  However, 
the Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to the trial subjects without prior approval from 
applicable agencies.  As soon as possible, the implemented deviation or change, the 
reasons for it and if appropriate the proposed protocol amendment should be submitted 
to the appropriate agencies.  Any deviations from the protocol must be explained and 
documented by the Investigator. 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites 
in accordance with Good Clinical Practice and the Declaration of Helsinki.  The 
Sponsor-Investigator is responsible for overseeing the treatment of all study subjects.                            
 
The Sponsor-Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
applicable regulations and guidelines regarding clinical trials both during and after 
study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will 
be collected and properly documented. 


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16.2. Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. 
 
 
 


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REFERENCES 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
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Cortina R, McCormick J, Kolm P, Perry RR. Management and prognosis of 
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Tejani MA, ter Veer A, Milne D, et al. Systemic therapy for advanced appendiceal 
adenocarcinoma: an analysis from the NCCN Oncology Outcomes Database for 
colorectal cancer. J Natl Compr Canc Netw. 2014;12(8):1123-1130. 
4. 
Borazanci E, Millis SZ, Feldman RA, Ghazalpour A, Ramanathan RK, Von Hoff DD. 
Potential actionable targets in appendiceal cancer detected by immunohistochemistry 
(IHC), fluorescent in situ hybridization (FISH), and mutational analysis. ASCO Meeting 
Abstracts. 2014;32(15_suppl):4143. 
5. 
Jimenez WA, Sardi A, Ledakis P, Nieroda C, Sittig M, Gushchin V. The role of VEGFR-
2 expression in outcomes and survival of patients with peritoneal carcinomatosis from 
appendiceal cancer. European Journal of Surgical Oncology (EJSO). 2013;39(12):1415-
1422. 
6. 
Chang MS, Byeon SJ, Yoon SO, et al. Leptin, MUC2 and mTOR in appendiceal 
mucinous neoplasms. Pathobiology. 2012;79(1):45-53. 
7. 
Nascimento I, Schaer R, Lemaire D, et al. Vascular endothelial growth factor (VEGF) 
levels as a tool to discriminate between malignant and nonmalignant ascites. APMIS. 
2004;112(9):585-587. 
8. 
Gotlieb WH, Amant F, Advani S, et al. Intravenous aflibercept for treatment of recurrent 
symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, 
randomised, double-blind, placebo-controlled study. Lancet Oncol. 2012;13(2):154-162. 
9. 
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(12):4774-4782. 
10. 
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. Lancet Oncol. 2014;15(2):143-155. 
11. 
Stopfer P, Rathgen K, Bischoff D, et al. Pharmacokinetics and metabolism of BIBF 1120 
after oral dosing to healthy male volunteers. Xenobiotica. 2011;41(4):297-311. 
12. 
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. 
2010;16(1):311-319. 
13. 
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(6):1374-1381. 
14. 
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(15_suppl):8034. 
15. 
Ledermann JA, Hackshaw A, Kaye S, et al. Randomized Phase II Placebo-Controlled 
Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 


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After Chemotherapy for Relapsed Ovarian Cancer. Journal of Clinical Oncology. 
2011;29(28):3798-3804. 
16. 
du Bois A, Kristensen G, Ray-Coquard I, et al. AGO-OVAR 12: a randomized placebo-
controlled GCIG/ENGOT-Intergroup phase III trial of standard frontline chemotherapy 
+/− nintedanib for advanced ovarian cancer. Abstracts from the 18th International 
Meeting of the European Society of Gynaecological Oncology (ESGO), 19–22 October 
2013, Liverpool, UK. Int J Gynecol Cancer. 2013;23(8 Suppl 1). 
17. 
Van Cutsem E, Prenen H, Guillen-Ponce C, Bennouna J, Di Benedetto M, Bouche O, et 
al.  A Phase I/II Open-label, Randomised Study of BIBF 1120 Plus mFOLFOX6 
Compared to Bevacizumab Plus mFOLFOX6 in Patients with Metastatic Colorectal 
Cancer.  Eur J Cancer 2011; 47 (suppl2): 8, LBA14. 
18. 
Cheng A-L, Yen C-J, Kim T-Y, Feng Y-H, Chao Y, Lin D-Y et al.  Efficacy and safety 
of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma 
(HCC): A randomized phase II trial.  J Clin Oncol 2015; 33 (suppl 3, abstr 339). 
19. 
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. 
  
 
 
 
 
 


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APPENDICES 
 
APPENDIX A 
Recommended Procedures for the follow-up of a potential DILI case (Hy’s Law case) in IIS 
with nintedanib  
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. 


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Definition 
The following changes in the laboratory values are considered to be a protocol-specific 
significant adverse event for all subjects: 
- 
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. 
Subjects showing these laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met.  
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 reported immediately via the SAE 
form to BI. 
3. An evaluation of the subject 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 


Protocol Number:  LCI-GI-APX-NIN-001 
Version 3: 04/18/2018 
Page 62 of 65 
 
hepatic conditions such as portal vein thrombosis or right heart failure. These 
data need to be collected, documented in the respective SAE form, updated 
and forwarded to BI 
 
- 
detailed history of current symptoms and concurrent diagnoses and medical 
history  
 
- 
detailed history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations and 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 Alkaline Phosphatase < 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 subjects with elevated liver enzyme and bilirubin 
elevations by repeat testing of ALT, AST, bilirubin (with fractionation into total and 


Protocol Number:  LCI-GI-APX-NIN-001 
Version 3: 04/18/2018 
Page 63 of 65 
 
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. 
 
 
 
 
 


Protocol Number:  LCI-GI-APX-NIN-001 
Version 3: 04/18/2018 
Page 64 of 65 
 
APPENDIX B: STRONG PGP INHIBITORS 
 
abiraterone 
Lopinavir and lopinavir-ritonavir 
Amiodarone 
Mefloquine 
Atorvastatin 
Mirabegron 
Azithromycin (systemic) 
Nicardipine 
Carvedilol 
Nilotinib 
Clarithromycin 
Ombitasvir 
Cobicistat and cobicistat containing 
coformulations 
Paritaprevir-ritonavir 
Crizotinib 
Progesterone 
Cyclosporine (systemic) 
Propranolol 
Daclatasvir 
Quinidine 
Darunavir 
Quinine 
Dipyridamole 
Ranolazine 
Dronedarone 
Reserpine 
Eliglustat 
Ritonavir and ritonavir containing 
coformulations 
Erythromycin (systemic) 
Saquinavir 
Flibanserin 
Simeprevir 
Grapefruit juice and grapefruit 
Sunitinib 
Ibrutinib 
Tacrolimus (systemic) 
Itraconazole 
Tamoxifen 
Ivacaftor 
Telaprevir 
Ketoconazole (systemic) 
Vandetanib 
Lapatinib 
Vemurafenib 
Ledipasvir 
Verapamil 
Lomitapide 
  
 
 
 
 
 
 
 
 


Protocol Number:  LCI-GI-APX-NIN-001 
Version 3: 04/18/2018 
Page 65 of 65 
 
STRONG PGP INDUCERS 
 
Amprenavir 
Carbamazepine 
Clotrimazole 
Dexamethasone 
Fosamprenavir 
Indinavir 
Morphine 
Nelfinavir 
Phenobarbital 
Phenothiazine 
Phenytoin 
Prazosin 
Retinoic acid 
Rifampin 
Ritonavir 
Saquinavir 
St John’s wort 
Tipranavir 
 

ICF_001.pdf: 
Official Title:  LCI-GI-APX-NIN-001: Nintedanib in Metastatic Appendiceal Carcinoma 
IRB-Approved Date:  10/20/2017
NCT03287947


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 1 of 13 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
 
 
CAROLINAS HEALTHCARE SYSTEM 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
 
 
Sponsor / Study Title: 
  
Levine Cancer Institute, Nintedanib In Metastatic Appendiceal 
Carcinoma 
 
Protocol Number: 
 
LCI-GI-APX-NIN-001 
Principal Investigator: 
 
Jimmy Hwang, MD 
Telephone: 
 
 (24 Hours) 
 (24 Hours) 
 
Address: 
Levine Cancer Institute 
 
 
 
 
This form is for use in a research study that may involve subjects who may or may not have the 
capacity to consent to take part in the study.  Accordingly, when the subject cannot legally consent 
to take part, pronouns “you” and “your” should be read as referring to the subject rather than the 
person (legally authorized representative) who is signing this form for the subject.  In cases where 
the subject’s representative gives consent, the subject should be informed about the study to the 
extent possible given his/her understanding.  During the course of the study, if the subject regains 
the capacity to consent, informed consent should be completed and the subject offered the ability to 
leave the study if desired. 
 
INTRODUCTION 
 
Dr. Hwang and his associates (the investigators) are asking you to participate in a research study at 
Levine Cancer Institute (LCI) and Carolinas HealthCare System (CHS) of patients with metastatic 
cancer of the appendix.    
 
You are being asked to take part in this study because you have cancer of the appendix which has 
spread and your first treatment, with standard chemotherapy, has failed or was not tolerated. The 
purpose of this study is to see if your cancer can be controlled by treatment with nintedanib. 
 
This is a clinical trial, a type of research study. Your study doctor and the study team will explain the 
clinical trial to you. Clinical trials include only people who choose to take part. Please take your time 
to make your decision about taking part. You have also been told that you have the option not to 
participate. You may discuss your decision with your friends and family. You can also discuss it with 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 2 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
your health care team. If you have any questions, you can ask your study doctor for more 
explanation.  
This study is being carried out under the sponsorship of Levine Cancer Institute (LCI).  Boehringer 
Ingelheim Pharmaceuticals is the company that makes nintedanib and will provide the study drug 
that will be used in this study. 
 
WHY IS THIS STUDY BEING DONE? 
 
Cancer of the appendix is a rare disease, so there is limited data regarding its treatment. The study 
drug, nintedanib, is approved by the U.S. Food and Drug Administration (FDA) for treating a 
medical condition called an idiopathic pulmonary fibrosis, a progressive condition which may lead to 
death.  
 
Nintedanib has shown antitumor activity in clinical trials of lung and ovarian cancer, and has been 
studied in advanced colorectal cancer; however, nintedanib is not currently FDA approved for the 
treatment of appendix cancer.  Given the similarities between appendiceal and colorectal cancer, and 
potentially ovarian cancer, and the limited information about the best way of treating metastatic 
appendiceal carcinomas, further investigation with nintedanib is needed.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
You will be one of approximately 39 subjects participating in this study at Levine Cancer Institute. 
 
 
HOW THE STUDY WORKS 
 
Before you begin the study (Pre-treatment/Screening/Prior to 1st dose of study drug): 
 
In order to participate in this study, you will need to: 
• Review, sign, and date this informed consent document and  
• Provide authorization for the release of your medical records for research purposes.  
 
In order to check if you are eligible to participate, the following will be done: 
• Information will be collected from your medical record about your demographics (i.e. age, 
race, etc.), medical history, your current disease, any treatments received before, and any 
medications you are taking. All of your medical history (oncological and relevant non-
oncological) findings that occurred prior to your signing this document will be documented.  
• If you are a woman who can have children, a urine or blood pregnancy test will be done. 
The test results must be negative in order to be in the study. You must also not be 
breastfeeding to participate in the study. 
• Office visit to conduct a physical exam and collect your height, weight, and vital signs (like 
temperature, pulse rate, respiratory rate, blood pressure).   
• Review of medications and supplements that you are currently taking 
• Collect about two tablespoons of blood for laboratory tests to check your blood counts and 
determine how well your kidneys, liver, and other organs function.    


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 3 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
• Urinalysis (examination of the urine) 
• Scans of your chest, abdomen and pelvis will be done using an x-ray machine that uses a 
computer to take pictures or computerized tomography (CT) scan.  
Specimen Collection for the Purposes of Research: 
 
If you agree to participate in this study, blood and ascites fluid may be collected and stored for 
future research. Ascites is a kind of fluid that may accumulate in the stomach. If your symptoms 
indicate a removal of the fluid, a procedure called a paracentesis will take place in order to remove it. 
A portion of this fluid (at least about 2 teaspoons) will be collected and stored for future analysis. At 
the same time you have blood drawn for routine labs, we will draw 1 tube of blood (about 2 
tablespoons) for future research. If the future analysis is not performed, your blood and/or ascites 
samples(s) will be destroyed. 
 
If you need to undergo repeated paracentesis, we would collect fluid each time for testing, and a 
portion of this will be stored.  
If you qualify for the study and agree to participate, you will be enrolled and we will make 
arrangements to supply you with the study drug. The first dose of study drug should be taken on the 
day of your enrollment visit on Cycle 1 Day 1. 
During the study (Intervention): 
During the treatment period, each 28 day period of time is considered a “cycle.” The cycles are 
repeated every 28 days and you are expected to complete at least 2 cycles, unless a study treatment 
delay is needed due to side effects. You will be removed from this study if your disease worsens 
during or after these 2 months. After this period, you may continue to participate in the study only 
if your disease is stable (about the same) or you are responding to the study treatment.   
Study treatment will be given to you to take home.  You will take two 100mg nintedanib capsules by 
mouth in the morning and two 100mg capsules in the evening (approximately every 12 hours) with 
food and a full glass of water (8 oz.). If side effects or complications from study treatment occur, 
your study doctor may tell you to temporarily stop taking the study drug or to adjust the dose. 
In addition to taking nintedanib twice daily, you must also do the following: 
• Swallow the capsule whole. Capsules should not be broken or crushed. 
• Keep the capsules in their original bottle. 
• If you miss a dose, you should not replace the missed dose but proceed to the next 
scheduled dose when it is due. 
• If vomiting occurs after taking a dose, an extra dose should not be taken. 
• Do not take any new prescription or herbal medication without first speaking with your 
study doctor or the clinical study staff. 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 4 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
You will meet with your study doctor and/or clinical study staff every four weeks on Day 1 of each 
cycle for as long as you are being treated on the study. During these visits, you will have a physical 
exam, ECOG performance status (we will ask you how you are doing in terms of your ability to take 
care of yourself, your daily and physical activities) and we will take some blood (about 2 
tablespoons) for research purposes and to check your blood counts, kidney and liver function. We 
will also check your vital signs and weight and ask about any side effects you may have experienced. 
We may ask that you have additional office visits and/or laboratory testing if you have symptoms or 
side effects.  
In addition to the visits on Day 1 of each cycle as referenced above, we will ask you to have your 
blood pressure taken and report to the study team member during a phone call for the first three 
weeks of Cycles 1 and 2. You may have your blood pressure taken at home if you have a blood 
pressure machine or you may go to another clinic of your choice (i.e. local pharmacy) for a blood 
pressure reading. 
There are multiple drugs (prescription and over the counter medications and dietary/herbal 
supplements including what are sometimes called “complementary” or “alternative” medicines) that 
may interact with nintedanib. Your study doctor or study staff will review all of the medications and 
supplements you are currently taking before starting you on this investigational drug. You should 
not take any new medications or dietary supplements without discussing with your study doctor or 
study staff first. 
A CT scan of your chest, abdomen, and pelvis (or acceptable alternative testing) will be planned at 
the completion of cycle 2 of receiving the study drug. You will continue to receive the study drug 
until your cancer gets worse, until side effects become unbearable even if they are being medically 
treated, or until you are too ill to continue. You also have the option to voluntarily discontinue study 
treatment and withdraw from the study at any time. If neither of the above mentioned scenario 
happens and you continue to receive the study drug, a CT scan (or acceptable alternative testing) will 
be necessary at the completion of every 2 cycles (e.g. cycles 4, 6, 8). 
In order to document the current status of your disease (which could be a response, stable disease, 
or progressive disease) we will make all efforts to obtain scans and assess your tumor every 8 weeks 
(+/- 2 weeks). If you decide to discontinue therapy, every effort will be made to obtain any future 
scan results unless your disease worsens or you start new treatment.    
Your study doctor may also choose to withdraw you from the study for any reason, including if you 
are unable to adhere to the study schedules and requirements. 
 
After you complete the intervention (End of treatment): 
Within 30 days of your last dose of study treatment, you will come in and meet with your study 
doctor and/or clinical study staff. At this visit, you will have a few procedures done which may 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 5 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
include but not limited to a physical exam, check of the vital signs, check of your current 
medications and a blood draw. 
Following this visit, research staff will contact you every 6 months, until you complete 3 years of 
follow-up after you stop taking the study drug. 
RISKS 
 
You may have side effects while you are on this study. Everyone taking part in the study will be 
carefully watched for side effects, especially for your liver enzymes. However, doctors don’t know all 
the side effects that may happen. Side effects can be mild or very serious. Your doctor may give you 
medicines to lessen side effects. In some cases, side effects can be serious in that they can be long 
lasting, may never go away, may result in hospitalization, or may result in death.   
 
The very common (occurring in more than 10% of patients treated with nintedanib) risks in adult 
patients are: 
 
• diarrhea 
• nausea 
• vomiting 
• increased liver function tests (blood tests that show that show that your liver is not working 
the way it should) 
• tiredness 
• decreased appetite 
• pain- abdominal pain, muscle cramps, chest pain, back pain, tumor pain  
• skin problems such as: itching, rash, hair loss, dry skin, hand foot syndrome, nail disorder 
• electrolyte imbalance (electrolytes are minerals in the blood) 
• abnormal skin sensations 
• bleeding e.g. nose bleeding, coughing up small amounts of blood, rectal bleeding 
• 
mouth ulceration   
 
The common (occurring in more than 1% and less than 10% of patients treated with nintedanib) risks 
in adult patients are: 
• taste changes  
• constipation 
• fever  
• high blood pressure 
• decrease in weight 
• headache 
• infections including those in the urine, chest and sinuses  
• dry mouth 
• flatulence (gas) 
• dizziness  


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 6 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
• dehydration 
• insomnia 
• blood clots in vein (venous thromboembolism) or in arteries (arterial thromboembolism 
including myocardial infarct) 
 
The rare (occurring in less than 1% of patients treated with nintedanib) risks in adult patients are: 
 
• cough 
• chills 
• vertigo (a feeling that the room is spinning) 
• low blood pressure 
• eye disorders, such as eye dryness, eye redness, conjunctivitis, vison blurred 
• allergic reaction to drug, like itching, rash   
• skin swelling 
• abnormal heart beats, fast or slow heart beats 
• low blood sugar   
• changes in kidney function 
• perforation (holes in the bowels) 
• bleeding into the brain 
• low production of the thyroid hormone 
• pancreatitis (swelling and inflammation of the pancreas) 
• In a few patients, an increase of bilirubin and liver enzymes was observed. This was fully 
reversible and appeared to be associated with progression of the underlying cancer disease 
and concomitant development of liver metastases. Enzyme elevations generally returned to 
normal upon temporarily stopping treatment in the majority of patients, and usually did not 
happen again after continuation of treatment at a lower dose. Your liver enzyme levels will 
be monitored closely during the conduct of this study.  
 
Extra blood samples and ultrasound images may be taken in order to clarify the potential 
underlying reason for the increased liver enzymes. If the cause of liver function changes 
cannot be found, further tests may be performed. This may include taking additional blood 
samples for further analysis of safety parameters, the analysis of the types and amounts of 
hormones, and the presence of viruses. Please inform your study doctor if you notice 
yellowing of the skin or of the white part of your eyes, which are signs of an increased 
bilirubin level in your body.  
• Previous animal studies suggest that decreased immune function may also occur when being 
treated with nintedanib. These animal studies also suggested that nintedanib in combination 
with natural sunlight or artificial UV radiation may cause effects to the skin or the eye. 
However, so far, these adverse events have not been reported in clinical trials with humans. 
 
You need to tell your study doctor immediately if you experience any side effects while 
taking part in the study. 
 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 7 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
Any medications (including over the counter and herbal supplements) that you are taking while 
taking nintedanib will be monitored by your study doctor or study staff. Some medications may 
affect the way nintedanib works. Please notify your study doctor or study staff immediately before 
you start taking any new medications. 
 
INFORMATION ON BIRTH CONTROL (For Female Trial Participants) 
As with any investigational drug, the effect of nintedanib on an unborn child is unknown. If you 
decide to take part in this trial and you are able to become pregnant, you must be willing to have a 
pregnancy test done before beginning your participation, and regularly at study visits and at the end 
of study treatment and beyond for at least 3 months after the last dose of nintedanib. Furthermore, 
you must avoid becoming pregnant while you take part in this trial. You cannot participate in this 
trial if you are pregnant, breastfeeding or plan to become pregnant during your trial participation.  
 
You must use a highly effective method of birth control.  Some of the acceptable methods of 
contraception are listed below: 
• an oral contraceptive (birth control pills) 
• an implantable or injectable contraceptive 
• an intrauterine device/system (IUDs / IUSs) 
• transdermal patch 
• double barrier method (two methods used at the same time) 
• bilateral tubal occlusion 
• vasectomized sexual partner (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate and provided that partner is the sole sexual partner of the participant 
• complete sexual abstinence when this is in line with the preferred and usual lifestyle of the study 
participant. When there is complete sexual abstinence, the patient refrains from any sort of 
sexual activity that could involve the spill of an ejaculate, even if the spill does not occur 
 
Your doctor will talk to you about the best method of birth control for you.  
If you are pregnant or think you could be pregnant, it is important for you to tell your doctor or 
research staff immediately. If you become pregnant during the trial, you will be removed from the 
trial and your health and your baby’s health will be monitored throughout your pregnancy. Even if 
you are no longer in the trial, you will be contacted after your baby is born to find out about the 
baby’s health. 
 
For MALE Trial Participants 
 
During study participation and for 3 months after your last study drug dose you should not father 
a child or donate sperm. 
 
 
 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 8 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
WILL I BENEFIT FROM PARTICIPATING IN THIS STUDY? 
 
The benefits of nintedanib to treat advanced and/or metastatic appendiceal carcinoma are not fully 
known and it might be that you do not gain any benefit by participating in this research.  With our 
current knowledge and understanding, nintedanib may have the potential to provide benefits to you 
or others like you, by slowing down the growth and spread of the tumor.  
 
Information from this study may help you and/or other people with your disease in the future. 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
You may choose not to participate in this study and receive routine care, or any standard treatment as 
recommended by your study doctor, such as other chemotherapy, or participation in other clinical 
trials. Your study doctor can discuss the alternatives and the risks and benefits of these alternatives 
with you. Please ask any questions you may have and take as much time as you need to make your 
decision. If you choose not to take part in this study, that will not harm your relationship with your 
doctor or with CHS. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
You and/or your health plan/insurance will need to pay for all routine care procedures. You may 
have to pay for these costs if they are not covered by your insurance company. If you choose to take 
part in the study, you will receive the study treatment, nintedanib, at no charge to you. Medicines 
that are not part of the study treatment will not be provided or paid for by LCI.  
 
You will not receive payment for taking part in this study.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage   You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this web site.   
 
Another way to get the information is to call 
 and ask them to 
send you a free copy.  
 
You may wish to discuss coverage with your insurance company before agreeing to participate in 
this research study. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
If you become ill or are hurt while you are in the study, you will get the medical care that you need 
right away. 
 
In the event that you are harmed as a result of your participation in this study, inform your doctor 
immediately so you can access medical treatment. You and/or your health plan will be charged for 
this treatment in the usual manner. The study will not pay for standard medical treatment. The drug 
manufacturing company (Boehringer Ingelheim) will not provide any compensation for injury that 
occurred during the course of this research trial with nintedanib. 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 9 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
You still have the right to make a claim through the legal system even if you sign this form, accept 
medical care, or accept payment for medical expenses. 
 
WHAT IF I WANT TO QUIT THE STUDY LATER ON? 
 
Your participation in this study is completely voluntary. You should feel under no pressure to be in 
the study.  If you decide not to be in the study, that will not in any way harm your relations with 
your doctors or with Carolinas HealthCare System.  You are free to stop being in the study if you 
change your mind after entering it.  This would not harm your relations with your doctors or 
Carolinas HealthCare System. Information contributed to the study will remain in the study even if 
you choose to withdraw.  If you choose to withdraw from the study, please notify the study doctor 
in writing at the address on page 1 of this consent form. 
 
Your study doctor may choose to involuntarily withdraw you from the study for any reason, 
including if you are unable to adhere to the study schedule or requirements. 
 
We will tell you about new medical findings that may affect your willingness to continue in the 
study. 
 
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
• Carolinas HealthCare System (CHS) 
• Boehringer Ingelheim, the company that manufactures nintedanib 
• Government agencies, like the Food and Drug Administration (FDA) that are involved in 
keeping research safe for people 
• Other persons/agencies as required by law or allowed by federal regulations  
 
The records of this study will be kept private.  In any sort of report we might publish, we will not 
include any information that will make it possible to identify a patient.  Your record for this study 
may, however, be reviewed and/or photocopied, by Carolinas HealthCare System, or by 
representatives of the Food and Drug Administration or other government agencies.  To that extent, 
confidentiality is not absolute. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. law. 
This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
 
To ensure that your information collected for this study will be kept private, your name will not be 
used whenever possible.  A code will be used instead of your name.  All of your study data will be 
kept in a secure location. 
 
 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 10 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
 
AUTHORIZATION 
  
If you wish to take part in this clinical study, you will be asked to sign this consent form.  It allows 
the study sponsor (LCI) and the sponsor-investigator (Dr. Jimmy Hwang) to collect and process any 
relevant personal health information collected from you during the study.  These are activities 
routinely carried out during all clinical studies.  
 
You have been told that personal information about you (including sensitive personal health 
information, such as your medical history and your racial/ethnic origin if relevant to the study) will 
be reviewed, collected on a computer database, stored in electronic or manual files, audited, and/or 
otherwise processed by: 
 
• the clinical study sponsor-investigator, investigators and research staff  
• regulatory or other governmental authorities of the United States and other countries, 
• other persons authorized by the study sponsor, 
• Carolinas HealthCare System employees, 
• other persons or agencies as required by law or allowed by federal regulations. 
 
You have been told that your personal data are being collected and processed to: 
 
• check your suitability to take part in the study, 
• monitor activity with the medication (nintedanib) under study. 
• compare results with those of other subjects in the study, 
• support the development of the other study protocols.  
 
You have been told that your personal information may be processed within the U.S, processing 
and/or storage by an associated company or a carefully selected third-party organization.  By signing 
this document, you explicitly consent to the transfer of your personal information, including 
sensitive personal information, collected during this clinical study, for review, processing and/or 
storage.  Your personal health information may be further shared by the groups above.  If shared by 
them, the information will no longer be covered by the Privacy Rule.  However, the groups are 
committed to keeping your personal health confidential. 
 
You may refuse this authorization to transfer your personal information.  If you choose not to agree 
to this authorization, you might be ineligible to participate in the study.  If you decide not to sign 
this authorization, that will not harm your relations with your doctors or with Carolinas HealthCare 
System.   
 
You have the right to inspect your medical record at any time.  Your research record may be 
unavailable until the conclusion of the study.  At that point, it will be available.  Please speak with 
the study doctor if you desire to access your record. 
 
You have been told whenever your personal information is processed, it will be kept confidential 
and secure, to the best of our ability.  It will be used only for the purpose for which it was collected. 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 11 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
 
This Authorization does not have an expiration date.  You have been told that according to the 
guidelines for good clinical practice, the study sponsor-investigator will keep your personal 
information for at least 6 years. If you do not withdraw this Authorization in writing, it will remain 
until the study is terminated.  If you wish to revoke authorization to use your personal information, 
you will notify the study doctor in writing at the address on page 1 of this consent form. 
 
Some of the data obtained from your record prior to your revocation may still be used if considered 
necessary for the study.     
 
FINANCIAL DISCLOSURE  
 
None of the doctors asking you to participate in this study has received or will receive money or 
other benefits for personal use from Boehringer Ingelheim, the company that developed the 
nintedanib used in this study. However, the funding company will give money or other benefits to a 
research fund, foundation, educational institution, or other organization with which the doctor or 
study staff is associated. 
 
GETTING ANSWERS TO YOUR QUESTIONS OR CONCERNS ABOUT THE STUDY 
 
You can ask questions about this consent form or the study (before you decide to start the study, at 
any time during the study, or after completion of the study).  Questions may include: 
 
• Who to contact in the case of a research-related injury or illness; 
• Payment or compensation for being in the study, if any; 
• Your responsibilities as a study subject; 
• Eligibility to participate in the research; 
• The study doctor’s or study site’s decision to exclude you from participation; 
• Results of tests and/or procedures; 
• Other questions, concerns, or complaints. 
 
Contact the study doctor or study staff at Carolinas Healthcare, listed on the first page of 
this form, with any questions, concerns or complaints.   
 
 
 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 12 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
GETTING ANSWERS TO YOUR QUESTIONS ABOUT YOUR RIGHTS AS A 
RESEARCH SUBJECT 
 
This study has been reviewed by an Institutional Review Board (IRB). This Committee reviewed this 
study to help ensure that your rights and welfare are protected and that this study is carried out in an 
ethical manner. 
 
For questions about your rights as a research subject, contact:  
• By mail: 
Study Subject Adviser 
 
 
 
• or call toll free:   
 
• or by email:   
 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00021617. 


Levine Cancer Institute / Protocol Number LCI-GI-APX-NIN-001 
Page 13 of 13 
 
 
Jimmy Hwang, MD 
Chesapeake IRB Approved Version 20 Oct 2017 
 
 
 
 
 
CONSENT AND AUTHROIZATION 
 
I have read this form and its contents were explained to me.  I agree to be in this research study for 
the purposes listed above.  All of my questions were answered to my satisfaction.  I will receive a 
signed and dated copy of this form for my records.  I am not giving up any of my legal rights by 
signing this form.  
 
___________________________________ 
____/____/____  _________ 
Signature of Research Subject 
               Date 
 Time 
 
___________________________________ 
Printed Name of Research Subject 
 
___________________________________                                ____/____/____  _________ 
Signature of Legally Authorized Representative (if applicable)                 Date  
Time 
 
___________________________________ 
Printed Name of Legally Authorized Representative (if applicable) 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject or the subject’s legally authorized representative the nature 
and purpose of the above study.  There has been an opportunity for the subject or the subject’s 
legally authorized representative to ask questions about this research study.  I have been available to 
answer any questions that the subject or the subject’s legally authorized representative has about this 
study. 
 
 
___________________________________ 
____/____/____  _________ 
Signature of Person Explaining Consent 
Date 
 Time 
 
___________________________________ 
Printed Name of Person Explaining Consent