Conditions: Esophagogastric Adenocarcinoma
Keywords: Nintedanib 14-094
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This is a phase II study of Nintedanib in patients with metastatic or recurrent esophagogastric cancer. The goal of the study is to evaluate the efficacy of Nintedanib, an orally available triple kinase inhibitor targeting the receptors of the vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and fibroblast growth factor (FGF) receptor pathways.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Nintedanib
Intervention descriptions: intervention 1: Nintedanib 200mg twice daily administered continuously. Patients will continue on treatment until progression of disease. Each cycle consists of 28 days continuously, unless interrupted for intolerable toxicity.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
Page 1 of 36 
 
 
 
 
Phase II trial of Nintedanib in patients with advanced esophagogastric cancer 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal 
Investigator/Department: 
Yelena Y. Janjigian, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
David H. Ilson, MD, PhD 
Elizabeth S. Won, MD 
Medicine 
Medicine 
Investigator(s)/Department: 
Marinela Capanu, PhD 
Robert Lefkowitz, MD 
Marc Z. Simmons, MD 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Andrew Epstein, MD 
James Harding, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Maeve Lowery, MD 
Eileen O’Reilly, MD 
Diane Reidy-Lagunes, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Zsofia Stadler, MD 
Kenneth H. Yu, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Nitya Raj, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Erica Kaufmann, NP 
Sree Chalasani, MD 
Han Xiao, MD 
Afsheen Iqbal, MD 
Leticia Smith, APN 
Janet Cogswell, CRN 
Avni Desai, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Jahan Aghalar, MD 
Juliana Eng, MD 
Jia Li, MD 
Wanqing Iris Zhi, MD, PhD 
Adriana Olivo, NP 
Lori Gofter, CRN 
Arlyn Apollo, MD 
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Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
Page 2 of 36 
 
 
 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Kenneth Ng, MD 
Erin Scansarole, CRN 
Krysti Corrado, CRN 
Philip Caron, MD 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
Chung-Han Lee, MD 
Gloria Wasilewski, CRN 
Jason Konner, MD 
Serena Wong, MD 
Jacqueline Bromberg, MD 
PhD 
Colette Owens, MD 
Loren Michel, MD 
Azadeh Namakydoust, MD 
Marina Shcherba, DO 
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Consenting 
Professional(s)/Department: 
Yelena Y. Janjigian, MD 
David H. Ilson, MD, PhD 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Andrew Epstein, MD 
James Harding, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Maeve Lowery, MD 
Eileen O’Reilly, MD 
Diane Reidy-Lagunes, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Zsofia Stadler, MD 
Kenneth H. Yu, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Elizabeth S. Won, MD 
Nitya Raj, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Erica Kaufmann, NP 
Sree Chalasani, MD 
Han Xiao, MD 
Afsheen Iqbal, MD 
Avni Desai, MD 
John Fiore, MD 
Medicine 
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Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
Page 3 of 36 
 
 
 
Stuart Lichtman, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Juliana Eng, MD 
Medicine 
Jia Li, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Philip Caron, MD 
Medicine 
Alice Zervoudakis, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Chung-Han Lee, MD 
Medicine 
Jason Konner, MD 
Medicine 
Serena Wong, MD 
Medicine 
Jacqueline Bromberg, MD 
Medicine 
PhD 
Colette Owens, MD 
Medicine 
Loren Michel, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Commack 
Monmouth 
Rockville Centre 
Westchester 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Page 4 of 36 
Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 6 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 12 
4.1 
Design......................................................................................................................... 12 
4.2 
Intervention ................................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 14 
6.1 
Subject Inclusion Criteria ............................................................................................. 14 
6.2 
Subject Exclusion Criteria ............................................................................................ 14 
7.0 
RECRUITMENT PLAN ..................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 16 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 20 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................ 23 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 25 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 26 
14.0 BIOSTATISTICS ................................................................................................................... 27 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES27 
15.1 Research Participant Registration .................................................................................... 27 
15.2 Randomization .............................................................................................................. 28 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 28 
16.1 Quality Assurance ....................................................................................................... 28 
16.2 Data and Safety Monitoring ......................................................................................... 28 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 29 
17.1 Privacy ........................................................................................................................ 30 
17.2 Serious Adverse Event (SAE) Reporting ..................................................................... 30 
17.2.1 ................................................................................................................................... 31 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 32 
19.0 REFERENCES ...................................................................................................................... 33 
20.0 APPENDICES ....................................................................................................................... 36 


Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
Page 5 of 36 
 
 
 
1.01.0 PROTOCOL SUMMARY AND/OR SCHEMA 
 
Protocol title: 
Phase II trial of Nintedanib in patients with advanced esophagogastric 
cancer 
Study Objectives: 
This is a phase II study of Nintedanib in patients with metastatic or 
recurrent esophagogastric cancer. The goal of the study is to evaluate 
the efficacy of Nintedanib, an orally available triple kinase inhibitor 
targeting the receptors of the vascular endothelial growth factor 
(VEGF), platelet derived growth factor (PDGF), and fibroblast growth 
factor (FGF) receptor pathways. 
 
The primary endpoint will be to evaluate the 6-month progression-free 
survival (PFS) of Nintedanib. With a total of 32 patients, we have 89% 
power to detect an improvement in the 6 month PFS from a historical 
control of 10% to 28%, with a type I and II error rate of 10%. 
Study population: 
Patients with metastatic or recurrent esophagogastric adenocarcinoma 
will be eligible.  Patients will be allowed to have up to a maximum of 
one prior chemotherapy regimen for metastatic disease.  Patients are 
allowed to have a maximum of two prior regimens if they previously 
received neoadjuvant/adjuvant chemotherapy or chemoradiotherapy 
for their initial localized disease. 
 
Study design: 
Single institution, open label, non-randomized, single arm phase II 
 
Number of patients: 
32 
 
Study drugs: 
Nintedanib, administered orally 
 
Dose and regimen: 
Nintedanib 200mg twice daily administered continuously.  Patients will 
continue on treatment until progression of disease. Each cycle 
consists of 28 days. 


Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
Page 6 of 36 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective: 
 
To evaluate the 6-month progression-free survival (PFS) of Nintedanib in patients with 
metastatic or recurrent esophagogastric adenocarcinoma. 
 
Secondary objectives: 
 
1) To evaluate the objective response rate, defined as both complete response (CR) and 
partial response (PR), as measured by RECIST response criteria. 
 
2) To evaluate the tolerability and incidence adverse event profile of Nintedanib in this 
patient population. 
 
3) To perform an exploratory correlative analysis assessing the relationship of FGFR 
amplification and overexpression with progression free survival and response. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Esophagogastric adenocarcinoma 
 
Globally, esophagogastric cancer is diagnosed in nearly one million individuals each year and 
is the second most common cause of cancer-related death.1   In the U.S., the incidence         
of adenocarcinoma of the distal esophagus, GE junction and gastric cardia has increased 4% 
to 10% per year among U.S. men since 1976 so that it is now the most common histology2,3 
Most patients with esophagogastric cancer present with stage IV disease, which is incurable. 
Despite this, systemic chemotherapy can lead to a decrease in cancer-related symptoms and 
prolong survival.4-7 However, even with treatment, for patients with metastatic or recurrent 
disease, chemotherapy results in response rates in 20-40% of patients and median survivals 
of only 8-10 months.8   There is clearly a need for more specific targeted therapies to improve 
the current status of systemic treatment beyond conventional chemotherapy. 
 
 
3.2 
Second line treatment for esophagogastric cancer 
 
There is no current standard of care for second line therapy. There have been a few recent 
trials comparing 2nd-line chemotherapy to best supportive care (BSC). Thuss-Patience et al. 
compared irinotecan to BSC in the first phase III trial of second-line therapy in gastric cancer.9   
The median OS was 4mos with irinotecan compared to 2.4mos in the BSC arm (HR 0.46, 
p=0.012) With irinotecan treatment, there was a median PFS of 2.5 mos (95% CI 1.6- 3.9mo). 
In a large Korean trial, Kang et al. compared second-line docetaxel or irinotecan vs          
BSC and showed improved OS with chemotherapy 5.3 mos vs 3.8mos with BSC (HR 0.66, 
p=0.07); there was no survival difference between docetaxel and irinotecan.10 Another trial by 


Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
Page 7 of 36 
 
 
 
Ueda et al compared irinotecan vs weekly paclitaxel in Japanese patients who were 
refractory to first-line 5FU/platinum.11 There was no OS or PFS difference between the two 
chemotherapy agents. Median OS was 8.4mo with irinotecan, 9.5mos with paclitaxel 
(HR1.13, p=0.38). The median PFS for irinotecan was 2.3 mos and 3.6 mos for paclitaxel. 
(HR1.14, p=0.33).  In this trial the estimated 6 month PFS was 16% with irinotecan and 
14.8% with paclitaxel.  These trials have established a benefit of 2nd line chemotherapy in 
advanced gastric cancer compared to BSC alone. 
 
There have been two large trials evaluating targeted agents in the second line setting.  The 
phase III GRANITE-1 trial of everolimus, an mTOR inhibitor, showed a median PFS of 1.68 
mos compared to 1.41 mos in the placebo arm in patients who progressed after first or 
second line chemotherapy.  The 6 month PFS in the everolimus group was 12% compared to 
4.3% in the placebo arm.12   This trial has not met its primary endpoint for survival and is not 
an FDA approved drug in this population. The phase III REGARD trial of ramucirumab 
compared to placebo in patients who progressed on first line therapy showed an overall 
survival benefit of 1.3 months compared to placebo.13   In the study, the ramucirumab arm had 
a median PFS of 2.1 mos vs 1.3 mos with placebo.  In this study, the estimated 6 month   
PFS was 18 months for ramucirumab compared to 4.5 months with placebo. 
Based on the studies referenced above, we now have data that 2nd line conventional 
chemotherapy is beneficial compared to best supportive care alone.   The REGARD study 
showed the 6 month PFS with placebo was 4.5% and with ramucirumab 18%. There is an 
unmet need in patients with metastatic and recurrent EG cancer to discover new novel 
agents. 
 
 
3.3 
Vascular endothelial growth factor (VEGF) and anti-angiogenic therapy 
 
Angiogenesis is involved in tumor growth and development of metastases.14 Weidner et 
al. showed a statistically significant correlation between the density of microvessels in 
histologic specimens of human breast cancer and clinical outcomes, including the 
incidence of metastases, as well as overall and relapse-free survival.15 
 
Of the identified angiogenic growth factors, Vascular Endothelial Growth Factor (VEGF) 
and its high affinity receptor VEGFR-2 have been identified as crucial regulators of both 
normal and pathologic angiogenesis. VEGF produces a number of biologic effects, 
including endothelial cell mitogenesis and migration, and induction of proteinases, leading 
to remodeling of the extracellular matrix, increased vascular permeability, and 
maintenance of survival for newly formed blood vessels.16 Increased  expression  of 
VEGF has been measured in most solid tumors, including tumors of the lung, breast, 
thyroid, gastrointestinal tract, kidney, bladder, ovary, as well as angiosarcomas. 11 
 
Suppression of neo-angiogenesis via inhibition of VEGFR-2 is a promising strategy for the 
treatment of solid cancers. Bevacizumab, a chimeric murine monoclonal antibody against 
VEGF, has been extensively studied in a number of solid tumor malignancies.  The 
addition of bevacizumab to cytotoxic chemotherapy has been shown in several phase III 
clinical trials to increase the efficacy of chemotherapy. Most recently, data was presented 


Page 8 of 36 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
 
showing bevacizumab leading to an improvement in overall survival in cervical cancer17 
and previous studies have shown benefits in progression free survival in colorectal 
cancer,18 lung cancer,19 and breast cancer.20 
 
 
3.4 Angiogenesis in esophagogastric cancer 
 
A number of studies have evaluated the role of the VEGF pathway in esophageal cancer 
as a prognostic marker and indicate the expression of VEGF in tumors correlates with 
more advanced tumor stage, the presence of nodal and distant metastasis, and with a 
poorer survival outcome.21,22 In esophageal adenocarcinoma, increasing VEGF 
expression correlates with the transition from Barrett’s esophagus to high grade dysplasia, 
and with the transition from microinvasive to locally advanced cancer.23 These pre-clinical 
data suggest that angiogenesis is a viable target for therapy in advanced esophagogastric 
cancer. 
 
Our group has previously performed a multicenter phase II evaluation of bevacizumab and 
cisplatin/irinotecan in patients with advanced gastric and GE junction adenocarcinoma. 
The addition of bevacizumab to cytotoxic chemotherapy significantly improve the time-to- 
progression (8.3 months; 95% CI, 5.5 to 9.9 months) and overall survival (12.3 months; 
95% CI, 11.3 to 17.2 months) of patients compared to the historical time-to-progression of 
5 months.24 Therapy was well tolerated, although a 6% incidence of gastric perforation or 
near-perforation and a 2% incidence of myocardial infarction were noted. 
 
In the phase III REGARD trial, ramucirumab, a monoclonal antibody VEGFR-2 antagonist 
prolonged survival in patients with advanced gastric cancer. Ramucirumab in patients who 
progressed on first line therapy showed an overall survival benefit compared to placebo.13 
FDA granted ramucirumab priority review for advanced gastric cancer. These results 
validate the role of VEGFR-2 signalling as an important therapeutic target in advanced 
gastric and esophageal adenocarcinoma. 
 
 
 
3.5 MSKCC Clinical data of multi-kinase inhibition in esophagogastric cancer 
 
There is clear clinical rationale to study more than one pathway in esophagogastric 
cancer, as indicated by our recently completed MSKCC initiated phase II study of single 
agent Sorafenib in patients with metastatic esophagogastric cancer (IRB 09-016, Proc 
ASCO 2013 Ku et al).25 Sorafenib is an oral multi-kinase inhibitor with activity against 
VEGFR, platelet-derived growth factor receptor (PDGFR), as well as against the 
serine/threonine kinases Raf-1. 
 
In our study of Sorafenib in 2nd/3rd line setting in patients with metastatic esophagogastric 
cancer, we met the primary endpoint of improving 2-month progression-free survival. The 
median PFS was 3.6 mos (95% CI 1.8 to 3.9 mos) with a median overall survival of 8.8 
mos (95% CI, 5.9 to 11.1 months). An ongoing complete response (44+ months) was 
observed in a patient with Stage IV esophageal adenocarcinoma with biopsy proven 
metastatic neck lymphadenopathy who developed recurrence after prior 
chemoradiotherapy and surgery. This patient continues to maintain a complete response. 
A second patient with gastroesophageal junction adenocarcinoma had protracted stable 


Page 9 of 36 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
 
disease in bulky celiac node disease (26+ months). The majority of tumors tested positive 
for phospho-ERK by immunohistochemistry (26/32, 82%). Twenty of the 34 evaluable 
patients (59%) were progression free at 2 months (p=0.08); with the pre-specified Type I 
and II error rates of 10% and historical 2-month PFS of 50% without treatment, this 
regimen shows promise and activity in gastroesophageal cancers. 
 
 
 
3.6 Targeting multiple relevant pathways in esophagogastric cancer 
 
Preclinical animal models suggest that targeting VEGF-VEGFR signaling is beneficial at the 
start of treatment, but with continued drug treatment and under pressure of the VEGF 
blockade, other signaling molecules provide alternate mechanisms to drive disease 
progression.26 Among the potential compensatory mechanisms include upregulation of the 
platelet-derived growth factor (PDGF) and fibroblast growth factor (FGR) pathways.27 The 
PDGF receptor (PDGFR) has a role in promoting angiogenesis, tumor growth and metastasis 
by regulating the migration and adherence of pericytes and smooth muscles cells to 
endothelial cells. The FGF receptor (FGFR) has been described as a potential escape 
mechanism with tumor cells switching from VEGF to FGF signaling to attract endothelial 
cells.22 
3.7 FGFR2 in gastric cancer 
 
The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical 
role in cell behaviors, such as proliferation, differentiation, migration and survival, and are 
fundamental to embryonic development, regulation of angiogenesis, and skeletal 
development.28 The FGFR ligands belong to the FGF family comprising of 18 secreted 
ligands-induced dimerization and bind to adapter proteins. Subsequent downstream 
signaling occurs through two main pathways via the intracellular receptor substrates FGFR 
substrate 2 and phospholipase C (PLC), leading ultimately to upregulation of the Ras- 
dependent mitogen-activated protein kinase (MAPK) and Ras-independent phosphoinositide 
3-kinase (PI3K)-Akt signaling pathways).29 
 
Activation of FGFRs as a result of amplification, mutation or translocation of FGFR genes or 
over-expression of FGFR proteins or overproduction of FGF ligands has been shown to be 
oncogenic. Inhibition of FGFR11may have clinical utility in cancers that overexpress FGFRs, 
such as breast30, esophageal31, bladder32, gastric33, and lung cancers34, or display a 
prevalence of FGFR mutations, such as in bladder cancer. 
 
FGFR gene amplification often leads to FGFR overexpression, which can provoke ligand- 
independent signaling. FGFR2 amplifications have been reported in up to 7% of gastric 
cancers, most of which are diffuse-type with relatively poor prognosis.35,36 The presence of 
FGFR2 gene amplifications in gastric cancer is associated with sensitivity to inhibition of 
FGFR signaling by tyrosine kinase inhibitors and monoclonal antibodies in preclinical 
models.23 The frequency of FGFR1 and FGFR2 overexpression is significantly larger than 
the frequency of amplification in gastric cancers, which is reported up to 41%,37,38 indicating 
that gene amplification is not the sole mechanism leading to receptor overexpression.33 
FGFR2 and PDGFR expression in esophageal and gastric cancers have also been shown to 


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Memorial Sloan Kettering Cancer Center 
IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
 
be associated with high metastatic potential, aggressive tumor biology, and poor 
outcomes.31,39 
 
Inhibition of FGFR2 in gastric cancers using a novel multi-kinase that specifically targets 
FGFR may provide more potent inhibition of the oncogenic pathways and result in improved 
therapeutic efficacy than seen with other tyrosine kinase inhibitors. Nintedanib with its 
favorable toxicity profile and multi-kinase targets may make this agent a promising agent and 
further development of this agent in esophagogastric malignancies is clearly indicated. 
 
 
3.8 
Nintedanib 
 
3.8.1 Pre-clinical rationale 
 
Nintedanib is an orally available potent small molecule triple kinase inhibitor inhibiting 
VEGFR 1-3, FGFR 1-3 as well as PDGF receptor  and ß in the low nanomolar range. 
VEGFR-2 is considered the crucial receptor involved in initiation of the formation as well 
as the maintenance of tumor vasculature. 
 
In vivo experiments demonstrated good anti-tumor efficacy at doses of 50 – 100 mg 
Nintedanib, leading to a substantial delay of tumor growth or even complete tumor stasis 
in xenografts of a broad range of differing human tumor types.40 Furthermore, established 
xenograft tumors rapidly responded to treatment with Nintedanib. Histological examination 
of treated tumors showed a marked reduction of tumor vessel density by approximately 
80%.26 In addition preclinical models show that Nintedanib may have a direct anti-tumour 
effect on those malignant cells which overexpress PDGFR and/or FGFR (e.g. H1703 
NSCLC cells).40 
 
3.8.2 
Clinical experience 
 
The safety and clinical activity of Nintedanib either alone41-44or in combination with 
chemotherapy45-47 has been examined in a series of phase I studies conducted in patients 
with solid tumors. 
 
The phase I dose selection studies have investigated the maximum tolerated dose (MTD), 
safety, and pharmacokinetics (PK) of Nintedanib.32,34  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. The studies 
revealed that Nintedanib is generally well tolerated with mild to moderate adverse effects 
such as gastrointestinal symptoms (nausea, diarrhea, vomiting, abdominal pain) and 
reversible elevations of liver enzymes. Initial signs of clinical activity included a complete 
response in a patient with renal cell carcinoma, 2 partial responses observed in patients 
with colorectal and renal cell carcinoma, and a disease stabilisation seen in 64% of 
patients for at least 2 treatment cycles (Mross et al) 
 
Nintedanib has been studied in a randomized phase II maintenance trial following 
chemotherapy in relapsed ovarian cancer.48 Patients were randomized to either 
Nintedanib or placebo therapy for 36 weeks. The 36 week PFS rates were 16.3% in the 
Nintedanib group and 5% in the placebo group (HR 0.65; 95% CI, 0.42-1.02).  The safety 


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Memorial Sloan Kettering Cancer Center 
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profile was similar to what was reported in the initial trials. The proportion of patients with 
any grade 3 or 4 adverse events was similar between the groups (34.9% for Nintedanib 
vs. 27.5% placebo, p=0.49). However, there was more grade 3 or 4 hepatotoxicity in the 
Nintedanib group (51.2%) compared to placebo (7.5%, p<.001) This clinical activity has 
lead to development of a phase III trial in which Nintedanib or placebo in combination with 
paclitaxel and carboplatin in the first line treatment of ovarian cancer is being evaluated 
(ClinicalTrials.gov Identifier NCT01015118). 
 
 
3.8.3 Nintedanib in Non-Small-Cell Lung Cancer (NSCLC) 
 
The clinical activity of Nintedanib in advanced non-small cell lung cancer (NSCLC) was 
first demonstrated in a phase I trial in combination with pemetrexed in patients previously 
treated with a platinum-based regimen.46 In this dose escalation study of continuous 
Nintedanib with pemetrexed 500mg/m2 given on day 1 over a 21 day cycle, the MTD dose 
was 200mg BID in combination with pemetrexed. 1 patient achieved a complete response 
44 days after starting treatment and disease stabilization seen in 50% as the best overall 
response.  Median PFS was 5.4 months for all patients. 
 
Nintedanib was also studied as a monotherapy in NSCLC patients in a phase II double- 
blind study.49 In this study, patients were randomized to either Nintedanib 250mg BID or 
Nintedanib 150mg BID, continuous dosing and assessed at 6 week intervals until disease 
progression. Disease stabilization was achieved in 48% of patients and there was one 
confirmed partial response seen at the Nintedanib 250mg BID dosing. Tumour 
stabilisation was achieved in 46% of patients (ECOG 0–1 patients: 59%), with one 
confirmed partial response (250 mg BID). 
 
The most commonly reported drug-related adverse events were nausea (57.5%), diarrhea 
(47.9%), vomiting (42.5%), anorexia (28.8%),  abdominal pain (13.7%)  and reversible 
alanine transaminase (ALT, 13.7%) and aspartate  aminotransferase elevations (AST, 
9.6%). The transaminase elevations were only seen at the higher dosing of the 
medication. 
 
Based on the promising phase I and II results, there were two multicenter phase III studies 
evaluating Nintedanib 200mg BID in combination with chemotherapy in advanced NSCLC: 
the LUME-Lung 1 and LUME-Lung 2 trials. The preliminary results of both trials were 
recently presented at the Annual ASCO 2013 Meeting. 
 
The LUME-Lung 1 trial evaluated Nintedanib plus docetaxel compared to placebo plus 
docetaxel in patients who progressed after first line therapy (ClinicalTrials.gov Identifier 
NCT00805194).50 The Nintedanib plus docetaxel group had a significantly PFS benefit 
(HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 months) compared to the docetaxel 
alone. In subset analysis, the overall survival was increased in the adenocarcinoma 
histology (HR 0.83; p=0.0359; median 12.6 vs 10.3 month). 
 
The LUME-Lung 2 trial compared Nintedanib plus pemetrexed compared to placebo plus 
pemetrexed in patients with advanced nonsquamous NSCLC in the second line setting 
(ClinicalTrials.gov Identifier NCT00806819).51 The study was stopped prematurely after 
713/1300 planned patients enrolled based on a pre-planned futility analysis. Ongoing 
patients were unblinded and follow-up was continued. The primary endpoint of PFS was 
met with the Nintedanib plus pemetrexed group showing a slightly improved median PFS 


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Memorial Sloan Kettering Cancer Center 
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Approved: 27-DEC-2016 
 
of median 4.4 vs 3.6 months in the pemetrexed arm (HR 0.83, 95% CI: 0.7–0.99, p=0.04). 
There was a higher incidence of grade 3-4 adverse events in Nintedanib plus pemetrexed 
compared to the pemetrexed alone arm (58.5% vs 42.3%). Withdrawals due to adverse 
events were similar between both groups. The most common reported drug-related 
adverse events (all grades) were ALT elevations (42.9%), AST elevations (37.2%), 
nausea (36.9%), diarrhea (34.9%), fatigue (33.7%), and decreased neutrophil count 
(21.6%). 
 
3.8.4 Rationale for Current Study 
 
There is a clear rational to study more than one VEGF targeted agent in esophagogastric 
cancers as has been indicated by experience in other solid tumor malignancies and other 
targeted agents. There have been inconsistent benefits for targeted agents within the 
spectrum of GI malignancies, underscoring the need to evaluate each new promising 
agent independently in each tumor type. 
 
For example, in GI malignancies, the EGFR tyrosine kinase inhibitors erlotinib  and 
gefitinib have been inactive as single agents in adenocarcinoma of the colon52, stomach,29 
and esophagus.30 However in pancreatic cancer, erlotinib plus chemotherapy with 
gemcitabine yielded positive results, including a progression free and overall survival 
benefit. On the other hand, the EGFR targeted antibody cetuximab failed when combined 
with chemotherapy in pancreatic cancer. This is in contrast to the single agent activity of 
cetuximab seen in colon cancer. 
 
It is clear that each new targeted agent, with individual variation in what specific targets 
are actually affected, needs to be evaluated in each solid tumor. Other than Human 
Epidermal Growth Factor Receptor (HER2), there are no validated treatment targets in 
esophagogastric 
cancer. Nintedanib is of particular 
interest 
in 
esophagogastric 
malignancies due to its ability to simultaneously target the VEGFR, PDGF, and FGFR 
pathways, which have been described and implicated in this disease. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single institution, open-label, non-randomized, phase II evaluation of oral Nintedanib 
at 200mg twice daily, continuous dosing in patients with metastatic or recurrent 
esophagogastric adenocarcinoma. 
 
Patients may have received up to one prior chemotherapy regimen for metastatic disease or 
up to two prior regimens if they previously received neoadjuvant/adjuvant chemotherapy or 
chemoradiotherapy for their initial localized disease.  All patients must be able to provide 
informed consent. 
 
See Section 10 for treatment schema. 
 
4.3 
Intervention 


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32 patients will be enrolled on this clinical trial.  Patients will receive Nintedanib 200mg twice 
daily continuously until disease progression, unacceptable toxicity, or serious intercurrent 
illness develops, or if patient consent is withdrawn. 
 
Patients must have measurable or evaluable disease and undergo a computerized 
tomography (CT) or magnetic resonance imaging (MRI) scan of their chest and abdomen 
within 28 days of study enrollment, then at eight weeks, and every eight weeks thereafter 
(every 2 cycles).  For the followup scans, a scheduling window of up to one to fourteen (1-14) 
days will be permitted. If a complete response is achieve and maintained for 12 months, 
patients with complete response will then be required to repeat CT or MRI evaluation every 4 
months up to 5 years post complete response status, then every 6 months thereafter, with a 
scheduling window of one to fourteen (1-14) days. Response assessment will be by RECIST 
1.1 criteria. The same imaging modality performed at baseline (CT or MRI) will be repeated 
at subsequent imaging. 
 
Therapy will be administered in the outpatient setting, with each cycle consisting of 28 days  
of continuous therapy. The cycle start date will coincide with the physician visit date.  A study 
diary will be completed by patients to ensure compliance with the study drug (Appendix        
I). 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Substance (INN): 
Nintedanib 
 
Other names: 
BIBF 1120 
Pharmaceutical form: 
Soft gelatine capsule 
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG 
 
Unit strength: 
100 mg and 150 mg capsules 
 
Daily dose: 
200 mg twice daily 
 
Duration of use: 
Continuous daily dosing; once cycle consists of 28 days. 
Patients are eligible for repeated treatment cycles in the 
absence of disease progression and undue adverse events (as 
per criteria in Section 9.2) 
 
Route of administration: 
Oral (swallowed) 
 
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, usually in the morning and the evening 
after food intake) 


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6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Pathologically or cytologically MSKCC confirmed esophagogastric adenocarcinoma. 
• 
Metastatic diseases measurable or evaluable on a CT or MRI scan according to 
RECIST 1.1 criteria. Locally recurrent disease that is not amenable to potentially 
curative surgery or radiation therapy is also allowed. Lesions must be ≥10mm in 
size.  Recurrent or metastatic disease within a prior radiation field is acceptable as 
long as the disease has progressed in the radiation field by RECIST criteria.  See 
Section 12.2 for definition of measurable lesions. 
• 
Patients are allowed to have had a maximum of 1 prior chemotherapy regimen for 
metastatic disease.  Patients are allowed to have a maximum of two prior regimens if 
they previously received neoadjuvant/adjuvant chemotherapy or chemoradiotherapy 
for their initial localized disease. 
• 
Patients aged 18 years or older. 
• 
Life expectancy of at least 6 months. 
• 
Karnofsky Performance Status (KPS) performance score ≥ 70%. 
• 
Patients must be able to reliably take and swallow oral medications. 
• 
Patients with prior deep vein thrombosis (DVT) or pulmonary embolism (PE) currently 
on anticoagulation regimen will be permitted. 
 
Adequate bone marrow, liver, and renal function as assessed by the following: 
• 
Hemoglobin ≥ 9.0 g/dL. 
• 
Absolute neutrophil count (ANC) ≥ 1,500/mm3. 
• 
Platelet count ≥ 100,000/mm3. 
• 
Total bilirubin within normal limits, 0–1 mg/dL. 
• 
AST and ALT< 1.5 times ULN. (For patients with liver involvement:  AST and ALT≤ 
2.5 ULN). 
• 
International normalized ratio (INR) < 2, prothrombin time (PT) < 20 sec, and partial 
thromboplastin time (PTT) < 55 sec . 
• 
Creatinine < 1.5 x the ULN or GFR<45 ml/min. 
 
6.3 
Subject Exclusion Criteria 
 
• 
HER-2 positive esophagogastric cancer. Patients with unknown HER2 status are 
permitted. 
• 
Patients receiving any concurrent anticancer therapy or investigational agents with 
the intention of treating esophagogastric cancer. Last prior therapy must have been 
completed at least 2 weeks (14 days) prior to starting Nintedanib. 
• 
Concurrent radiotherapy is not permitted for disease progression on treatment on 
protocol.  However, symptomatic treatment for pre-existing non-target lesions would 
be allowed with approval from the principal investigator. 
• 
Prior treatment with VEGFR inhibitor. 
• 
Brain metastases or leptomeningeal disease. 
• 
History of arterial thromboembolic (arterial blood clot) or hemorrhagic event with the 
exception of patients with pulmonary embolism stable on an anticoagulation regimen. 
• 
Patients with a cerebrovascular accident or transient ischemic attack within the past 
six months. 


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• 
Patients on warfarin for any reason. 
• 
Patient with known pre-existing interstitial lung disease. 
• 
History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure, New York Heart Association 
(NYHA) functional classification of 3, unstable angina or poorly controlled arrhythmia. 
Myocardial infarction within 6 month prior to the study entry. 
• 
Patients with history of proteinuria grade ≥ 2. 
• 
Women of childbearing potential (WOCBP), or men who are able to father a child, 
unwilling to use a medically acceptable method of contraception during the trial and 
for at least three months after the end of active therapy. 
• 
Women who are pregnant or breast-feeding. 
• 
Persistence of clinically relevant therapy related toxicity from previous chemotherapy 
and/or radiotherapy. This does not include hemoglobin or other hematologic or 
laboratory criteria, as long as eligibility criteria are met as outlined in 6.1. 
• 
Other malignancies within the past 5 years other than non-melanoma superficial skin 
cancer or carcinoma in situ of the cervix. 
• 
Concurrent medical conditions or injury which may increase the risk of toxicity, 
including ongoing or active infection, history of significant bleeding disorder unrelated 
to cancer (congenital bleeding disorders, acquired bleeding disorders within one 
year),  history of HIV-positive, or active or chronic hepatitis C and/or B infection. 
• 
Known or suspected active drug or alcohol abuse. 
• 
Gastrointestinal disorders or abnormalities that would interfere with absorption of the 
study drug. Patients who are unable to orally swallow the study medication. 
• 
Known hypersensitivity to trial drug. 
 
 
7.0 
RECRUITMENT PLAN 
 
This will be a single institution, phase II study. Patient with metastatic or recurrent 
esophageal, gastric, and gastroesophageal (GE) junction cancer that are eligible will be 
identified for enrollment from MSKCC clinical practice and clinic lists.  No additional 
measures, e.g. advertisement, payment to patients, will be employed to recruit patients. 
Patients will be accrued to this study without regard for gender or minority status. 
Inclusion of women and minorities 
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. There will be no limitations with regards to race or 
gender. 
 
Our institutional demographics for accrual of patients on esophageal and GE junction cancer 
trials reflect the national incidence of this disease. 10-15% of our patients have been 
women.  African-American males comprise 3-5% of patients treated on protocol. Given that 
our protocol accrual closely reflects the national incidence of this disease, no specific 
strategy will be undertaken to recruit women or persons of color on this trial. 
 
This protocol does not include children because the number of children with esophageal, 
gastric and GE junction cancer is very small and because the majority are already accessed 
by a nation-wide pediatric cancer research network. This statement is based on exclusion 4b 


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of the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research 
Involving Human Subjects. 
 
8.1 
PRETREATMENT EVALUATION 
 
To be completed within 2 weeks of study entry: 
 
• 
History and physical exam including vitals, height, weight, performance status. 
• 
Evaluation of concomitant medications and toxicity assessment. 
• 
Serum pregnancy test for women of childbearing potential (WOCP) 
In addition, all WOCP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant at any time during the study participation. 
• 
Laboratory evaluation including a complete blood count, PT/PTT, comprehensive 
chemistry panel (includes BUN, creatinine, ALT, AST, albumin, glucose, total protein, 
calcium, bilirubin, bicarbonate, sodium, chloride, potassium, alkaline phosphatase). 
 
To be completed within 4 weeks of study entry: 
 
• 
Electrocardiogram 
• 
CT scan or MRI documenting all measurable or evaluable disease. All measurable 
lesions used to define response must be >10mm in size. The primary tumor is 
excluded. Lesions within prior radiation fields are permitted as long as these lesions 
have documented progression in size. 
 
To be completed any time prior to starting therapy: 
 
• 
Histological confirmation of esophagogastric adenocarcinoma prior to study 
enrollment. 
• 
Available tumor tissue (20 unstained slides or tumor block) will be submitted for future 
molecular analysis (SEE SECTION 10 “Correlative Studies”) but not be required prior 
to registration. Note: if tissue is depleted, patient will still be eligible after discussion 
with the PI. 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 
Agent administration 
 
Treatment will be administered on an outpatient basis. Nintedanib is supplied as 100mg and 
150mg capsules. The starting dose of Nintedanib is 200mg orally twice daily for 28 days 
continuously, unless interrupted for intolerable toxicity. There is no planned interruption 
between treatment cycles unless clinically indicated. The cycle start date will coincide with 
the physician visit date. Because of the potential need for physician visit scheduling to vary 
(due to both physician and patient issues), to avoid violation of, and deviation from, the 
protocol, physician visits may vary by up to one to fourteen (1-14) days from a strict 28 day 
schedule. 


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Nintedanib will be taken on days 1-28 of each 28-day cycle.  Patients will swallow the soft gel 
capsule whole with approximately 250 mL of water each morning and evening after eating. 
The capsule cannot be crushed or dissolved. 
 
In case of misdosing, patients should proceed with the intake of medication according to the 
predefined schedule and take the next scheduled dose when it is due.  Patients with emesis 
should not take a replacement dose. A study diary will be completed by patients to ensure 
compliance with Nintedanib (see Appendix I). 
 
 
Concomitant Therapy 
The use of investigational or anticancer agents is not allowed while patients are on this 
study.  However, symptomatic treatment of tumor associated symptoms is allowed; such as 
radiation therapy with palliative intent and symptom control, provided that radiation does not 
affect target lesions and the reason for radiation does not reflect progressive disease. 
Concomitant medication, or therapy to provide adequate supportive care, may be given as 
necessary. If concomitant therapy is clinically indicated, patients may temporarily 
discontinue Nintedanib therapy and resume treatment following consultation with the treating 
physician and Principal Investigator. 
 
9.3 
Dose delay/modification 
 
Intrapatient dose reduction will be allowed depending on the type and severity of toxicity 
encountered provided that criteria for patient withdrawal from study treatment have not been 
met. The dose levels for Nintedanib are as described below: 
 
Starting dose 0 
Nintedanib 200mg twice daily 
Dose level -1 
Nintedanib 150mg twice daily 
Dose level -2 
Nintedanib 100mg twice daily 
If further dose reduction is required, the patient should be taken off-protocol. 
 
If the dose of Nintedanib is reduced due to toxicity, it will stay at the lower dose level for the 
entire time of administration on protocol. 
 
Patients who require a treatment delay of ≥21 consecutive days should also be taken off- 
protocol. 
 
 
9.4 
Suggested Medical Management of Nintedanib associated toxicities 
 
9.4.1 Management of diarrhea 
 
CTCAE Grade 
Action for Nintedanib and Anti- 
diarrheal treatment 
Action for 
Nintedanib after recovery of 
diarrhea 1 


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Grade 1 
Continue Nintedanib 
No Anti-diarrheal treatment 
No dose reduction of Nintedanib 
Grade 2 
Continue Nintedanib 
Anti-diarrheal treatment according to 
the local standard e.g. Loperamide p.r.n. 
No dose reduction of Nintedanib 
Grade 2 > 7 days despite optimal medical management  OR 
Grade > 3 
OR 
Any diarrhea independent of CTCAE grade leading to hospitalization of the patient 
First episode 
STOP Nintedanib until recovery1 
AND 
Anti-diarrheal treatment according to 
the local standard e.g. Loperamide p.r.n 
Reduce Nintedanib dose to 
150 mg BID after recovery of 
diarrhea 1 
Second episode 
STOP Nintedanib until recovery1 
AND 
Anti-diarrheal treatment according to 
the local standard e.g. Loperamide p.r.n. 
Reduce Nintedanib dose to 
100 mg BID after recovery of 
diarrhea 1 
Third episode 
PERMANENTLY discontinue 
Nintedanib treatment 
AND 
Anti-diarrhoeal treatment according to 
the local standard e.g. Loperamide p.r.n. 
PERMANENTLY discontinue 
Nintedanib treatment 
1 Until resolution to less than or equal to the patient’s pre-therapy status at study enrollment. 
 
9.4.2 Management of Liver Enzyme Elevations 
 
If liver enzyme elevations are considered to be related to Nintedanib, the following 
algorithm should be followed. This recommendation for the management of Nintedanib - 
induced liver toxicity is valid ONLY for patients with inclusion criteria: AST/ALT < 1.5 ULN 
and bilirubin ULN in patients with no metastases in liver and, AST/ALT < 2.5 ULN and 
bilirubin ≤ ULN in patients with metastases in liver. 
 
 
 
ALT, AST and bilirubin elevation 
1st episode 
2nd episode 
3rd episode 
ALT and/or AST ≤ 5x ULN with 
bilirubin ≤ 1.5 ULN 
Continue 
Nintedanib, No 
dose reduction 
Continue 
Nintedanib, No 
dose reduction 
Continue 
Nintedanib, No 
dose reduction 


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ALT or AST > 5x ULN 
or 
ALT or AST > 2.5 ULN in 
conjunction with bilirubin >1.5 ULN 
STOP 
Nintedanib until 
recovery* 
then reduce 
Nintedanib dose1 
STOP 
Nintedanib until 
recovery* 
then reduce 
Nintedanib dose1 
PERMANENT 
discontinuation 
of Nintedanib 
treatment 
*CTCAE grade ≤ 1 or baseline at study enrollment. 
1Nintedanib dose reductions : from 200 mg bid to 150 mg bid and from 150 mg bid to 100 mg bid 
 
CTCAE grades for AST/ALT (version 3.0): 
Grade 1 means ALT or AST = ULN- 2.5 x ULN 
Grade 2 means ALT or AST > 2.5-5.0 x ULN 
Grade 3 means ALT or AST > 5-20.0x x ULN 
Grade 4 means ALT or AST > 20.0 x ULN 
 
CTCAE grades for bilirubin (version 3.0): 
Grade 1 means > ULN- 1.5 ULN 
Grade 2 means > 1.5 ULN – 3x ULN 
Grade 3 means > 3x ULN – 10 ULN 
Grade 4 means > 10 x ULN 
 
 
9.4.3 Management of Nausea and Vomiting 
In order to reduce the occurrence and the intensity of emesis the patients should be treated 
according to the following recommendations: 
 
 
 
CTCAE Grade 
Antiemetic treatment 
Dose of Nintedanib 
Nausea =1 
No antiemetic treatment 
No dose reduction 
Nausea 2 and / or 
Vomiting =1 
No Nintedanib treatment pause 
Antiemetic treatment according to local standard 
of care e.g., metoclopramide or 
prochlorperazine 
If ineffective, patients should be treated accor- 
ding to treatment of vomiting >2 or nausea 
CTCAE Grade ≥ 3. 
No dose reduction 


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Vomiting ≥2 and/ or 
Nausea ≥ 3 
First episode 
Second episode 
Third episode 
Treatment with Nintedanib discontinued and 
resumed upon recovery1 
Antiemetic treatment according to local standard 
of care e.g.: with 5-HT3 receptor antagonist* 
and/or corticosteroid 
Treatment with Nintedanib discontinued and 
resumed upon recovery1 
Treatment as above 
As above 
Nintedanib: dose 
reduction2 
Nintedanib: dose 
reduction2 
Nintedanib 
discontinuation 
 
 
1CTCAE grade ≤ 1 or baseline at study enrollment. 
2Nintedanib dose reductions : from 200 mg bid to 150 mg bid and from 150 mg bid to 100 mg bid 
* Note: Tropisetron and dolasetron should be avoided due to genetically polymorphic metabolism 
by CYP2D6. 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
 
 
Any 
time 
prior 
to 
start 
≤4 
weeks 
prior 
to 
start 
≤2 
weeks 
prior 
to 
start 
Cycle 11 
Cycle 2 and 
onwards2 
End of 
treatment visit3 
Week # 
1 
2 
3 
4 
1 
2 
3 
4 
Histological 
confirmation of 
diagnosis 
X 
Informed 
consent 
X 
History, 
concomitant 
medications and 
toxicity 
X 
X 
X 
X 
X 
X 


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assessment 
Physical exam, 
vital signs4, and 
performance 
status 
X 
X 
X 
X 
X 
X 
Complete blood 
count, 
comprehensive 
metabolic panel5 
X 
X 
X 
X 
X 
X 
PT/PTT 
X 
ECG7 
X 
Serum 
Pregnancy Test8 
X 
Radiographic 
tumor 
assessment9,10 
X 
X 
Nintedanib pill 
diary/compliance 
review 
X 
X 
X 
Nintedanib 
dosing 
Nintedanib 200mg Twice Daily, 
Every Day 
 
 
1. 
Each treatment cycle consists of 28 days and will be repeated until tumor progression (PD according to 
RECIST version 1.1) confirmed by tumor imaging. 
2. 
Beginning with Cycle 2, each cycle start date will coincide with the physician visit date. 
3. 
End of treatment (EOT) visit: within 14 days after permanent termination of trial drug(s).  If permanent 
discontinuation of study drugs falls on a scheduled visit, examinations as defined for EOT should be 
preformed instead of the examination of the scheduled visit. 
4. 
Vital signs: includes respiratory rate, pulse, temperature and blood pressure. 
5. 
Comprehensive metabolic panel (CMP) includes: BUN, creatinine, ALT, AST, albumin, glucose, total protein, 
calcium, bilirubin, bicarbonate, sodium, chloride, potassium, alkaline phosphatase. 
6. 
12-Lead resting electrocardiogram (ECG) will be performed at screening 
7. 
For women of childbearing potential 
8. 
A CT or MRI will be obtained at baseline within four weeks of study enrollment.  Repeat radiographic 
evaluation will be obtained after the first eight weeks, and then every eight weeks ±14 days thereafter. 
Patient may have CT or MRI scan on an earlier or later date than allowed by the window of ±14 days, if 
clinically indicated at the investigators discretion. Patient with a partial/complete response require a 
confirmatory scan at least four weeks after the initial scan documenting response (see Section 12.0). If a 
complete response is achieved and maintained for 12 months, patients with complete response will then be 
required to repeat CT or MRI evaluation every 4 months up to 5 years post complete response status, then 


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every 6 months thereafter, with a scheduling window of one to fourteen (1-14) days. The same imaging 
modality performed at baseline (CT or MRI) will be repeated at subsequent imaging. 
9. 
Because of the potential need for blood tests, CT/MRI scan, and physician visit scheduling to vary (due to 
both physician and patient issues), to avoid violation of, and deviation from the protocol, blood tests, CT/MRI 
scans, and physician visits (including physical exam, vitals, blood pressure, performance status, and 
concomitant medications) may vary by up to one week (7 days) before and 1 week (7 days) after the 
scheduled date The study treatment will not be interrupted, with the next cycle beginning before the patient is 
evaluated for toxicity. 
 
 
Evaluations during treatment 
 
Please note, because of the potential need for blood tests, CT/MRI scan, and physician visit 
scheduling to vary (due to both physician and patient issues), to avoid violation of, and 
deviation from the protocol, blood tests, CT/MRI scans, and physician visits (including 
physical exam, vitals, blood pressure, performance status, and concomitant medications) 
may vary by up to one to week (7 days) before and 1 week (7days) after the scheduled date. 
The study treatment will not be interrupted, with the next cycle beginning before the patient is 
evaluated for toxicity. 
 
• 
History, concomitant medications and toxicity assessment, physical exam, vital signs, 
and performance status assessment on Week 1, Week 2, Week 3 of Cycle 1, then on 
Week 1 of Cycle 2, and each cycle thereafter. 
• 
Complete blood count, comprehensive metabolic panel on Week 1, Week 2, Week 3 
of Cycle 1, then on Week 1 of each cycle thereafter. 
• 
Nintedanib diary to be collected on Week 1 of each new cycle. 
• 
A repeat CT or MRI of evaluable or measurable disease at baseline, then at eight 
weeks, and then every eight weeks thereafter.  CT or MRI may be performed more 
frequently if determined necessary per investigator discretion. The same imaging 
modality performed at baseline (CT or MRI) will be repeated at subsequent imaging 
 
Evaluations at End of Treatment visit 
 
• 
History, concomitant medications and toxicity assessment. 
• 
Physical exam, vital signs, and performance status assessment. 
• 
Nintedanib diary to be collected. 
• 
Complete blood count, comprehensive metabolic panel. 
• 
Unused study medication to be returned to MSKCC pharmacy. 
 
 
 
Correlative studies 
 
Exploratory biomarker analysis will be performed on archival tissue or any new tissue 
procurement that becomes clinically available (i.e. no additional biopsy will be procured for 
the purpose of these studies.) 
 
We will define the frequency and predictive impact of FGFR overexpression and 
amplification in patients with treatment refractory esophagogastric cancer enrolled on this 


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study. Protein expression of FGFR1, 2, 3 will be assessed by immunohistochemistry and 
measured. FGFR genomic alterations and amplification will be assessed by massively parallel 
sequencing using the IMPACT assay and proteomics-based CEER assay. We will also 
compare the mutational status of archival tumor samples collected for clinical purposes. 
 
Patients with available tumor tissue will be separately consented for protocol 12-245, “Tumor 
Genomic Profiling in Patients Evaluated for Targeted Cancer Therapy.” 
 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
For definition of dose limiting toxicity and suggested medical management of Nintedanib 
associated toxicities refer to Section 9.1 and 9.2. 
 
Nintedanib (Nindetanib) 
 
Nintedanib has shown an acceptable safety profile, on the basis of results from the phase I 
and phase II studies conducted to date. The most commonly reported treatment-emergent 
adverse events (TEAEs) were GI disorders including nausea, vomiting, diarrhea, and 
AST/ALT/bilirubin elevations. Below is a list of TEAEs based on their likelihood of 
occurrence at a dose of ≤200mg BID: 
Likely: (>7% incidence all grades)54 
 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Decreased appetite 
• 
Fatigue 
• 
Asthenia 
• 
Weight loss 
• 
Abdominal pain 
• 
Aspartate aminotransferase elevation 
• 
Alanine aminotransferase elevation 
• 
Gamma-glutamyltransferase elevation 
• 
Hyperkalemia 
• 
Hyponatremia 
 
Less Likely (≤5% all grades)54,55 
 
• 
Abdominal pain 
• 
Constipation 
• 
Headache 
• 
Hypertension 
• 
Alkaline phosphatase elevation 


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Special warning and precautions for use: 
 
During treatment with Nintedanib, all study patients will be advised to avoid sun exposure or 
artificial UVA/UVB radiation in solaria or tanning booths. If exposure to sunlight cannot be 
avoided, protective clothing and broad spectrum (UVA/UVB) sunscreens should be used. 
After discontinuation of Nintedanib treatment all protective measures should be continued for 
at least 2 weeks 
 
11.1 Definitions of Adverse Events 
 
Adverse Event 
An adverse event (AE) shall mean any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient or clinical investigation subject 
administered a pharmaceutical product. The medical occurrence does not necessarily have a 
causal relationship with the treatment. 
Serious Adverse Event 
 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability/incapacity, requires or prolongs 
patient hospitalization, is a congenital anomaly/birth defect; or based upon appropriate 
medical judgment, may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definitions. 
 
Severity of adverse event 
The severity of adverse event should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medications, concomitant diseases, and relevant 
history. Assessment of causal relationship must be recorded for each adverse event. 
 
Causality will be reported as either “Yes” or “No.” 
 
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the AE 
 
No: 
There is no causal relationship between the investigational product 
administered and the AE 
 
 
 
11.2 Malignant disease progression 
 
Expected fluctuations or expected deterioration of the underlying disease should not be 
recorded as an AE unless at least one of the following criteria is me: 


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• 
The worsening of the disease constitutes an SAE 
• 
Additional treatment is required, i.e., concomitant medication is added or changed 
• 
An unexpected deterioration from baseline has occurred in the opinion of the 
investigator 
 
11.3 Worsening of pre-existing conditions 
 
A pre-existing condition present at baseline, which remains unchanged during the trial, does 
not need to be recorded as adverse event.  Any worsening of any pre-existing baseline 
condition should be recorded as an adverse event. Examples of worsening of a pre-existing 
condition that should be recorded as an AE are given below: 
 
• 
Worsening of condition meets the criteria for an SAE 
• 
Action is taken with the investigational drug (i.e. dose is reduced of treatment is 
discontinued) 
• 
Treatment is required (concomitant medication is added or changed) 
• 
The investigator believes a patient has shown a clear deterioration from baseline 
symptoms 
 
11.4 
Documentation and Reporting of adverse events 
 
All adverse events occurring after the subject has signed the informed consent must be fully 
recorded in the subject’s case record form. 
 
Each serious adverse event (SAE) must be followed up until resolution or stabilization by 
submission of updated reports to the designated person. An isolated laboratory abnormality 
that is assigned grade 4, according to CTC definition, is not reportable as an SAE, unless the 
investigator assesses that the even meets the standard ICH criteria for an SAE. CTC grade 
4 baseline laboratory abnormalities that are part of the disease profile should not be reported 
as an SAE, specifically when they are allowed or not excluded by the protocol 
inclusion/exclusion criteria. 
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients who receive at least one week of Nintedanib will be evaluable for toxicity and 
response. Patients who are unable to complete one week of therapy will not be evaluated for 
toxicity or response and will be replaced by a new patient. 
12.1 
Measurement of effect 
 
Patients will undergo a baseline CT/MRI assessment and be re-evaluated after two cycles, 
i.e., 8 weeks of treatment and then every two cycles or eight weeks thereafter. If determined 
clinically necessary by treating physician, CT/MRI assessment may be performed more 
frequently. The same imaging modality performed at baseline (CT or MRI) will be repeated at 


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subsequent imaging. Response and progression will be evaluated in this study using 
standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1.53 
Target lesions must have a minimum size of at least one diameter of 10mm for liver, soft 
tissue lesions, lung, and skin. Pathological nodes must be at least 15mm in the short axis to 
be considered target lesions. The primary tumor is not considered measurable disease. 
Recurrent or metastatic lesions within a prior radiation field are acceptable as long as 
disease has progressed in the radiation field by RECIST 1.1 criteria. 
12.2 
Progression-free survival 
 
The primary endpoint is to evaluate the 6-month progression free survival (PFS); hence 
patients with evaluable disease by RECIST are eligible for the trial. This is defined as the 
duration of time from start of treatment to time of progression or death from any cause. 
Patients who are taken off-study because of drug-related toxicity or other adverse event but 
who are alive and have stable or responding disease at the time of trial discontinuation will 
continue to follow per protocol, however, if they start another therapy, they will be considered 
as failure of therapy at that time and will be removed from protocol. 
 
12.3 
Evaluation of objective response rate 
 
The secondary endpoints include objective response rate, safety and tolerability.  The 
objective response rate will be the best overall response, or the best response recorded from 
the start of treatment until disease progression/recurrence. The patient’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria 
by RECIST and defined as complete response (CR), and partial response (PR). 
 
The type, frequency, severity, timing, and relationship of each adverse event will be 
determined as per the NCI Common Toxicity Criteria, version 3.0. Given the small sample 
size, the analysis of correlative biomarkers will be exploratory and hypothesis generating. 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time, the patient develops progressive disease he/she will be taken off study and 
referred for alternative therapy. If at any time the patient develops unacceptable toxicity that 
fails to resolve after a maximum treatment delay of 4 weeks, he/she will be removed from 
study.  Before being removed from the study, patients will be scanned to assess the 
response. If the off study scan shows progression of disease then the patient will be 
considered as a non-responder, while a CR or PR will be considered as response.  A patient 
will be withdrawn from the study treatment in the following circumstances: 
 
• 
Patient is no longer able to participate in the study (e.g. AE, surgery, concomitant 
diagnoses, concomitant therapies or administrative reasons); in such a case the 
Investigator’s reason for patient’s removal must be recorded in CRDB. 
• 
Patient withdrawal of consents or election to discontinue participation in the trial. 


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• 
Significant deviation from the protocol or eligibility criteria; such patients will be 
considered protocol violations and removed from study. 
• 
Non-compliance with study or follow-up procedures. 
• 
Drug related AE(s) that have not resolved after 3 weeks of treatment interruption. 
Exception to this in patients who derive obvious clinical benefit according to the 
investigator’s judgment could be considered upon discussion with Principal 
Investigator. The dose reduction scheme provided should be followed in this case. 
• 
Repeat episodes of drug related toxicity despite dose reduction to Nintedanib 100mg 
twice daily dose. 
• 
Documented progressive disease. 
• 
Patients who become pregnant while on study. 
 
As soon as a patient is withdrawn from the study treatment, the End of Treatment (EOT) visit has to 
be performed (not in case patient has withdrawn consent).  Every effort should be made to follow-up 
patients in case an adverse event is still ongoing at the time of withdrawal. 
 
14.0 
BIOSTATISTICS 
 
This is a single institution, open-label, non-randomized, single-arm phase II evaluation. The primary 
objective of this study is to determine the 6 month progression free survival (PFS) for patients with 
advanced or recurrent EG cancer treated with Nintedanib 200 mg twice per day. PFS is defined in 
Section 12.2. 
We are using 6 month PFS as the primary endpoint in this study of 2nd line treatment for advanced 
EG cancer. Previous studies have estimated the 6 months to be 4.5% with placebo, 12% with 
everolimus and 18% for ramucirumab. Based on this information, a 6 month PFS of 10% or less will 
be considered unacceptable while 28% or more will be considered promising. Using an exact 
binomial single stage design we require 32 patients to differentiate between 6-month PFS of 10% 
and 28% with type I and II error rates of 10% each. If 6 or more patients are alive and progression 
free at 6 months, the regimen is declared promising. With a total of 32 patients, we also have 89% 
power to detect an improvement in the response rate from 5% to 20% with a one-sided type I error 
rate of 10%. We assume an accrual rate of 1-2 patients per month for study duration of 18-35 
months. 
 
 
Secondary endpoints involve an assessment of the overall response rate (complete and partial 
responses), as determined by RECIST criteria. Toxicities will also be assessed and tabulated. 
Correlative analyses will be exploratory in nature. We will assess the relationship between FGFR 
amplification (by FISH) and FGFR overexpression (by IHC) with progression free survival using log- 
rank test.  Fisher’s exact test will be employed to assess these relationships with response. 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 


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Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.3 
Randomization 
 
This research study does not require randomization procedures. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
The principal investigator will be responsible for the data collection and management with the 
assistance of a research study assistant (RSA) who will be assigned to the study. The 
responsibilities of the RSA include project compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database.  Source 
documentation will be available to support the computerized patient record. 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness  
of registration data.  Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rate and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team. Random-sample data quality and protocol compliance audits 
will be conducted by the study team. 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled, “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 


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Safety Monitoring Plans can be found on the MKSCC Intranet at:  
http://mskweb2.mkscc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion with the patient. It will be reviewed that 
participation in this clinical trial is voluntary and that the patient may withdraw consent at any 
time. The study is designed with careful safety monitoring for toxicity including physician  
visits and serial laboratory monitoring. Specific guidelines for symptom management are in 
place to protect the study participation. The financial costs of the study will be discussed; 
Nintedanib will be provided free of charge. Correlative tests will be performed without charge 
to the patient. The patient will be responsible for the cost of standard medical care and all 
hospitalization, even for complications of treatment. 
 
No incentives will be offered to patients/subjects to participate in the study. 
 
Inclusion of women and minorities 
MSKCC has file forms HHS 44 (civil rights), HHS 641 (handicapped individual), HHS 639-A 
(sex discrimination) and HHS 680 (age discrimination); we also take due notice of the 
NIH/ADAMHA policy concerning inclusion of women and minorities in clinical research 
populations.  Patients of all races, both males and females, will be enrolled into the protocol. 
In the New York metropolitan area, there are a high proportion of minority patients (e.g. 
African-American, Hispanic). In general, about 15% of patients at MSKCC are members of 
minority ethnic groups. We will actively try to recruit minority patients to this protocol. 
 
Exclusion of children and lactating or pregnant women 
Children are excluded from this protocol because there is insufficient data to determine the 
safety of Nintedanib in children. In addition, the incidence of esophagogastric cancer in 
children is limited and because the majority are already access by a nationwide pediatric 
cancer research network.  This statement is based on exclusion 4b for the NIH Policy and 
Guidelines on the Inclusion of Children as Participants in Research Involving Human 


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Subjects.  Similarly, lactating and pregnant women are excluded because of the potential 
teratogenicity and embryotoxicity of Nintedanib. 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled. 
o A description of the subject’s condition. 
o Indication if the subject remains on the study. 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 


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17.3.1 Adverse event and serious adverse event reporting 
 
Upon inclusion into a trial, the patient’s condition is assessed (e.g. documentation of 
history/concomitant diagnoses and diseases), and relevant changes from baseline are noted 
subsequently. 
 
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the trial follow-up period of 28 days 
following the last administration of the drug) will be collected, documented and reported by 
the investigator.  For each adverse event, the investigator will provide the onset date, end 
date, intensity, treatment required, outcome, seriousness, and action taken with the 
investigational drug. The investigator will determine the relationship and expectedness with 
the investigational drug to all AEs as defined in the listed adverse event section of 
Boehringer Ingelheim’ s Investigator Brochure for the product. 
 
If not stipulated differently in the pharmacovigilance agreement, SAEs are to be reported to 
BI using the BI IIS Serious Adverse Event Report Form including a documented causal 
relationship assessment and providing as much detail regarding the SAE as possible. With 
receipt of follow-up information, all remaining fields on the SAE form are to be completed or 
updated. 
 
 
17.3.2 Protocol-specified events of special interest 
The following events are considered as Protocol-specified events of special interests: 
 
Any gastrointestinal- and non-gastrointestinal perforation, leakage, fistula formation, 
abscess 
In such case the following additional information need to be collected, documented in the 
respective comment field of the CRF page and the respective narratives of the SAE. That 
has to be forwarded to Boehringer Ingelheim: 
• 
Location of perforation, leakage, fistula, abscess 
• 
Location/extent of abdominal tumor manifestations 
• 
Imaging & reports (CT, ultrasound, endoscopy, pathology, etc.) 
• 
Prior surgery (location, wound healing complications) 
• 
Concomitant diseases with GI involvement (e.g., M Crohn, vasculitis, tuberculosis, 
diverticulitis) 
• 
Thromboembolic events (or predisposition) 
 
Drug-induced liver injury (DILI) 
 
Drug-induced liver injury is under constant surveillance by BI 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 


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• 
An elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of bilirubin 
to >1.5 fold ULN measured in the same blood draw sample 
 
 
Patients showing above laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met and according to Appendix II of this clinical trial 
protocol. 
 
Protocol-specified AESI are to be reported in an expedited manner similar to Serious 
Adverse Events, even if they do not meet any of the seriousness criteria. 
 
17.3.3 Responsibilities for SAE reporting 
The investigator shall report all SAEs, non-serious AEs occurring at the same time and/or 
which are medically related to the SAE and AEs of Special Interests independent from their 
seriousness to Boehringer Ingelheim Pharmaceuticals, Inc. In the event of such an event, 
the investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures. 
 
 
The investigator shall report all SAEs, non-serious AEs relevant to a reported SAE, and AEs 
of Special Interest by fax to the Boehringer Ingelheim Unique Entry Point as detailed below in 
accordance with the following timelines: 
• within five (5) calendar days upon receipt of initial and follow-up SAEs containing at 
least one fatal or immediately life-threatening event; 
• within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
Boehringer Ingelheim Pharmaceuticals, Inc 
Boehringer Ingelheim Pharmaceuticals, Inc. 
900 Ridgebury Road 
Ridgefield, CT 06877 
Fax: 1-203-837-4329 
E-mail: PV_global_casemanagement@boehringer-ingelheim.com 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to   
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 


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3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
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IRB#: 14-094 A (5) 
Approved: 27-DEC-2016 
 
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20.0 
APPENDICES 
 
Appendix I 
Patient Pill Diary 
 
Appendix II 
Drug-Induced Liver Injury (DILI) Guideline