Clinical trial NCT02902484
Conditions: Cancer of Pancreas
Sponsor: University of Texas Southwestern Medical Center
Start date: 2017-09-07; Completion date: 2021-10-26
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will perform a clinical study evaluating the safety and tolerability of nintedanib when combined with standard chemotherapy (Gemcitabine + nab-Paclitaxel) for metastatic pancreatic cancer. It will utilize advanced imaging correlates including dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) which correlates with tumor grade and microvessel density.

Detailed description:
Preclinical data suggest nintedanib inhibits primary tumor growth in in vivo xenograft models of pancreatic cancer, as well as inhibiting metastasis in pancreatic cancer models. This effect appears primarily due to nintedanib anti-angiogenic properties. The study will perform a clinical study evaluating the safety and tolerability of nintedanib when combined with standard chemotherapy (Gemcitabine + nab-Paclitaxel) for metastatic pancreatic cancer. It will utilize advanced imaging correlates including dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) which correlates with tumor grade and microvessel density.

For each patient, treatment will have two phases: nintedanib monotherapy for a two week period (Days 1-14) followed by combination phase of nintedanib plus chemotherapy (Cycle 2+).

Arms: arm 1: One cycle of Nintedanib monotherapy followed by a total of eight cycles of both Nintedanib and the chemotherapeutic agents, or until disease progression, whichever comes first.

1. Nintedanib dose escalation: 150, 200 mg PO BID
2. Nab-paclitaxel: 125 mg/m2 day 1,8,15 every 28 days
3. Gemcitabine: 1000 mg /m2 day 1,8,15 every 28 days
Interventions: intervention 1: Nintedanib
Intervention descriptions: intervention 1: Nintedanib Monotherapy Followed by Combination Therapy of Nintedanib and Gemcitabine Plus nab-Paclitaxel

Protocol documents:
Prot_SAP_002.pdf: 
 
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Cover Page 
 
Official Title: A Phase 1b and Pharmacodynamic Study of Nintedanib Monotherapy 
Followed by Combination Therapy of Nintedanib and Gemcitabine Plus nab-
Paclitaxel for Advanced Pancreatic Cancer 
NCT number: NCT02902484 
Document Date: 06/06/2022 


Protocol: SCCC-06216 
 
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SCCC-06216 
 
A Phase 1b and Pharmacodynamic Study of Nintedanib Monotherapy Followed by Combination Therapy of 
Nintedanib and Gemcitabine Plus nab-Paclitaxel for Advanced Pancreatic Cancer 
 
Principal Investigator:  
Salwan Al Mutar, MD 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd., NB2.418 
 
 
 
 
Dallas, TX 75390-9179 
 
 
 
 
Phone:  214-648-4008 
 
 
 
 
Fax:  214-648-1578 
 
 
 
 
Email:  salwan.almutar@UTSouthwestern.edu 
 
Sub-Investigator(s): 
 
Suzanne Cole, MD 
 
 
 
 
Quyen Do, PhD 
 
 
 
 
David Gerber, MD 
David Gerber, MD 
 
 
 
 
Leticia Khosama, MS, APRN, NP-C, AOCNP  
 
 
 
 
Syed Kazmi, MD 
Alyssa Macchiaroli, MD 
Aravind Sanjeevaiah, MD 
Samira Syed, MD 
Qing Yuan, PhD 
 
Biostatistician: 
 
Chul Ahn, Ph.D.  
 
 
 
 
Professor, Department of Clinical Science 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd. 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
Phone:  214-648-9418 
 
 
 
 
Email:  Chul.Ahn@UTSouthwestern.edu 
 
Study Drug/Treatment: 
Nintedanib 
 
IND/IDE Number: 
 
132361 (Exempt) 
 
IND/IDE Holder Name:  
Boehringer Ingelheim Pharmaceuticals, Inc. 
 
Funding Source:  
 
Boehringer Ingelheim Pharmaceuticals, Inc. 
 
Initial version: 
1.0  
04/17/2015 
Amended: 
 
2.0 
08/15/2015 
 
 
3.0 
10/28/2015 
 
 
4.0 
05/24/2016 
 
 
5.0 
11/07/2016 
 
 
6.0 
08/24/2018 
 
 
7.0 
03/17/2020 
8.0        05/03/2022 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 


Protocol: SCCC-06216 
 
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Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ..................................................................... 2 
STUDY SCHEMA…………………………………………………………………………………………3 
PROTOCOL SYNOPSIS………………………………………………………………………………... 4 
LIST OF ABBREVIATIONS……………………………………………………………………………...6 
1.0 BACKGROUND .................................................................................................................... 8 
1.1 DISEASE BACKGROUND…………………………………………………. ................................ 8 
1.2  STUDY AGENT(S) BACKGROUND AND ASSOCIATED KNOWN TOXICITIES .................. 9 
1.2.1 Nintedanib .......................................................................................................................... 9 
1.2.2 Gemcitabine + nab-Paclitaxel (ABRAXANE) .................................................................... 14 
1.3. STUDY RATIONALE .......................................................................................................... 15 
1.4. BENEFIT – RISK ASSESSMENT ....................................................................................... 16 
2.0 STUDY OBJECTIVES ......................................................................................................... 17 
2.1 PRIMARY OBJECTIVES: .................................................................................................... 17 
2.2 SECONDARY OBJECTIVES: ............................................................................................. 17 
3.0 PATIENT SELECTION………………………………………………………………………... ...... 17 
3.1 INCLUSION CRITERIA ....................................................................................................... 17 
3.2 EXCLUSION CRITERIA ...................................................................................................... 18 
4.0 TREATMENT PLAN ............................................................................................................ 20 
4.1 AGENT ADMINISTRATION ................................................................................................ 20 
5.0 FOLLOW UP ....................................................................................................................... 25 
5.1 DURATION OF FOLLOW UP.............................................................................................. 25 
5.2 CRITERION FOR REMOVAL FROM STUDY ..................................................................... 25 
5.3 PATIENT REPLACEMENT ................................................................................................. 25 
6.0 DOSING SELECTION / DELAYS / DOSE MODIFICATIONS .............................................. 26 
6.1 CRITERIA FOR INITIATION OF NINTEDANIB TREATMENT (MONOTHERAPY): ............. 26 
6.2 CRITERIA FOR INTERRUPTION OF TREATMENT WITH NINTEDANIDNIB 
(MONOTHERAPY OR COMBINATION PHASE) ........................................................... 26 
6.3 CRITERIA TO RESTART NINTEDANIB TREATMENT IF PREVIOUSLY INTERRUPTED 
(MONOTHERAPY OR COMBINATION PHASE) ........................................................... 27 
6.4 DOSE MODIFICATION OF NINTEDANIB ........................................................................... 27 
6.5 DOSE ADJUSTMENTS FOR GEMCITABINE + NAB-PACLITAXEL ................................... 28 
6.6 MANAGEMENT OF ADVERSE EVENTS............................................................................ 30 
6.7 PERMANENT DISCONTINUATION TREATMENT WITH NINTEDANIB ............................. 31 
6.8 ADDITIONAL PRECAUTIONS FOR NINTEDANIB ............................................................. 31 
6.9 CONCURRENT CANCER TREATMENTS RESTRICTIONS............................................... 33 
7.0 STUDY EVENTS................................................................................................................. 33 
7.1 SCREENING ASSESSMENTS ........................................................................................... 33 
7.2 ON-STUDY TREATMENT ASSESSMENTS ....................................................................... 34 
7.3 STUDY CALENDAR: .......................................................................................................... 40 
8.0 MEASUREMENT OF EFFECT ............................................................................................ 44 


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8.1 ANTITUMOR EFFECT- SOLID TUMORS ........................................................................... 44 
9.0 ADVERSE EVENTS…………………………………………………. ........................................ 47 
9.1 EXPERIMENTAL THERAPY…………………………. .......................................................... 47 
9.2 ADVERSE EVENT MONITORING……………………………………. .................................... 47 
9.3 STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED 
REPORTING…………………………………. .................................................................. 51 
9.4 ADVERSE EVENTS AND LABORATORY VALUES OF SPECIAL INTERESTError! Bookmark not defined
9.5 DOSE LIMITING TOXICITY (DLT) FOR PHASE I TRIALS OF NINTEDANIBError! Bookmark not defined.
9.6 SAFETY ASSESSMENT FORM…………………………………………………………… ........ 53 
9.7 STOPPING RULES ............................................................................................................. 54 
10.0 PHARMACEUTICAL INFORMATION ............................................................................... 54 
10.1  NINTEDANIB (STUDY DRUG) ......................................................................................... 54 
10.2 GEMCITABINE AND NAB-PACLITAXEL ARE COMMERCIALLY AVAILABLE ................. 55 
10.2.1  Agent: Gemcitabine: ...................................................................................................... 55 
10.2.2  Agent:  Nab-paclitaxel (Abraxane)………………………………………………………. ...... 58 
11.0 CORRELATIVE STUDIES ................................................................................................ 61 
11.1 DCE-MRI…………………………………………………………………………………………. .. 61 
11.2 PHARMACODYNAMIC SAMPLES ................................................................................... 61 
11.3 BIOPSIES…………………………………………………………………………………… ........ 62 
11.4 SPECIMEN BANKING…………………………………………………………………….. ......... 62 
12.0 STATISTICAL CONSIDERATIONS .................................................................................. 62 
12.1 MTD DETERMINATION: ................................................................................................... 62 
12.2 DATA ANALYSIS PLANS ................................................................................................. 63 
12.3 IMAGINING CORRELATES .............................................................................................. 63 
13.0 STUDY MANAGEMENT ................................................................................................... 64 
13.1 CONFLICT OF INTEREST ................................................................................................ 64 
13.2 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ........................... 64 
13.3 REQUIRED DOCUMENTATION (FOR MULTI-SITE STUDIES) ....................................... 64 
13.4 PATIENT RECRUITMENT ................................................................................................ 64 
13.5 REGISTRATION PROCEDURES ..................................................................................... 65 
13.6 DATA MANAGEMENT AND MONITORING/AUDITING………….. .................................... 65 
13.7 ADHERENCE OF THE PROTOCOL ................................................................................. 66 
13.8 AMENDMENTS TO THE PROTOCOL .............................................................................. 67 
13.9 RECORD RETENTION ..................................................................................................... 67 
13.10 OBLIGATIONS OF INVESTIGATORS ............................................................................ 68 
14.0 REFERENCES.................................................................................................................. 69 
15.0 APPENDICES…………………………………………………………………………………….. 71 
 
 


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STUDY SCHEMA 
 
 


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PROTOCOL SYNOPSIS 
Title: 
Phase 1b and Pharmacodynamic Study of Nintedanib Monotherapy 
Followed by Combination Therapy of Nintedanib and Gemcitabine Plus 
Nab-paclitaxel for Advanced Pancreatic Cancer 
Short Title: 
Phase 1b Study of Nintedanib and Chemotherapy for Advanced 
Pancreatic Cancer  
Protocol Number: 
SCCC-06216 
Phase: 
Phase 1b 
Methodology: 
Single arm, open label study 
Study Duration: 
24 months (enrollment) 
Study Center(s): 
Multicenter: 
1) UT Southwestern Medical Center at Dallas 
2) UT Health Sciences San Antonio 
Objectives 
Primary Objectives: 
1. Determine safety and tolerability of nintedanib administered with 
gemcitabine plus Nab-paclitaxel in advanced pancreatic cancer. 
Secondary Objectives: 
    1. Determine pharmacodynamic effects (blood and imaging) of  
nintedanib on angiogenesis and tumor microenvironment in advanced 
pancreatic cancer. 
2. Determine preliminary efficacy (response rate, progression-free 
survival, overall survival) of nintedanib in combination with 
gemcitabine plus Nab-paclitaxel in advanced pancreatic cancer. 
Number of Patients 
20 (evaluable for safety analysis) 
Diagnosis and Main 
Inclusion Criteria 
1. Locally advanced and metastatic pancreatic adenocarcinoma; 
2. Good ECOG performance status of 0-1; 
3. Preserved hematologic, hepatic, and renal function. 
Study Product(s), 
Dose, Route, Regimen 
1. Nintedanib dose escalation: 150, 200 mg PO BID 
2. Nab-paclitaxel: 125 mg/m2 day 1,8,15 every 28 days 
3. Gemcitabine: 1000 mg /m2 day 1,8,15 every 28 days 
Duration of 
administration 
One cycle of Nintedanib monotherapy followed by a total of eight cycles 
of both Nintedanib and the chemotherapeutic agents, or until disease 
progression, whichever comes first. 


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Reference therapy 
Historical (MPACT study, Von Hoff et al, ASCO 2013) 
http://meetinglibrary.asco.org/content/116827-132 
Statistical 
Methodology 
All patients receiving at least one dose of nintedanib will be considered 
evaluable for safety analysis. However only patients experiencing a 
dose limiting toxicity (DLT) or those who receive all scheduled full dosing 
regimen of nintedanib/gemcitabine/nab-paclitaxel will be considered 
evaluable for DLT assessment. In addition to the evaluation and 
categorization of adverse events, listing of laboratory test results 
collected at baseline and during the study will be generated. Descriptive 
statistics summarizing the changes in those laboratory tests over time 
will be collected. 
Patients who have received at least 2 cycles of therapy and had at least 
one disease assessment following the initiation of therapy will be 
considered evaluable for response. The antitumor activity (RECIST) will 
be exploratory. 
 
 


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List of Abbreviations  
 
AEs – adverse events 
ALT – alanine amino transferase  
AST – aspartate amino transferase  
ATP - adenosine triphosphate 
BIBF1120 – Nintedanib 
BID – twice daily 
BUN – blood urea nitrogen 
CBC – complete blood count 
CI – confidence interval 
Cmax – maximum plasma concentrations 
CR - complete response 
 
CRF – case report form 
 
CRO – Clinical Research Office 
 
CT – computed tomography 
 
CTCAE - Common Terminology Criteria for Adverse Events 
 
DLT – dose-limiting toxicity 
DSMC - Data and Safety Monitoring Committee  
ECOG - Eastern Oncology Cooperative Group  
EGFR – epidermal growth factor receptor 
Flt-3 – Fms-related tyrosine kinase 3 
FGF/FGFR – fibroblast growth factor/fibroblast growth factor receptor 
FOLFIRINOX – folinic acid, fluorouracil, irinotecan, oxaliplatin 
FOLFOX – folinic acid, fluorouracil, oxaliplatin 
LDH – lactate dehydrogenase 
IPF – idiopathic pulmonary fibrosis 
IRB – institutional review board 
Nab-paclitaxel – albumin-bound paclitaxel 
TKI – tyrosine-kinase inhibitor 
PDGF/PDGFR – platelet-derived growth factor/ 
platelet-derived growth factor receptor 
VEGF/VEGFR – vascular endothelial growth factor/ vascular endothelial growth factor receptor 
γ-GT – gamma-glutamyl transpeptidase 
PD - pharmacodynamics 
NSCLC – Non-Small Cell Lung Cancer 
MCRC – metastatic colorectal cancer 


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RET – ret proto-oncogene 
Lck – lymphocyte-specific protein tyrosine kinase 
 
OS – overall survival 
PFS – progression free survival 
NCCN – national comprehensive cancer network 
DCE-MRI – dynamic contrast-enhanced MRI 
PI - principal investigator 
PR - partial response 
 
RECIST - Response Evaluation Criteria in Solid Tumors 
 
SCCC -Simmons Comprehensive Cancer Center 
 
TDP - time to disease progression 
MRI – magnetic resonance imaging 
SD – stable disease 
PD – progressive disease 
 
 


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1.0 BACKGROUND 
1.1. Disease Background 
Metastatic pancreatic adenocarcinoma is a universally fatal disease accounting for most of 
the approximately 40,000 deaths from pancreatic cancer in the United States annually1. 
Whereas the mainstay of therapy for metastatic cancer has been systemic chemotherapy, 
currently available treatment strategies for pancreatic cancer have been unable to make a 
significant impact on long term outcomes. Gemcitabine has long been used for management 
of stage IV pancreatic cancer due to a reduction of cancer-related symptoms and 
improvement in performance status.2 
 
Anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib gained 
approval for first-line treatment, when given in combination with gemcitabine, based on a 
modest improvement in overall survival2. Recently, the first non-gemcitabine combination 
therapy FOLFIRINOX (5-fluorouracil/ leucovorin given in combination with oxaliplatin and 
irinotecan) demonstrated activity in the PRODIGE trial 3, but broad applicability of this 
regimen has been hampered by its high toxicity rate. In addition, studies are underway to 
evaluate FOLFIRINOX with Algenpantucel-L in locally advanced pancreatic cancer.   
Encouraging Phase I/II study of 67 patients treated with a combination of nab-paclitaxel (a 
nanoparticle albumin-bound (nab) formulation of paclitaxel) and gemcitabine 4 lead to a 
larger Phase III ‘MPACT’ study which was initially reported at the 2013 Gastrointestinal 
Cancers 
Symposium. 
Combination 
therapy 
with 
Gemcitabine 
and 
nab-paclitaxel 
demonstrated a statistically significant improvement in overall survival over gemcitabine 
alone (8.5 vs 6.7 months) and an increase overall response rate (23% vs. 7%). Given the 
lack of significant activity of currently used treatments, and the toxicity of FOLFIRINOX, the 
success of combination of gemcitabine and nab-paclitaxel may prove to be a major turning 
point for pancreatic cancer patients who are in great need of more effective systemic 
therapy.  
 
Angiogenesis is crucial for the growth of malignant tumors and metastases. 
Angiogenesis inhibitors offer a novel approach for cancer therapy. Most drugs target 
VEGF as an important proangiogenic factor that can drive tumor angiogenesis, although 
platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) also play an 
important role. PDGF receptor tyrosine kinases, expressed on the surface of pericytes 
and smooth muscle cells, contribute to the stability of blood vessel walls; PDGF signaling 
is important for pericyte survival and maintaining pericyte-endothelial cell contacts 5. FGF 
receptor (FGFR) tyrosine kinases are expressed on the surfaces of endothelial cells and 
smooth muscle cells. FGFR signaling pathways promote cell proliferation and survival, 
playing a role in the development and stabilization of blood vessels 6. PDGF and FGF 
may also be upregulated in tumors trying to escape from sustained VEGF inhibition 7,8. In 
recent years, there has been increasing interest in targeting angiogenesis either in 
monotherapy or in combined therapeutic strategy.  
 
 
 
 
 


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1.2  STUDY AGENT(S) BACKGROUND AND ASSOCIATED KNOWN TOXICITIES 
 
1.2.1 Nintedanib 
 
Preclinical studies of Nintedanib 
 
Nintedanib is a potent, orally available triple kinase inhibitor targeting VEGFRs, PDGFRs, 
and FGFRs. Nintedanib inhibits the signaling cascade mediating angiogenesis by binding 
to the adenosine triphosphate (ATP) binding pocket of the receptor kinase domain, thus 
interfering with cross-activation via auto-phosphorylation of the receptor homodimers. The 
specific and simultaneous abrogation of these pathways results in effective growth 
inhibition of both endothelial 
and, via PDGF- and FGF-
receptors of perivascular cells, 
which may be more effective 
than inhibition of endothelial 
cell growth via the VEGF 
pathway alone. Furthermore, 
signaling by FGF-receptors 
has been identified as a 
possible escape mechanism 
for tumor angiogenesis when 
the VEGF pathway is 
disrupted.  
 
In vitro, the target receptors 
are all inhibited by nintedanib 
in low nanomolar concentrations. In in vivo nude mouse models, nintedanib showed good 
anti-tumor efficacy at doses of 50 – 100 mg/kg, leading to a substantial delay of tumor 
growth or even complete tumor-stasis in xenografts of a broad range of differing human 
tumor types. Histological examination of treated tumors showed a marked reduction of 
tumor vessel density by approximately 
80% (Figure 1)12.Besides inhibition of neo-
angiogenesis, it may alter tumor 
maintenance by inducing apoptosis of 
tumor blood vessel endothelial cells. 
Inhibition of receptor kinases may also 
interfere with autocrine and paracrine 
stimulation of tumor angiogenesis via 
activation loops involving VEGF, PDGF, 
and bFGF utilized by vascular and 
perivascular cells such as pericytes and 
vascular smooth muscle cells (Figure 2). 
 
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 


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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 urine5. The metabolic characteristics are 
predominantly independent of cytochrome P450-catalysed metabolic pathways13 
In addition preclinical models show that nintedanib may have a direct anti-tumor effect on 
those malignant cells which overexpress PDGFR and/or FGFR (e.g. H1703 NSCLC cells). 
 
 
 
IC50  (nmol/L) 
VEGFR (1 / 2 / 3) 
34 / 21 / 13 
PDGFR (α / β) 
59 / 65 
FGFR (1 / 2 / 3) 
69 / 37 / 108 
Flt-3 
26 
RET 
35 
Src, Lck, Lyn 
156 / 16 / 195 
 
 
A soft gelatin capsule formulation of nintedanib is used in man. After oral administration, 
nintedanib is absorbed quickly. Maximum plasma concentrations (Cmax) generally occur 2 
to 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 faeces13. 
 
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.  
 
Clinical development of Nintedanib  
 
Nintedanib is being evaluated in several cancers. Additionally, nintedanib  was approved for 
use in the U.S. in 2014 for the non-cancer indication idiopathic pulmonary fibrosis (IPF). As 
of 15th April 2014, 3470 cancer patients, over 1000 patients with IPF, and 143 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 monotherapy studies revealed that nintedanib is generally well 
tolerated with mild to moderate adverse effects such as gastrointestinal symptoms (nausea, 
diarrhea, vomiting, abdominal pain), decreased appetite, anorexia, asthenia and reversible 
elevations of liver enzymes. Initial signs of clinical activity including an encouraging rate of 
patients with stabilization of their tumor of 54% and 68% respectively, have been observed 
in patients with various solid tumors9.  
 
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 twice daily (BID).  
 
The maximum tolerated dose for combination therapy of nintedanib in combination with 
pemetrexed, docetaxel, paclitaxel/carboplatin and FOLFOX is 200mg twice daily. 
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 reversible13. 
 
 
NSCLC 
In a phase II trial in NSCLC patients the safety profile of nintedanib observed in phase I 
trials could be confirmed. Most commonly reported drug-related AEs were nausea (57.5%), 
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. Tumor stabilization was achieved in 46% of 
patients (ECOG 0–1 patients: 59%), with one confirmed partial response (250 mg BID.)10.  .  
 
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 


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histologies) who had progressed after 1st line chemotherapy were randomized in 1:1 
fashion to either receive Nintedanib 200mg BID + Docetaxel (n=655) or Placebo BID + 
Docetaxel (n=659).  
 
LUME-Lung 1 met its primary endpoint by showing a statistically significant improvement of 
PFS for all patients regardless of histology (median PFS 3.4 versus 2.7 months; HR 0.79, 
p=0.0019) for Nintedanib in combination with docetaxel. A significant improvement in OS 
was demonstrated in patients with adenocarcinoma; 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 
group. 
 
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). 
 
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). 
 
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 randomized, double-blind, phase III study of nintedanib plus 
pemetrexed versus placebo plus pemetrexed in patients with advanced non-squamous non-
small cell lung cancer after failure of first line chemotherapy.  
 
Based on a preplanned futility analysis of investigator-assessed PFS, enrollment 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 


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was based on conditional power; there was no formal testing of null hypothesis as planned 
for primary analysis no safety issues were identified. 
 
Even though the study was stopped prematurely, the primary endpoint of this Phase III trial 
was met; treatment with nintedanib plus pemetrexed resulted in a significant prolongation of 
centrally reviewed PFS compared with placebo plus pemetrexed (median PFS 4.4 vs. 3.6 
months with a HR 0.83; p=0.0435).  The disease control rate was also increased 
significantly in nintedanib-treated patients. There was no improvement in OS in nintedanib-
treated patients. Nintedanib 200 mg BID in combination with pemetrexed had an acceptable 
and manageable safety profile, with no new or unexpected safety findings. The most 
frequent AEs were reversible increases in liver enzymes and gastrointestinal events. 
 
 
Ovarian Cancer 
A randomized phase II maintenance trial in ovarian cancer in which the efficacy and safety 
of nine months of continuous twice daily doses of nintedanib following chemotherapy was 
investigated, has identified the potential activity of nintedanib with a 36-week PFS of 15.6 % 
compared to 2.9 % in the control group. The safety profile was consistent with findings 
previously reported for nintedanib administered as monotherapy as mentioned above11.   
 
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 toxicity (DuBois [8]).   
 
 
Colorectal Cancer 
A Phase I/II, open-label, randomized study of nintedanib plus mFOLFOX6 compared to 
bevacizumab plus mFOLFOX6 in 126 patients with metastatic colorectal cancer was 
performed, demonstrating an acceptable safety profile of nintedanib in combination with 
mFOLFOX 6. In comparison to bevacizumab, nintedanib showed a similar magnitude of 
efficacy, a similar safety/tolerability profile, a similar exposure and dose intensity of 
mFOLFOX6 (van Cutsem [9]).  
 
An ongoing Phase III study evaluating the efficacy of nintedanib in patients with metastatic 
colorectal cancer (mCRC) after failure of previous treatment with standard chemotherapy 
and biological agents can be found on 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 diarrhea, nausea, fatigue and 
infection, whereas AEs more frequent in the sunitinib arm consisted of bleeding, anemia, 
hypertension, hand-foot syndrome and stomatitis (Eisen [10]). 
 


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Hepatocellular Cancer  
The efficacy and safety of nintedanib versus sorafenib in Asian Patients with Advanced 
Hepatocellular Carcinoma was investigated in a randomized phase II trial. Nintedanib 
showed similar efficacy to sorafenib, with a favorable and manageable AE profile. More 
patients in the sorafenib arm had severe AEs and drug-related AEs compared with patients 
in the nintedanib arm, and more patients in the sorafenib arm required dose reduction 
compared with the nintedanib arm. Nintedanib AEs were manageable; in the nintedanib arm 
there were fewer hypertension, palmar-plantar erythrodysesthesia syndrome, and 
transaminase elevation events (Yen [11]).  
 
For more details please refer to the investigator drug brochure for nintedanib (Version 14). 
1.2.2 Gemcitabine + nab-Paclitaxel (ABRAXANE)   
 
Preclinical studies have demonstrated that nab-paclitaxel may play a role in sensitizing the 
tumor to chemotherapeutic agents and specifically increases the antitumor efficacy when 
combined with gemcitabine.  While the mechanism of action for the synergy is unclear, 
preclinical studies have generated hypothetical models.  One hypothesis is a remodeling and 
weakening of the stromal barrier, allowing the chemotherapeutic agents to have better access 
to the tumor cells. Weakening the tumor-stroma barrier is particularly important in cancer that 
is characterized by dense stroma, such as pancreatic cancer. In mice with primary patient 
derived pancreatic tumor xenografts, nab-paclitaxel plus gemcitabine versus gemcitabine 
alone resulted in increased tumor regression and depleted the desmoplastic stroma as 
observed by the less dense, disorganized, wisps of collagen type1 fibers after 4 weeks of 
treatment4. In this study, the intratumoral concentration of gemcitabine was increased by 2.8-
fold after 5 days of treatment when nab-paclitaxel was added to gemcitabine. It was 
hypothesized that nab-paclitaxel may play a role in reducing the dense stroma and may have 
contributed to the increased intratumoral gemcitabine uptake.  Additional preclinical studies in 
a genetically engineered mouse model of pancreatic adenocarcinoma, coadministration of 
nab-paclitaxel and gemcitabine also demonstrated tumor regression and increased 
intratumoral gemcitabine levels after 8 days of treatment.  Apoptosis of tumor epithelial cells 
were observed; however, there were no changes in stromal components or collagen density in 
this short term treatment model (Frese, 2012). The increased intratumoral gemcitabine levels 
were attributed to a marked decrease in the primary gemcitabine metabolizing enzyme, 
cytidine deaminase, by nab-paclitaxel. Finally, a recent clinical study in  patients with 
resectable pancreatic cancer treated with neoadjuvant nab-paclitaxel plus gemcitabine showed 
reduction in fibrotic collagenous stroma, further supporting a stroma active mechanism for nab-
paclitaxel (Alvarez-Gallego, 2013). 
In a clinical Phase 1/2 dose ranging study (CA040, NCT003980860), nab-paclitaxel plus 
gemcitabine antitumor activity and tolerability were established in patients who had no prior 
treatment for metastatic pancreatic cancer4. The maximum tolerated dose and recommended 
dose for further studies was determined to be 125 mg/m2 nab-paclitaxel in combination with 
1000 mg/m2 gemcitabine. 


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In the subsequent randomized international Phase 3 study (MPACT, CA046, NCT00394251) 
that enrolled 861 patients with metastatic pancreatic cancer, nab-paclitaxel in combination with 
gemcitabine exhibited a clinically meaningful, statistically significant improvement in OS and 
progression-free survival (PFS). The median OS (primary endpoint) in the intent-to-treat 
population was 8.5 months (95% CI = 7.89-9.53) with nab-paclitaxel/gemcitabine compared 
with 6.7 months (95 % CI = 6.01-7.23) with gemcitabine, p < 0.0001, HR = 0.72 (95% CI = 
0.617-0.835). Long-term survival was improved in the nab-paclitaxel/gemcitabine arm versus 
gemcitabine alone, with a 59% increase at 1 year (35% versus 22%) and doubling at 2 years 
(9% versus 4%). The secondary (PFS, overall response rate [ORR]) and all other efficacy 
endpoints showed consistent, statistically significant improvements with nab-
paclitaxel/gemcitabine, supporting the results from the primary analysis of OS. Specifically, 
PFS (by independent review) was 5.5 months (95% CI = 4.47-5.95) versus 3.7 months (95% 
CI = 3.61-4.04) in the nab-paclitaxel/gemcitabine arm versus gemcitabine alone arms, 
respectively p < 0.0001; HR =0 .69; 95% CI = 0.581-0.821). The improvement in PFS 
corresponded to a 31% reduction in the risk of progression or death with nab-
paclitaxel/gemcitabine. Furthermore, in this study of metastatic unresectable adenocarcinoma 
of the pancreas, patients in the combination arm were on therapy longer than those receiving 
single agent gemcitabine, indicating disease improvement and tolerable treatment24. The 
suitability of the dosing regimen was confirmed by the observation that the majority of patients 
did not require a dose reduction, and that 71% of nab-paclitaxel doses were delivered at the 
starting dose of 125 mg/m2. The safety profile for both regimens was consistent with previous 
reports. Serious life threatening toxicities were not increased; AEs were acceptable and 
manageable. The most notable differences in toxicity between the two treatment arms was 
peripheral neuropathy, which was cumulative and rapidly reversible with dose delay and 
reduction, and neutropenia, which was manageable with dose delays and dose reductions. 
The incremental risks of sepsis and pneumonitis were managed by protocol amendments to 
increase awareness, and for early diagnosis and treatment to reduce the risk of fatal 
outcomes. 
To date, the only other trial that resulted in clinically meaningful improvement in OS in 
pancreatic adenocarcinoma was the Phase 2/3 FOLFIRINOX versus gemcitabine study, which 
was conducted in one country (Conroy, 2011).  While numerous promising Phase 2 studies 
have been conducted in advanced pancreatic cancer, most subsequent large Phase 3 studies 
have failed to show significant improved survival (Colucci, 2010; Cunningham, 2009; Kindler, 
2010; Oettle, 2005; Philip, 2010; Poplin, 2009; Rocha Lima, 2004). 
As a result of the clinically meaningful benefit observed in the MPACT trial, the 2013 NCCN 
guidelines were updated to include nab-paclitaxel plus gemcitabine under treatment option 
category 1 for patients with metastatic pancreatic adenocarcinoma (NCCN, 2013). 
1.3.  Study Rationale 
Our preclinical data suggest nintedanib inhibits primary tumor growth in in vivo xenograft 
models of pancreatic cancer, as well as inhibiting metastasis in pancreatic cancer models 14. 
(See figure 1 and figure 2). This effect appears primarily due to nintedanib anti-angiogenic 
properties. 
 


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We would like to perform a clinical study evaluating the safety and tolerability of nintedanib 
when combined with standard chemotherapy (Gemcitabine + nab-Paclitaxel) for metastatic 
pancreatic cancer.  
 
We will utilize advanced imaging correlates including dynamic contrast enhanced Magnetic 
Resonance Imaging (DCE-MRI) which correlates with tumor grade and microvessel 
density15. 
 
1.4. 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 pancreatic cancer. 
 
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 
pancreatic cancer by slowing tumor progression and metastasis, since its cellular target is 
expressed on the tumor vasculature in most malignancies. Induction of endothelial cell 
apoptosis may result in subsequent degradation of tumor vessels and subsequent tumor 
necrosis. Additionally tumor growth may be affected by direct anti-tumor effects, e.g. tumor 
cells that express VEGFR, PDGFR, or FGFR.  
 
The risks of antiangiogenic therapy with nintedanib as single agent or in combination with 
standard doses of chemotherapy in adult patients are primarily related to: the gastro-intestinal 
tract (nausea, vomiting, diarrhea, abdominal pain), increases in liver enzymes (AST, ALT, γ-
GT), fatigue, anorexia, low white blood cell count, peripheral neuropathy and rashes.  
 
Liver enzymes must be followed closely during treatment with nintedanib. Therapy with the trial 
drugs must be interrupted in the event of relevant hepatic toxicity and further treatment is to be 
withheld until recovery of the abnormal laboratory parameters.  
 
Impairment of immune and of kidney function, thromboembolic events and GI perforations are 
considered possible side effects of treatment with nintedanib as they have been reported for 
some other drugs in the class of angiogenesis inhibitors. Thus far these side effects have been 
observed in the trials conducted with nintedanib, but not to a relevant degree. Hypertension is 
also supposed to be a possible side effect of VEGFR inhibitors and a slightly increased 
frequency of hypertension has been observed in the trials with nintedanib to a mild to 
moderate degree and only few cases of CTCAE grade 3 or 4 hypertension have been 
observed.  
 


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Based upon a non-clinical safety study in vitro, nintedanib may have a potential risk of 
phototoxicity (skin and eyes) in vivo. Few cases of photosensitivity reactions (less than 1 %) 
and of CTCAE Grade 1 intensity only have been reported from the clinical studies to date. If 
adequate precautions are taken (avoidance of prolonged ultraviolet (UV) exposure, use of 
broad spectrum sunscreen and sunglasses), treatment with nintedanib is considered safe.  
  
In addition for combination trials: 
The major clinical side effects observed after therapy with gemcitabine + nab-Paclitaxel are 
distinct from nintedanib induced adverse events, yet some overlap may occur e.g. regarding 
mild gastrointestinal toxicity or hepatotoxicity (please refer to the labels included in the 
investigator site file for listed adverse events of gemcitabine + nab-Paclitaxel). In view of the 
low potential for drug-drug interactions of nintedanib, it is not likely that enhanced toxicity due 
to pharmacokinetic interaction between the drug and the cytotoxic chemotherapy will occur. 
2.0  
STUDY OBJECTIVES  
  
2.1 Primary Objective: 
 
 
2.1.1 Determine safety and tolerability of nintedanib administered with gemcitabine plus 
nab paclitaxel in advanced pancreatic cancer. 
 
2.2 Secondary Objectives: 
 
  2.2.1 Determine pharmacodynamic effects (blood and imaging) of nintedanib on 
angiogenesis and tumor microenvironment in advanced pancreatic cancer;   
2.2.2 Determine preliminary efficacy (response rate, progression-free survival, overall 
survival) of nintedanib in combination with gemcitabine plus nab paclitaxel in advanced 
pancreatic cancer. 
 
3.0 
PATIENT SELECTION 
Eligibility waivers are not permitted. In the case that the principal investigator would like 
consideration of an exception, a request must be submitted to the DSMC Chair or designee for 
approval prior to registration of any patient. 
3.1 Inclusion Criteria 
3.1.1 Signed and dated written informed consent prior to admission to the study; 
3.1.2 Histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of 
the pancreas; 
3.1.3 At least one measurable disease lesion according to Response Evaluation Criteria In Solid 
Tumors (RECIST, version 1.1); 
3.1.4 Age ≥ 18 years; 
3.1.5 No more than one prior line of non-gemcitabine/nab-paclitaxel containing systemic therapy 
for metastatic/locally advanced pancreatic cancer; 
3.1.6 Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1; 
3.1.7 Women of childbearing potential must have a negative urine pregnancy test (or serum) 
within 14 days prior to registration; (Note: Patients will be considered to be of childbearing 


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potential unless surgically sterilized by hysterectomy or bilateral tubal 
ligation/salpingectomy, or post-menopausal for at least two years.)  
3.1.8 Adequate biological parameters at baseline (obtained within 14 days prior to registration). 
 
Absolute Neutrophil Count (ANC) 
≥1,500 cells/mm3 
Platelets 
≥100,000 cells/mm3 
Hemoglobin 
≥9 g/dl 
AST (SGOT) / ALT (SGPT) 
AST and ALT ≤ 1.5 x ULN (2.5 x ULN in 
case of liver metastases) 
Total Bilirubin 
≤ ULN 
INR 
≤ 2 
PT / PTT 
≤ 50% increase from institutional ULN 
Serum Creatinine 
≤ 1.5 x ULN  
 
If elevated liver function tests develop at the time of initial presentation or develop during 
workup and are the result of mechanical obstruction of the biliary drainage by tumor 
compression or invasion, a biliary drain may be placed. If drainage allows the liver 
function tests to come within inclusion criteria, the patient may be enrolled. 
3.2 Exclusion Criteria 
3.2.1 More than one systemic therapy regimen of any type for metastatic or locally advanced 
disease. Adjuvant gemcitabine that ended more than 6 months prior to diagnosis of 
recurrent disease is not considered as a regimen; 
3.2.2 Prior treatment with nintedanib or any other VEGFR inhibitor;  
3.2.3 Known hypersensitivity to nintedanib, gemcitabine and nab-Paclitaxel, peanut or soy or any 
other trial drug, their excipients; 
3.2.4 Chemotherapy, hormonal therapy, radiotherapy (except for brain and 
extremities),immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase 
inhibitors within the past 4 weeks prior to treatment with the trial drug; 
3.2.5  Target lesions that have previously received radiation must have shown radiographic 
progression following radiation or must have other non-radiated lesions present 
3.2.6 Persistence of clinically relevant therapy related toxicity from previous chemo and/or 
radiotherapy; 
3.2.7 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 before 
registration); 


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3.2.8 Leptomeningeal disease;  
3.2.9 Radiographic evidence of cavitary or necrotic tumors; 
3.2.10 Treatment with other investigational drugs or treatment in another clinical trial within the 
past 4 weeks before start of therapy or concomitantly with the trial; 
3.2.11 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); 
3.2.12 Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with 
incomplete wound healing and/or planned surgery during the on-treatment study period; 
3.2.13 History of clinically significant hemorrhagic or thromboembolic event in the past 6 months; 
3.2.14 Known inherited predisposition to bleeding or thrombosis; 
3.2.15 Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina, 
history of infarction within the past 12 months prior to  start of study treatment, congestive 
heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion); 
3.2.16 Proteinuria CTCAE grade 2 or greater;  
3.2.17 Creatinine > 1.5 x ULN or GFR < 45 mL/min;  
3.2.18 Hepatic function: total bilirubin outside of normal limits; ALT or AST > 1.5 ULN in pts 
without liver metastasis. For Pts with liver metastasis: total bilirubin outside of normal 
limits, ALT or AST > 2.5 ULN; 
3.2.19 Coagulation parameters: International Normalized Ratio (INR) > 2, prothrombin time (PT) 
and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN; 
3.2.20 Absolute neutrophil count (ANC) < 1500/mL, platelets < 100,000/mL, Hemoglobin   < 9.0 
g/dl; 
3.2.21 Any known active cancer other than pancreatic primary;  
3.2.22 Active serious infections in particular if requiring systemic antibiotic or antimicrobial 
therapy; 
3.2.23 Known or chronic hepatitis C and/or B infection; 
3.2.24 Gastrointestinal disorders or abnormalities that would interfere with absorption of the study 
drug; 
3.2.25 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 patient inappropriate for entry into 
the study; 
3.2.26 Pregnancy or breast feeding female;  


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3.2.27 Psychological, familial, sociological or geographical factors potentially hampering 
compliance with the study protocol and follow-up schedule; 
3.2.28 Active alcohol or drug abuse; 
3.2.29 Significant weight loss (> 20% of BW) within past 6 months prior to inclusion into the trial 
or actual body weight of less than 50 kg; 
3.2.30 Patients who are sexually active and unwilling to use a medically acceptable method of 
contraception (e.g. such as implants, injectable, combined oral contraceptives, some 
intrauterine devices, sexual abstinence or vasectomized partner for participating females, 
condoms for participating males) during the trial and for at least three months after end of 
active therapy. 
4.0 TREATMENT PLAN 
4.1 Agent Administration  
For each patient, treatment will have two phases:  
- Nintedanib monotherapy for a two week period (Days 1-14) followed by  
- Combination phase of nintedanib plus chemotherapy (Cycle 2+).  
Using standard phase 1 3+3 dose escalation rules, two dose levels of nintedanib will be explored: 
150 mg BID and 200 mg BID.    
After completion of 150 mg BID cohort, the dose of nintedanib will be increased to 200 mg BID for 
the next cohort.  No intrapatient dose escalation is planned. No dose escalation of gemcitabine and 
nab-paclitaxel will be performed. 
4.1.1 Monotherapy Phase, Cycle 1 (Nintedanib only) 
The capsules of the defined dose should be swallowed whole with a glass of water of about 250 
mL. The time between each dose of nintedanib should be of around 12 hours at the same times 
every day, usually in the morning and the evening after food intake.  
In case of a missed dose patients should proceed with the intake of medication according to the 
predefined schedule and take the next scheduled dose when it is due. 
        See section 6 for dosing schedule/delays/dose modifications. 
         Vomited dose will not be replaced. 
4.1.2 Combination Therapy Phase, Cycle 2+  
The combination phase will include Gemcitabine + Nab-Paclitaxel, and Nintedanib. Patient 
treatment will consist of
- 
Gemcitabine (1000 mg/m2)   
- 
Nab-Paclitaxel (125 mg/m2) 


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Treatment will be administered intravenously on days 1, 8, 15 every 28 days.  
 
Nintedanib dose in the combination phase will be the same dose given in the monotherapy 
phase. 
Future cycles will only include combination therapy. 
Gemcitabine dosing schedule/delays/dose modifications: See Section 6  
Nab-Paclitaxel dosing schedule/delays/dose modifications: See Section 6  
4.1.3 General Concomitant Medication and Supportive Care Guidelines 
 
Follow local standards. 
 
See Table 1 for a treatment overview and supportive medications: 
 
 
Table 1: Treatment Overview 
 
Agent 
Supportive pre-
Medications 
 
Dose 
 
Route 
 
Frequency 
Cycle 
Length 
Monotherapy 
Phase 
Nintedanib  
150 or 200 mg, 
BID 
Orally 
Twice daily, 
Days 1-14 
2 
weeks 
(Days 
1-14) 
Combination Therapy 
Phase 
Nab-
paclitaxel 
 
Antiemetics per 
institutional 
standard of care 
125 mg/m2 
IV over 30 
minutes 
Days 1, 8, 15 
4 
weeks 
(28 
days) 
Gemcitabine 
1000 mg/m2 
IV over 30 
minutes 
after 
infusion of 
Nab-
paclitaxel 
Days 1, 8, 15 


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Nintedanib  
150 or 200 mg 
Orally  
Twice daily, 
Days 1-28. 
NOTE: For 
safety 
reasons, 
Nintedanib 
should not be 
given the 
same days as 
chemotherapy, 
Days 1, 8, and 
15 
 
5.0 
FOLLOW UP  
5.1 Duration of Follow Up 
Patient will be followed once at 4 weeks after ‘End of Treatment Visit’ (completion of therapy or 
early withdrawal from study). If there are unresolved AEs, this visit will be repeated every 4 
weeks until all study related AEs have resolved to grade 1 or less.  
The patient will be considered ‘off study’ if at 4 weeks post ‘End of Treatment Visit’ all AE’s have 
resolved or patient has expired, whichever comes first. At this point, the patient will only be 
followed for survival at the discretion of the investigator. 
5.2 Criterion for Removal from Study  
Patients can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation must be documented and may include: 
a) Patient voluntarily withdraws from treatment (follow-up permitted); 
b) Patient withdraws consent (termination of treatment and follow-up); 
c) Patient is unable to comply with protocol requirements; 
d) Patient demonstrates disease progression (unless continued treatment with study drug is 
deemed appropriate at the discretion of the investigator); 
e) Patient experiences toxicity that makes continuation in the protocol unsafe; 
f) Treating physician determines that continuation on the study would not be in the patient’s best 
interest; 
g) Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
h) If a research patient cannot be located to document survival after a period of 2 months, the 
patient may be considered “lost to follow-up.” All attempts to contact the patient during the two 
months must be documented. 
5.3 Patient Replacement 
Three patients within a dose level must be observed for the DLT period (comprising of 4 weeks 
of the combination phase) before accrual to the next higher dose level may begin. 


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If a patient is withdrawn from the study prior to completing 28 days of combination therapy 
without experiencing a DLT, an additional patient may be added to that dose level.  
If a patient misses 2 doses of gemcitabine or nab-paclitaxel during DLT period for reasons other 
than adverse events, an additional patient may be added to that dose level. 
Once the maximum tolerated dose has been established using phase 1 3+3 dose escalation 
rules, the remaining patients will be treated as part of the ‘expansion cohort’ .No patient 
replacement will occur in the expansion cohort. The final assessments on patient replacement or 
determination of DLT will be made at the discretion of the PI and cohort review committee. 
6.0 
DOSING SELECTION / DELAYS / DOSE MODIFICATIONS 
Including management of side effects. 
Criteria for initiation, subsequent treatments, interruption of administration, and re-challenge, as 
well as recommendations for dose adaptations will be assessed for each drug.  
Treating investigators will determine attribution of AEs as being related to nintedanib, 
gemcitabine or nab-paclitaxel and the following guideline will be used in AE 
management and dose modifications.  
Recommendations for modification of therapy and appropriate supportive treatments are 
outlined in this section. 
6.1 
CRITERIA FOR INITIATION OF NINTEDANIB TREATMENT (MONOTHERAPY): 
 
Table 2: Criteria for initiation of Nintedanib treatment, provided inclusion & 
exclusion criteria are met: 
All of the following criteria have to be met 
□ Nausea CTCAE grade ≤ 1 
□ Vomiting CTCAE grade 0 
□ Diarrhea CTCAE grade ≤ 1 
□ AST and ALT ≤ 1.5 x ULN (2.5 x ULN in case of liver metastases) 
□ Total bilirubin  ≤ upper normal limit 
□ ANC ≥ 1500 /µL (* or WBC > 3000/µL) 
□ Platelet count ≥ 100,000/µL 
□ Hemoglobin ≥ 9 g/dl 
□ No uncontrolled infection 
 
 
6.2 
CRITERIA FOR INTERRUPTION OF TREATMENT WITH NINTEDANIDNIB 
(MONOTHERAPY OR COMBINATION PHASE): 
Treatment with nintedanib has to be interrupted in case any of the criteria listed in Table 3 is not 
fulfilled. 


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Table 3: Criteria when to interrupt treatment with nintedanib due to an adverse event 
If one criterion is met, nintedanib has to be interrupted 
□ Nausea of CTCAE grade ≥ 3 despite supportive care 
□ Vomiting of CTCAE grade ≥ 2 despite supportive care 
□ Diarrhea of CTCAE grade ≥ 2 for more than 3 consecutive days despite supportive 
care 
□ AST and/or ALT 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 and fever > 38.5° 
□ *Neutropenia  CTCAE grade 4 for more than 7 days without fever 
□ * Platelets <50,000mm³ with bleeding 
 
6.3 CRITERIA TO RESTART NINTEDANIB TREATMENT IF PREVIOUSLY INTERRUPTED 
(MONOTHERAPY OR COMBINATION PHASE)  
A patient is eligible to restart Nintedanib if ALL criteria listed in Table 4 are met.  
 
If a patient has to interrupt intake of Nintedanib due to an adverse event for more than 14 
days, the decision to restart treatment with nintedanib needs to be discussed and agreed 
upon between the investigator and the study PI. 
 
Table 4: Criteria to assess eligibility to restart Nintedanib treatment  
All criteria have to be met in order to restart Nintedanib, meaning AEs have to return to 
Grade 1 or baseline except as detailed below 
□ Nausea CTCAE grade ≤ 2 
□ Vomiting CTCAE grade ≤ 1 
□ Diarrhea CTCAE grade < 2 
□ 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 patient’s pre-therapy 
value at study enrolment 
□ *Platelets CTCAE grade ≤ 1 or equal to the patient’s pre-therapy value at study 
enrolment 
 
6.4 DOSE MODIFICATION OF NINTEDANIB 
As initial measure for the management of side effects (see section 6.6 Management of Adverse 
Events) treatment with nintedanib should be temporarily interrupted until the specific adverse 
reaction has resolved to levels that allow continuation of therapy.  


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Nintedanib treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per 
day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are 
recommended as described in Table 1.  
In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg 
twice daily, treatment with nintedanib should be discontinued.  
The following dose modification will be used in case dose adjustments are required for 
management of toxicity (see table 5 and 6).   
Table 5: Nintedanib dose level- starting dose 150 mg twice daily 
Dose-level: 
0 
-1 
-2 
-3 
Dose: 
150 mg BID  
100 mg BID 
STOP 
STOP 
 
Table 6: Nintedanib dose levels –starting dose of 200mg twice daily 
Dose-level: 
0 
-1 
-2 
-3 
Dose: 
200 mg BID  
150 mg BID  
100 mg BID  
STOP 
 
Of note!  
If the dose of nintedanib had to be reduced due to toxicity, dose will stay on the lower dose 
level for the entire time of administration. 
6.5 DOSE ADJUSTMENTS FOR GEMCITABINE + NAB-PACLITAXEL 
The most common adverse events noted with the MPACT study that resulted in a dose 
reduction, delay or withholding of chemotherapy was neutropenia and thrombocytopenia25.  
Standard recommended dose modifications for gemcitabine and nab-paclitaxel per the MPACT 
trial as highlighted in Tables 7, 8 and 9: 
 
 
 
 
 
 
 


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Table 7: Nab-Paclitaxel + Gemcitabine Dose Adjustments 
Dose level 
Nab-Paclitaxel 
(mg/m2) 
Gemcitabine 
(mg/m2) 
0 / Full dose 
125 
1000 
-1 
100 
800 
-2 
75 
600 
Additional 
Discontinue 
Discontinue 
 
Table 8: Dose Modifications for Hematologic Toxicities of Gemcitabine + nab-
Paclitaxel (modified per MPACT study) 
Cycle Day 
ANC 
(cells/mm3) 
 
Platelet count 
(cells/mm3) 
Modification 
Day 1 
 
<1500 
OR 
<100,000 
Delay treatment  until 
recovery 
Day 8 
 
500 to <1000 
OR 
50,000-75,000 
Reduce 1 dose level 
and treat 
<500 
OR 
<50,000 
Withhold dose by one 
week 
Day 15 – If Day 8 doses were reduced or given without modification 
 
500 to <1000 
OR 
50,000-75,000 
Reduce 1 dose level 
from Day 8 
<500 
OR 
<50,000 
Withhold doses 
Day 15 – If Day 8 doses were withheld 
 
≥ 1000 
OR 
≥75,000 
Reduce 1 dose level 
from Day 1 
500 - <1000 
OR 
50,000- 
<75,000 
Reduce 2 dose levels 
from Day 1 
<500 
OR 
<50,000 
Withhold doses 
 


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Table 9 – Chemotherapy Dose Modifications for Non-Hematologic Toxicities 
Adverse Reaction 
Modification 
Febrile neutropenia: Grade 
3 or 4 
. Withhold treatment until fever resolves and ANC ≥ 1500 
cells/mm3 
. Resume at next lower dose level 
Peripheral neuropathy: 
Grade 3 or 4 
. Withhold Nab-paclitaxel until improvement to Grade ≤ 1 
. Resume Nab-paclitaxel at next lower dose level 
Cutaneous toxicity: Grade 
2 or 3 
. Reduce 1 dose level of gemcitabine and nab-paclitaxel 
. Discontinue treatment if toxicity persists 
Gastrointestinal toxicity: 
Grade 3 mucositis or 
diarrhea 
. Withhold doses until improvement to Grade ≤ 1 
. Resume at next lower dose level for all drugs 
Other toxicity: Grade 3 or 4 
. Withhold doses until improvement to Grade ≤ 1 
. Resume at next lower dose level for all drugs 
 
Decision guidelines for chemotherapy (Gemcitabine and nab-Paclitaxel) 
Day 1 of each Cycle: 
If patient does not meet above day 1 criteria, treatment will be delayed in one week intervals 
until recovery. Day 1 can be delayed for a maximum of 4 weeks.  
If Day 1 of any cycle is delayed by more than 14 days (with no Day 8 or Day 15 reductions), 
future Day 1 doses will be decreased by 1 level for future cycles.  
If Day 1 of any cycle is delayed and the prior cycle Day 8 or Day 15 doses required dose 
reduction, then the dose for that Cycle Day 1 will be reduced by 1 dose level.   
If the dose for Day 8 or Day 15 of the previous cycle was reduced and the day 1 of current 
cycle has not been delayed, then prescribe the same dose on Day 1 of the current cycle as 
was administered on day 1 of the previous cycle. 
 
6.6 MANAGEMENT OF ADVERSE EVENTS 
• 
Diarrhea 
• 
Nausea and vomiting 
• 
Liver enzyme elevations  
• 
Other non-hematological or hematological adverse reaction 
 


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un 
      Table 10: Recommended dose adjustments for Nintedanib 
 
CTCAE* Adverse reaction 
Dose adjustment 
    Diarrhea ≥ grade 2 for more than 7 
consecutive days despite anti-diarrheal 
treatment**   
   OR 
   diarrhea ≥ grade 3 
   despite anti-diarrheal treatment** 
For dose level starting at 200 mg twice 
daily: 
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  
 
For dose level starting at 150 mg twice daily: 
 
1st episode 
Reduce dose from 150 mg twice daily to  
100 mg twice daily 
 
2nd 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-hematological or hematological 
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: Common Terminology Criteria for Adverse Events 
  
** see also section 6.8. Additional precautions  
6.7 
PERMANENT DISCONTINUATION TREATMENT WITH NINTEDANIB 
Patients should PERMANENTLY discontinue treatment with nintedanib in the event of: 
• Intolerable Adverse Events (CTCAE grade 3 or 4) that cannot be managed by best supportive 
care and dose reduction. 
6.8 
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 the clinical trial LUME-Lung 1. The 
majority of patients had mild to moderate diarrhea. 6.3 % of the patients had diarrhea of grade 


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≥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. 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 patients treated with 
nintedanib in combination with docetaxel as compared to treatment with docetaxel alone in the 
clinical trial LUME-Lung 1. Subsequent complications such as sepsis or febrile neutropenia 
have been observed. 
 
Blood counts should be monitored during therapy, if nintedanib 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 bilirubin levels are recommended 
to be closely monitored after start of therapy with nintedanib (periodically, i.e. in the 
combination phase with chemotherapy at the beginning of each treatment cycle).  
 
If relevant liver enzyme elevations are measured, interruption, dose reduction or 
discontinuation of the therapy with nintedanib may be required. 
 
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. 


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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. 
 Rescue medication and additional treatments 
Rescue medication to reverse the actions of nintedanib is not available. Potential side 
effects of nintedanib have to be treated symptomatically. 
6.9 CONCURRENT CANCER TREATMENTS RESTRICTIONS 
- Additional chemo-, immuno-, hormone- or radiotherapies are not allowed during the active 
treatment period of this trial.  
- Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases 
in extremities after discussion with the Principle Investigator, provided that the radiotherapy does 
not affect target lesions, and the reason for the radiotherapy does not reflect progressive disease. 
 
Combined inducers of CYP3A4 and P-gp should be avoided. Drugs that are combined inhibitors of 
CYP3A4 and P-glycoprotein (i.e. both a moderate or strong inhibitor of CYP3A4 and an inhibitor of P-
glycoprotein) should be used with caution. Drugs that are inducers of CYP3A4 and P-glycoprotein 
recognized as both a moderate-to-strong inducer of CYP3A4 and an inducer of P-glycoprotein should be 
avoided (may decrease nintedanib exposure.) 
 
7.0 
STUDY EVENTS 
7.1 Screening Assessments  
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
All screening procedures must be performed within 21 days prior to registration unless 
otherwise stated. The screening procedures include: 
• 
Informed Consent 
• 
Medical history 


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• 
Demographics 
• 
Inclusion/Exclusion criteria 
• 
Concomitant Medications assessment 
• 
Physical Exam (PE)  
• 
Height and weight 
• 
ECOG Performance Status (PS) 
• 
Vital Signs (blood pressure, pulse, temperature, respirations) 
• 
Hematology including Hemoglobin, Platelets, WBC, ANC  
• 
Comprehensive Metabolic Panel including Albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, total bilirubin, and total protein 
• 
Other labs:  LDH and uric acid 
• 
Serum pregnancy test (WOCBP)  
• 
Coagulation including PT/INR, PTT  
• 
Urinalysis  
• 
RECIST Tumor assessment  
• 
CT or MRI of chest, abdomen, and pelvis 
• 
DCE-MRI for correlative studies 
• 
ECG  
• 
Blood draw for correlative studies  
• 
Biopsy tissue for correlative studies(If archival tissue is available a fresh biopsy will not be 
needed) 
• 
PROMIS QOL Assessment 
 
 
Performed within 14 days prior to registration:  
• 
Hematology including Hemoglobin, Platelets, WBC, ANC  
• 
Comprehensive Metabolic Panel including Albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, total bilirubin, and total protein 
• 
Other labs:  LDH and uric acid 
• 
Urinalysis 
• 
Serum pregnancy test (WOCBP)  
• 
Coagulation including PT/INR, PTT 
• 
Height and weight  
• 
Completion of Inclusion/ Exclusion checklist  
7.2 On-Study Treatment Assessments  
 
7.2.1 Monotherapy (Cycle 1, Days 1-14) 
Cycle 1, Day 1 
• 
Vital Signs 
• 
PE and History  
• 
Weight 
• 
ECOG PS 
• 
AE Assessment 
• 
ConMeds Assessment 
• 
Review criteria for initiation of nintedanib (section 6.1) 


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• 
Hematology,  
• 
Comprehensive Metabolic Panel  
• 
LDH  
• 
Uric Acid 
• 
 PT/INR  
• 
CA19-9 
• 
Provide Patient Diary 
• 
Start oral Nintedanib Monotherapy 
• 
PROMIS QOL Assessment (if needed) 
• 
Blood draw for correlative studies (if not done during screening) 
Cycle 1, Day 8 (+/- 3) 
• 
Vital Signs 
• 
Symptom-directed PE (as clinically indicated) 
• 
Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid 
• 
Confirm Nintedanib Monotherapy 
• 
AE Assessment 
• 
ConMeds Assessment 
 
Cycle 1, Day 10-14 
• 
AE Assessment 
• 
Conmed Assessment 
• 
Symptom-directed PE (as clinically indicated)  
• 
DCE-MRI for correlative studies (all efforts will be made to perform MRI before starting 
‘Combination Therapy and Chemotherapy’ phase) 
• 
Blood draw for correlative studies 
• 
End Nintedanib Monotherapy (Day 14) 
7.2.2 Combination Therapy 
 
  Cycle 2, Day 1 (Study Day 15)  
• 
Vital Signs 
• 
PE and History  
• 
Weight 
• 
ECOG PS  
• 
PROMIS QOL Assessment 
• 
AE Assessment  
• 
ConMeds Assessment 
• 
Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid, PT/INR CA 19-9 
• 
Collect and review Patient Diary from previous cycle for AE’s and drug compliance 
• 
Provide new Patient Diary for nintedanib 
• 
Begin Nintedanib Combination Therapy – NOTE: Nintedanib will NOT be administered on 
chemotherapy days 1, 8, and 15 of the 28 day cycle 
• 
Gemcitabine/nab-Paclitaxel Administration 
• 
Blood draw for correlative studies 
Cycle 2 Day 8 (+/- 3) 
• 
Vital Signs 
• 
Symptom-directed PE (as clinically indicated) 
• 
AE Assessment  


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• 
ConMeds Assessment 
• 
DLT Evaluation 
• 
Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid  
• 
Nintedanib Combination Therapy - NOTE: Nintedanib will NOT be administered on 
chemotherapy days 1, 8, and 15 of the 28 day cycle 
• 
Gemcitabine/nab-Paclitaxel Administration 
Cycle 2 Day 15 (+/- 3) 
• 
Vital Signs 
• 
Symptom-directed PE (as clinically indicated) 
• 
AE Assessment  
• 
ConMeds Assessment 
• 
DLT Evaluation 
• 
Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid 
• 
Nintedanib Combination Therapy - NOTE: Nintedanib will NOT be administered on 
chemotherapy days 1, 8, and 15 of the 28 day cycle;  
• 
Gemcitabine/nab-Paclitaxel Administration 
Cycle 2, Day 22-28 
• 
Chemo Holiday from Gemcitabine + nab-Paclitaxel 
• 
Nintedanib Combination Therapy 
• 
DLT Evaluation 
• 
AE Assessment  
Cycles 3+, Day 1 (+/- 3) 
•    Vital Signs 
•    PE and History  
•  Weight 
• 
ECOG PS  
• 
PROMS QOL Assessment 
•    AE Assessment  
•    ConMeds Assessment 
•    Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid, -PT/INR  
•  CA19-9 (after cycle 3 performed on odd cycles only) 
• Urinalysis 
•  Safety Assessment Form after cycle 2 (Appendix D) – only required on cycle 3 day 1 
•    Collect and review Patient Diary from previous cycle for AE’s and drug compliance 
• Provide new Patient Diary for Nintedanib Combination Therapy – NOTE: Nintedanib will 
NOT be administered on chemotherapy days 1, 8, and 15 of the 28 day cycle 
• Gemcitabine/nab-Paclitaxel Administration 
•  Blood draw for correlative studies 
Cycles 3+, Day 8 (+/- 3) 
• Vital Signs 
• Symptom-directed PE (as clinically indicated) 
• Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid 
•   Nintedanib Combination Therapy - NOTE: Nintedanib will NOT be administered on 
chemotherapy days 1, 8, and 15 of the 28 day cycle;  
• Gemcitabine/nab-Paclitaxel Administration 


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• AE Assessment 
• ConMeds Assessment 
Cycles 3+, Day 15 (+/- 3) 
• 
Vital Signs 
• 
Symptom-directed PE (as clinically indicated) 
• 
Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid  
•   Nintedanib Combination Therapy - NOTE: Nintedanib will NOT be administered on 
chemotherapy days 1, 8, and 15 of the 28 day cycle;  
• 
Gemcitabine/nab-Paclitaxel Administration 
• 
AE Assessment 
• 
ConMeds Assessment  
 
Cycles 3+, Days 22-28 
• 
Chemo Holiday from Gemcitabine + nab-Paclitaxel 
• 
Nintedanib Combination Therapy 
• 
CT or MRI Chest/Abdomen/Pelvis (odd cycles only) 
• 
RECIST Tumor Assessment (odd cycles only) 
• 
AE Assessment 
7.2.3 End of Treatment Visit or Early-Withdrawal Visit (+/- 7) 
Cycle 9, Day 22-28 = ‘End of Treatment Visit’ or ‘Early-Withdrawal’ Visit 
• 
Vital signs 
• 
PE and History  
• 
ECOG PS 
• 
Weight 
•     PROMIS QOL Assessment  
• 
AE Assessment 
• 
Conmed Assessment 
• 
Hematology  
• 
Comprehensive Metabolic Panel  
• 
LDH 
• 
 uric acid 
• 
 PT/INR 
• 
Serum  Pregnancy (WOCBP only),  
• 
CA 19-9 
• 
Urinalysis 
• 
Blood work for correlative studies 
• 
CT or MRI Chest/Abdomen/Pelvis 
• 
RECIST Tumor Assessment 
• 
End nintedanib Combination Therapy 
• 
Collect and review Patient Diary for AE and patient compliance 
7.2.4 Follow-Up Visit  
Follow-up Visit (+/- 7) 
After completion of the ‘End of Treatment’ or ‘Early-Withdrawal’ visit, a Follow-Up Visit will 
be performed within 4 weeks. If there are unresolved AEs this visit will be repeated every 4 


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weeks until all AEs have resolved to ≤ grade 1 or baseline. The following procedures will be 
performed at this visit: 
• Vital Signs 
• PE and History  
• ECOG PS 
• Weight 
• AE Assessment 
• Conmed Assessment 
• Hematology, Comprehensive Metabolic Panel, LDH, Uric Acid, -PT/INR Urinalysis, 
CA19-9 
7.2.5 Survival Follow-Up 
Survival follow-up will be performed at the discretion of the study team and the investigator. 
Non-intrusive procedures will be performed such as reviewing the patient’s medical chart for 
survival status or placing a call to the patient or patient’s family to confirm survival status. 
The patient will be considered lost to follow-up after three attempts have been made to 
confirm survival status.  
7.2.6 Safety Laboratory Investigations 
 
Blood samples have to be collected at the specified time points as detailed in study table. 
Safety laboratory examinations will include hematology, Comprehensive Metabolic Panel, 
coagulation parameters.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The following parameters will be reviewed: 
 
 
 
 
 
 
 
 
 
 
 
  
*
i
n
 
c
a
s
e
 
o
f
 
e
l
evated bilirubin, please provide direct and indirect bilirubin levels 
Hematology 
Comprehensive 
Metabolic Panel 
Other Labs 
Coagulation 
Tumor Markers 
• Hemoglobin 
• Glucose 
• LDH 
• PT/INR 
• CA19-9 
• WBC 
• Sodium 
• Uric Acid 
• aPTT 
 
• ANC 
• Calcium 
 
 
 
• Platelets 
• Potassium 
• Chloride 
• Bicarbonate (CO2) 
• Creatinine 
• Albumin 
• Aspartate Amino 
transferase (AST) 
 
 
 
 
• Alanine Amino 
Transferase (ALT) 
 
 
 
 
• Alkaline 
Phosphatase (ALK) 
 
 
 
 
• Bilirubin* 
 
 
 
 
• BUN 
 
 
 
 
• Total protein 
 
 
 


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7.3 Study Calendar: 
Study 
Procedures 
Screening  
(-21 
Days) 
Screening 
(-14 
Days) 
Monotherapy 
Nintedanib 
Combined Therapy 
Nintedanib with Gem + nab-Paclitaxel 
Follow 
- Up 
±7 
Survival 
Cycles 
 
Cycle 1 
Cycle 2 
Subsequent  
Cycles 3, 4, 5 …9 
End of 
Tx Visit 
or ET 
±7 
Study Days 
1 
8 
±3 
10-14 
1 
8 
±3 
15 
±3 
22-28 
1 
±3 
8 
±
3 
15 
±3 
22-28 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of I/E 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completion of 
Inclusion/ Exclusion 
checklist (Appendix D) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review criteria for 
Nintedanib initiation  
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
PE and History  
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Weight and Height a 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Symptom-Driven 
PE (as clinically 
indicated) 
 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
 
 
 


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ECOG Performance 
Status 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
DLT Evaluation 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Safety Assesment – 
End of Cycle 2 
(Appendix E) 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
 
AE Assessment  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Conmed 
Assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Blood for correlative 
studies (Research) 
X 
 
Xd 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
Biopsy for 
correlative studies  
(Research) 
X*& 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DCE-MRI 
(Research) 
X 
 
 
 
X% 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI 
Chest/Abdomen/Pel
vis  
X 
 
 
 
 
 
 
 
 
 
 
 
X$ 
X 
 
 
Disease 
Assessment per 
RECIST 1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
X$ 
X 
 
 
CA 19-9 
 X 
 
X 
 
 
X 
 
 
 
Xf 
 
 
 
X 
X 
 
CBC with 
differential  
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 


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42 
 
Comprehensive 
Metabolic Panel  
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
LDH, Uric Acid 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
PTT 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
X 
X  
 
X  
 
 
X 
 
 
 
X 
X 
 
Serum Pregnancy 
(WOCBP) Only 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Proteinuria 
assessment g 
X 
 
X 
 
 
 
 
 
 
Xf,g 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nintedanib (Study 
Drug)@ 
 
 
 
 
 
 
Gemcitabine+nab-
Paclitaxel 
 
 
 
 
 
X 
X 
X  
X 
X 
X  
 
 
 
Review of Patient’s 
Chart OR Phone 
call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PROMIS QOL 
Assessment 
X# 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
Review of  
Patient Study Drug 
Diary 
 
 
Xb 
X 
 
Xb 
 
 
 
Xb 
 
 
 
X 
 
 
$ 
Scan at end of cycle 3 then every 2 cycles 


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* 
Archival biopsy tissue 
& 
At baseline, if archival tissue is available, a fresh biopsy will not be needed. 
% 
All efforts will be made to perform MRI before starting ‘Combination Therapy and Chemotherapy’ phase. Fail to perform DCE-
 
MRI would not affect continuous treatments.  
# 
PROMIS QOL can also be completed prior to initial treatments on cycle 1 day 1.  
$  
CT or MRI chest/abdomen/pelvis need to be done at the end of cycle 3 and every two cycles thereafter. 
@  tPatient should not take Nintedanib (study drug) on days 1, 8 and 15 (days of IV chemo) of the combination chemotherapy cycle.  
a. 
height only at screening/baseline 
b. 
collect previous cycles completed drug diary provide a new patient drug diary and (except cycle 1 day 1) 
c. 
refer to section 6.1 
d. 
if not completed during screening 
e. 
complete the form after 28 days of treatment  
f. 
perform at cycle 3 then at odd cycles  
g. 
must be ≤ grade 2 
 
 


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8.0 MEASUREMENT OF EFFECT 
8.1 Antitumor Effect- Solid Tumors  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. 
8.1.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with study drug. 
Evaluable for objective response: Only those patients who have measurable disease 
present at baseline, have received at least one cycle of combination therapy, and have had 
their disease re-evaluated will be considered evaluable for response. These patients will 
have their response classified according to the definitions stated below. (Note: Patients who 
exhibit objective disease progression prior to the end of cycle 2 will also be considered 
evaluable.) 
8.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter 
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 6 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  


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8.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 21 days before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
For timing of imaging, refer to section 7.3. Other procedures/imaging will be done per 
discretion of the MD. 
 
  
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less. As is described in RECIST v1.1, when CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations 
(e.g. for body scans). More details concerning the use of both CT and MRI for 
assessment of objective tumor response evaluation are provided in RECIST v1.1. 
8.1.4 Response Criteria 
8.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two 
separate observations conducted not less than 4 weeks apart. There can be no 
appearance of new lesions. Any pathologic lymph nodes must have reduction in short 
axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameters 
(LD) of target lesions, taking as reference the baseline sum diameters LD. There can 
be no appearance of new lesions. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters LD 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). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD diameters since 
the treatment started. 
8.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. 


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Incomplete Response/Stable Disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
8.1.4.3 Evaluation of Best Overall Response 
  
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall Response 
Best Response for 
this Category Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least 
once >4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or 
CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 


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Note: If patients respond to treatment and are able to have their disease resected, the patient’s 
response will be assessed prior to the surgery. 
8.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
  8.1.6 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression. 
 8.1.7 Safety / Tolerability 
 
      Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.0 for reporting of non-hematologic adverse 
events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic 
adverse events. 
 
9.0  
Adverse Events 
9.1  Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
 
9.2  Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. Additionally, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring of subject safety and 
care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study therapy, 
will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  


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48 
 
➢ any abnormal laboratory values have returned to baseline;  
➢ there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
➢ death. 
 
9.2.1 Definition  
Adverse Events will be reported as indicated by the appropriate following table (see 
below).    
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE will be 
scored on the Adverse Event log according to the general guidelines provided by the NCI 
CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 


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adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study. 
9.2.2 Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include any 
incident, experience, or outcome that meets each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely or probably related to participation in the research AND  
• 
Serious or a possible unexpected problem in that the research places subjects or 
others at greater risk of harm than was previously known or recognized. Note: Any serious 
adverse event would always suggest a greater risk of harm. 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
9.2.3 Reporting 
The UTSW IRB requires reporting of all UPIRSOs according to the guidance below. For 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. All SAEs occurring during the protocol-specified 
monitoring period should be submitted to the UTSW study team within 2 business days of 
the center learning of the event. 
 
9.2.3.1 UPIRSOs occurring on the study require expedited reporting, and are submitted to 
the UTSW IRB through the UTSW eIRB by the UTSW study team and to the SCCC 
DSMC Coordinator.  Hardcopies or electronic versions of the eIRB report; FDA Form 
#3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the UTSW study team and will be 
forwarded to the DSMC Coordinator.  The DSMC Coordinator forwards the 
information onto the DSMC Chairman who determines if immediate action is 
required.  Follow-up eIRB reports, and all subsequent SAE documentation that is 
available are also submitted to the DSMC Chair who determines if further action is 
required. (See Appendix IV of the SCCC DSMC Plan for a template Serious Adverse 
Event Form which may be utilized when a sponsor form is unavailable and SAE 
submission to the eIRB is not required). 
  
All serious adverse events which occur on research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. Hardcopies or electronic versions of the FDA Form #3500A forms, or 
other sponsor forms, if applicable; and/or any other supporting documentation available 
should be forwarded to the DSMC Coordinator.   
 
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 


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Cancer Center, the DOT Manager or lead coordinator ensures that all participating sites 
are notified of the event and resulting action, according to FDA guidance for expedited 
reporting. DSMC Chairperson reviews all serious adverse events upon receipt from the 
DSMC Coordinator.  The DSMC Chairperson determines whether action is required and 
either takes action immediately, convenes a special DSMC session (physical or 
electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
Telephone reports to: 
Investigator:  Dr. Salwan Al Mutar 
                       214-648-4008 
 
 
Written reports to: 
Investigator:  Dr. Salwan Al Mutar  
                        c/o Phase 1 Manager 
                        5323 Harry Hines Blvd., NB2.402 
                        214-648-1578 (fax) 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
 
SAE reporting to Boehringer Ingelheim (BI) Pharmaceutical, Inc. 
 
The investigator/Lead coordinator shall report all SAEs and non-serious AEs, which are 
relevant to a reported SAE, by fax using BI IIS SAE form to BI Unique Entry Point as detailed 
below in accordance with the following timelines:  
 
• Within five (5) calendar days upon receipt of initial and follow-up SAEs containing at  
 
    least one fatal or immediately life-threatening event;  
 
• Within ten (10) calendar days upon receipt of any other initial and follow-up SAEs.  
 
 
 
 
Boehringer Inglehiem Pharmaceuticals, Inc 
 
 
900 Ridgebury Road 
 
 
Ridgefield, CT  06877 
 
 
Fax: 1-203-837-4329 
 
 
 
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the clinical trial (including any protocol specified 
follow-up period), it should be reported to BI if investigator considers it as relevant to the BI 
study drug.  
1. 
SAEs 
Serious adverse events (SAEs) for studies where the SCCC DSMC is the DSMC of record 
 


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require reporting to the DSMC coordinator within 2 working days of PI awareness, or as 
described in the protocol.   
2. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
Local Serious Adverse Event UPIRSOs require reporting to the UTSW IRB within 48 
hours of PI awareness of the event (life threatening or fatal events experienced by 
subjects enrolled by the investigator(s) under UTSW IRB jurisdiction).   
Local UPIRSOs (non-serious events experienced by subjects enrolled by the 
investigator(s) under UTSW IRB jurisdiction) require reporting to the UTSW IRB within 5 
business days of PI awareness of the event. 
External UPIRSOs including those that occur as non-local events require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs 
and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM227351.pdf 
9.3      Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 
attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: 
Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
the current known adverse events listed in the Agent Information Section 
of this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
 


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9.4 
Adverse Events and Laboratory Values of Special Interest 
The following events are considered as Protocol-specified adverse events of special 
interests (AESI): 
 
Any gastrointestinal- and non-gastrointestinal perforation, leakage, fistula formation, 
abscess 
 
In such case the following additional information need to be collected, documented in the 
respective comment field of the CRF page and the respective narratives of the SAE.  
That has to be forwarded to Boehringer Ingelheim: 
• 
Location of perforation, leakage, fistula, abscess 
• 
Location/extent of abdominal tumor manifestations, 
• 
Imaging & reports (CT, ultrasound, endoscopy, pathology, etc.) 
• 
Prior surgery (location, wound healing complications) 
• 
Concomitant diseases with GI involvement (e.g., M Crohn, vasculitis, tuberculosis,  
diverticulitis) 
• 
Thromboembolic events (or predisposition) 
 
Drug-induced liver injury is under constant surveillance by sponsors and regulators and is 
considered a protocol-specified adverse event of special interest (AESI). Timely detection, 
evaluation, and follow-up of laboratory alterations of selected liver laboratory parameters to 
distinguish an effect of the investigational drug from other causes are important for patient 
safety and for the medical and scientific interpretation of the finding. The following are 
considered as protocol-specified AESI: 
 
• 
An elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in the 
same blood draw sample 
• 
An elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of 
bilirubin to >1.5 fold ULN measured in the same blood draw sample 
 
Patients showing above laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met.  
 
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. 
9.5  DOSE LIMITING TOXICITY (DLT) FOR PHASE I TRIALS OF NINTEDANIB 
Dose limiting toxicity (DLT):  
DLT will be defined by the occurrence of any of the following toxicities possibly or probably 
related to drug during cycle 2 (combination phase) only as defined by CTCAE version 4.03 
(Adverse events occurring during the monotherapy period (cycle 1) will not be considered 
DLT) 
a) Any drug related grade 3 or grade 4 non-hematological toxicity, except alopecia, or 
asymptomatic elevation of hepatic transaminases thought to be secondary to gemcitabine or 
as defined below. 


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Grade ≥ 3 diarrhea, vomiting, or nausea that persists for > 3 days despite optimal 
supportive care. 
b)  Hematological toxicity 
- 
CTCAE Grade 4 neutropenia that is uncomplicated (not associated with fever 
≥38.5°C) only if continuing for > 7 Days 
- 
CTCAE Grade 4 febrile neutropenia of any duration if associated with fever ≥  
38.5ºC 
- 
Platelet decrease to CTCAE Grade 4, or decrease to CTCAE grade 3 associated 
with bleeding or requiring transfusions. 
      c) Nintedanib related liver toxicity except GGT*** as specified below: 
  
AST/ALT > 5x ULN*  independent of  bilirubin  
AST/ALT > 2.5 x ULN together with total bilirubin > 1.5 ULN 
 
*** isolated GGT elevation with no corresponding ALT/AST increase will not be considered as DLT 
 
d) Missing two consecutive weekly doses of gemcitabine and nab-paclitaxel because of       
unresolved toxicity.  
e) Any other toxicity possibly or probably related to treatment in the view of the 
investigator that represents a clinically significant hazard to the patient. 
f) Inability to resume nintedanib dosing within 14 days of stopping due to treatment 
related toxicity 
• 
In case adverse events with CTCAE Grade 3/4 were not judged as DLT from a clinical 
point of view, Boehringer Ingelheim may obtain a confirmation from the investigator 
regarding the appropriateness of the judgment.  
• 
Adaptations should be considered according to the combination to be investigated and the 
respective adverse event profiles of the combinations partners 
 
Maximum tolerated dose (MTD):  
MTD will be determined by: 
• 
If a dose limiting toxicity (DLT) is observed in 1 out of 3 patients at a given dose level, up 
 
to 3 additional patients will be enrolled and treated at that dose level. 
• 
If 2 out of 3-6 patients at that dose level have DLTs, the dose will be decreased to the 
previous dose level, and up to 3 additional patients will be enrolled at that dose level for a 
total of 6 patients. 
• 
When up to 3 additional patients are added to a given dose level, if 0-1 of 6 patients has a 
DLT then the dose will be recommended as MTD. 
 
9.6 Safety Assessment Form 
The Safety Assessment: End of Cycle 2 form (Appendix D) must be completed and provided 
to the phase 1 manager either via fax to the  attention the Phase 1 Operations Manager or 
Designee at 214-648-1578. This form will be reviewed by the Principal Investigator then 


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submitted to the DSMC for review and approval for dose escalation. Allow at least 48 hours for 
the cycle 2 safety assessment review process and once approval to proceed to the next dose 
level has been received, an email notification from the Phase 1 Operations Manager or Designee 
will be sent.  
9.7 Stopping Rules 
In the absence of progressive disease or unacceptable toxicity, therapy will continue for 9 
cycles. At this stage continuing study drug and chemotherapy will be based on treating 
physician/PI discretion. 
10.0 PHARMACEUTICAL INFORMATION  
10.1  Nintedanib (Study Drug) 
 
Pharmaceutical form  
 
 
Soft gelatin capsule 
 
Pharmaceutical code  
 
 
Nintedanib 
 
Source: 
 
 
 
 
Boehringer-Ingelheim Pharma GmbH & Co. KG 
 
Unit Strength  
 
 
 
100 mg and 150 mg capsules 
 
Daily Dose: 
 
 
 
 
300 mg or 400 mg (150 mg or 200 twice daily), dose  
 
 
 
 
 
 
reduction according to Section 5 
 
Duration of Use: 
 
 
 
Continuous daily dosing until progression of  
 
 
 
disease or until criteria for interruption of treatment 
 
 
 
(section 6) are met, no intake of nintedanib on days 
 
 
 
of chemotherapy administration. The maximum  
 
 
 
planned time on treatment will be 34 weeks. 
 
Route of Administration 
 
 
Oral. 
 
Posology 
 
 
Twice daily (to be swallowed unchewed with a  
 
 
 
glass of water of about 250 mL with a dose interval  
 
 
 
of around 12 hours at the same times every day, 
 
 
 
ususally in the morning and the evening after food 
 
 
 
intake).  
 
 
< Very common (equal or more than 10%) risks and adverse drug reactions may include: 
o 
diarrhea 
o 
nausea 
o 
vomiting 
o 
increased liver function tests (blood tests that show the liver is not working the way it 
 
should) 
o 
tiredness 
o 
decreased appetite 
o 
low white blood cell count (which can make it easier to catch an infection) 


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o 
Pain e.g., abdominal pain, muscle cramps, chest pain, back pain, tumor pain…  
o 
skin problems such as: itching, rash, hair loss, dry skin, hand foot syndrome, nail disorder 
o 
electrolyte imbalance 
o 
abnormal skin sensations 
o 
bleeding e.g. epistaxis, coughing up small amounts of blood, rectal bleeding  
o 
mouth ulceration 
 
Common (equal or above 1% but below 10%) risks and adverse drug reactions may 
include:  
o 
taste changes 
o 
constipation 
o 
fever  
o 
anemia (low level of hemoglobin in your blood) 
o 
high blood pressure 
o 
decrease in weight 
o 
headache 
o 
infections including those in the urine, chest and sinuses 
o 
dry mouth,  
o 
flatulence (gas) 
o 
dizziness  
o 
dehydration 
o 
insomnia 
o 
blood clots in vein (venous thromboembolism) or in arteries (arterial 
 
thromboembolism including myocardial infarct) 
o 
Low blood platelet count which increases the risk of bruising and bleeding 
 
Uncommon (less than 1%):  
o 
cough 
o 
chills 
o 
vertigo 
o 
low blood pressure 
o 
eye disorders, such as eye dryness, eye redness, conjunctivitis, vison blurred 
o 
drug hypersensitivity  
o 
skin swelling 
o 
abnormal heart beats, fast or slow heart beats 
o 
low blood sugar   
o 
changes in kidney function 
o 
perforation (holes in the bowels) 
o 
bleeding into the brain 
o 
underfunction of the thyroid 
o 
pancreatitis (swelling and inflammation of the pancreas) 
 
 
10.2 Gemcitabine and nab-paclitaxel are commercially available 
10.2.1  Agent: Gemcitabine: 
Brand Name (U.S.):  
 
 
Gemzar® (Gemcitabine) 
 
Source: 
 
 
 
 
Eli Lilly and Company; Gemcitabine Package Insert 


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Duration of Use: 
Pancreatic Cancer: Recommended Dose and  
 
Schedule The recommended dose of Gemzar® 
(Gemcitabine) is 1000 mg/m2 over 30 minutes 
intravenously. The recommended treatment 
schedule is as follows:  
 
**Weeks 1-8: weekly dosing for the first 7 weeks 
followed by one week rest. 
 
**After week 8: weekly dosing on Days 1, 8, and 15 
of 28-day cycles. 
 
Route of Administration: 
 
 
Intravenous 
 
Preparation for Intravenous 
Infusion Administration: 
 
 
Reconstitute the vials with 0.9% Sodium Chloride 
 
 
 
 
 
 
Injection without preservatives.  
 
Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. 
These dilutions each yield a Gemzar® concentration 
of 38 mg/mL. Complete withdrawal of the vial 
contents will provide 200 mg or 1 g of Gemzar®. 
Prior to administration the appropriate amount of 
drug must be diluted with 0.9% Sodium Chloride 
Injection. Final concentrations may be as low as 0.1 
mg/mL  
 
Reconstituted Gemzar® is a clear, colorless to light 
straw-colored solution. Inspect visually prior to 
administration and discard for particulate matter or 
discoloration. Gemzar® solutions are stable for 24 
hours at controlled room temperature of 20° to 25°C 
(68°to 77°F).  
 
 
 
 
Do not refrigerate as crystallization can occur. 
 
Adverse Reactions Significant  
Frequency of adverse reactions reported for single-agent use of gemcitabine only. 
>10%: 
Cardiovascular: Peripheral edema (20%), edema (13%) 
Central nervous system: Fever (38% to 41%), somnolence (11%) 
Dermatologic: Rash (28% to 30%), alopecia (15% to 16%), pruritus (13%) 
Gastrointestinal: Nausea/vomiting (69% to 71%; grade 3: 10% to 13%; grade 4: 1% to 2%), 
diarrhea (19% to 30%), stomatitis (10% to 11%) 


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Hematologic: Anemia (68% to 73%; grade 4: 1% to 2%), leukopenia (62% to 64%; grade 4: 
≤1%), neutropenia (61% to 63%; grade 4: 6% to 7%), thrombocytopenia (24% to 36%; grade 
4: ≤1%), hemorrhage (4% to 17%; grades 3: ≤2%; grade 4: <1%); myelosuppression is the 
dose-limiting toxicity 
Hepatic: AST increased (67% to 78%; grade 3: 6% to 12%; grade 4: 2% to 5%), alkaline 
phosphatase increased (55% to 77%; grade 3: 7% to 16%; grade 4: 2% to 4%), ALT 
increased (68% to 72%; grade 3: 8% to 10%; grade 4: 1% to 2%), bilirubin increased (13% to 
26%; grade 3: 2% to 6%; grade 4: ≤2%) 
Renal: Proteinuria (32% to 45%; grades 3/4: <1%), hematuria (23% to 35%; grades 3/4: 
<1%), BUN increased (15% to 16%) 
Respiratory: Dyspnea (10% to 23%) 
Miscellaneous: Flu-like syndrome (19%), infection (10% to 16%; grade 3: 1% to 2%; grade 4: 
<1%) 
1% to 10%: 
Local: Injection site reactions (4%) 
Neuromuscular & skeletal: Paresthesia (10%) 
Renal: Creatinine increased (6% to 8%) 
Respiratory: Bronchospasm (<2%) 
<1% (Limited to important or life-threatening; reported with single-agent use or with 
combination therapy): Acute/adult respiratory distress syndrome, anaphylactoid reaction, 
arrhythmias, bullous skin eruptions, cellulitis, cerebrovascular accident, CHF, desquamation, 
fulminant hepatic failure, gangrene, GGT increased, hemolytic uremic syndrome (HUS), 
hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive liver disease), hepatotoxicity 
(rare), hyper-/hypotension, interstitial pneumonitis, liver failure, MI, neuropathy, peripheral 
vasculitis, petechiae, pulmonary edema, pulmonary fibrosis, radiation recall, renal failure, 
respiratory failure, reversible posterior leukoencephalopathy syndrome (RPLS), sepsis, 
supraventricular arrhythmia, thrombotic thrombocytopenic purpura 
Contraindications  
Hypersensitivity to gemcitabine or any component of the formulation 
Warnings/Precautions: 
Concerns related to adverse effects: 
• Bone marrow suppression: May cause bone marrow suppression (leukopenia, 
thrombocytopenia, and anemia); myelosuppression is generally the dose-limiting toxicity. 
Monitor blood counts; dosage adjustments are frequently required. 
• Fever: May cause fever in the absence of clinical infection. 
• Hemolytic uremic syndrome: Hemolytic uremic syndrome (and/or renal failure) has been 
reported; monitor for evidence of microangiopathic hemolysis (elevation of bilirubin or LDH, 
reticulocytosis, severe thrombocytopenia, and/or renal failure). 


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• Hepatotoxicity: Serious hepatotoxicity (including liver failure and death) has been reported 
(when alone or used in combination with other hepatotoxic medications); use with caution in 
patients with hepatic impairment (history of cirrhosis, hepatitis, or alcoholism) or in patients 
with hepatic metastases; may lead to exacerbation of hepatic impairment. Dose adjustments 
may be considered with elevated bilirubin. 
• Pulmonary toxicity: Pulmonary toxicity has been observed; discontinue if severe and institute 
supportive measures. 
Ethanol: Avoid ethanol (due to GI irritation). 
Pregnancy Risk Factor D  
 
10.2.2 Drug: Nab-paclitaxel (Abraxane) 
Paclitaxel (nanoparticle albumin bound): Drug information 
Brand Name: 
Abraxane® (Nab-paclitaxel) is supplied as a 
white to yellow, sterile, lyophilized powder for 
reconstitution with 20 mL of 0.9% Sodium 
Chloride Injection, UPS prior to intravenous 
infusion. 
 
Source: 
Abraxane® is a registered trademark of Abraxis 
BioScience, LLC, manufactured for Celgene 
Corporation – Package Insert. 
 
Dosing: 
The recommended dose of Abraxane® is 125 
mg/m2 administered as an intravenous infusion 
over 30-40 minutes on Days 1, 8 and 15 of each 
28-day cycle. Administer gemcitabine 
immediately after Abraxane on days 1, 8, and 15 
of each 28-day cycle. 
 
Route of Administration:  
 
     Intravenous 
Preparation for Intravenous Infusion Administration:  
 
1.   Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, 
USP.  
2.   Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 
minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE 
VIAL.  
3.   DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized 
cake as this will result in foaming.  
4.   Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure 
proper wetting of the lyophilized cake/powder.  


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5.   Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of 
any cake/powder occurs. Avoid generation of foam.  
6.   If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. 
 
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. Calculate the exact 
total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = 
Total dose (mg)/5 (mg/mL).  
The reconstituted suspension should be milky and homogenous without visible particulates. If 
particulates or settling are visible, the vial should be gently inverted again to ensure complete 
resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. 
Discard any unused portion.  
Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile intravenous 
bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. 
The use of specialized DEHP-free solution containers or administration sets is not necessary 
to prepare or administer ABRAXANE infusions. The use of an in-line filter is not 
recommended.  
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration whenever solution and container permit.  
Stability  
Unopened vials of ABRAXANE are stable until the date indicated on the package when stored 
between 20ºC to 25ºC (68ºF to 77ºF) in the original package. Neither freezing nor 
refrigeration adversely affects the stability of the product.  
Stability of Reconstituted Suspension in the Vial  
Reconstituted ABRAXANE in the vial should be used immediately, but may be refrigerated at 
2ºC to 8ºC (36ºF to 46ºF) for a maximum of 8 hours if necessary. If not used immediately, 
each vial of reconstituted suspension should be replaced in the original carton to protect it 
from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the 
Infusion Bag The suspension for infusion when prepared as recommended in an infusion bag 
should be used immediately but may be stored at ambient temperature (approximately 25ºC) 
and lighting conditions for up to 4 hours. Discard any unused portion. 
 
ALERT: U.S. Boxed Warning  
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for 
a concise summary of this information. For verbatim wording of the boxed warning, consult 
the product labeling or www.fda.gov. 
Brand Names: U.S. Abraxane® 
Adverse Reactions Significant  


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Adverse reactions and incidences reported are associated with monotherapy unless 
otherwise stated. 
>10%: 
Cardiovascular: ECG abnormal (60%; 35% in patients with a normal baseline) 
Central nervous system: Fatigue (25% combination therapy for NSCLC) 
Dermatologic: Alopecia (56% [combination therapy for NSCLC] to 90%) 
Gastrointestinal: Nausea (27% to 30%; grades 3/4: 3%), diarrhea (15% to 27%; grades 3/4: 
<1%), vomiting (12% to 18%; grades 3/4: 4%), appetite decreased (17% combination therapy 
for NSCLC), constipation (16% combination therapy for NSCLC) 
Hematologic: Neutropenia (80%; grades 3/4: 34%; combination therapy for NSCLC: 85%; 
grades 3/4: 47%), anemia (33%; grades 3/4: 1%; combination therapy for NSCLC: 98%; 
grades 3/4: 28%), thrombocytopenia (2%; grades 3/4: <1%; combination therapy for NSCLC: 
68%; grades 3/4: 18%), myelosuppression (dose-related) 
Hepatic: AST increased (39%), alkaline phosphatase increased (36%), GGT increased 
(grades 3/4: 14%) 
Neuromuscular & skeletal: Sensory neuropathy (71%; grades 3/4: 10%; dose dependent; 
cumulative), weakness (47%; severe 8%; combination therapy for NSCLC: 16%), 
myalgia/arthralgia (44%; combination therapy for NSCLC: 10% to 13%) 
Ocular: Vision disturbance (13%; severe [keratitis, blurred vision]: 1%) 
Renal: Creatinine increased (11%; severe 1%) 
Respiratory: Dyspnea (12%) 
Miscellaneous: Infection (24%; primarily included oral candidiasis, respiratory tract infection, 
and pneumonia) 
1% to 10%: 
Cardiovascular: Edema /fluid retention (10%), peripheral edema (10% combination therapy 
for NSCLC), hypotension (5%), cardiovascular events (grades 3/4: 3%; included chest pain, 
cardiac arrest, supraventricular tachycardia, thrombosis, pulmonary thromboembolism, 
pulmonary emboli, and hypertension) 
Dermatologic: Rash (10% combination therapy NSCLC) 
Gastrointestinal: Mucositis (7%; grades 3/4: <1%) 
Hematologic: Bleeding (2%), neutropenic fever (2%) 
Hepatic: Bilirubin increased (7%) 
Neuromuscular & skeletal: Peripheral neuropathy (grade 3: 10%; combination therapy for 
NSCLC: 3%) 
Respiratory: Cough (7%), epistaxis (7% combination therapy for NSCLC) 


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Miscellaneous: Hypersensitivity reaction (4%, includes anaphylactic reactions, chest pain, 
dyspnea, flushing, hypotension; severe: <1%) 
<1% (Limited to important or life-threatening): Arrhythmia, autonomic neuropathy, 
bradycardia, cardiac ischemia, cerebrovascular attack, congestive heart failure, cranial nerve 
palsies, cystoid macular edema (transient), dehydration, embolism, hand-foot syndrome (in 
patients previously exposed to capecitabine), injection site reaction (mild), interstitial 
pneumonia, intestinal obstruction, intestinal perforation, ischemic colitis, left ventricular 
dysfunction, maculopapular rash, MI, motor neuropathy, optic nerve damage (rare), 
pancreatitis, 
pancytopenia, 
paralytic 
ileus, 
photosensitivity 
reaction, 
pneumonitis, 
pneumothorax, pulmonary embolism, radiation pneumonitis with concurrent radiation therapy, 
radiation recall, Stevens-Johnson syndrome, stroke, thrombosis, toxic epidermal necrolysis, 
transient ischemic attack, ventricular dysfunction, vocal cord paresis 
Adverse reactions reported with paclitaxel, which may occur with paclitaxel (protein bound): 
Cellulitis, conjunctivitis, extravasation recall, hepatic encephalopathy, hepatic necrosis, 
induration, lacrimation increased, lung fibrosis, neutropenic enterocolitis (typhlitis), optic nerve 
damage (persistent), phlebitis, pulmonary embolism, skin exfoliation, skin fibrosis, skin 
necrosis 
Pregnancy Risk Factor D  
 
11.0 CORRELATIVE STUDIES 
 
11.1 DCE-MRI 
We will utilize advanced imaging correlates including dynamic contrast enhanced Magnetic 
Resonance Imaging (DCE-MRI) which correlates with tumor grade and microvessel density 15. 
The DCE-MRI has been shown to positively correlate with the tumor MVD in multiple human 
cancer specimens 16-18. 
 
Another study demonstrated a significant correlation between histopathologic parameters 
including fibrosis content and MVD counts in focal lesions and nontumoral tissue and DCE 
MRI quantitative parameters derived from two pharmacokinetic models in pancreatic solid 
lesions and in nontumoral pancreatic tissue. The f and vi were positively correlated with MVD 
counts 19. DCE-MRI has also shown to predict early response to therapy in a pancreatic 
cancer preclinical models 20,21. Ktrans changes in the tumor on day 3 of therapy correlated 
with 21 day decrease in microvessel densitity20.  
 
Additionally, a clinical experience of DCE MRI demonstrated changes in Ktrans after 
treatment of pancreatic cancer with antiangiogenic therapy 22,23. Therefore, DCE-MRI is a 
feasible and relevant tool for detecting response to therapy in pancreatic cancer.  
 
Research MRI will be obtained before the monotherapy phase and prior to starting 
combination therapy.  
11.2 Pharmacodynamic Samples 
Approximately 16 mL of blood sample will be obtained from patients at each time point and 
analyzed for correlative studies. The timing of collections is indicated in the study calendar. 


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Assay methodology for correlative studies and the tested biomarkers will be determined by 
the investigators of the trial. Details of the blood processing procedures can be found in 
Appendix C.  
     11.3 Biopsies 
FNA or core biopsy of most accessible lesion as determined by physician will be performed 
by Gastroenterology or Interventional radiology as indicated on diagnosis. If archival tissue is 
available a fresh biopsy will not be needed prior to starting treatment in the monotherapy 
phase.  
 
11.4 Specimen Banking 
Patient samples collected for this study will be retained in storage areas designated by the 
study PI. Specimens will be stored indefinitely or until they are used up. If future use is 
denied or withdrawn by the patient, best efforts will be made to stop any additional studies 
and to destroy the specimens.  
 
PI and Co-I of this study will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of UT Southwestern Medical Center. 
Collaborators will be required to complete an agreement (a Material Transfer Agreement or 
recharge agreement) that states specimens will only be released for use in disclosed 
research. Any data obtained from the use of clinical specimen will be the property of UT 
Southwestern Medical Center for publication and any licensing agreement will be strictly 
adhered to.   
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the patient that 
there is the potential for financial gain by UT Southwestern Medical Center, the investigator 
or a collaborating researcher or entity.   
 
The following information obtained from the patient's medical record may be provided to 
research collaborators when specimens are made available:  
 
•     Diagnosis   
•     Collection time in relation to study treatment  
•     Clinical outcome – if available  
•     Demographic data 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 MTD Determination: 
The maximum tolerated dose (MTD) will be determined using a standard 3+3 phase I design. 
Three patients will be enrolled at the first dose level. If none of the first three patients 
experiences DLT, then the following three patients are enrolled at the next dose level 
(escalated). If one of three patients experiences DLT at a given dose level, three more 
patients are enrolled at the same dose level. If two or more patients experience DLT at a 
given dose level, no further escalation is allowed and MTD is determined to be the previous 
dose level. Six patients are to be enrolled at the highest attainable dose level even if no DLT 


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has been recorded. After MTD has been determined, no patient can be dose escalated 
beyond that dose level.  
Accrual will then continue at the MTD to complete a total of 20 patients on this study. 
If 2 or more patients experience a DLT at the first dose level, a lower (- l dose level) will be 
explored after discussion with the cohort review committee. 
 
12.2 Data Analysis Plans  
All patients receiving at least one dose of nintedanib will be considered evaluable for safety 
analysis, however only patients who received full dosing regimen of nintedanib in 
combination with gemcitabine+nab-paclitaxel will be considered evaluable for dose limiting 
toxicity (DLT). In addition to the evaluation and categorization of adverse events, listing of 
laboratory test results collected at baseline and during the study will be generated. 
Descriptive statistics summarizing the changes in those laboratory tests over time will be 
collected. 
Patients who have received at least 2 cycles of combination therapy and had at least one 
disease assessment following the initiation of therapy will be considered evaluable for 
response. The antitumor activity (RECIST) will be exploratory. 
The dose-limiting toxicity (DLT) and the maximum tolerable dosage (MTD) will be determined 
based on this Phase I design. The assessment of safety will be mainly based on the 
frequency of adverse effects. The incidence of AEs together with the 95% confidence interval 
will be reported. The overall complete response rate and corresponding 95% confidence 
interval will be presented. The rate from this trial will be compared with the rate for historical 
controls using Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) 
will be described using Kaplan-Meier curves with appropriate summary statistics. The PFS 
and OS from this trial will be compared with those for historical controls using a two-sided 
log-rank test. 
12.3 Imaging Correlates 
 The correlation between each DCE MRI parameter (Ktrans, Kep etc) and each RECIST 
response (PR, SD, PD, CR etc) will be quantified based on generalized linear regression 
model. We will conclude that there is a significant association if p-value<0.05. 
Measurements at Day 10-14 will be used to assess change in microvessel 
density/vasculature with monotherapy NINTEDANIB alone.  
The exploration of DCE MRI parameters at each designated point will enable detection of the 
most relevant marker which can, in turn, be used to design and power a larger follow up, 
clinical study.  
Sample size: 20. 
Preliminary data from Akisik et al22 evaluating DCE-MRI changes with antiangiogenic therapy 
in pancreatic cancer demonstrated a significant reduction in median K trans from 1.36 
mL/mL/ min (pretreatment) to 0.27 mL/mL/min (posttreatment) (p=0.02). Based on t-test for 
paired samples and preliminary data from previous study23, 20 patients will distinguish a one 


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standard error (0.023) difference in means of pre and post treatment Ktrans with 94% power 
at a one-sided 5% significance level. 
13.0 STUDY MANAGEMENT 
13.1 Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on 
Conflicts of Interest.  All investigators will follow the University conflict of interest policy. 
13.2 Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and protocol. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki. 
  
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local or 
state regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the 
study, the patient will be asked to give consent to participate in the study by signing an IRB 
approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient  and by the person who conducted the informed 
consent discussion. 
13.3 Required Documentation (For Multi-Site Studies)  
Before the study can be initiated at any site, the following documentation must be provided to 
the Simmons Cancer Center – Clinical Research Office: 
• A copy of the official IRB approval letter for the protocol and informed consent; 
• IRB membership list or Federal wide Assurance letter; 
• CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study; 
• PI signature on the protocol signature page; 
• A copy of the IRB approved consent form; 
• CAP and CLIA Laboratory certification numbers and institution lab normal values; 
• Executed clinical research agreement (CTA) 
13.4 Patient Recruitment 
Eligible study patients will be recruited, screened, enrolled, and treated at the following 
institutions: 


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1) University of Texas Southwestern Medical Center (UTSW):      
a. Harold C. Simmons Comprehensive Cancer Center; 
b. 
University Hospital – William Clements, Jr; 
c. 
University Hospital – Zale Lipshy;    
   
 
 
Study patients will be recruited from the practices of the researchers. Potentially eligible 
patients will be approached by their health care providers who can refer them to the study 
coordinator for screening. 
13.5 Registration Procedures  
13.5.1 Study Patient Identification Number 
All patients will be assigned a study number that is not linked to their personal 
identifiers to prevent loss of confidentiality. The number will be the Site Number, 01, 
02, etc. followed by a sequential number starting with number 001. For example, the 
first patient enrolled from site # 01 will be assigned study patient number 01-001; the 
next will be 01-002, and so forth. For this protocol, current sites are: 01 – UTSW, 02 – 
PHHS, 03 – UTHSCSA. Any additional sites added to this protocol will be numbered 
sequentially…04, 05, etc. This number will be assigned by the UTSW - Clinical 
Research Manager (CRM) or delegate upon confirmation of patient eligibility during 
the patient registration process.  
13.5.2 Patient Registration 
Following completion of baseline assessments and confirmation of patient eligibility, 
patients will be assigned a patient identification number by the UTSW - CRM or 
delegate and registered into Velos, the UTSW Clinical Trial Management System 
(CTMS). Patient registration will be confirmed (within 24 hours) once the following 
documents have been received by the UTSW-CRM or delegate.  
• 
Signed copy of the Informed Consent signature page; 
• 
Inclusion/Exclusion Checklist completed and signed by both the coordinator and 
treating physician;  
• 
Completed patient eligibility verification registration form  
• 
Source documentation (which includes, but not limited to, pathology, labs, 
progress notes, etc) that confirms all eligibility items on the inclusion-exclusion 
checklist has been met 
 
All patients must be registered with the UTSW - CRM before enrollment to study. To register 
a patient, fax the above supporting documents to: Phase 1 Operations Manager or Designee 
at 214-648-1578 or call 214-648-7007, Monday through Friday, 8:30a.m.to 4:30p.m. CST. 
13.6   Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for this and all SCCC Investigator Initiated Trials. REDCap will be used for 
electronic case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements. 


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Other institutions participating in this trial as sub-sites will be expected to enter data into 
REDCap and upload de-identified source materials when instructed by the Simmons 
Comprehensive Cancer Center study team to facilitate remote source to case report form 
verification.  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, which includes 
but is not limited to accuracy of case report forms, protocol compliance, timeless and 
accuracy of Velos entries and AE/SAE management and reporting. Documentation of trial 
monitoring will be maintained along with other protocol related documents and will be 
reviewed during internal audit.   
 
Toxicity and dose escalation reviews will be performed at the Phase 1 DOT meetings.  
These reviews will be documented by the meeting minutes. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles. 
 
13.7 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted exactly 
as described in the approved protocol.  
13.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial patients without prior IRB approval.  
For any such emergency modification implemented, an IRB modification form must be 
completed within five (5) business days of making the change. 


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13.7.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned 
variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
If {non-Research Office} managed study, please maintain the following language in 
your protocol: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) 
weeks of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.  
13.8 Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the study Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design or 
the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the IRB 
for approval prior to implementation.  
13.9 Record Retention  
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 


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Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
Government agency regulations and directives require that the study investigator retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference 
on Harmonization (ICH) region. In all other cases, study documents should be kept on file 
until three years after the completion and final study report of this investigational study. 
13.10 Obligations of Investigators  
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of 
all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of the 
study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 


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14.0 REFERENCES 
 
1. 
 Siegel R, Miller K and Jemal Al. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29. 
2. 
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine 
alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of 
Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-6. 
3. 
Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX Compared With 
Gemcitabine on Quality of Life in Patients With Metastatic Pancreatic Cancer: Results From the 
PRODIGE 4/ACCORD 11 Randomized Trial. J Clin Oncol 2012. 
4. 
Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active 
regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:4548-54. 
5. 
Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces 
tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. 
FASEB J 2004;18:338-40. 
6. 
Presta M, Dell'Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast 
growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005;16:159-78. 
7. 
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic 
targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299-309. 
8. 
Fernando NT, Koch M, Rothrock C, et al. Tumor escape from endogenous, extracellular matrix-
associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 
2008;14:1529-39. 
9. 
Mross K, Stefanic M, Gmehling D, et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in 
patients with advanced solid tumors. Clin Cancer Res 2010;16:311-9. 
10. 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. Ann Oncol 2011;22:1374-81. 
11. 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 After Chemotherapy for 
Relapsed Ovarian Cancer. J Clin Oncol 2011;29:3798-804. 
12. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor 
blockade and good antitumor efficacy. Cancer Res 2008;68:4774-82. 
13. Stopfer P, Rathgen K, Bischoff D, et al. Pharmacokinetics and metabolism of BIBF 1120 after oral 
dosing to healthy male volunteers. Xenobiotica 2011;41:297-311. 
14. Kutluk Cenik B, Ostapoff KT, Gerber DE, Brekken RA. BIBF 1120 (nintedanib), a triple angiokinase 
inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and 
pancreatic cancer. Molecular Cancer Therapeutics 2013;12:992-1001. 
15. Ahn SJ, An CS, Koom WS, Song HT, Suh JS. Correlations of 3T DCE-MRI quantitative parameters 
with microvessel density in a human-colorectal-cancer xenograft mouse model. Korean J Radiol 
2011;12:722-30. 
16. Chang Q, Wu N, Ouyang H, Zou SM, Huang Y. [Characteristics of 3.0T dynamic contrast-enhanced 
magnetic resonance imaging of lung cancer and its correlation with microvessel density]. Zhongguo Yi 
Xue Ke Xue Yuan Xue Bao 2009;31:242-7. 
17. Unetsubo T, Konouchi H, Yanagi Y, et al. Dynamic contrast-enhanced magnetic resonance imaging 
for estimating tumor proliferation and microvessel density of oral squamous cell carcinomas. Oral 
Oncol 2009;45:621-6. 


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18. Schlemmer HP, Merkle J, Grobholz R, et al. Can pre-operative contrast-enhanced dynamic MR 
imaging for prostate cancer predict microvessel density in prostatectomy specimens? Eur Radiol 
2004;14:309-17. 
19. Bali MA, Metens T, Denolin V, et al. Tumoral and nontumoral pancreas: correlation between 
quantitative dynamic contrast-enhanced MR imaging and histopathologic parameters. Radiology 
2011;261:456-66. 
20. Kim H, Folks KD, Guo L, et al. Early therapy evaluation of combined cetuximab and irinotecan in 
orthotopic pancreatic tumor xenografts by dynamic contrast-enhanced magnetic resonance imaging. 
Mol Imaging 2011;10:153-67. 
21. Casneuf VF, Delrue L, Van Damme N, et al. Noninvasive monitoring of therapy-induced 
microvascular changes in a pancreatic cancer model using dynamic contrast-enhanced magnetic 
resonance imaging with P846, a new low-diffusible gadolinium-based contrast agent. Radiat Res 
2011;175:10-20. 
22. Akisik MF, Sandrasegaran K, Bu G, Lin C, Hutchins GD, Chiorean EG. Pancreatic cancer: utility of 
dynamic contrast-enhanced MR imaging in assessment of antiangiogenic therapy. Radiology 
2010;256:441-9. 
23. Kim JH, Lee JM, Park JH, et al. Solid pancreatic lesions: characterization by using timing bolus 
dynamic contrast-enhanced MR imaging assessment--a preliminary study. Radiology 2013;266:185-96. 
24. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel 
plus gemcitabine. N Engl J Med 2013;369:1691-703. 
 
 


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15.0 APPENDICES 
 
Appendix A – ECOG Performance Status Scale 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
These criteria will be used to assess how the disease of a patient is progressing, to assess how the 
disease affects the daily living abilities of the patient, and to determine appropriate treatment and 
prognosis.   
 
Grade   ECOG   
0           Fully active, able to carry on all pre-disease performance without restriction   
1           Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light house work, office work)   
2           Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.   
3           Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours   
4           Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair   
5           Dead 


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Appendix B – PROMIS QOL Assessment  
 
PROMIS Global – QOL (v 1.0-1.1 SF) 
 
Patient ID: ___________________  
 
Date of Assessment: ____________________ 
 


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PROMIS Global – QOL (v 1.0-1.1 SF) 
 
Patient ID: ___________________  
 
Date of Assessment: ____________________ 
 
  
 
 


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Appendix C - Pharmacodynamic Studies 
Isolation of Peripheral Blood Mononuclear Cells (PBMC)  
 
Blood samples will be obtained using BD Vacutainer CPTTM Cell Preparation Tubes. A total of 16 
mL (8 mL x 2 tubes) of blood will be collected at each time point as indicated in the study calendar.  
After collection, store CPT upright at room temperature until centrifugation. Sample should be 
centrifuged within 2 hours of collection. Remix the blood sample immediately prior to centrifugation 
by gently inverting several times.   
1. Centrifuge CPT at room temperature for 30 minutes at 1700 g (RCF). After centrifugation,  
mononuclear  cells  will  be  in  the  layer  above  the  gel  and  below  the plasma layer.   
2. Remove approximately half of the plasma, without disturbing the cell layer.   
3. Transfer the cell layer to a 15-ml polypropylene conical tube: It is difficult to pipet out just the 
cell layer, so transfer the entire remainder of the contents above the gel into the 15-ml   conical 
tube. Add cold PBS to bring volume to 14 ml. Mix by inverting several times.   
4. Centrifuge at 300 g for 15 min. at 4°.   
 
5. Aspirate as much supernatant as possible without disturbing the cell pellet. Resuspend cell 
pellet in 10 ml of cold PBS.   
 
6. Centrifuge at 300 g for 10 min. at 4°.   
 
7. Aspirate off supernatant. RESUSPEND CELL PELLET in 1 ml of cold PBS and count cell 
number. *   
   *When  cells  are  counted,  remove  10  µl  of  cells  for  counting.  Add 90µl trypan blue. To  
determine  the  cell  number  using  a  hemocytometer,  count  the  number  of  cells  in  4  
large squares. To determine the count of cells/ml, the number counted in 4 large squares is 
divided by 4 and then multiplied by 104. This number must then be multiplied by 10 to account 
for the dilution in trypan blue.   
       cells/ml = # cells counted in 4 large squares /4 x 104 x 10 (dilution factor)   
 
8. PBMCs can be placed at -80°C for use in western blotting at a later date.   
 
9. Samples  should  be  delivered  to  the  Biomarker  Research  Core  at  the  Harold  C.  
Simmons  Cancer  Center  at  UT  Southwestern  or other designated vendors on  dry  ice  or  
room  temperature  as appropriate.  Contact information for the Simmons Biomarker Research 
Core: 
 
Simmons Cancer Center Biomarker Research Core 
Harold C. Simmons Comprehensive Cancer Center 
University of Texas Southwestern Medical Center 
5323 Harry Hines Blvd., ND2. 210K  
Dallas, Texas 75390-8807 
Phone:  (214) 645-6371 
Fax:      (214) 645-6347 
                                                  


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Appendix D – Safety Assessment Form 
 
 


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Appendix E:  
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. 
 
Definition 
 
The following changes in the laboratory values are considered to be a protocol-specific significant 
adverse event for all patients with normal values for ALT/AST at baseline: 
  
- 
an elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in the same 
blood draw sample 
- 
 an elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of bilirubin to >1.5 fold 
ULN measured in the same blood draw sample.  
 


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These definitions are in line with the current dose reduction recommendations as outlined in all study 
protocols for BIBF 1120. 
 
Patients showing these laboratory abnormalities need to be followed up until the protocol specific 
retreatment criteria have been met. 
 
For patients with elevated ALT/AST values at baseline special considerations apply, if they are eligible 
for inclusion into the trial, e.g. if liver metastasis are present and do not qualify as exclusion criterion. For 
those special cases, the BI contact person should be involved. 
 
Procedures 
1. Protocol-specified significant events are to be reported in an expedited manner similar as Serious 
Adverse Events, even if they do not meet any of the seriousness criteria and documented in the 
eCRF. 
 
2. Replication of the following laboratory tests for confirmation within 48 hours: 
 
- 
AST, ALT 
- 
Bilirubin measurement (total and direct bilirubin) 
- 
Alkaline Phosphatase 
- 
Haptoglobin 
- 
Complete blood count and cell morphology 
- 
Reticulocyte count 
- 
CK 
- 
LDH 
The results of these repeated laboratory tests must be documented on the eCRF /CRF forms and 
reported immediately via the SAE form to BI. 
3. An evaluation of the patient within 48 hours with respect to but not limited to: 
 
- 
Abdominal ultrasound or clinically appropriate other imaging and investigations 
adequate to rule out biliary tract, pancreatic,  intra- or extrahepatic pathology, e.g. bile 
duct stones,  neoplasm, hepatic tumor involvement, biliary tract, pancreatic or 
intrahepatic pathology, vascular hepatic conditions such as portal vein thrombosis or 
right heart failure. These data need to be collected, documented in the respective field 
of the eCRF / CRF / additional documentation form, and the respective SAE form has 
to be updated and forwarded to BI 
- 
detailed history of current symptoms and concurrent diagnoses and medical history  
- 
detailed history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations and eg steroids as concomitant, 
supportive treatment), alcohol use, recreational drug use, and special diets detailed 
history of exposure to environmental chemical agents 
 
4. In case that both imaging and laboratory value did not unequivocally confirm cholestasis as the 
reason of ALT / AST increase, in particular if AP < 2x ULN,  
then please complete the following laboratory tests: 
 


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- 
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, tumor marker 
TSH* 
- 
Hematology 
Thrombocytes*, eosinophils* 
*If clinically indicated and in case additional investigations are needed (e.g 
immunocompromised patients.) 
 
5. Initiate close observation of all patients with elevated liver enzyme and bilirubin elevations by 
repeat testing of ALT, AST,  bilirubin (with fractionation into total and direct) and AP at least 
weekly until the laboratory values return to normal or to the values as defined in the protocol.  
 
6. In case that transaminases and/or bilirubin increase despite cessation of the experimental 
therapy, more frequent intervals will be warranted.  
Depending on further laboratory changes, additional parameters identified e.g. by reflex testing 
will be followed up based on medical judgement and Good Clinical Practices 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F:       Monotherapy Patient Diary  
 
 


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APPENDIX G:  
Combination Therapy Patient Diary  
 
 


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ICF_003.pdf: 
Cover Page
Official Title: A Phase 1b and Pharmacodynamic Study of Nintedanib
Monotherapy Followed by Combination Therapy of Nintedanib and
Gemcitabine Plus nab-Paclitaxel for Advanced Pancreatic Cancer
NCT number: NCT02902484
Document Date: 06/06/2022


STU022016-083, Al Mutar, FormE-Consent, Mod_27, 06-06-22 
 
 
Page 1 of 20 
DO NOT DISCLOSE   
Protocol Version: 8 dated May 03, 2022   
Consent Version #9 May 04, 2022   
The University of Texas Southwestern Medical Center    
 
CONSENT TO PARTICIPATE IN RESEARCH   
Treatment Consent   
Title of Research:  
A Phase 1b and Pharmacodynamic Study of Nintedanib   
Monotherapy Followed by Combination Therapy of   
Nintedanib and Gemcitabine Plus nab-Paclitaxel for   
Advanced Pancreatic Cancer   
Sponsor:  
UT Southwestern Medical Center with funding support   
from Boehringer Ingelheim Pharmaceuticals, Inc.    
Study Doctor:  
Salwan Al Mutar, MD   
You may call the study doctor or research personnel during regular office hours at 214-  
648-4180. At other times, you may call them at 214-645-4673.   
 
Instructions:   
Please read this consent form carefully and take your time making a decision about   
whether to participate.  As the researchers discuss this consent form with you, please   
ask him/her to explain any words or information that you do not clearly understand.  The  
purpose of the study, risks, inconveniences, discomforts, and other important   
information about the study are listed below.  If you decide to participate, you will be   
given a copy of this form to keep.   
 
Why is this study being done?   
This study is being done to find out whether an oral investigational drug (non-FDA   
approved), Nintedanib (a tyrosine kinase inhibitor) taken alone, and in combination with  
gemcitabine plus nab-Paclitaxel (standard of care chemotherapy) will work better to   
decrease the blood supply to your tumor -- causing the tumor to shrink.   
 
As your tumor grows it activates blood vessel growth (angiogenesis) by secreting   
growth factors that are important in the growth process. Therefore, the researchers   
believe that discontinuing the growth process with a tyrosine kinase inhibitor like,   
Nintedanib, in combination with standard chemotherapy is thought to be more effective  
than using a tyrosine kinase inhibitor alone or using the standard therapy alone.    
 
Why is this considered research?    
This is a research study because the combination of Nintedanib with gemcitabine plus   
nab-Paclitaxel has not been previously used in combination for metastatic pancreatic   
carcinoma. Although, Nintedanib is approved by the U.S. Food and Drug Administration  
(FDA), it is an investigational drug and has not been approved by the U.S. Food and   
Drug Administration (FDA) for the treatment of advanced pancreatic cancer.   
 
 
 
IRB Approved Date: 6/6/2022


STU022016-083, Al Mutar, FormE-Consent, Mod_27, 06-06-22 
 
 
Page 2 of 20 
DO NOT DISCLOSE   
Protocol Version: 8 dated May 03, 2022   
Consent Version #9 May 04, 2022   
 
 Gemcitabine plus nab-Paclitaxel  has been approved by the FDA as the standard   
treatment for advanced pancreatic cancer  and is not considered an   
investigational treatment;   
 Nintedanib with gemcitabine plus nab-Paclitaxel is being compared to   
gemcitabine plus nab-Paclitaxel alone, the standard treatment for your cancer,   
which has already been approved by the FDA.  The researchers are interested in   
learning which therapy is more effective and/or safer in treating your tumor.   
 
The following definitions may help you understand this study:    
 Standard medical care means the regular care you would receive from your   
personal doctor if you choose not to participate in this research.   
 Researchers means the study doctor and research personnel at the University of   
Texas Southwestern Medical Center and its affiliated hospitals.   
 
Why am I being asked to take part in this research study?   
You are being asked to take part in this study because you have advanced pancreatic  
cancer.   
 
Do I have to take part in this research study?   
No.  You have the right to choose whether you want to take part in this research study.    
If you decide to participate and later change your mind, you are free to stop participation  
at any time.   
 
If you decide not to take part in this research study it will not change your legal rights or  
the quality of health care that you receive at this center.   
 
How many people will take part in this study?   
About 20 people will take part in this study at UT Southwestern Medical Center   
 
What is involved in the study?   
If you volunteer to take part in this research study, you will be asked to sign this consent  
form and will have the following tests and procedures.  Some of the procedures may be  
part of your standard medical care, but others are being done solely for the purpose of   
this research study.   
 
Screening Procedures (1 or 2 Days)   
To help decide if you qualify to be in this study, the researchers may ask you  
questions about your health, including medications you take and any surgical  
procedures you have had.   
 
You may also have to fill out certain forms or have the following exams, tests or   
procedures that must be completed 21 days prior to registration:    
 Completion of Informed Consent (Research Procedure)   
 Collection of your demographics (age, gender, race) (Research Procedure)   
 Review of your past and present medical history (Standard of Care   
procedure)   
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 Review of any medications that you are taking or have taken (Standard of   
care procedure)    
 Review of any side effects that you may have experienced (Adverse Events)   
assessment (Research procedure)    
 Physical Exam (PE) (Standard of Care procedure)   
 Height and weight (Standard of care procedure)   
 ECOG Performance Status (PS) to determine your ability to perform everyday   
activities (Standard of Care procedure)   
 Vital signs – Blood pressure, pulse, temperature, and breathing rate   
measurements (Standard of care procedure)   
 Blood tests (standard blood work);   
 Biopsy of Pancreas - A fresh biopsy of your pancreas tumor may be   
necessary for researchers to archive for future analysis if archived tumor   
tissue is not available (research procedures)   
 Urinalysis – (urine will be collected to check the function of your kidneys)   
standard of care procedure   
 For women of child bearing potential only - about 1 teaspoon of blood will be   
collected for a pregnancy test (standard of care procedures)   
 Tumor Imaging Scans (standard of care procedures)   
o CT-Scan or MRI of your chest, abdomen, pelvis   
 Electrocardiogram (ECG) – to check the activity of your heart (Standard of   
care procedures)   
 Research blood work for DNA analysis and correlative studies   
 Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) for research 
purposes   
 Completion of the PROMIS Quality of Life (QOL) assessment to determine   
how you feel about your physical, mental and social quality of life     
 
The following exams, tests or procedures must be completed 14 days prior to  
registration:   
 
Blood will be drawn to check the function of your heart, liver and kidneys  
 
Urinalysis – (urine will be collected to check the function of your kidneys)   
 Pregnancy test will be done for women of childbearing potential   
 Check your height and weight   
 
Study Treatment   
Treatment Overview   
If you decide to participate in this study you will take a low dose of only   
Nintedanib, twice daily for about the first 2 weeks. Once the researchers have   
determined that you can tolerate the low dose of Nintedanib, and have not   
experienced any study drug side effects that would stop you from continuing your   
treatment, you will receive the same low dose or a higher dose of Nintedanib   
along with gemcitabine plus nab-Paclitaxel as described in the table below:   
 
 
 
 
 
IRB Approved Date: 6/6/2022


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NOTE: Nintedanib will not be taken on the days that chemotherapy is  
infused – Days 1, 8 and 15 of the 28-day cycles. 
   
 
You will be given a daily pill diary to complete as you are taking the study  
drug Nintedanib. Bring the completed form with you to every clinic visit to  
be reviewed by the researcher.    
 
Monotherapy Phase: Treatment will start with Nintedanib monotherapy in a two   
week period (Days 1-14) before the combination phase is started, study MRIs will  
be obtained before the monotherapy phase and prior to the combination therapy  
phase. Archival tissue or a fresh biopsy will be obtained prior to starting   
treatment in the monotherapy phase.   
 
Combination Therapy Phase: The combination phase will include gemcitabine +  
nab-paclitaxel, and Nintedanib. The treatment will consist of gemcitabine + nab-  
 
Paclitaxel administered intravenously on days 1, 8, and 15 every 28 days.   
Nintedanib will be taken by mouth twice a day except on chemotherapy treatment  
days. You will stop Nintedanib the night before your chemotherapy and take   
Nintedanib on days 2, 9, and 16, if no treatment conditions exist that would   
prevent continued treatment with Nintedanib.    
 
Treatment Assessments   
Participation in this study will involve several procedures.  Many of these procedures   
are part of the normal process of treating tumors such as yours.  However, some of   
these procedures can be uncomfortable, inconvenient or painful.  In addition to the   
procedures associated with the administration of Nintedanib and gemcitabine plus nab- 
paclitaxel as detailed above, you will be asked to participate in other procedures as part  
of your involvement in this study.   
 
1. Blood tests (including standard blood work and research blood work for   
DNA analysis and correlative studies):  Blood will be drawn from your vein or   
central line prior to the administration of Nintedanib and gemcitabine plus nab-  
paclitaxel up until the time you are no longer receiving Nintedanib. No more than   
45 ml (3 tablespoons) of blood will be collected at any one time. Research draws   
will include draws for pharmacogenomics (DNA sample)_and pharmacodynamics   
(PD) samples for correlative studies.   
Monotherapy   
Phase    
(2 weeks)   
Combination Phase   
Nintedanib 150  
mg twice daily,  
Days 1-14   
Nintedanib 150  
mg twice daily,  
Days 1-28   
Gemcitabine   
1000 mg/m2,   
Days 1, 8, and 15   
Nab-Paclitaxel  
125mg/m2 Days  
1, 8, 15   
Nintedanib 200  
mg twice daily,  
Days 1-14   
Nintedanib 200  
mg twice daily,  
Days 1-28   
Gemcitabine   
1000 mg/m2,   
Days 1, 8, and 15   
Nab-Paclitaxel  
125mg/m2 Days  
1, 8, 15   
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2. Tumor Imaging (CT or MRI) Scans: Imaging test will be performed prior to   
enrollment in the study and every 8 weeks up until the time you are no longer   
receiving Nintedanib. These are standard of care procedures. A research-related   
DCE-MRI will also be performed at the end of the monotherapy phase.    
3. Physical Exam including Vital Signs: At the beginning of each new treatment   
cycle (Day 1, of each cycle), a Physical Exam, performance status with vital   
signs will be performed;   
4. Side Effect and Medication Assessment:  Information on side effects of both   
treatments and new medications will be recorded. These are a research   
procedures to document drug toxicity assessment and drug compliance and   
accountability.   
5. PROMIS Quality of Life (QOL) assessment:  You will complete this   
questionnaire to determine how you feel about your physical, mental and social   
quality of life These are research procedures.    
6. Study Drug Diary:  You will be asked to complete a daily “diary” to note the date   
and time that you take your capsules of Nintedanib and to record any side effects   
that you may experience. These are research procedures.   
 
Post-Treatment Follow-up (3-4 Hours)   
After you have stopped taking Nintedanib, you will be asked to complete the following  
procedures:   
1. Blood tests:  Blood will be drawn from your vein or central line for safety   
evaluations post study drug;   
2. Urinalysis: Urine will be collected to determine safety evaluation post study drug;   
3. Tumor Imaging (CT or MRI) Scans: Imaging test will be performed to assess   
your tumor post study drug;   
4. Physical Exam including Vital Signs: a Physical Exam, performance status   
with vital signs will be performed to assess your condition post study drug;   
4. Side Effect and Medication Assessment – Information on side effects or both   
treatments and new medications will be recorded   
 
Follow-Up Phase (10 min)   
During the follow-up phase of this study, we will contact you via phone, review of your  
medical record, or certified mail to collect survivorship information.    
 
How long can I expect to be in this study?   
This study includes a treatment phase of up to 9 cycles and long-term follow-up for   
survivorship.  Based on your response to treatment and at your doctor’s clinical   
assessment and determination, you may continue to receive the study drugs after the 9  
cycles. Clinical assessment will help your doctor to determine how many cycles of the   
drugs you are able to tolerate. You will have one follow-up visit within 7 days of stopping  
Nintedanib and an additional follow-up visit within 30 days of stopping Nintedanib for a   
safety evaluation. These visits will consist on standard blood test, imaging, and   
evaluation of any side effects that you may have experienced on the study.   
 
You can choose to stop participating for any reason at any time. However, if you decide  to 
stop participating in the study, we encourage you to tell the researchers.  You may be  
asked if you are willing to complete some study termination tests.   
 
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What are the risks of the study?   
Study Procedure/Intervention   
Because of your participation in this study, you are at risk for the following side effects.  
You should discuss these with the researchers and your regular health care provider.   
If you receive active trial medication, then side effects may occur. Some of those side  
effects can be treated. Some side effects may go away when you stop taking the trial   
medication. Some side effects can be mild, but others may continue longer or become  
permanent. Some may be life-threatening or fatal.    
 
As with any drug, an allergic reaction can occur. Allergic reactions can be mild or more  
serious, and can even result in death. Common symptoms of an allergic reaction are   
rash, itching, skin problems, swelling of the face and throat, or breathing difficulties. If  
you think you are having an allergic reaction, call the trial doctor right away. Patients   
who have known allergies to the study medications or its ingredients should not take   
part in this study.   
In clinical trials, the most frequently reported side effects associated with the use of nintedanib 
include diarrhea, nausea and vomiting, abdominal pain, decreased   
appetite, weight decreased and hepatic enzyme increased. All identified side effects of  
nintedanib are listed below:    
 
Gastrointestinal disorders  
Diarrhea   
Vomiting   
Nausea   
Abdominal pain   
Pancreatitis   
 
Hepatobiliary disorders   
Drug-induced liver injury   
Hepatic enzyme increased   
 Alanine aminotransferase (ALT) increased   
 Aspartate aminotransferase (AST) increased   
 Blood alkaline phosphatase (ALKP) increased   
 Gamma glutamyltransferase (GGT) increased   
 
Hyperbilirubinemia   
 
Vascular disorders   
Hypertension   
Bleeding (this term represents a group of events that describe a broader medical   
concept rather than a single condition or MedDRA preferred term; non-serious and  
serious bleeding events, some of which were fatal, have been observed in the post- 
marketing period)   
 
Blood and lymphatic system disorders  
Thrombocytopenia   
 
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Metabolism and nutrition disorders  
Decreased appetite   
Weight decreased   
 
Skin and subcutaneous tissue disorders  
Rash   
Pruritus  
Alopecia (hair loss) 
 
Nervous system disorders 
Headache  
 
The risks of this study are primarily related to the combination chemotherapy   
(Nintedanib and gemcitabine plus nab-paclitaxel), and the biopsy of your pancreatic  
tumor. The risks listed below are based on a total of 1932 subjects who have been  
treated with Nintedanib.    
 
Treatment with Nintedanib alone as single agent or in combination with standard  
doses of chemotherapy   
Very common (equal or more than 10%):   
o diarrhea (loose stools)   
o nausea   
o vomiting   
o increased liver function tests (blood tests that show the liver is not working   
the way it should)   
o decreased appetite   
o low white blood cell count (which can make it easier to catch an infection)   
o pain e.g., abdominal pain, chest pain, back pain, tumor pain, severe   
stomach pain    
o skin problems such as: itching rash, hair loss, hand-foot syndrome, nail   
disorder    
o abnormal skin sensations   
o bleeding e.g. epistaxis (nose bleeds), coughing up small amounts of blood,   
rectal bleeding    
o mouth ulceration   
o weight loss   
o weakness, numbness, and pain from nerve damage   
o Fatigue   
o Shortness of breath, inflammation of the nasal cavaties, inflammation of the   
lungs, cough and scarring of the lungs   
o Alopecia (hair loss) 
 
Common (equal or above 1% but below 10%):    
o Taste changes   
o Constipation   
o Fever    
o Anemia (low level of hemoglobin in your blood)   
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o High blood pressure   
o Headache   
o Infections (including those in the urine, chest, and sinuses)   
o Dry mouth   
o Flatulence (gas)   
o Dizziness    
o Dehydration   
o Insomnia (difficulty sleeping)   
o Chest pain   
o Thromboembolism (obstruction of blood vessel by blood clot) 
Neutropenia - Low white blood cell count (which can make it easier to catch 
an infection) 
o Hyperbilirubinemia - High levels of bilirubin in blood (which can cause 
yellowing of skin)   
o low thyroid function 
o respiratory infection   
o pneumonia (infection of one or both of the lungs)   
o Sepsis ( body’s response to an infection that releases chemicals to fight off   
infection).   
o Abscesses (collection of pus that has built up within the tissue of the body)   
 
Uncommon (less than 1%):    
o Cough   
o Chills   
o Vertigo (loss of balance)   
o Low blood pressure or high blood pressure   
o Eye disorders, such as eye dryness, eye redness, conjunctivitis (pink eye),   
 blurred vision 
o Drug hypersensitivity (which can be a reaction or intolerance of the drug)   
o Skin swelling   
o Abnormal heart beats, fast or slow heart beats   
o Low blood sugar     
o Changes in kidney function   
o Perforation (holes in the bowels)   
o Bleeding into the brain   
o Pancreatitis (swelling and inflammation of the pancreas)   
o Constipation   
o Depression   
o Dry skin and hair   
o Hoarseness or husky voice   
o Muscle cramps and stiffness   
o Tiredness  or weakness   
o Weight gain   
o Low blood platelet count which increases the risk of bruising and bleeding 
 
These treatment-related adverse events were usually reversible and most of these   
adverse events can be treated or resolved by temporarily or permanently stopping   
Nintedanib. If you experience any of these side effects or any other side effect which   
might be related to the intake of the study drug(s), your study doctor may adjust your  
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medication and give you advice on how you can minimize these side effects.    
 
In a few patients a concurrent increase of bilirubin and liver enzymes was observed. This  
was fully reversible and appeared in the context of progression of the underlying cancer  
disease and concomitant development of liver metastases. Enzyme elevations generally  
normalized upon interruption of treatment in the majority of patients and did usually not   
recur after continuation of treatment at a reduced dose. The level of liver enzymes will   
be monitored closely during the conduct of this study. Extra blood sampling and imaging  
by e.g. ultrasound may be performed in order to clarify the potential underlying reason   
 
for the increased liver enzyme values. If the cause for the altered liver function cannot   
be found, further investigations may be performed, this may include additional blood   
sampling for e.g. an extended analysis of safety parameters, the analysis of the types   
and amounts of hormones and the presence of viruses. Please tell your research doctor  
if you notice yellowing of the skin or of the white part of your eyes which are signs of an  
increase of the bilirubin-level in your body system.    
  
   
Pre-clinical studies in animals indicate that impairment of immune function may also   
occur when being treated with Nintedanib. Such pre-clinical studies also indicated that  
Nintedanib in combination with natural sunlight or artificial UV radiation may cause   
effects to the skin or the eye. However, thus far, these adverse events have not been   
reported in clinical trials with humans.   
You need to tell your trial doctor or a member of the trial team immediately if you  
experience any side effects.   
 
Nab-Paclitaxel Risks    
In a previous study in patients with metastatic pancreatic cancer, an increase of blood   
infections was observed in patients who received the combination of nab®-paclitaxel   
and gemcitabine. You may not have the same risk of blood infections as metastatic   
pancreatic cancer patients; however, contact your study doctor immediately if you   
develop a fever. Your study doctor will evaluate if your fever is an early sign of a serious  
infection, for which antibiotics may be provided.   
 
A particular lung illness, known as pneumonitis (inflammation of lung tissue), was   
observed in subjects (less than 1%) receiving nab®-paclitaxel alone or gemcitabine   
alone, but appears to occur more often (3%) when the two drugs are given together.   
This illness requires early detection and treatment as it may be life-threatening or even  
fatal. Therefore, it is important that you promptly tell your study doctor if you have   
worsening shortness of breath, difficulty breathing, fever, or a dry cough (not   
productive), for further evaluation and possible treatment.   
 
The following is a list of the most common side effects reported in previous studies and   
considered to be related to nab®-paclitaxel. In some cases, side effects can be serious,   
long-lasting, or can cause death.  Some side effects go away soon after you stop the   
study drug/therapy and some may never go away.  The study doctor may alter the   
dosage regimen of nab®-paclitaxel or give you medicines to help lessen the side effects.   
This is not a complete list of all side effects that may occur.  For more information about  
risks and side effects, please ask the study doctor.     
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Very common (a 10% or more chance that this will happen):   
 Anemia (a decrease in the number of red blood cells which may make you feel   
weak or tired)    
  Low number of white blood cells with or without fever (that may make it easier to   
get infections)    
 A decrease in the number platelets, the cells that help your blood to clot (which   
may lead to unusual bleeding or bruising under the skin)    
 Constipation    
 Diarrhea    
 Nausea    
 Vomiting    
 Stomach pain   
 Pain, swelling or sores on the inside of the mouth   
 Dizziness      
 Feeling tired or weak    
 Pain (including muscle, joints, and chest pain)    
 Swelling caused by fluid held in the tissues, especially of the ankles, feet or   
 fingers    
 Fever   
 Chills    
 Decreased appetite    
 Change in taste   
 Weight loss   
 Difficulty sleeping   
 Depression   
 Neuropathy, a disorder of the nerves which can cause tingling or numbness, with   
 weakness, or decreased sensation or movement    
 Cough    
 Shortness of breath    
 Hair loss    
 Rash, possible red, bumpy or generalized   
   Itchiness   
 Change in nails, including discoloration or separation from nailbed   
 Abnormal liver functions test results   
 Dehydration (loss of water and minerals in the body)   
 Nose bleed   
 Decreased potassium levels in blood    
 
Common (between a 1% to less than 10% chance that this will happen):   
 Bone marrow depression which is a severe reduction of red or white blood cells   
 and platelets (at nearly the same time) which can cause weakness, bruising, or   
 make infections more likely    
 Watery eyes    
 Change in vision or blurry vision    
   Indigestion or upset stomach     
 Trouble swallowing     
 Abnormal chemistry or electrolyte blood test results   
   Inflammation of the lung passages   
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 Thickening, inflammation or scarring in the lungs which may cause   
 breathlessness, cough   
  Inflammation of the bowel causing abdominal pain or diarrhea     
  Infections, including pneumonia of the lung, mouth, gallbladder, urinary tract,   
nail, or hair follicle  (which may be bacterial, fungal or viral)    
 A very severe infection of the blood which may include a decrease in blood   
pressure    
 Blockage of the intestine   
 Trouble swallowing   
   Indigestion or upset stomach   
 Abnormal chemistry or electrolyte blood test results   
 Acute kidney failure   
 Blood in urine   
   Lack of muscle coordination   
 Muscle weakness   
 Anxiety   
 Nasal congestion   
 Mouth and throat pain   
 Dry mouth, nose, and throat   
 Coughing up blood or bloody sputum     
 Fluid in the chest cavity     
 Blood clot in the lungs or deep vein     
 Changes in nails, including discoloration     
 Red or flushed skin   
 Dry skin   
 Hand-foot syndrome, involving reddening, swelling, numbness and peeling of palms   
 and soles of feet     
 High blood pressure     
   Low blood pressure    
 Faster heartbeat 
      Headache 
 A decrease in the heart’s ability to pump blood to all parts of the body and   
 possibly heart failure   
   Infusion site reactions (described as discomfort, bleeding or bruising/swelling at   
 the needle site, and in some instances infection or leaking of IV fluid outside of   
 the blood vessel into the surrounding tissue.   
  Localized swelling due to build-up of lymph fluid 
 
Uncommon (between a 0.1% to less than 1% chance that this will happen):    
  Irregular or slow heart beat   
 A decrease in the left side of the heart’s ability to pump blood to all parts of the   
 body and possibly heart failure    
 Stopping of the heart   
 Syndrome involving abnormal blood clotting, with decreased platelets, bruising   
(including tiny red or purple spots under the skin), and possible leading to blood   
clots.   
   Irritation and redness of the thin membrane covering the eye   
    Inflammation of the cornea    
 Feeling unwell     
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 Sleepiness     
 Allergic reaction (may include skin inflammation, rash, trouble breathing; trouble   
 speaking; fever, and/or diarrhea); sometimes fatal     
 Too much fluid in the body     
 Scaly or peeling skin     
 Hives    
 
Additional side effects that have been reported by patients who have taken nab- 
paclitaxel outside of a study, not otherwise noted above include:    
 
 Edema/swelling and cyst formation of the macular area of the retina     
 A loss of nerve function in the muscles of the face     
   Lack of movement in the vocal cords with possible voice changes     
 Skin sensitivity to sunlight     
 Potentially life threatening condition of the skin and oral mucous membranes (may   
 include lesions in the mouth, itching and  blistering skin)     
 Skin or tissue damage from prior radiation therapy can become damaged again,   
 when a person receives chemotherapy after having had radiation therapy. This is   
 referred to as radiation recall and may involve redness, peeling, pain, and swelling.    
 Skin changes have been noted to range from mild redness to tissue death. Radiation   
 recall may also occur in the lungs and other internal organs     
Gemcitabine Risks   
The most common side effects of gemcitabine include:   
   Low platelet count (which can lead to bruising or bleeding)  
   Low red blood cell count   
   Infections due to low white cell blood count   
 Abnormal liver function   
 Blood and protein in the urine   
 Nausea and vomiting   
 Diarrhea (loose stools)   
 Constipation (difficult bowel movement)   
 Mouth and lip sores   
 Fluid retention (swelling of the hands, feet or face)   
 Fever   
 Rash   
 Difficulty breathing   
 Flu-like symptoms (fever, feeling tired, loss of appetite, chills and cough)  
 Hair loss   
 Tingling, prickling of the skin   
    Itching   
The least common side effects of gemcitabine include:   
  Irritation and bruising at site of infusion   
 Allergic reaction   
 Failure of your kidneys   
 Severe difficulty breathing   
 Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may   
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cause headache, seizure, blindness    
You should inform your study doctor if you are planning any invasive medical procedures  
while receiving treatment with gemcitabine, as some subjects have an increased risk of   
bleeding.     
 
Risk of Pancreatic Tumor Biopsy:   
Occasional (Less than 20% of patients):   
• Pain at site of biopsy   
 
Rare but serious (Less than 2% of patients):   
• Bleeding from pancreas   
• Difficulty breathing    
• Death   
 
Loss of Confidentiality   
Any time information is collected; there is a potential risk for loss of confidentiality.    
Every effort will be made to keep your information confidential; however, this cannot be  
guaranteed.    
 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant   
Males: Being in this research may damage your sperm, which could cause harm to a   
child that you may father while on this study. If you take part in this study and are   
sexually active, you must agree to use a medically-acceptable form of birth control while  
participating in this study and for 3 months after your last dose of the study drug.    
Medically-acceptable forms of birth control include:   
(1) Surgical sterilization (vasectomy); or   
(2) A condom used with a spermicide (a substance that kills sperm).   
 
Females: As with any investigational drug, the effect of Nintedanib on an unborn child is  
unknown. If you are part of this study while pregnant or breast-feeding an infant, it is   
possible that you may expose the unborn child or infant to risks.  For that reason,   
pregnant and breast-feeding females cannot participate in the study.  If you can become  
pregnant, a blood pregnancy test will be done (using 1 teaspoon of blood drawn from a  
vein by needle-stick), and it must be negative before you participate in this study.    
You must be willing to have a pregnancy test done before beginning your participation,   
regularly at trial visits, and at the end of the trial and beyond for at least 3 months after   
the last dose of Nintedanib (for Nintedanib monotherapy), or up to 3 months (for   
combination therapy: duration is defined by the compound with the longest   
contraception duration according to the respective label) after end of active treatment.   
If you take part in this study and you are sexually active, you and any person that you   
have sex with must use medically-acceptable birth control (contraceptives) during the   
study and for 3 months after your last dose of the study drug.    
 
 Medically-acceptable birth control (contraceptives) includes:   
(1) Surgical sterilization (such as hysterectomy or “tubes tied”);   
(2) Approved hormonal contraceptives (such as birth control pills, patch or ring;   
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Depo-Provera, Depo-Lupron, Implanon);   
(3) Barrier methods (such as condom or diaphragm) used with a spermicide (a   
substance that kills sperm); or    
(4) An intrauterine device (IUD).   
 
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.   
 
If you are pregnant or think you could be pregnant, it is important for you to tell the trial  
doctor or trial 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, your trial doctor will   
contact you after your baby is born to find out about the baby’s health.   
 
Risks of Radiation-Diagnostic Test   
The radiation dose that you will get from diagnostic tests is medically indicated for your  
condition and it is the same that you would get if you were not involved in this research  
study.   
 
CT-Scan   
Computed tomography (CT) scans use X-ray radiation. Some CT scans require you to   
take a “contrast solution”. It is possible that the contrast solution may cause you to have  
nausea, vomiting, itching, or skin rash. In rare cases, it may cause your throat to swell   
and make it hard to breathe. These may be signs of an allergic reaction so tell the study   
doctor right away if you have any of these side effects. You may have some discomfort  
from lying still in an enclosed space for a prolonged period of time.    
 
MRI   
An MRI does not use x-ray radiation, but it takes a little longer and participants   
sometimes have to lie in a more enclosed space. A contrast agent may be injected into  
your vein before the scan is done to help the doctor see the tumor more clearly.    
There are no known risks from exposure to magnetic fields. You may experience   
nervousness and/or anxiety due to the loud banging made by the machine while it is   
taking pictures and from confinement in a tight space (claustrophobia). If you become  
anxious, you can stop the procedure at any time.   
 
You may also experience some discomfort and fatigue from lying still during imaging.   
 
If you have any metal clips or plates in your body, you should tell the investigator. MRI   
may not be appropriate if you are pregnant or are trying to become pregnant. MRI may  
not be appropriate if you have permanent eyeliner or eyebrows or any pieces of metal in  
your body, such as the following:   
 
• heart pacemaker, heart valve replacement, or aortic clips   
• metal fragments in your eyes, skin, or elsewhere in your body   
• brain clips or pieces of metal used in aneurysm surgery or intercranial bypass   
• venous umbrella   
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• pieces of metal in the body resulting from work as a sheet-metal worker or welder  
• clips placed in an internal organ   
• prosthetic devices, such as middle ear, eye, joint, or penile implants   
• joint replacement.   
• hearing aid that cannot be removed   
• neurostimulator   
• insulin pump   
• intrauterine device (IUD)   
• shunts or stents   
• metal mesh or coil implants   
• metal plate, pin, screws, or wires, or any other metal implants   
 
If you have a history of an implanted device or clips in your pelvis (involving your uterus  
or fallopian tubes) or under your skin, acting as a contraceptive to prevent pregnancy,   
the MRI technologist will obtain specific information about the make and model of your  
implanted device to determine if it is safe for you to receive the MRI examination.   
 
The contrast agent you will receive is FDA-approved and used routinely for MRI exams.   It 
contains a material called Gadolinium (dye solution used to highlight organs or tissues  
during imaging).  The injection of Gadolinium may cause discomfort like headache,   
nausea, strange taste, or coldness at site of injection.  These symptoms occur in less   
than 1 out of 20 patients receiving Gadolinium and go away quickly.   There is a small   
 
risk of a severe allergic reaction that can cause breathing difficulties and/or low blood  
pressure, and these symptoms are extremely rare (approximately 1 in 10,000 to 1 in  
100,000 administrations).  In the unlikely event you experience these symptoms, a   
physician and nursing staff will be available to evaluate and, if necessary, provide   
treatment.     
 
People with severe kidney failure who receive Gadolinium (dye solution used to   
highlight organs or tissues during imaging) are at risk of developing a disorder called   
Nephrogenic Systemic Fibrosis (NSF).  This disease can cause wide spread tissue   
scarring or hardening (fibrosis).  In rare cases NSF can lead to lung and heart problems  
and cause death.  If you have severe kidney failure and receive gadolinium, the risk of   
developing NSF is 1-5%.  We may perform a blood test 30 days before your MRI to   
check how well your kidneys are working before you receive the Gadolinium.  This test   
may be repeated closer to your MRI appointment if your medical condition has changed.    
If your kidneys are working at levels known to be at risk for NSF, you will not receive   
Gadolinium.  You will not receive Gadolinium for research purposes if you have sickle   
cell disease  (a disease of the blood cells) since it may put you at risk of developing   
hemolysis (breakdown of blood cells).     
 
Risks of Blood Drawing   
Risks associated with drawing blood from your arm include minimal discomfort and/or   
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although  
unlikely.   
 
You will have approximately 39 tablespoons of blood collected because you are in this  
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research study. The amount collected may vary depending on how long you are able to  
participate.   
 
Other Risks   
There may possibly be other side effects that are unknown at this time. If you are   
concerned about other, unknown side effects, please discuss this with the researchers.   
 
How will risks be minimized or prevented?     
Study risks will be minimized or prevented by several measures at the beginning of the  
study and throughout your participation in the study.  You will be screened prior to   
enrollment to assure that you meet the safety requirements of the study.  All treatments  
will be modified within the study parameters to match your treatment needs. These   
modifications will include the area being treated with chemotherapy.  Throughout your   
participation in the study you will be evaluated by personnel trained to recognize,   
minimize, and treat side effects of your treatment.  You will be withdrawn from the study  
if you experience an adverse event which causes unacceptable risk as determined by   
the research doctors. You will continue to receive standard medical care if you are no   
longer participating in the study.   
 
 
While you are part of this study, the researchers will follow you closely to determine   
whether there are problems that need medical care.  It is your responsibility to do the   
following:   
 Ask questions about anything you do not understand;   
 Keep your appointments;   
 Follow the researchers’ instructions;   
 Let the researchers know if your telephone number or address changes.   
 Store study materials and capsules in a secure place at home away from   
 anyone who is unable to read and understand labels, especially children;   
 Tell the researchers before you take any new medication, even if it is prescribed   
 by another doctor for a different medical problem or something purchased over   
 the counter;   
 Tell your regular doctor about your participation in this study;   
 Report to the researchers any injury or an illness while you are on study, even if   
you do not think it is related.    
 
If I agree to take part in this research study, will I be told of any new risks that   
may be found during the course of the study?   
Yes.  You will be told if any new information becomes available during the study that   
could cause you to change your mind about continuing to participate or that is important  
to your health or safety.   
 
What should I do if I think I am having problems?   
If you have unusual symptoms, pain, or any other problems while you are in the study,  
you should report them to the researchers right away.  Telephone numbers where they  
can be reached are listed on the first page of this consent form.   
 
What will my responsibilities be during the study?     
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If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the  
nearest hospital emergency room, or call 911 (or the correct emergency telephone   
number in your area).  Tell emergency personnel about any medications you are taking,  
including any medications you are taking for this study.     
 
What are the possible benefits of this study?   
If you agree to take part in this study, there may or may not be direct benefits to you.    
The researchers cannot guarantee that you will benefit from participation in this   
research.   
 
We hope the information learned from this study will benefit others with advanced   
pancreatic cancer in the future.  Information gained from this research could lead to  
better care and treatment.     
 
 
What options are available if I decide not to take part in this research study?   
You do not have to participate in this research to receive care for your medical problem.  
Instead of being in this study, you have the following options:   
 
 To receive standard of care treatment as advised by their physician.    
 To not receive any care.   
 To participate in another clinical trial.   
 
Please talk to the researchers or your personal doctor about these options.    
 
Will I be paid if I take part in this research study?   
No.  You will not be paid to take part in this research study. There are no funds   
available to pay for parking expenses, transportation to and from the research center,  
lost time away from work and other activities, lost wages, or child care expenses.   
 
Will my insurance provider or I be charged for the costs of any part of this   
research study?   
Yes, Most of the procedures during this study are considered standard of care and will  
be billed to you and/or your insurance provider.    
 
However, procedures during this study that are preformed specifically for the research  
study (e.g.: second biopsy (optional), research blood (biomarkers and DNA), and study  
drug (Nintedanib) will be paid for by the sponsor of the study.    
 
What will happen if I am harmed as a result of taking part in this study?   
It is important that you report any illness or injury to the research team listed at the top  
of this form immediately.   
 
Compensation for an injury resulting from your participation in this research is not  
available from the University of Texas Southwestern Medical Center or Boehringer  
Ingelheim.   
 
You retain your legal rights during your participation in this research   
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Can I stop taking part in this research study?   
Yes.  If you decide to participate and later change your mind, you are free to stop taking  
part in the research study at any time.   
 
If you decide to stop taking part in this research study, it will not affect your relationship  
with the UT Southwestern staff or doctors.  Whether you participate or not will have no  
effect on your legal rights or the quality of your health care.   
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status  
will not be affected in any way.   
 
Your doctor is a research investigator in this study.  S/he is interested in both your   
medical care and the conduct of this research study.  At any time, you may discuss your  
care with another doctor who is not part of this research study.  You do not have to take  
part in any research study offered by your doctor.   
 
If I agree to take part in this research study, can I be removed from the study   
without my consent?   
Yes.  The researchers may decide to take you off this study if:   
 Your medical problem remains unchanged or becomes worse.   
 The researchers believe that participation in the research is no longer safe for   
you.   
 The researchers believe that other treatment may be more helpful.   
 The sponsor or the FDA stops the research for the safety of the participants.   
 The sponsor cancels the research.   
 You are unable to keep appointments or to follow the researcher’s instructions.   
 
Will my information be kept confidential?   
Medical information collected during this study and the results of any test or procedure  
that may affect your medical care may be included in your medical record. The   
information included in your medical record will be available to health care providers   
and authorized persons including your insurance company.   
 
You should know that certain organizations that may look at and/or copy your medical   
records for research, quality assurance, and data analysis include:   
 Simmons Comprehensive Cancer Center Phase 1 Disease Oriented Team   
 Simmons Comprehensive Cancer Center Data Safety and Monitoring Committee    
 Representatives of government agencies, like the U.S. Food and Drug   
Administration (FDA), involved in keeping research safe for people; and   
 The UT Southwestern Institutional Review Board;    
 Boehringer Ingelheim, the drug suppler and its authorized agents;   
 Governmental agencies in other countries where the study drug may be   
considered for approval.   
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as   
required by the 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  
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Web site at any time.   
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and  
Disclosure of Protected Health Information”. This authorization will give more details   
about how your information will be used for this research study, and who may see   
and/or get copies of your information.   
 
Whom do I call if I have questions or problems?   
For questions about the study, contact Salwan Al Mutar, MD at: 214-648-4008; during  
regular business hours and at 214-645-4673, after hours and on weekends and   
holidays.     
 
For questions about your rights as a research participant, contact the UT Southwestern  
Institutional Review Board (IRB) Office at 214-648-3060.   
 
 
 
 
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SIGNATURES:   
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP.   
Your signature below certifies the following:   
 You have read (or been read) the information provided above.   
 You have received answers to all of your questions and have been told who to   
 call if you have any more questions.   
 You have freely decided to participate in this research.   
 You understand that you are not giving up any of your legal rights.   
 
____________________________________________ 
  
   
Name of Participant (Printed)  
  
   
 
____________________________________________ 
________ 
_______ AM / PM  
Signature of Participant  
Date  
Time   
____________________________________________ 
  
   
Legally Authorized Representative’s Name (Printed)  
  
   
 
____________________________________________ 
________ 
_______ AM / PM  
Legally Authorized Representative’s Signature  
Date  
Time   
____________________________________________ 
  
   
Name of Person Obtaining Consent (Printed)  
  
   
 
____________________________________________ 
________ 
_______ AM / PM  
Signature of Person Obtaining Consent  
Date  
Time   
 
 
 
 
 
IRB Approved Date: 6/6/2022