Multicenter Phase 2 Study of Nintedanib for Patients With Advanced Carcinoid Tumors
Phase: PHASE2
Conditions: Carcinoid Tumor, Metastatic Carcinoid Tumor, Neuroendocrine Neoplasm
Sponsor: Roswell Park Cancer Institute

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TITLE: Multicenter Phase 2 Study of Nintedanib for Patients with Advanced Carcinoid 
Tumors
Roswell Park Cancer Institute
Study Number:
Initial Date:
Amendment #1:
Amendment #2:
Amendment #3:
Amendment #4:
Amendment #5:
Amendment #6:
Amendment #7:
Amendment #8:
I259114   NCT02399215   
07 November 2014 03 
March 2015 
08 April 2015
25 June 2015
08 March 2016 
11 May 2016
26 October 2016 22 
February 2017 08 
March 2018
Principal Investigator:
Renuka V. Iyer, MD
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-3099
Renuka.Iyer@RoswellPark.org
Sponsor:
Funding:
Industry/Other Supporter:
Roswell Park Cancer Institute
NCCN
Boehringer Ingelheim
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above. The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party (ies) above.
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Study Contacts 
(Study personnel outside of RPCI CRS who will be housing essential study documents)
Name
Institution
Email
Role
Diane Reidy-Lagunes, 
MD
Memorial Sloan Kettering 
Cancer Center
Reidyd@MSKCC.org
IMPACT Assay
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SYNOPSIS
Title / Phase
Multicenter Phase 2 Study of Nintedanib for Patients with 
Advanced Carcinoid Tumors
Roswell Park Cancer Institute Study 
Number
I 259114
Roswell Park Cancer Institute Investigator
Renuka V. Iyer, MD
Sponsor
Roswell Park Cancer Institute
Funding Organization
NCCN
Industry Support
Boehringer Ingelheim
Study Drug
Nintedanib (BIBF1120: provided by Boehringer Ingelheim)
Objectives
Primary:

To assess progression free survival (PFS), defined as the time 
interval from initiation of therapy, to its cessation for 
documentation of progressive disease (PD) or death
Secondary:

To assess the clinical response (complete response + partial 
response) in all patients with measurable disease (using 
standard RECISTv1.1 criteria).

To assess overall survival (OS) in all patients.

Assess changes in QOL throughout treatment using the 
EORTC QLQ – GI.NET21 questionnaire for carcinoid patients 
with gastrointestinal neuroendocrine tumors, in all patients who 
have filled out at least two QOL questionnaires and, will be 
reported by groups based on response (response, stable disease 
or progressive disease).

Steady-state PK of nintedanib, biomarkers, Treg and cytokine 
expression and growth factors will be analyzed for all patients 
and reported in groups based on response.

Gene mutations and copy number alterations analysis in the 
mTOR pathway (will be performed only on the first 10 
patients), protein expression of activation of Akt (as well as 
other downstream targets).

Toxicity (graded using the NCI CTCAE version 4.0) will be 
closely monitored and all toxicities will be tabulated
Study Design
This is an open label, multi-center phase II study in all patients with 
advanced low and intermediate grade neuroendocrine cancers 
(carcinoids), excluding PNETS (pancreatic neuroendocrine tumors).
Target Accrual and Study Duration
Two participating institutions will enroll maximum of 30 evaluable 
patients over a 24 month period.
Study Procedures
Physical Examination (including pre –existing conditions, vital 
signs, and body weight): Baseline, Day 1 of every cycle beginning 
with Cycle 2, End of Treatment 
Hematology: Baseline, Cycle 1-Week 1-Day 1, Cycle 1-Week 3-
Day 15, Day 1 of subsequent cycles, End of Treatment.
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Chemistry: Baseline, Cycle 1-Week 1-Day 1, Cycle 1-Week 3-Day 
15, Day 1 of subsequent cycles, End of Treatment.
Serum serotonin, Chromogranin A: Baseline, every 8 weeks (x24 
weeks) prior to treatment beginning at Cycle 3-Week 1-Day 1 
followed by every 12 weeks (on same day as imaging).
Urine Sample (24-hr urine 5-HIAA test): Baseline
Urine protein/Creatine ratio: . Baseline and, prior to treatment 
every 8 weeks for 24 weeks followed by evaluations at every 12 
week  or as clinically indicated
Plasma Biomarkers: Baseline, 8 weeks (+/- 3 days)  after start of 
treatment
EORTC QLQ – GI.NET21: Baseline, prior to treatment every 8 
weeks from start of treatment (x24 weeks) followed by evaluations 
every 12 weeks (on same day as imaging)., End of Treatment
Pregnancy test (serum): Baseline
ECOG Performance Status: Baseline, prior to treatment every 8 
weeks from start of treatment (x24 weeks) followed by evaluations 
every 12 weeks (on same day as imaging)., End of Treatment
Immune biomarkers: Baseline
CT scan of (chest, abdomen, & pelvis): Baseline, restaging will be 
performed every 8 weeks from start of treatment (x24 weeks), 
followed by every 12 weeks.
Electrocardiogram: Baseline
Tumor/Disease assessment: Baseline, every 8 weeks from start of 
treatment for 24 weeks, followed by every 12 weeks
Concomitant Medications: Baseline, Cycle 1-Week 1-Day 1, 
Cycle 1-Week 3-Day 15, Day 1 of subsequent cycles, End of 
Treatment, PFS Follow-Up.
Adverse Events: Baseline, Cycle 1-Week 1-Day 1, Cycle 1-Week 
3-Day 1, Day 1 of subsequent cycles, End of Treatment, PFS 
Follow-Up.
Statistical Analysis
Sample Size Determination: Two participating institutions will 
enroll maximum of 30 evaluable patients over a 24 month 
period.The sample size calculation is based on testing the 
hypotheses concerning the PFS rate at 16 weeks in patients treated 
under the proposed therapy: H0: p ≤ p0 versus HA: p > p0. This 
single-stage design requires a total of n patients in order to achieve 
approximately 1-β power to detect differences of ∆ percentage 
points (p0 versus p0 +∆). For this study α = 0.10 and 1-β =0.90; with 
p0=0.40 and =0.24 for this population of carcinoid patients. 
Efficacy Analysis: The primary objective of this study is to assess 
the efficacy of the investigational agent nintedanib in carcinoid 
patients. Let p represent the PFS rate at 16 weeks. A true PFS rate 
at 16 weeks of less than p0 =0.40 is considered unacceptable in 
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carcinoid, and evidence of such will deem the treatment not worthy 
of further study. The null and alternative hypotheses to be tested are 
H0: p ≤ p0 versus HA: p > p0. A one-sided exact binomial test (at a 
nominal α=0.10) and corresponding decision rules will be used to 
evaluate these hypotheses:

If 15 patients or less have not progressed at 16 weeks, 
then it is concluded that the therapy is not promising.

If 16 patients or more have not progressed at 16 weeks, 
then it will be concluded that the therapy is promising.
Secondary Analysis: The time-to-event outcomes (PFS and OS) will 
be reported using standard Kaplan-Meier methods. Ninety-five 
percent confidence intervals for the median PFS and OS will be 
calculated using Greenwood's formula. Exact 90% confidence 
interval estimates using the Clopper-Pearson method will be given 
for the response and toxicity rates. An exact 90% confidence 
interval will be given for the rate of improved QOL. Changes in 
pre- and post- treatment cytokine expression and growth factors will 
be analyzed using permutation paired t-tests. Dichotomous 
variables, such as response and QOL, will be analyzed using the 
logistic regression to investigate their association with quantified 
variables, such as biomarker expression and gene mutation. The 
association between survival and quantified variables will be 
investigated using the Cox-proportional hazard model.
Safety Analysis: The frequency of toxicities will be tabulated by 
grade across all dose levels and cycles. All participants who receive 
any study treatment will be considered evaluable for toxicity.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: Multicenter Phase 2 Study of Nintedanib for Patients with Advanced Carcinoid 
Tumors.
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
o
Patient must be on a stable dose of octreotide LAR or lanreotide for 
3 months prior to study enrollment.
o
Patients must have histologically or cytologically confirmed well 
differentiated or moderately differentiated (low grade or intermediate 
grade) neuroendocrine tumor that is locally advanced or metastatic and 
not of pancreatic origin
o
Measurable disease determined by CT or MRI.
o
Age ≥ 18 years of age.
o
Have an ECOG Performance Status of 0 – 2.
o
Life expectancy greater than 3 months.
o
Have the following clinical laboratory values: 
o
Leukocytes ≥ 3,000/μL
o
Absolute neutrophil count ≥1,500/μL
o
Total bilirubin ≤ 2 mg/dL
AST / ALT, 
o
AST/ALT ≤ 1.5 X ULN and bilirubin ≤ ULN for patients 
without liver metastases.
o
AST/ALT ≤ 2.5 X ULN and bilirubin ≤ ULN for patients with 
liver metastases.
o
Patients with Gilbert syndrome and bilirubin < 2 X ULN and 
normal AST/ALT 
o
Creatinine ≤1.5 mg/dl
o
Prior treatment will be permitted including surgery ≥ 4 weeks), cytotoxic 
chemotherapy (maximum of 2 prior regimens); radiation, interferon, 
targeted growth factors ≥ 4 weeks); and prior treatment with octreotide, 
will be allowed.
o
Ability to swallow and retain oral medication.
o
Participants of child-bearing potential must agree to use adequate 
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
contraceptive methods (e.g., hormonal or barrier method of birth control; 
abstinence) prior to study entry. Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.
o
Participant or legal representative must understand the investigational 
nature of this study and sign an Independent Ethics 
Committee/Institutional Review Board approved written informed 
consent form prior to receiving any study related procedure.
o
Archival tissue of carcinoid biopsy  must be available.
Investigator Signature: ___________________________________
Date: ___________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: Multicenter Phase 2 Study of Nintedanib for Patients with Advanced Carcinoid 
Tumors.
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Uncontrolled hypertension, unstable angina, New York Heart 
Association Grade II or greater congestive heart failure, unstable 
symptomatic arrhythmia requiring medication, or clinically significant 
peripheral vascular disease (Grade II or greater). Refer to Appendix C.
2.
Presence of brain metastases.
3.
Major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to day 0, or anticipated need for major surgical 
procedure during the course of the study, or fine needle aspirations or 
core biopsies within 7 days prior to day 0.
4.
Significant proteinuria at baseline (> 500 mg/ 24 h)
5.
Serious non-healing wound, ulcer or bone fracture
6.
Evidence of bleeding diathesis or coagulopathy.
7.
Recent (< 6 months) arterial thromboembolic events, including transient 
ischemic attack, cerebrovascular accident, unstable angina, or myocardial 
infarction.
8.
Poorly differentiated neuroendocrine carcinoma, high-grade 
neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or 
small cell carcinoma.
9.
Hepatic artery embolization or ablation of hepatic metastasis within 3 
months of enrollment,  prior PRRT within 4 months or any other cancer 
therapy within 4 weeks .  (As long as all toxicities are resolved).
10. Intolerance or hypersensitivity to octreotide.
11. Severe or uncontrolled medical conditions.
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements.
13. Pregnant or nursing female participants.
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
14. Unwilling or unable to follow protocol requirements.
15. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
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TABLE OF CONTENTS
1
Background ............................................................................................................................16
1.1
Carcinoid (Neuroendocrine) Tumors..................................................................................16
1.2
Nintedanib...........................................................................................................................17
1.3
Preclinical Development and Pharmacokinetics of Nintedanib .........................................17
1.4
Clinical Studies with Nintedanib........................................................................................19
1.4.1
Phase I.............................................................................................................................19
1.4.2
NSCLC............................................................................................................................20
1.4.3
Ovarian Cancer ...............................................................................................................21
1.4.4
Renal Cell Cancer ...........................................................................................................21
1.4.5
Hepatocellular Cancer.....................................................................................................21
1.4.6
Colorectal Cancer............................................................................................................22
1.5
Correlative Studies..............................................................................................................22
1.5.1
Tissue biomarkers ...........................................................................................................22
1.5.2
Plasma Markers/Modeling ..............................................................................................23
1.5.3
Immune Biomarkers........................................................................................................23
1.5.4
Quality of Life.................................................................................................................24
1.6
Risks and/or Benefits..........................................................................................................24
2
Rationale.................................................................................................................................25
3
Objectives...............................................................................................................................26
3.1
Primary Objective...............................................................................................................26
3.2
Secondary Objectives .........................................................................................................26
4
Methodology ..........................................................................................................................26
4.1
Study Design.......................................................................................................................26
4.2
Target Accrual and Study Duration....................................................................................27
5
Participant Selection...............................................................................................................27
5.1
Inclusion Criteria ................................................................................................................27
5.2
Exclusion Criteria ...............................................................................................................28
5.3
Inclusion of Women and Minorities...................................................................................28
6
Treatment Plan .......................................................................................................................29
6.1
Dosing and Administration.................................................................................................29
6.2
Dose Modifications.............................................................................................................29
6.2.1
Management of Diarrhea ................................................................................................30
6.3
Management of Proteinuria ................................................................................................31
6.3.1
Dose Reduction...............................................................................................................31
6.4
General Concomitant Medication and Supportive Care.....................................................32
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6.4.1
Additional precautions and supportive care....................................................................32
6.4.2
Concomitant medications................................................................................................33
6.5
Duration of Treatment ........................................................................................................33
6.6
Treatment Discontinuation .................................................................................................33
6.7
Compliance.........................................................................................................................34
7
Investigational Product...........................................................................................................34
7.1
Active Substance and Source..............................................................................................34
7.2
Drug Shipment....................................................................................................................34
7.3
Storage and Stability...........................................................................................................35
7.4
Handling and Disposal........................................................................................................35
8
Study Procedures....................................................................................................................35
8.1
Baseline Evaluations (≤ 28 Days Prior to Registration).....................................................35
8.2
Evaluations Performed at Cycle 1-Week 1-Day 1..............................................................36
8.3
Evaluations Performed at Cycle 1-Week 3-Day 15............................................................36
8.4
Evaluations Performed at Cycle 2-Week 1-Day 1 (± 3 days).............................................37
8.5
Evaluations Performed Every 8 Weeks (x24) from the Start of Study Treatment (±3 days)
37
8.6
Evaluations Performed at End of Treatment (± 3 days) .....................................................38
8.7
Post-Treatment Follow-Up Evaluations (± 3 days)............................................................38
8.8
Long Term Follow-Up Evaluations....................................................................................38
8.8.1
Patients  off treatment due to reasons other than disease progression will be monitored 
every 3 months (± 7 days) after 30-day follow-up for 3 years (telephone contact is acceptable).38
8.8.2
Patients off treatment due to disease progression will be monitored every 6 month (± 7 
days) after 30-day follow-up for overall survival..........................................................................38
8.8.3
Participants who are unavailable for follow-up evaluations should be classified as lost 
to follow-up for 1 of the following reasons:..................................................................................38
8.9
Schedule of Procedures and Observations..........................................................................39
8.10
Plasma Biomarker/Steady-State PK Blood Sample Collection and Processing.................42
8.11
Immune Biomarkers Blood Sample....................................................................................43
8.12
Pathology ............................................................................................................................44
8.12.1
Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples........................................44
8.12.2
Tissue Samples for IMPACT Assay ...............................................................................44
9
Efficacy Evaluations...............................................................................................................45
9.1
Objective Tumor Response.................................................................................................45
9.2
Target Lesions ....................................................................................................................45
9.3
Non-Target Lesions ............................................................................................................45
9.4
Evaluation of Response ......................................................................................................46
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9.5
Guidelines for Evaluation of Measurable Disease..............................................................47
9.6
Retrospective Review of Disease status .............................................................................49
10
Safety Evaluation................................................................................................................50
10.1
Adverse Events ...................................................................................................................50
10.1.1
Definition ........................................................................................................................50
10.1.1.1
Diagnosis Versus Signs and Symptoms ......................................................................50
10.1.1.2
Adverse Events Occurring Secondary to Other Events...............................................50
10.1.1.3
Abnormal Laboratory Values......................................................................................50
10.1.1.4
Preexisting Medical Conditions (Baseline Conditions) ..............................................51
10.1.1.5
Vital Signs, ECG and Physical Examination Results..................................................51
10.2
Adverse Events of Special Interests (AESI).......................................................................51
10.2.1
Grading and Relationship to Drug ..................................................................................52
10.2.2
Reporting Adverse Events ..............................................................................................53
10.3
Serious Adverse Events ......................................................................................................53
10.3.1
Definition ........................................................................................................................53
10.3.2
Reporting Serious Adverse Events .................................................................................54
10.4
Investigator Reporting: Notifying Boehringer Ingelheim (BI) and NCCN........................54
10.5
Follow-Up for Serious Adverse Events..............................................................................55
10.6
Unanticipated Problems......................................................................................................55
10.6.1
Definition ........................................................................................................................55
10.6.2
Reporting Unanticipated Problems .................................................................................55
11
Data and Safety Monitoring................................................................................................56
12
Statistical Methodology......................................................................................................56
12.1
Endpoints ............................................................................................................................56
12.1.1
Primary............................................................................................................................56
12.1.2
Secondary........................................................................................................................56
12.2
Sample Size Determination ................................................................................................56
12.3
Demographics and Baseline Characteristics.......................................................................57
12.4
Efficacy Analysis................................................................................................................57
12.4.1
Adverse Event.................................................................................................................57
12.5
Replacement .......................................................................................................................57
12.6
Interim Analysis and Criteria for Early Termination of the Study.....................................58
13
Correlative Data Analysis...................................................................................................58
13.1
Plasma Biomarker PK/PD Modeling..................................................................................58
13.2
IMPACT Assay ..................................................................................................................59
14
Ethical and Regulatory Standards.......................................................................................59
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14.1
Ethical Principles................................................................................................................59
14.2
Informed Consent ...............................................................................................................60
15
Study Responsibilities ........................................................................................................60
15.1
Data Collection ...................................................................................................................60
15.2
Maintenance of Study Documents......................................................................................61
16
Administrative Rules ..........................................................................................................61
16.1
Revisions to the Protocol....................................................................................................61
16.2
Termination of the Study....................................................................................................61
16.3
Confidentiality ....................................................................................................................61
17
Appendices .........................................................................................................................62
18
References...........................................................................................................................80
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IN-TEXT TABLES
Table 1
Potency [IC50, nm] of nintedanib in in vitro Kinase Assays......................................18
Table 2
Criteria to Interrupt Nintedanib Treatment due to an Adverse Event .........................29
Table 3
Management of Adverse Events..................................................................................30
Table 4
Guideline for the Management of Diarrhea ................................................................31
Table 5
Nintedanib Dose Level Reduction ..............................................................................32
Table 6
Schedule of Procedures and Observations ..................................................................40
Table 7
Time Point Response Criteria (+/- non-target disease) ...............................................46
Table 8
Time Point Response Criteria (non-target disease only).............................................47
Table 9
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness) ................................................................................................................................53
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APPENDICES
Appendix A
Instructions for Network Sites .............................................................................63
Appendix B
ECOG Performance Status Scores.......................................................................66
Appendix C
New York Heart Association Classification ........................................................67
Appendix D
IMPACT Assay (MSKCC) ..................................................................................68
Appendix E
Drug-Induced Liver Injury Follow-Up Procedures .............................................69
Appendix F
Study Medication Diary for Nintedanib...............................................................73
Appendix G
Procedure for Obtaining a Urine Protein/ Creatinine Ratio.................................74
Appendix H
Isolation of Mononuclear Cells............................................................................75
Appendix I
     Protocol for Cryopreserving PBMCs ..................................................................77
Appendix J
In vivo P-gp Transporter Inhibitors and Inducers ................................................78
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1
BACKGROUND
1.1 Carcinoid (Neuroendocrine) Tumors
Neuroendocrine tumors, also known as carcinoids, are uncommon tumors arising from various 
primary sites. Although thought to be rare, the incidence of neuroendocrine tumors is rising and 
the estimated prevalence in the United States is 103,312 cases, which is more than gastric and 
pancreatic cancer combined(1). Nearly 50% of patients with neuroendocrine tumors have 
metastatic disease at presentation, and 65% will die within 5 years of diagnosis.
Carcinoids are generally slow growing tumors, but in the advanced setting can be very disabling 
and impact quality of life (QOL) due to diarrhea, bowel obstructions, pain, weight loss, 
depression and fatigue. Many of the abdominal symptoms are caused by the dense adhesions. 
Mid gut carcinoids often secrete serotonin that acts synergistically with platelet derived growth 
factor (PDGF) and stimulates DNA synthesis in fibroblasts acting through 5–HT1B receptors 
coupled to a Gi-protein(2). This may, in part explain the dense fibrotic reaction seen in small 
bowel carcinoids and subsequent obstructive symptoms. Carcinoids are highly vascular and 
VEGF, PDGF and FGF are all also thought to drive disease with the additional serotonin 
mediated fibroblast proliferation driving symptom progression.
Nintedanib is a promising new orally bioavailable targeted agent that targeted VEGFR1-3, FGFR 
1/3 and PDGFR. Several agents targeting VEGF and PDGF have shown promising activity in 
pancreatic neuroendocrine tumors. However response rates for patients with non-pancreatic 
carcinoid tumors have been low. We hypothesize, that since fibroblast proliferation is a major 
driver of disease and clinical progression in non-pancreatic carcinoids that is shown in animal 
models to be driven by serotonin (5-HT) through FGFR2 (3) that targeting angiogenesis and 
FGFR merits study in this tumor. There are no prospectively validated predictors of response to 
FGFR inhibitor, but studies in in a study done by(4) in lung NET (neuroendocrine tumor) patient 
samples, FGFR1 amplification was seen in 52% of small cell neuroendocrine cancer and 19% of 
bronchial carcinoids. These expression data are much higher than those reported in breast, lung 
or bladder cancers, and make it much more likely to see activity with FGF inhibition.
Targeting angiogenesis with sunitinib has been shown to improve outcomes in patients with 
PNETs (5). Similar benefit was seen in patients with PNETs with everolimus, an oral agent that 
targets the mTOR pathway known to drive NET progression (6). Unfortunately median treatment 
duration was ~ 8 months and progression free survival was ~ 11 months in both trials and upon 
progression, unfortunately patients have no further options that palliate symptoms that can be 
disabling for PNETs due to hormonal overproduction and pain from bony metastases that seem 
to occur with reasonable frequency in these patients.
Furthermore, this is an area of unmet need as there are no approved anti-tumor agents for 
patients with carcinoids that are not of pancreatic origin. Octreotide is shown to improve 
symptoms and frequently used in these patients. Recently in a phase 3 trial, therapy with 
everolimus and octreotide was shown to prolong PFS compared to placebo (7). Results from 
RADIANT-4 may confirm PFS with everolimus in this population of ~11 months but, given the 
long overall survival of these patients and morbidity from symptoms, clearly there remains a 
need for newer tolerable agents to continue to offer symptom and tumor control. These data form 
the background and rationale for our hypothesis that the combination of nintedanib with 
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octreotide LAR may offer disease control and clinical benefit in patients with carcinoid tumors 
and PNETs.
Lastly, a landmark study in carcinoid (small intestinal NETs) was recently published. They 
sequenced 48 small bowel tumors using massively parallel, next-generation DNA sequencing.  
Not surprisingly a paucity of mutations were identified: however, 197 protein-altering somatic 
SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, 
MLF1, CARD11, VHL, NONO, and SMAD1 were noted(8). Integrative analysis of SNVs and 
somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: 
chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate 
therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family 
genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 
was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. All 
of these genes are included in our IMPACT next generation sequencing platform. (8)We will 
therefore sequence 10 tumors to see if response and/or resistance to nintedanib is influence by 
these deregulated pathways.
Given the mutation alterations identified in the AKT1 or AKT2 genes, we also hypothesize that 
Akt activation may predict response and/or resistance to treatment. Pre-archived and post-
treatment biopsies will be assessed for activity and will be determined by blotting for the 
phosphorylation of Akt downstream targets including p-Foxo, p-GSK3, p-PRAS40. IHC analysis 
of total AKT, p-Akt Ser473, PTEN, total 4E-BP1, p-4E-BP1Thr70, p-eIF-4G Ser1108 (peIF-
4G), total S6, p-S6 Ser235/236 and Ser240/244, and proliferation marker Ki-67 will also be 
performed in formalin-fixed paraffin-embedded sections from the tumor samples
1.2 Nintedanib
Nintedanib (BIBF 1120) is a small molecule TKI of VEGFR 1/2/3 (IC50 34/21/13 nM), FGFR 
1/2/3 (IC50 69/37/109 nM), and PDGFR A/B (IC50 59/65 nM), with additional activity against 
Flt-3, RET, Src, Lck, and Lyn. In preclinical colorectal cancer models, anti-tumor efficacy has 
been demonstrated, with a marked reduction in tumor vessel density. Maximum plasma 
concentrations occur 2-4 hours following administration with a terminal half-life of 7-19 hours. 
Based upon phase I data, the recommended phase II dose is 200 mg orally twice daily, as a single 
agent as well as in combination with chemotherapy. When administered as monotherapy, the 
most common side effects are nausea, diarrhea, vomiting, abdominal pain and fatigue. Liver 
enzyme increases were the most common DLT in early phase trials and a common AE in later 
stage studies, though predominantly seen at higher doses (>200 mg bid) and largely reversible 
with cessation of therapy.
1.3 Preclinical Development and Pharmacokinetics of Nintedanib
Nintedanib (BIBF1120) is a potent, orally available triple kinase inhibitor targeting VEGFRs, 
PDGFRs, and FGFRs.
Nintedanib inhibits the signalling cascade mediating angiogenesis by binding to the adenosine 
triphosphate (ATP) binding pocket of the receptor kinase domain, thus interfering with cross-
activation via auto-phosphorylation of the receptor homodimers.
The specific and simultaneous abrogation of these pathways results in effective growth inhibition 
of both endothelial and, via PDGF- and FGF-receptors of perivascular cells which may be more 
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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 tumour 
angiogenesis when the VEGF pathway is disrupted.
Besides inhibition of neo-angiogenesis, it may alter tumour maintenance by inducing apoptosis 
of tumour blood vessel endothelial cells. Inhibition of receptor kinases may also interfere with 
autocrine and paracrine stimulation of tumour angiogenesis via activation loops involving 
VEGF, PDGF, and bFGF utilized by vascular and perivascular cells such as pericytes and 
vascular smooth muscle cells.
In addition preclinical models show that nintedanib (BIBF1120) may have a direct anti-tumour 
effect on those malignant cells which overexpress PDGFR and/or FGFR (e.g. H1703 NSCLC 
cells). In vitro, the target receptors are all inhibited by nintedanib in low nanomolar 
concentrations (Table 1).
Table 1
Potency [IC50, nm] of nintedanib in in vitro Kinase Assays
Kinase
IC50 (nmol/L)
VEGFR (1 / 2 / 3)
34 / 21 / 13
PDGFR (α / β)
59 / 65
FGFR (1 / 2 / 3)
69 / 37 / 108
Flt-3
26
RET
35
Src, Lck, Lyn
156 / 16 / 195
In in vivo nude mouse models, nintedanib showed good anti-tumour efficacy at doses of 50 – 
100 mg/kg, leading to a substantial delay of tumour growth or even complete tumour-stasis in 
xenografts of a broad range of differing human tumour types. Histological examination of treated 
tumors showed a marked reduction of tumour vessel density by approximately 80% (9).
The metabolism of nintedanib (BIBF1120) was predominantly characterized by the ester 
cleavage of the methyl ester moiety yielding BIBF 1202, which was further metabolized by 
conjugation to glucuronic acid yielding the 1-O-acylglucuronide.  Data collected in this study 
show that nintedanib (BIBF1120) has a favorable PK and excretion profile with almost no 
elimination via the urine, only 0.7% of total [14C] radioactivity was eliminated via the urine [5]. 
The metabolic characteristics are predominantly independent of cytochrome P450-catalysed 
metabolic pathways (10).
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 hr. Nintedanib is mainly eliminated via 
faeces (10).
Nintedanib (BIBF1120) is non-mutagenic, even at high doses.
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Two exploratory studies in rats revealed a teratogenic effect of nintedanib (BIBF1120) with a 
steep dose/effect relationship and an early onset of embryofetal deaths at low dosages. This 
effect was observed at dose levels resulting in plasma drug concentrations comparable to or 
below those in humans. Because the concentration of nintedanib (BIBF1120) in semen is 
unknown, males receiving nintedanib (BIBF1120) and having sexual intercourse with females of 
childbearing potential should use latex condoms. Women of childbearing potential should be 
advised to use adequate contraception during and at least 3 months after the last dose of 
nintedanib.
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of 
nintedanib can be found in the Investigator’s Brochure.
1.4 Clinical Studies with Nintedanib
Nintedanib is being evaluated in several cancers. Additionally, nintedanib has been FDA 
approved for the non-cancer indication idiopathic pulmonary fibrosis (IPF). As of 15 Feb 2013, 
3556 cancer patients, over 1000 patients with IPF, and 140 healthy volunteers had been treated 
with nintedanib or nintedanib matching placebo, in monotherapy or in combination with 
chemotherapy.
1.4.1
Phase I
Phase I dose selection studies revealed that nintedanib (BIBF1120) is generally well tolerated 
with mild to moderate adverse effects such as gastrointestinal symptoms (nausea, diarrhea, 
vomiting, abdominal pain) and reversible elevations of liver enzymes. Initial signs of clinical 
activity including an encouraging rate of patients with stabilization of their tumour of 54% and 
68%, respectively; have been observed in patients with various solid tumors(11).
Based on the Phase I dose escalation trials with nintedanib (BIBF1120) monotherapy, the 
maximum tolerated dose was defined to be 250 mg for twice daily dosing in Caucasians and 
200 mg twice daily in Japanese patients with a manageable safety profile in advanced cancer 
patients. Based on the overall safety profile, the RP2D for nintedanib as monotherapy is 200 mg 
bid.
The maximum tolerated dose for combination therapy of nintedanib (BIBF1120) in combination 
with pemetrexed, docetaxel, paclitaxel/carboplatin and FOLFOX is 200 mg bid. Combination of 
nintedanib (BIBF1120) with other anti-cancer drugs revealed a similar adverse event profile as 
compared to nintedanib (BIBF1120) monotherapy except for the chemotherapy related toxicities. 
There was no change of the pharmacokinetic parameters of nintedanib (BIBF1120) or of the 
cytotoxic compounds due to the combined treatment. Dose limiting toxicity consisted mostly of 
liver transaminase elevations as in the monotherapy phase I trials with the exception of the 
combination of nintedanib (BIBF1120) with pemetrexed, where fatigue was the most relevant 
dose limiting toxicity.
Available pharmacokinetic data indicate that the systemic exposure needed for biological activity 
can be achieved starting with doses of 100 mg nintedanib (BIBF1120) once daily.
The predominant adverse events were nausea, 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 
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200 mg and were reversible after discontinuation of nintedanib treatment. All adverse events 
observed after single administration of single doses of nintedanib to healthy volunteers were only 
of CTCAE grade 1 severity and fully reversible (10).
1.4.2
NSCLC
In a phase II trial in NSCLC patients the safety profile of nintedanib (BIBF1120) observed in 
phase I trials could be confirmed. Most commonly reported drug-related AEs were nausea 
(57.5%), diarrhea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and 
reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%) In 
conclusion it was generally well tolerated and displayed single agent activity in advanced or 
recurrent NSCLC patients. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative 
Oncology Group (ECOG) 0–1 patients (n = 56) had a median PFS of 11.6 weeks and a median 
OS of 37.7 weeks. Tumour stabilization was achieved in 46% of patients (ECOG 0–1 patients: 
59%), with one confirmed partial response (250 mg bid.)(12).
LUME-Lung 1 was an international, randomized, double-blind, phase III trial assessing the 
efficacy and safety of docetaxel plus nintedanib as second line therapy for non-small-cell lung 
cancer (NSCLC).  In total, 1314 patients with Stage IIIB/IV or recurrent NSCLC (all histologies) 
who had progressed after 1st line chemotherapy were randomized in 1:1 fashion to either receive 
Nintedanib 200 mg BID + Docetaxel (n=655) or Placebo BID + Docetaxel (n=659). 
LUME-Lung 1 met its primary endpoint by showing a statistically significant improvement of 
PFS for all patients regardless of histology (median PFS 3.4 versus 2.7 months; HR 0.79, 
p=0.0019) for Nintedanib in combination with docetaxel.
A significant improvement in OS was demonstrated in patients with adenocarcinoma (HR 0.83, 
p=0.0359, median 10.3 to 12.6 months).
Patients with a poor prognosis defined as time since start of 1st line therapy <9 months also 
experienced significant OS improvement from the addition of nintedanib to docetaxel (HR 0.75, 
p=0.0073, median OS 7.9 to 10.9 months).
The predominant adverse events were nausea, diarrhea, vomiting, abdominal pain and fatigue of 
mostly low to moderate intensity after monotherapy with nintedanib (BIBF1120). Dose limiting 
toxicities were dose dependent hepatic enzyme elevations that were reversible after 
discontinuation of nintedanib (BIBF1120) treatment. These liver enzyme elevations were only in 
few cases accompanied by a simultaneous increase of bilirubin. In general common terminology 
criteria for adverse events (CTCAE version 3, grade three liver enzyme increases were reported 
in the dose groups of 250 mg twice daily or higher. They also were reversible and usually 
occurred within the first two months of treatment. 
Hypertension or thromboembolic events were rare and did not suggest an increased frequency as 
a consequence of therapy with nintedanib (BIBF1120)(13).
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, enrolment was halted after 
713/1300 planned patients had been enrolled. The analysis (based on conditional power for PFS 
by investigator assessment) suggested that the study was futile and that the primary endpoint of 
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centrally assessed PFS would likely not be met. The futility analysis was based on conditional 
power; there was no formal testing of null hypothesis as planned for primary analysis no safety 
issues were identified.
Even though the study was stopped prematurely, the primary endpoint of this Phase III trial was 
met; treatment with nintedanib plus pemetrexed resulted in a significant prolongation of centrally 
reviewed PFS compared with placebo plus pemetrexed (median PFS 4.4 vs. 3.6 months with a 
HR 0.83; p=0.0435). The disease control rate was also increased significantly in nintedanib-
treated patients. There was no improvement in OS in nintedanib-treated patients. Nintedanib 200 
mg bid in combination with pemetrexed had an acceptable and manageable safety profile, with 
no new or unexpected safety findings. The most frequent AEs were reversible increases in liver 
enzymes and gastrointestinal events (14).
1.4.3
Ovarian Cancer
A randomized phase II maintenance trial in ovarian cancer in which the efficacy and safety of 
nine months of continuous twice daily doses of nintedanib (BIBF1120) following chemotherapy 
was investigated, has identified the potential activity of nintedanib (BIBF1120) with a 36-week 
PFS of 16.3 % compared to 5.0 % in the control group. The safety profile was consistent with 
findings previously reported for nintedanib (BIBF1120) administered as monotherapy as 
mentioned above(15).
Nintedanib was evaluated in a Phase III randomized, placebo‐controlled, double‐blind, 
multicentre ovarian study with 1366 patients.  Patients received nintedanib plus paclitaxel and 
carboplatin or placebo plus paclitaxel and carboplatin for six cycles. This was followed by 
monotherapy nintedanib or placebo for up to 120 weeks. The trial met its primary endpoint by 
demonstrating a statistically significant improvement in progression-free survival (HR 0.84; 
95%CI 0.72 - 0.98; p=0.0239, median PFS 17.3 months for nintedanib and 16.6 months for 
placebo). Overall survival data are immature but currently show no trend in either direction. 
Main adverse events were GI side effects and increased hematological toxicity(16).
1.4.4
Renal Cell Cancer
Nintedanib has been studied in a randomized phase II study in metastatic clear cell RCC with 
sunitinib as the control arm. Similar efficacy was seen in both arms of this study. AEs observed 
more frequent in the nintedanib arm included diarrheal, nausea, fatigue and infection, whereas 
AEs more frequent in the sunitinib arm consisted of bleeding, anaemia, hypertension, hand-foot 
syndrome and stomatitis(17).
1.4.5
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(18).
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1.4.6
Colorectal Cancer
A Phase I/II, open-label, randomized study of nintedanib plus mFOLFOX6 compared to 
bevacizumab plus mFOLFOX6 in 120 patients with metastatic colorectal cancer was performed, 
demonstrating an acceptable safety profile of nintedanib in combination with 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 (19). This is in 
contrast to multiple prior trials of small molecule inhibitors of VEGFR-2 with demonstrated 
increased toxicity and, as a result, decreased efficacy(20).
A Phase III study is going to start in late 2014 to evaluate the efficacy of nintedanib in patients 
with metastatic colorectal cancer (mCRC) after failure of previous treatment with standard 
chemotherapy and biological agents (ClinicalTrials.gov Identifier: NCT02149108).
For more details please refer to the investigator drug brochure for nintedanib (BIBF1120).
1.5 Correlative Studies
1.5.1
Tissue biomarkers
1.5.1.1 Fibroblast Growth Factors (FGFs)
The family of fibroblast growth factors (FGFs) regulates a variety of developmental processes 
and the 18 mammalial FGFs are grouped into 6 subgroups based on sequence homology and 
phylogeny(21). The FGF ligands carry out their diverse functions by binding and activating FGFR 
family tyrosine kinase receptors. Investigators from our group at Roswell Park recently found 
that response to another FGFR inhibitor, dovitinib correlated with FRS2 phosphorylation, 
FGFR2 mRNA levels and FGFR2 IIIb expression but not phosphorylation of VEGFR2 and 
PDGFRβ in pancreatic xenografts(22). Using FGFR2 mRNA levels tumor sensitivity to FGFR 
inhibition among the tumor xenografts was able to be identified.  The intracellular kinase domain 
of FGFRs is structurally similar to VEGFR2 and PDGFR. The extracellular domains II and III of 
FGFRs constitute the binding site for FGF ligands (23). Alternative splicing in domain III in 
FGFR1–3, not FGFR4, creates isoforms (IIIb and IIIc) with varying binding affinity to various 
FGF ligands. Response to FGFR inhibition with dovitinib correlated with FGFR IIIb isoform but 
not FGFR2IIIc in our studies. This may be because isoform IIIc is associated with epithelial to 
mesenchymal transformation(24). This forms the rationale for our hypothesis that high FGFR IIIb 
to IIIc ratio in tumors along with proliferative index (Ki-67) and microvessel density that are 
known predictors of biology in this tumor will predict benefit from nintedanib.
We hypothesize that a high FGFR IIIb/IIIc ratio (quantified using an image analyzer) and low 
Ki-67, microvessel density at baseline measured by IHC using validated methods in formalin-
fixed paraffin embedded biopsy tissue will correlate with improved response to nintedanib(25, 26).
1.5.1.2 mTOR Pathway Mutations
We hypothesize that mutations along the mTOR pathway may predict response and/or resistance 
to nintedanib therapy. To test this hypothesis, we propose to determine mutations and copy 
number alterations in 341 cancer associated genes using a novel technology called IMPACT 
(Integrated Mutation Profiling of Actionable Cancer Targets conducted in the Berger Laboratory 
at Memorial Sloan Kettering Cancer Center (MSKCC).
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In addition, given the mutation alterations identified in the AKT1 or AKT2 genes, we also 
hypothesize that Akt activation may predict response and/or resistance to treatment. Pre-archived 
and post-treatment biopsies will be assessed for activity and will be determined by blotting for 
the phosphorylation of Akt downstream targets including p-Foxo, p-GSK3, p-PRAS40. IHC 
analysis of total AKT, p-Akt Ser473, PTEN, total 4E-BP1, p-4E-BP1Thr70, p-eIF-4G Ser1108 
(peIF-4G), total S6, p-S6 Ser235/236 and Ser240/244, and proliferation marker Ki-67 will also 
be performed in formalin-fixed paraffin-embedded sections from the tumor samples.
We will send all samples to MSKCC for testing. In patients with a partial response by RECIST 
i.e., “outliers” (pre-archived and post-treatment biopsies) will be assessed for activity and will be 
determined by blotting for the phosphorylation of Akt downstream targets. This will also be done 
in those with long PFS (>/= 6 months). There they will extract DNA from core tissue and 
cytology specimens (and patient-matched normal tissue) using Qiagen nucleic acid extraction 
kits. They will prepare barcoded sequence libraries (New England Biolabs, Kapa Biosystems) 
and perform exon capture on barcoded pools by hybridization (Nimblegen SeqCap) using custom 
oligonucleotides to capture all exons and select introns of 341 cancer genes. DNA will 
subsequently be sequenced on an Illumina HiSeq 2000 to 500-1000X coverage in order to 
maximize sensitivity for detecting mutations.
DNA samples will be prepped and captured for sequencing, libraries will be sequenced, and 
FASTQ sequence files will be prepared all through MSKCC Diagnostic Molecular Pathology. 
Sequence data will be analyzed through MSKCC Diagnostic Molecular Pathology.
1.5.2
Plasma Markers/Modeling
Elevated plasma cytokine levels (e.g., Serum VEGF) often correlate with poor prognosis and 
changes in these markers have not been predictive of clinical outcomes to any anti-angiogenic 
agent. (27). Our group evaluated sunitinib PK and modeled change in soluble VEGFR2 and this 
PK/PD model was able to successfully predict clinical benefit (PFS) to potent anti-VEGF 
therapy.
Using the previously developed PK/PD model (see Section 13.1), it will be determined if using 
decrease in circulating cytokines such as soluble vascular endothelial growth factor receptor 
(sVEGFR), fibroblast growth factor (FGF) and FGFR by ELISA before treatment and at week 8 
(± 3 days) with steady state PK done in the same sample drawn at week 8 will correlate with 
drug level following start of therapy, with changes in cytokines post therapy compared to pre 
therapy in the model to see if it correlates with clinical benefit and has the potential to be a 
biomarker. We hypothesize that drug exposure combined with FGF and FGFR levels measured 
by ELISA and sVEGFr2- a pharmacodynamic marker validated prospectively may yield a 
noninvasive biomarker of response to this agent (28).
1.5.3
Immune Biomarkers
Carcinoid tumors are well known to have a variable biology and reasons for this are poorly 
understood. We have comprehensively studied and shown that immune dysfunction is a hallmark 
of cancer in peripheral blood samples taken from patients with liver cancer (29). In two ongoing 
NCCN funded trials we are prospectively validating our preliminary data that antiangiogenic 
therapy results in immune changes that may have a functional impact on patient’s anti-tumor 
immunity. We have successfully conducted these studies in banked frozen PBMCs and propose 
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to 
explore 
the 
biomarker 
potential 
of 
baseline 
Treg 
numbers 
defined 
as 
(CD3+CD4+Foxp3+CD127− cells) on outcomes with nintedanib therapy and may provide insight 
into the patients biology. Banked specimens will allow future comprehensive assessment and 
given that immunotherapy is now a real option for treatment of some cancers, and will be the 
next frontier and major focus of oncology research, it may allow selection of patients who may 
benefit from other therapies in development.
1.5.4
Quality of Life
The EORTC QLQ – GI.NET21 questionnaire is intended for use among patients with G.I. 
related neuroendocrine tumors, who vary in disease stage and treatments. The module comprises 
21 questions assessing disease symptoms, side effects of treatment, body image, disease related 
worries, social functioning, communication and sexuality.
The module has been found to be a valid and responsive tool for assessing quality of life in gut, 
pancreas and liver neuroendocrine tumors (30).
1.6 Risks and/or Benefits
The risks of therapy with nintedanib (BIBF1120) in adult patients are primarily related to:

the gastro-intestinal tract (nausea, vomiting, diarrhea, abdominal pain-including upper 
and lower abdominal pain)

increases in liver enzymes (AST, ALT, γ-GT)

fatigue or asthenia

decreased appetite, dehydration due to gastrointestinal side effects
Liver enzymes must be followed closely during treatment with nintedanib (BIBF1120).
Therapy with the trial drugs must be interrupted in the event of relevant hepatic toxicity and 
further treatment is to be withheld until recovery of the abnormal laboratory parameters.
Impairment of immune and of kidney function, thromboembolic events and GI perforations are 
considered possible side effects of treatment with nintedanib (BIBF1120) as they have been 
reported for some other drugs in the class of angiogenesis inhibitors. Thus far these side effects 
have been observed in the trials conducted with nintedanib (BIBF1120), but not to a relevant 
degree. Hypertension is also supposed to be a possible side effect of VEGFR inhibitors and a 
slightly increased frequency of hypertension has been observed in the trials with nintedanib 
(BIBF1120) to a mild to moderate degree and only few cases of CTCAE grade 3 or 4 
hypertension have been observed. With respect to bleeding as one of the potentially serious side 
effects of antiangiogenesis agents in the LUME –Lung 1 trial involving 1314 patients more 
bleeding events were reported for nintedanib-treated squamous cell carcinoma (SCC) patients 
(all grades: 17.1% vs. 10.9%; grade ≥3: 2.9% vs. 1.3%) than for those with adenocarcinoma (all 
grades: 10.9% vs. 11.1%; grade ≥3: 1.5% vs. 1.3%). Fatal bleeding events, serious skin 
reactions, thrombosis, and perforations occurred at a low frequency and were balanced between 
both arms regardless of histology.
Based upon a non-clinical safety study in vitro, nintedanib (BIBF1120) may have a potential risk 
of phototoxicity (skin and eyes) in vivo. Few cases of photosensitivity reactions (less than 1 %) 
and of CTCAE grade 1 intensity only, have been reported from the clinical studies to date. If 
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adequate precautions are taken (avoidance of prolonged ultraviolet (UV) exposure, use of broad 
spectrum sunscreen and sunglasses), treatment with nintedanib (BIBF1120) is considered safe.
2
RATIONALE
Patients with progressing metastatic carcinoid tumors have no approved options and are a 
population with a clear unmet need. Targeting angiogenesis and the mammalian target of 
rapamycin (mTor) pathways has been shown to improve outcomes in patients with pancreatic 
NETs but have not proven to be beneficial in carcinoids.  Studies, suggest, however that a subset 
of carcinoid patients may be sensitive to these therapies. Therapy is palliative and intended to 
improve quality of life (QOL).
Furthermore, this is an area of unmet need as there are no approved anti-tumor agents for 
patients with carcinoids that are not of pancreatic origin. Octreotide is shown to improve 
symptoms and frequently used in these patients. Recently in a phase 3 trial, therapy with 
everolimus and octreotide was shown to prolong PFS compared to placebo (7). Results from 
RADIANT-4 may confirm PFS with everolimus in this population of ~11 months but given the 
long overall survival of these patients and morbidity from symptoms, clearly there remains a 
need for newer tolerable agents to continue to offer symptom and tumor control. Carcinoids are 
highly vascular and VEGF, PDGF and FGF are all also thought to drive disease with the 
additional serotonin mediated fibroblast proliferation driving symptom progression. Nintedanib 
is a promising new orally bioavailable targeted agent that targeted VEGFR1-3, FGFR 1/3 and 
PDGFR. Several agents targeting VEGF and PDGF have shown promising activity in pancreatic 
neuroendocrine tumors. However response rates for patients with non-pancreatic carcinoid 
tumors have been low. We hypothesize, that since fibroblast proliferation is a major driver of 
disease and clinical progression in non-pancreatic carcinoids that is shown in animal models to 
be driven by serotonin (5-HT) through FGFR2 that targeting angiogenesis and FGFR merits 
study in this tumor. There are no prospectively validated predictors of response to FGFR 
inhibitor, and in lung NET patient samples, FGFR1 amplification was seen in 52% of small cell 
neuroendocrine cancer and 19% of bronchial carcinoids.  These expression data are much higher 
than those reported in breast, lung or bladder cancers and make it much more likely to see 
activity with FGF inhibition. As progression free survival is a valid endpoint in this disease given 
the long overall survival, we hypothesize that:
1. Targeting angiogenesis and the fibroblast growth factor pathway with nintedanib will result 
in clinical benefit measured as progression free survival (PFS) and radiographic response or 
stable disease in patients with carcinoid tumors progressing within the 12 months prior to 
study entry.
2. This therapy will be safe and tolerable in combination with octreotide. This will also lead to 
improved QOL measured using the EORTC QLQ – GI.NET21 questionnaire.
These data form the background and rationale for our hypothesis that the combination of 
nintedanib with octreotide LAR may offer disease control and clinical benefit in patients with 
carcinoid tumors and PNETs.
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3
OBJECTIVES
3.1 Primary Objective

To assess progression free survival (PFS), defined as the time interval from initiation of 
therapy, to its cessation for documentation of progressive disease (PD) or death.
3.2 Secondary Objectives

To assess the clinical response (complete response + partial response) in all patients with 
measurable disease (using standard RECISTv1.1 criteria).

To assess overall survival (OS) in all patients.

Assess changes in QOL throughout treatment using the EORTC QLQ – GI.NET21 
questionnaire for carcinoid patients with gastrointestinal neuroendocrine tumors, in all 
patients who have filled out at least two QOL questionnaires and, will be reported by 
groups based on response (response, stable disease or progressive disease).

Steady-state PK of Nintedanib, biomarkers, Treg and cytokine expression and growth 
factors will be analyzed for all patients and reported in groups based on response.

Gene mutations and copy number alterations analysis in the mTOR pathway (will be 
performed only on the first 10 patients), protein expression of activation of Akt (as well 
as other downstream targets).

Toxicity (graded using the NCI CTCAE version 4.0) will be closely monitored and all 
toxicities will be tabulated.
4
METHODOLOGY
4.1 Study Design
This is an open label, multi-center phase II study in all patients with advanced low and 
intermediate grade neuroendocrine cancers (carcinoids), excluding PNETS.
Therapy will consist of Nintedanib (BIBF1120) 200 mg PO BID + Octreotide (or lanreotide) q 4 
weeks.
CT (chest, abdomen, & pelvis) scan restaging q 8 weeks x 24 weeks and then q12 weeks. 
In a subset of patients (10 total), post treatment biopsy samples for tissue studies to understand 
mechanisms of resistance will be done  at progression if they are willing to have a second biopsy.
Quality of life questionnaires using the EORTC QLQ – GI.NET21 questionnaire (Appendix K) 
will be completed at baseline and at the same time points as imaging studies while on study. 
Treat until progression/ unacceptable toxicity.
Formalin-fixed paraffin embedded tumor biopsy samples from patients enrolled at the 
participating institutions will be sent to RPCI Core Pathology Laboratory for IHC studies. This is 
to be done in all patients accrued at all sites who may have additional studies for the gene 
expression studies described in the protocol.
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All participants will sign an informed consent prior to study related tests. All participants will 
meet the inclusion and exclusion criteria summarized in Section 5.1 and Section 5.2 Participants 
will be treated on an outpatient basis.
4.2 Target Accrual and Study Duration
Two participating institutions will enroll maximum of 30 evaluable patients over a 24 month 
period.
5
PARTICIPANT SELECTION
5.1 Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Patient must be on a stable dose of octreotide (Sandostatin®) LAR or lanreotide for 
3 months prior to study enrollment.
2. Patient must have histologically or cytologically confirmed well differentiated or 
moderately differentiated (low grade or intermediate grade) neuroendocrine tumor that is 
locally advanced or metastatic and not of pancreatic origin.
3. Measurable disease determined by CT or MRI.
4. Age ≥ 18 years of age.
5. Have an ECOG Performance Status of 0 - 2. Refer to Appendix B.
6. Life expectancy greater than 3 months.
7. Have the following clinical laboratory values:

Leukocytes ≥3,000/μL

Absolute neutrophil count ≥ 1,500/μL

Total bilirubin ≤ 2 mg/dL

AST /ALT  
o
AST/ALT ≤ 1.5 X ULN and bilirubin ≤ ULN for patients without liver 
metastases.
o
AST/ALT ≤ 2.5 X ULN and bilirubin ≤ ULN for patients with liver 
metastases.
o
Patients with Gilbert syndrome and bilirubin < 2 X ULN and normal 
AST/ALT  
o
creatinine ≤1.5 mg/dl
8. Prior treatment will be permitted including surgery (≥ 4 weeks), cytotoxic chemotherapy 
(maximum of 2 prior regimens); radiation, interferon, targeted growth factors 
(≥ 4 weeks); and prior treatment with octreotide, will be allowed.
9. Ability to swallow and retain oral medication.
10. Participants of child-bearing potential (both male and female) must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) 
prior to study entry. Should a woman become pregnant or suspect she is pregnant while 
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she or her partner is participating in this study, she should inform her treating physician 
immediately.
11. Participant or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
12. Archival tissue of carcinoid biopsy must be available.
5.2 Exclusion Criteria
Participants will be excluded from this study for the following:
1. Uncontrolled hypertension, unstable angina, New York Heart Association Grade II or 
greater congestive heart failure, unstable symptomatic arrhythmia requiring medication, 
or clinically significant peripheral vascular disease (Grade II or greater). Refer to 
Appendix C.
2. Presence of brain metastases.
3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to day 0, or anticipated need for major surgical procedure during the course of the 
study, or fine needle aspirations or core biopsies within 7 days prior to day 0.
4. Significant proteinuria at baseline (> 500 mg/ 24 h).
5. Serious non-healing wound, ulcer or bone fracture.
6. Evidence of bleeding diathesis or coagulopathy.
7. Recent (< 6 months) arterial thromboembolic events, including transient ischemic attack, 
cerebrovascular accident, unstable angina, or myocardial infarction.
8. Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, 
adenocarcinoid, goblet cell carcinoma, or small cell carcinoma.
9. Hepatic artery embolization or ablation of hepatic metastasis within 3 months of 
enrollment,  prior PRRT within 4 months or any other cancer therapy within 4 weeks (as 
long as all toxicities are resolved).
10. Intolerance or hypersensitivity to octreotide.
11. Severe or uncontrolled medical conditions.
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
13. Pregnant or nursing female participants.
14. Unwilling or unable to follow protocol requirements.
15. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
5.3 Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
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6
TREATMENT PLAN
6.1 Dosing and Administration
Treatment will be administered on an outpatient basis. Reported adverse events (AEs) and 
potential risks are described in Section 1.6. Appropriate dose modifications are described in 
Section 6.2.
All patients have to be on octreotide LAR or lanreotide, and dose has to be stable for 3 months 
prior to study enrolment. Nintedanib 200 mg PO BID will be given as an outpatient in 28 day 
cycles. The pills are to be swallowed, un-chewed, with a glass of water of about 250 mL with a 
dose interval of approximately 12 hours at the same times every day, at least 30 minutes after a 
meal. If a patient misses a dose he/she will be instructed to skip that dose and take their next dose 
at their scheduled time.
Reported adverse events (AEs) and potential risks are described in Section 1.6. Appropriate dose 
modifications are described in Section 6.2. No other investigational or commercial drugs or 
therapies other than those described below may be administered with the intent to treat the 
patient. Patients will continue nintedanib until disease progression, unacceptable toxicity, 
investigator’s decision to remove patient from the study, patient refusal to continue, or 
alternative treatment.
Throughout the study, all patients will still continue on their scheduled dose of either Octreotide 
or Lanreotide: dosing information about Octreotide or Lanreotide should be tracked in the drug 
administration eCRF.
6.2 Dose Modifications
As initial measure for the management of side effects (Table 2) treatment with Nintedanib 
should be temporarily interrupted until the specific adverse reaction has resolved to levels that 
allow continuation of therapy. Nintedanib treatment may be resumed at a reduced dose. Dose 
adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual 
safety and tolerability are recommended as described in Table 3. 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 and the patient will be taken off study.
*Nintedanib, maybe held per physician discretion for 2-4 weeks. Any extension beyond this 
duration will be on a case by case basis per primary investigator discretion.
Table 2
Criteria to Interrupt Nintedanib Treatment due to an Adverse Event
If one criterion is met, nintedanib is to be interrupted

Nausea of CTCAE grade  3 despite optimal supportive care

Vomiting of CTCAE grade  2 despite optimal supportive care

Diarrhea of CTCAE grade  2 for more than 7 consecutive days despite optimal supportive care

AST and/or ALT > 3 X ULN conjunction with bilirubin of  1.5 X ULN

AST and/or ALT of CTCAE grade  5 X ULN

Other non-hematological adverse event of CTCAE grade  3 considered drug-related
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
Neutropenia and fever > 38.5°C

Neutropenia  CTCAE grade 4 for more than 7 days without fever

Platelets <50,000 /mm³ with bleeding
Table 3
Management of Adverse Events
Grade of Event
Management / Next Dose
≤ Grade 1
No change in dose.
Grade 2
Hold until ≤ Grade 1. Resume at same dose level.
Grade 3
Hold1 until < Grade 2. Resume at 1 dose level lower, if indicated.2
Grade 4
Off protocol therapy.
1
Participants requiring a delay of > 2 weeks should go off protocol therapy (see section 6.2 for further 
reference).
2
Participants requiring > 2 dose reductions should go off protocol therapy.
Recommended management for nausea and vomiting: antiemetics.
*Recommended management for diarrhea: Loperamide antidiarrheal therapy. Dosage schedule: 4 mg at first 
onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum dosage: 
16 mg / 24 hours) Adjunct antidiarrheal therapy is permitted and should be recorded when used.
*Please refer to table 4 for management of diarrhea.
6.2.1
Management of Diarrhea
For the disease population in this study, frequency of bowel movements may already be an issue 
with some patients prior to initiation of nintedanib treatment. Therefore, for this population, 
number/frequency of bowel movements will be documented at baseline prior to initiation of 
nintedanib and subsequent CTCAE grading of diarrhea will be evaluated relative to the patient’s 
baseline evaluation.
Guidelines for the management of diarrhea are found in Table 4.
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Table 4
Guideline for the Management of Diarrhea
CTCAE Grade
Action for Nintedanib and Anti-Diarrheal 
Treatment
Action for
Nintedanib After Recovery of Diarrhea
Grade 1*
Continue nintedanib.
No Antidiarrheal treatment.
No dose reduction of nintedanib.
Grade 2
Continue nintedanib.
Antidiarrheal 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.
1st Episode
Temporarily STOP nintedanib until recovery 
(≤ Grade 1).
AND
Antidiarrheal treatment according to the local 
standard (e.g., Loperamide p.r.n.).
Reduce nintedanib 1 dose level after 
recovery of diarrhea.
2nd Episode
Temporarily STOP nintedanib until recovery.
AND
Antidiarrheal treatment according to the local 
standard (e.g., Loperamide p.r.n.).
Reduce nintedanib 1 dose level after 
recovery of diarrhea.
3rd Episode
PERMANENTLY discontinue nintedanib 
treatment
AND
Antidiarrheal treatment according to the local 
standard (e.g., Loperamide p.r.n.).
PERMANENTLY discontinue nintedanib 
treatment.
*For this patient population, bowel movements equal to 3 or 4 per day may be present and 
considered baseline. Once treatment starts, CTCAE grading will be based on the number of 
bowel movements/day above baseline.
6.3 Management of Proteinuria

For proteinuria of ≥2+: Confirm total urine protein with a 24-hour urine collection 
or urine protein to creatinine (UPC) ratio. 

For urine protein 2-3.4 g/24hours or UPC ratio 2-3.4: Delay Nintedanib until 
urine protein improves to UPC < 2. If Nintedanib is delayed more than 4 weeks due 
to proteinuria, then discontinue treatment.

For urine protein ≥ 3.5 g/24 hours or UPC ratio ≥3.5: Discontinue treatment.
6.3.1
Dose Reduction
The following dose levels (Table 5) will be used in case dose reductions are required for 
management of undue toxicity. Nintedanib dosing will start at 200 mg PO BID for all patients.
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Table 5
Nintedanib Dose Level Reduction
Dose Level
Nintedanib Dose
1
200 mg (two, 100 mg capsules) twice a day (starting dose)
- 1
150 mg twice a day 
- 2
100 mg twice a day
6.4 General Concomitant Medication and Supportive Care
6.4.1
Additional precautions and supportive care

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 ≥3 in combination treatment compared to 3.6 % treated with docetaxel alone. Diarrhea 
should be treated at first signs with adequate hydration and antidiarrheal medicinal products, 
e.g. loperamide, and may require interruption, dose reduction or discontinuation of therapy 
with nintedanib (see Section 6.2.1).

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 (BIBF1120) 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 (BIBF1120) 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.

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 
(BIBF1120) 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 (BIBF1120) (periodically, i.e. 
in the combination phase with docetaxel at the beginning of each treatment cycle). If relevant 
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liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the 
therapy with nintedanib may be required (see Appendix E for procedures for follow-up for 
potential drug-induced liver injury).
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics.
6.4.2
Concomitant medications
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.
Metabolism of nintedanib by CYP450 enzymes plays only a minor role (5%). Additionally, 
nintedanib did not show relevant induction or inhibition of the major drug metabolizing 
cytochrome P450 enzymes and specifically no irreversible CYP3A4 inhibition. However, if co-
administered with nintedanib, strong P-gp inhibitors may increase exposure to nintedanib (e.g. 
ketoconazole or erythromycin. Thus, such medications are to be avoided unless deemed to be 
absolutely necessary. In such cases, patients should be monitored closely for tolerability of 
nintedanib. Management of side effects may require interruption, dose reduction or 
discontinuation of therapy with nintedanib.
Strong P-gp inducers, e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort, may 
decrease exposure to nintedanib. Co-administration with Nintedanib and potential alternative 
therapies should be carefully considered.
See Appendix J for additional examples of in vivo inhibitors and inducers of the P-gp 
transporter.
Because there is a potential for interaction of drug with other concomitantly administered drugs, 
the electronic case report form (eCRF) must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies. The Investigator should be alerted by the 
Research Coordinator if the participant is taking any agent known to affect, or with the potential 
to affect, selected CYP450 isoenzymes, P-gp inducers or inhibitors.
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics.
Rescue medication to reverse the actions of nintedanib (BIBF1120) is not available. Potential 
side effects of nintedanib (BIBF1120) have to be treated symptomatically.
6.5 Duration of Treatment
Participants may remain on study and continue to receive treatment in the absence of: disease 
progression, unacceptable toxicity or withdrawal from study, intercurrent illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
oral medication regime, or participant withdraws from study.
6.6 Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
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Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the participant’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Toxicity; related or unrelated toxicity

Investigator judgment

The Investigator may discontinue a participant if, in his/her judgment, it is in the best 
interest of the participant to do so.

Participant voluntary withdrawal

A participant may withdraw from the study at any time, for any reason. If a participant 
discontinues treatment, an attempt should be made to obtain information regarding the 
reason for withdrawal.

Sponsor decision.

NCCN decision

Boehringer Ingelheim Decision
6.7 Compliance
Patients will be supplied with a medication diary to track self-administration of nintedanib 
(Appendix F). Additionally, nintedanib pill counts will be performed at the conclusion of each 
cycle.
7
INVESTIGATIONAL PRODUCT
7.1 Active Substance and Source
Nintedanib is provided as soft gelatin capsules containing a suspension of milled active as the 
ethane sulphonate salt. It is available for clinical investigations in two dose strengths 
corresponding to 100 mg (peach or orange oblong capsules) and 150 mg (brown or orange 
oblong capsules). The capsule fill is composed of medium chain triglycerides, hard fat and 
lecithin in addition to the drug substance.
7.2 Drug Shipment
Nintedanib will be provided and shipped by Boehringer Ingelheim Pharmaceuticals Inc. to each 
participating site. Study specific order forms will be provided.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
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7.3 Storage and Stability
Nintedanib should be stored below 30°C. Specific information on the expiration date of each 
batch will be made available either on the drug labels or on the packing slips for each shipment. 
The capsules should be protected from exposure to high humidity which is ensured by storage in 
the original package. Please refer to investigator’s brochure for complete details.
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified by Boehringer Ingelheim 
and in accordance with the applicable regulatory requirements.
Drug storage temperature will be maintained and recorded, as applicable.
7.4 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Boehringer Ingelheim exercising accepted medical and 
pharmaceutical practices. Study drugs must be handled as cytotoxic agents and appropriate 
precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. It is the 
Principal Investigator’s responsibility to ensure that an accurate record of investigational drug 
issued and returned is maintained.
Excess drug (BIBF1120) will be destroyed according to standard practices after properly 
accounting for dispensing: study drug will not be re-used for other participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
8
STUDY PROCEDURES
Informed consent MUST be completed prior to receiving any study related procedures.
Unless otherwise defined in the written protocol text, all procedures/assessments will be 
conducted in accordance with RPCI Clinical Research Services Standard Operating Procedures.
8.1 Baseline Evaluations (≤ 28 Days Prior to Registration)
The following will be performed within 4 weeks prior to first dose of study drug:

Medical history and pre-existing conditions  (including all prior anti-tumoral therapy 
related to neuroendocrine cancer)

Physical examination

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, body weight, and 
height)

Hematology: complete blood count (CBC) with automated differentials.
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
Chemistry [complete metabolic panel (CMP)]: chloride, CO2, potassium, sodium, BUN, 
glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).

Serum serotonin and chromogranin A

Urine Sample for 24-hr 5-HIAA test

Urine protein/ creatinine ratio (Appendix G)

Plasma marker blood draw

EORTC QLQ – GI.NET21 Questionnaire (Appendix K)

Pregnancy test (serum) in females of childbearing potential. Note: This must be done 
within 7 days prior to the first dose of study drug (i.e., Cycle 1-Week 1-Day 1)

ECOG Performance Status (Appendix B)

Immune biomarker blood draw

Electrocardiogram

Tumor/Disease Assessment (CT scan of chest, abdomen, & pelvis)

Archival Tissue Sample

Concomitant Medications: List any medications ongoing or stopped within 1 week prior 
to first dose of study drug (to include Octreotide or Lanreotide dosing).
8.2 Evaluations Performed at Cycle 1-Week 1-Day 1

Vital signs

Hematology

Chemistry

ECOG Performance Status

Nintedanib and study medication diary provided to study participant

Concomitant Medications: List any ongoing medications with dose changes, as 
applicable (to include Octreotide or Lanreotide dosing).

Adverse Events
8.3 Evaluations Performed at Cycle 1-Week 3-Day 15

Vital signs

Hematology

Chemistry

Concomitant Medications: List any ongoing medications with dose changes, as 
applicable (to include Octreotide or Lanreotide dosing).

Adverse Events
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8.4 Evaluations Performed at Cycle 2-Week 1-Day 1 (± 3 days)
The following evaluations will be performed prior to daily study drug treatment:

Physical examination, including vital signs

Hematology

Chemistry

Nintedanib and study medication diary provided to study participant.

Concomitant Medications: List any ongoing medications with dose changes, as 
applicable (to include Octreotide or Lanreotide dosing).

Adverse Events
8.5 Evaluations Performed Every 8 Weeks (x24) from the Start of Study Treatment (±3 
days)
The following evaluations will be performed every 8 weeks from the start of study treatment 
(x24 weeks, (prior to daily study drug treatment), followed by evaluations to be performed every 
12 weeks until disease progression or toxicity or patient/ physician preference.

Physical examination (starting at cycle 2), including vital signs

Hematology

Chemistry

Serum serotonin and chromogranin A

Urine protein/ creatinine ratio Baseline and, prior to treatment every 8 weeks for 24 
weeks followed by evaluations at every 12 week  or as clinically indicated

EORTC QLQ – GI.NET21 Questionnaire (Appendix K)

ECOG Performance Status

Tumor/ Disease Assessment (CT scan of (chest, abdomen, & pelvis))

Concomitant Medications: List any ongoing medications with dose changes, as 
applicable (to include Octreotide or Lanreotide dosing).

Adverse Events
8.5.1 Plasma Biomarker/Steady-State PK Blood Sample Collection

Plasma Biomarkers at Baseline and at Week 8 prior to nintedanib dosing 
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8.6 Evaluations Performed at End of Treatment (± 3 days)
The following evaluations will be performed at the end of treatment or at time of treatment 
discontinuation:

Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight.)

Hematology: complete blood count (CBC) with automated differentials.

Chemistry [complete metabolic panel (CMP)]: chloride, CO2, potassium, sodium, BUN, 
glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap)

Urine protein/ creatinine ratio: 

EORTC QLQ – GI.NET21 Questionnaire (Appendix K)

ECOG Performance Status

Concomitant medication: List any ongoing medications with dose changes, as applicable 
(to include Octreotide or Lanreotide dosing).

Adverse events
8.7 Post-Treatment Follow-Up Evaluations (± 3 days)
Follow-up safety evaluations will occur 30 days (± 3 days) after last dose of study drug or until 
resolution of any drug-related toxicity (telephone contact is acceptable).

Concomitant medications: List any ongoing medications with dose changes, as applicable 
(to include Octreotide or Lanreotide dosing).

Adverse events 
8.8 Long Term Follow-Up Evaluations
8.8.1
Patients  off treatment due to reasons other than disease progression will be 
monitored every 3 months (± 7 days) after 30-day follow-up for 3 years (telephone 
contact is acceptable).

Concomitant medications: List any ongoing medications with dose changes, as applicable 
(to include Octreotide or Lanreotide dosing).

Adverse events
8.8.2
Patients off treatment due to disease progression will be monitored every 6 month (± 
7 days) after 30-day follow-up for overall survival.
8.8.3
Participants who are unavailable for follow-up evaluations should be classified as 
lost to follow-up for 1 of the following reasons:

Lost to follow-up: For a participant to be considered lost to follow-up, the investigator 
must make two separate attempts to re-establish contact with the participant. The 
attempts to re-establish participant contact must be documented (e.g., certified letter).
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
Death: Date and cause of death will be recorded for those participants who die within 
30 days after last dose of study drug (telephone verification is acceptable).
8.9 Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Table 6 below.
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Table 6
Schedule of Procedures and Observations
Evaluation
Baseline:
≤ 28 Days Prior 
to Registration1
Cycle 1
Week 1
Day 12
Cycle 1
Week 3
Day 15
Cycle 2 
Week 1 Day 1
(± 3 days)3
8 Weeks From 
Start of Study 
Treatment (± 3 
days)
End of Treatment 
(± 3 days)
Post 
Treatment 
Follow up 
Evaluation 
(± 3 days)4  
Progression 
Free 
Survival
Follow-Up 
(± 7 days)5
Medical History
X
Pre-Existing 
Conditions
X
Physical 
Examination
X
X
X
X
Vitals
X
X
X
X
X
X
Hematology6
X
X
X
X
X
X
Chemistry7
X
X
X
X
X
X
Urine Sample 
(24-hr 5-HIAA 
test
X
Serum  
serotonin and 
chromogranin 
A8
X
X8
Urine sample 
for Urine 
protein/ 
creatinine ratio9
X
X9
X
Plasma 
Biomarkers10
X
X
EORTC QLQ – 
GI.NET21 11
X
X11
X
Pregnancy Test 
(Serum)12
X
ECOG 
Performance 
Status13
X
X
X13
X
Immune 
Biomarkers14
X
Electrocardiogr
am
X
Tumor/Disease 
Assessment15
X
X15
Archival Tissue 
Sample
X
Nintedanib16
X
X
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Concomitant 
Medications
X17
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
1
Performed  < 28 days prior to registration start, except serum pregnancy (within 7 days prior to day 1).
2
Evaluations to be performed prior to treatment.
3
Evaluations performed prior to treatment on Day 1 (± 3 days) of subsequent cycles (1 cycle = 28 days).
4
Follow-up safety evaluations will occur 30 days (± 3 days) after last dose of study drug, (telephone contact is acceptable).
5
Participants will be monitored every 3 months (± 7 days) for 3 years (telephone contact is acceptable). Refer to Section 
8.8.1.
6
Hematology: complete blood count (CBC) with automated differentials.
7
Chemistry: complete metabolic panel (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total 
protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion 
gap).
8
Serum serotonin and chromogranin A: to be assessed at baseline and, prior to treatment every 8 weeks for 24 weeks, 
followed by evaluations at every 12 week (i.e., at all imaging time points).
9
Baseline and, prior to treatment every 8 weeks for 24 weeks followed by evaluations at every 12 week  or as clinically 
indicated.
10
Plasma biomarkers:  1, 10 mL purple-top EDTA collection tube for correlative studies at Baseline and at 8 weeks (± 
3days) after the start of treatment (Section 8.10).
11
Baseline and, prior to treatment every 8 weeks for 24 weeks, followed by evaluations at every 12 weeks (Appendix K).
12
Within 7 days prior to Day 1.
13
Baseline and, prior to treatment every 8 weeks for 24 weeks, followed by evaluations at every 12 week.
14 40 ml blood (4, 10 mL green-top heparinized collection tubes) will be collected at baseline and processed according to 
Section8.11.
15
CT scan of (chest, abdomen, & pelvis) restaging will be performed every 8 weeks for 24 weeks, followed by every 
12 weeks.
16
Study drug (nintedanib) to be dispensed at the beginning of each new cycle.
17
Medications ongoing or stopped within 1 week prior to first dose of study drug (to include Octreotide or Lanreotide 
dosing).
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8.10 Plasma Biomarker/Steady-State PK Blood Sample Collection and Processing
Whole blood samples for correlative cytokine levels will be collected via venipuncture using 1, 
10 mL purple top EDTA collection tube
Sample collection will be obtained at Baseline and at Week 8 prior to nintedanib dosing.
Samples for the correlative analyses will be collected in the Phlebotomy Laboratory and sent to 
the Hematological Procurement Facility for processing.
The steady-state pharmacokinetic analysis for Nintedanib will be done on the plasma samples 
obtained at week 8 (Bioanalytics, Metabolomics & Pharmacokinetic Core Facility, see below).
Plasma will be separated from whole blood within 60 minutes following the extraction.
NOTE: Any samples that have been hemolyzed should be re-drawn if possible.
Nintedanib is degraded by plasma esterases; therefore, whole blood samples should be 
immediately maintained in an ice bath until centrifuged. Centrifugation for separation of plasma 
should be done within 60 min after sampling: 

Centrifuge whole blood samples as soon as possible at 4°C using a refrigerated centrifuge 
at approximately 3000 rpm for about 10 min.

Transfer at least 500 µL of the supernatant plasma into polypropylene vials (e.g., Nunc 
cryo-tubes, 1.8 mL).
NOTE: Strictly avoid contamination with erythrocytes: If this occurs, the specimen must be 
centrifuged again.
 Plasma will be aliquoted into 2 cryovials per time-point. The screw cap polypropylene 
cryogenic tube will be labeled with the participant’s MR number,(for RPCI participants) 
participant’s initials, participant’s study number, clinical study number, protocol time point, 
dose, and protocol day. The samples will immediately be frozen at -70ºC or below until 
analyzed. Frozen samples will then be analyzed in RPCI’s Bioanalytics, Metabolomics & 
Pharmacokinetic Core Facility.
Samples collected at RPCI will be processed and stored at RPCI’s Hematological Procurement 
Facility. Frozen samples will then be analyzed in RPCI’s Bioanalytics, Metabolomics & 
Pharmacokinetic Core Facility:
Roswell Park Cancer Institute
Bioanalytics, Metabolomics & Pharmacokinetic Core Facility
Center for Genetics and Pharmacology, Room L1-140
Attn: Regarding Study # – I 259114
Elm & Carlton Streets
Buffalo, New York 14263
PKPDcore@RoswellPark.org
Note: All laboratories housing research samples need to maintain current Temperature Logs 
and study-specific Sample Tracking and Shipping Logs. The Principal Investigator/Laboratory 
Manager must ensure that the stated lab(s) have a process in place to document the 
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receipt/processing/storage/shipping of study-related samples/specimens (ICH 8.3.25). This is 
required for both observational and interventional clinical studies collecting clinical samples.
NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes will be labeled with the Subject ID # (unique to Network patients), initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day.  
Frozen samples will be batched and then-shipped via Fed Express Overnight on dry ice with 
delivery on Mon-Fri. NO SATURDAY OR SUNDAY DELIVERY. Notification via email 
should also be made to PKPDcore@RoswellPark.org to include tracking number, time of 
shipment, site name . All samples should be shipped to the address above with a copy of the 
Shipping Log.
For additional information regarding the handling of pharmacokinetic samples please contact 
RPCI’s Bioanalytics, Metabolomics & Pharmacokinetic Core Facility laboratory at 716-845-3303 
(Tel) or 716-845-1579 (Fax).
8.11 Immune Biomarkers Blood Sample
Whole blood samples for immune biomarker analysis will be collected via venipuncture at 
Baseline (Four, 10 ml green-top heparinized collection tubes).
PBMC’s will be separated from whole blood within 30 minutes following the extraction (refer to 
Appendix H: Isolation of Mononuclear Cells, for isolation details), and immediately frozen 
at -80ºC for cryopreservation procedure. PMBC’s will be aliquoted into 2 cryovials per time-
point. The screw cap polypropylene cryogenic tube will be labeled with the participant’s MR 
number,(for RPCI participants) participant’s initials, participant’s study number, clinical study 
number, protocol time point, dose, and protocol day. Samples collected at RPCI will be 
processed and stored at RPCI’s Hematological Procurement Facility. Frozen samples will then 
be analyzed in RPCI’s Flow Cytometry Core Laboratory by Dr. Hans Minderman (see below for 
contact information).
NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes will be labeled with the Subject ID # (unique to Network patients), initials, the 
participants study number, clinical study number, protocol time point, dose, and protocol day.  
Frozen samples will be batched and then shipped via Fed Express Overnight on dry ice with 
delivery on Mon-Fri. NO SATURDAY OR SUNDAY DELIVERY. Notification via email 
should also be made to HansMinderman@RoswellPark.org with tracking number, site 
name and time of shipment. All samples should be shipped to the address below with a copy of 
the Shipping Log:
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Roswell Park Cancer Institute
Flow Cytometry Research Services Core Laboratory
Cancer Cell Center (CCC), Room C-311A
Attn: Dr. Hans Minderman – I 259114
Elm & Carlton Streets
Buffalo, NY 14263-001
Tel: 716-845-1162 (office)
Tel: 716-845-3470 (lab)
Fax: 716-845-8806
Hans.Minderman@RoswellPark.org 
Note: All laboratories housing research samples need to maintain current Temperature Logs 
and study-specific Sample Tracking and Shipping Logs. The Principal Investigator/Laboratory 
Manager must ensure that the stated lab(s) have a process in place to document the 
receipt/processing/storage/shipping of study-related samples/specimens (ICH 8.3.25). This is 
required for both observational and interventional clinical studies collecting clinical samples.
8.12 Pathology
8.12.1 Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples
The following sections of tissue from carcinoid biopsy that exists in the Paraffin Archive in the 
Department of Pathology (or outside institution) will be collected:
1. Eight unstained sections cut at 4 microns on plus glass slides.
2. One H&E stained section
The study coordinator or designee will be responsible for entering the order into the EMR using 
the standard format for all clinical trial pathology requirements.
For Network Sites, de-identified tissue samples and de-identified pathology reports, using study-
specific subject ID number and tissue accession number, are to be sent to RPCI Correlative 
Science Pathology Office (Attn: Protocol Lab Team). The shipping label should read as follows:
Roswell Park Cancer Institute
Elm & Carlton Streets
Correlative Science Pathology Office
Gratwick Basic Science Building, S-636
Attn: Protocol Lab Team, I 259114 Samples
Buffalo, NY 14263
(716) 845-8917
Email: CRSLabPathTeam@RoswellPark.org 
Samples will be analyzed in RPCI’s Core Pathology Laboratory by Dr. Omilan’s group.
8.12.2 Tissue Samples for IMPACT Assay
The IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets) will be 
performed on a maximum of 10 patients who have adequate pre-treatment tumor tissue and post-
treatment biopsies. Ideally patients with good responses (aka the “outliers”) will be chosen for 
biopsy upon disease progression. We will use MSK-IMPACT to perform NGS in pre-treatment 
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and drug-resistant tumor with germ-line DNA (whole blood) as a reference. Refer to 
Appendix D for additional details on sample requirements.
9
EFFICACY EVALUATIONS
9.1 Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. RECIST 1.1 will be used to assess objective tumor response.
9.2 Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline. Target lesions will be selected on the basis of their size. Lesions with the 
longest diameter (short axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph 
nodes, > 20 mm CXR and are for accurate repetitive measurements (either by imaging 
techniques or clinically) will be chosen. A sum of the longest diameter (short axis for lymph 
nodes) of all target lesions will be calculated and reported as the baseline sum diameters. This 
will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease.

Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must 
have a reduction in short axis to < 10 mm. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response 
are first met.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. Changes in tumor measurements 
must be confirmed by repeat studies performed no less than 6 weeks after the criteria for 
response are first met.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. The appearance of one or more 
new lesions is also considered progression.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameter while on study. 
Participants having a documented response with no confirmation of the response will be 
listed with stable disease.
9.3 Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
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measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images 
drawing a regularly-shaped Region of Interest. Measurements of the non-target lesions will not 
be performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.

Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm 
short axis).

Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.

Progressive Disease: Appearance of 1 or more new lesions or the unequivocal 
progression of existing non-target lesions. Although a clear progression of non-target 
lesions is exceptional, in such circumstances, the opinion of the treating physician should 
prevail and the progression status should be confirmed at a later time.
9.4 Evaluation of Response
Time point response assessments will be performed every 8 weeks for 24 weeks, followed by 
assessments at every 12 weeks (timed to coincide with the end of a cycle) with a confirmatory 
assessment (required for non-randomized trials) no less than 6 weeks after a PR or CR is 
deemed. To determine time point response, refer to Table 7 and Table 8 below.
Table 7
Time Point Response Criteria (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
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Table 8
Time Point Response Criteria (non-target disease only)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for assessment of 
efficacy in trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until the 
end of treatment taking into account any requirement for confirmation. In general, the 
participant’s best response assignment will depend on the achievement of both measurement and 
confirmation criteria and will be determined by combining the participant’s status of target 
lesions, non-target lesions, and new lesions.

Residual Disease: Provide the appropriate information that pertains to this study.

Symptomatic Deterioration: Participants with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease progression 
at that time, and not related to study treatment or other medical conditions should be 
reported as progressive disease due to “symptomatic deterioration.” Every effort should 
be made to document objective progression even after discontinuation of treatment due to 
symptomatic deterioration. Symptomatic deterioration that may lead to discontinuation of 
treatment include, but is not limited to, symptoms such as:
o
Weight loss > 10% of body weight.
o
Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).
o
Decline in performance status of > 1 level on ECOG scale.
9.5 Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.

Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.
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
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.

PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.

Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances.

Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.

Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.

Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
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The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.

FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG PET imaging can be identified according to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD.

FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
9.6 Retrospective Review of Disease status
Due to indolent biology of neuroendocrine tumors, disease status prior to enrollment onto this 
clinical trial can help further inform primary endpoint of the study. Treating physician and/or PI 
at respective site are to review images on patients enrolled on study to determine disease status 
prior to enrollment on trial. All imaging modalities utilized prior to enrollment onto study are 
acceptable and RECIST evaluations are not required. Clinician/PI are to review images and 
clinical evaluations prior to being enrolled on this trial and determine disease status. Progressive 
disease can be captured as “radiographic progression”, “clinical progression”, or “clinical and 
radiographic progression”. If in the year prior to enrollment the patient had radiographic stable 
disease, please note “stable disease” and comment further on reason for change in treatment. 
Furthermore, imaging modalities utilized for above retrospective review are to be captured. Date 
for scan and/or clinical evaluation where progression is noted are to be entered in EDC. 
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10 SAFETY EVALUATION
10.1 Adverse Events
10.1.1 Definition
An adverse event or adverse experience (AE) is defined as any untoward medical occurrence 
(including an exacerbation of a pre-existing condition) associated with the use of a drug in 
humans, whether or not considered drug related (i.e., the event does not necessarily have to have 
a causal relationship with the treatment). Therefore, an AE can be ANY unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not considered 
related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’). In addition, each study site will also be responsible for 
reporting causality of AEs to Boehringer Ingelheim as per Section 10.2.1.
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
10.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
10.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
10.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
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cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
10.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
10.1.1.5 Vital Signs, ECG and Physical Examination Results
Changes in vital signs, ECG and physical examination test results will be recorded as an AE in 
the CRF, if they are judged clinically relevant by the investigator.
10.2 Adverse Events of Special Interests (AESI)
The following events are considered as Protocol-specified events of special interests:

Any gastrointestinal and non-gastrointestinal perforation, leakage, fistula formation, or 
abscess.
In such cases the following additional information will need to be collected, documented in the 
respective comment field of the CRF page and the respective narratives of the SAE, and be 
forwarded to Boehringer Ingelheim:
o
Location of perforation, leakage, fistula, abscess
o
Location/extent of abdominal tumor manifestations
o
Imaging & reports (CT, ultrasound, endoscopy, pathology, etc.)
o
Prior surgery (location, wound healing complications)
o
Concomitant diseases with GI involvement (e.g., M Crohn, vasculitis, tuberculosis, 
diverticulitis)
o
Thromboembolic events (or predisposition)

Drug-induced liver injury.
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 
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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:
o
An elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in 
the same blood draw sample
o
An elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of 
bilirubin to >1.5 fold ULN measured in the same blood draw sample
o
Patients showing the above laboratory abnormalities need to be followed up until the 
protocol specific retreatment criteria have been met and according to Appendix E 
[Boehringer Ingelheim: Procedures for the follow-up of drug-induced liver injury 
(DILI)].
Protocol-specified AESI are to be reported to Boehringer Ingelheim an expedited manner similar 
to Serious Adverse Events (Section 10.2), even if they do not meet any of the seriousness 
criteria.
10.2.1 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
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Boehringer Ingelheim Reporting Requirements

The severity of the AE should be judged based on the following:

The severity of adverse events should be classified and recorded in the eCRF according 
to the Common Terminology Criteria for Adverse Events (CTCAE) CTEP Version 4 of 
the NCI CTCAE located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm Causal 
relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship must be recorded for each adverse event.
Causality will be reported as either “Yes” or “No”:

Yes: There is a reasonable causal relationship between the investigational product 
administered and the AE (“Yes” is equivalent to: Possible, Probable or, Definite).

No: There is no reasonable causal relationship between the investigational product 
administered and the AE (“No” is equivalent to Unrelated or Unlikely).
10.2.2 Reporting Adverse Events
Table 9
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring from cycle 1 day 1, until 30 days after the last intervention or until the 
event has resolved, the study participant is lost to follow-up, the start of a new treatment, or until 
the study investigator assesses the event(s) as stable or irreversible, will be reported. New 
information will be reported after it is received.
10.3 Serious Adverse Events
10.3.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from 
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the reaction as it occurred. It does NOT include an AE that, had it occurred in a more 
severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
Patients may be hospitalized for administrative or social reasons during the trial (e.g. days on 
which infusion takes place, long distance from home to site). These and other hospitalizations 
planned at the beginning of the trial do not need to be reported as an SAE.
10.3.2 Reporting Serious Adverse Events 
Network Sites follow Appendix A: Instructions for Network Sites
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 10.6 for details on reporting Unanticipated Problems.
10.4 Investigator Reporting: Notifying Boehringer Ingelheim (BI) and NCCN
The investigator will report all SAEs and non-serious AEs which are relevant to a reported SAEs 
and AESIs by fax using BI IIS SAE form, or MedWatch 3500A, with the completed BI Fax 
Cover Sheet to BI Unique Entry Point and NCCN, as detailed below in accordance with the 
following timelines:

Within 5 calendar days upon receipt of initial and follow-up SAEs containing at least 
one fatal or immediately life-threatening event.

Within 10 calendar days upon receipt of any other initial and follow-up SAEs.
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road
Ridgefield, CT  06877
Fax: 1-203-837-4329
AND
NCCN at
ORPReports@nccn.org 
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or
(215) 358-7699
For each adverse event, the investigator will provide the onset date, end date, intensity, treatment 
required, outcome, seriousness, and action taken with the investigational drug. The investigator 
will determine the relationship and expectedness with the investigational drug to all AEs as 
defined in the listed adverse event section of Boehringer Ingelheim’s (BI’s) Investigator 
Brochure for the Product. 
The investigator does not need to actively monitor patients for adverse events once the clinical 
trial has ended. However, if the investigator becomes aware of an SAE(s) that occurred after the 
patient has completed the clinical trial (including any protocol specified follow-up period), it 
should be reported to BI if considered relevant by the investigator.
10.5 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible. New information will be reported when it is received.
10.6 Unanticipated Problems
10.6.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
b) The characteristics of the participant population being studied.
o
Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research).
o
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized and if in relation to an AE is also deemed Serious per 
Section 10.3.
10.6.2 Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Reportable 
New Information (RNI) Form will be submitted to the CRS Compliance Office within 1 business 
day of becoming aware of the Unanticipated Problem.
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When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems, to the IRB 
in accordance with their local institutional guidelines.
11 DATA AND SAFETY MONITORING
The RPCI Data and Safety Monitoring Board will assess the progress of the study, the safety 
data, and critical efficacy endpoints. The DSMB will review the study annually and will make 
recommendations that include but not limited to; (a) continuation of the study, (b) modifications 
to the design (c) or termination of the study. Per request, all annual DSMB study outcomes will 
be made available to NCCN and BI.
12 STATISTICAL METHODOLOGY
12.1 Endpoints
12.1.1 Primary
The primary endpoint is PFS, defined as the time interval from initiation of therapy, to its 
cessation for documentation of progressive disease (PD) or death. Disease progression will be 
determined by radiographic assessment every 8 weeks for first 24 weeks and then q 12 weeks 
thereafter.
12.1.2 Secondary
Clinical response (complete response + partial response) measured using standard RECISTv1.1 
criteria will be reported in all patients with measurable disease. Median overall survival will be 
reported in all patients. Change in QOL throughout treatment using the EORTC QLQ – 
GI.NET21 questionnaire will be analyzed in all patients who have filled out at least two QOL 
questionnaires and reported in three groups based on response (response, stable disease or 
progressive disease). The circulating marker levels (Steady state PK, FGF and FGFR and 
sVEGFR2) and with dynamic contrast enhanced CT parameters will be reported and predictive 
value assessed using the PK/PD model previously developed by our group to explore association 
with PFS, clinical response, QOL and overall survival. The ratio of FGFR IIIb/IIIc and Ki-67, 
MVD scores will be obtained to investigate association with PFS, clinical response, QOL and 
survival. Gene mutations and copy number alterations in the several pathways particularly 
mTOR pathway will be evaluated as exploratory endpoints, and will be analyzed for all patients 
and correlated with clinical outcomes. Biomarkers, Treg and cytokine expression and growth 
factors will be analyzed for all patients and reported in groups based on response.
12.2 Sample Size Determination
Two participating institutions will enroll maximum of 30 evaluable patients over a 24 month 
period.
The sample size calculation is based on testing the hypotheses concerning the PFS rate at 16 
weeks in patients treated under the proposed therapy: H0: p ≤ p0 versus HA: p > p0. This single-
stage design requires a total of n patients in order to achieve approximately 1-β power to detect 
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differences of ∆ percentage points (p0 versus p0 +∆). For this study α = 0.10 and 1-β =0.90; with 
p0=0.40 and =0.24 for this population of carcinoid patients. 
12.3 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
12.4 Efficacy Analysis
The primary objective of this study is to assess the efficacy of the investigational agent 
nintedanib in carcinoid patients. Let p represent the PFS rate at 16 weeks. A true PFS rate at 16 
weeks of less than p0 =0.40 is considered unacceptable in carcinoid, and evidence of such will 
deem the treatment not worthy of further study.
The null and alternative hypotheses to be tested are H0: p ≤ p0 versus HA: p > p0. A one-sided 
exact binomial test (at a nominal α=0.10) and corresponding decision rules will be used to 
evaluate these hypotheses:

If 15 patients or less have not progressed at 16 weeks, then it is concluded that the 
therapy is not promising.

If 16patients or more have not progressed at 16 weeks, then it will be concluded that the 
therapy is promising.
Additionally, a confidence interval for the 16-week PFS rate will be obtained using Jeffrey’s 
prior method.
Secondary Analysis: The time-to-event outcomes (PFS and OS) will be reported using standard 
Kaplan-Meier methods. Ninety-five percent confidence intervals for the median PFS and OS will 
be calculated using Greenwood's formula. Exact 90% confidence interval estimates using the 
Clopper-Pearson method will be given for the response and toxicity rates. An exact 90% 
confidence interval will be given for the rate of improved QOL. Changes in pre- and post- 
treatment cytokine expression and growth factors will be analyzed using permutation paired t-
tests. Dichotomous variables, such as response and QOL, will be analyzed using the logistic 
regression to investigate their association with quantified variables, such as biomarker expression 
and gene mutation. The association between survival and quantified variables will be 
investigated using the Cox-proportional hazard model.
12.4.1 Adverse Event
The frequency of toxicities will be tabulated by grade across all dose levels and cycles. All 
participants who receive any study treatment will be considered evaluable for toxicity.
Toxicity (graded using the NCI CTC version 4.0) will be closely monitored and all toxicities will 
be tabulated. The PI, Data Safety Monitoring Board and IRB will monitor toxicities and close the 
study if the therapy appears too toxic.
12.5 Replacement
Patients that do not have a response assessment completed by 16-weeks are considered 
unevaluable for the primary end-point and will be replaced.
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12.6 Interim Analysis and Criteria for Early Termination of the Study
There are no planned interim analyses (unless for safety reasons) or early termination criteria.
13 CORRELATIVE DATA ANALYSIS
Preliminary Data
Thalidomide is believed to be an inhibitor of FGF2 induced angiogenesis and Dr. Shah and 
others (31, 32) have shown in phase 2 trials that thalidomide has activity in neuroendocrine cancers. 
The cytokine assays are commercially available and the PK/PD model proposed to be used (see 
below) has already been developed and validated. The rationally selected IHC assays have been 
previously standardized by our group.
Recently our colleagues at Johns Hopkins and MSKCC determined the exomic sequences of 10 
nonfamilial pNETs and then screened the most commonly mutated genes in 58 additional 
pNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 
44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a 
component of a histone methyltransferase complex, and 43% had mutations in genes encoding 
either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX 
(death-domain–associated protein) and ATRX (α thalassemia/mental retardation syndrome X-
linked). They also found mutations in genes in the mTOR (mammalian target of rapamycin) 
pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for 
treatment with mTOR inhibitors. These findings were provocative. However, clinical 
descriptions of these patients are unavailable. In addition, none of these tumors were 
resequenced at another point in time to better understand the evolution of these tumors. Indeed, 
most of the tumors were in patients that had early stage disease that was resected.
In addition, researchers at the Mayo clinic recently performed whole genome sequencing in 
small bowel carcinoids.
Our group has established assays for assessment of several immune subsets (29) showing T reg 
frequency and number in HCC patients being prospectively studied in another NCCN funded 
trial.
13.1 Plasma Biomarker PK/PD Modeling
A mechanistic PK/PD model will be developed to characterize the time course of nintedanib 
concentrations in relation to target decreases in sVEGFR-2, FGF23, along with cytokine 
modulation.  Subsequently, diagnostic plots will be created to ascertain whether a trend exists 
among sVEGFR-2 levels, FGF23, immunological response, and progression free survival (PFS). 
 If trends exist, these endpoints will also be included in the PK/PD model.  A variety of 
compartmental population PK models will be evaluated using a nonlinear mixed effects 
modeling approach. The PK models explored will be described by the estimation of mean 
structural parameters (e.g., plasma volumes of distribution and clearances), the magnitude of 
inter-individual variability (IIV) in these parameters, and residual variability (RV). The model 
for IIV will be assumed that the variance is proportional with respect to the typical value of the 
PK parameter. This analysis will include evaluation of the influence of a limited number of 
patient covariates, such as demographics along with other cofactors, on the variability in select 
PK/PD parameters. Based on our sparse sampling approach, prior information on PK parameters 
and variances can be used with a Bayesian estimation method.  For comparisons of hierarchical 
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models, the change in the minimum value of the objective function (MVOF), a statistic that is 
proportional to minus twice the log likelihood of the data, will be examined. A change in the 
MVOF of greater than 7.88 between two hierarchical models represents a statistical difference at 
a p-level of 0.005 for the addition of one parameter (df = 1). The goodness-of-fit analyses will be 
additionally assessed by: (1) scatterplots of measured concentrations and weighted residuals 
versus population predicted concentrations, and weighted residuals versus time since first and 
last dose; (2) scatterplots of measured concentrations, individual weighted residuals, and 
absolute individual weighted residuals versus individual predicted concentrations; (3) the 
precisions of the parameter estimates as measured by the percent standard error of the mean 
(%SEM = standard error/parameter estimate * 100% ); (4) changes in the estimates of IIV and 
RV; and (5) histograms, boxplots, and plots of quantiles of individual and population weighted 
residuals versus quantiles of the normal distribution (QQ plots).
13.2 IMPACT Assay
These assays will be done in the first 10 patients who have adequate pre-treatment tumor tissue 
and, will have post treatment biopsies. Ideally patients with good response (aka the “outliers) 
will be chosen for biopsy upon disease progression.
Akt activity will be determined by blotting for the phosphorylation of Akt downstream targets 
including p-Foxo, p-GSK3, p-PRAS40. IHC analysis of total AKT, p-Akt Ser473, PTEN, total 
4E-BP1, p-4E-BP1Thr70, p-eIF-4G Ser1108 (peIF-4G), total S6, p-S6 Ser235/236 and 
Ser240/244, and proliferation marker Ki-67 will also be performed in formalin-fixed paraffin-
embedded sections from the tumor samples (Refer to Appendix D).
14 ETHICAL AND REGULATORY STANDARDS
14.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) at each investigational site. Each participant (or legal 
guardian) shall read, understand, and sign an instrument of informed consent prior to 
performance of any study-specific procedure. It is the responsibility of the investigator to ensure 
that the participant is made aware of the investigational nature of the treatment and that informed 
consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with 
good clinical practice and the applicable regulatory requirements and according to the guidelines 
in this protocol, including attached appendices.
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14.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from 
each participant or the participant's legally authorized representative in accordance with GCP 
guidelines using the approved informed consent form, before any study specific procedures 
(including screening procedures) are performed. The informed consent form acknowledges all 
information that must be given to the participant according to applicable GCP guidelines, 
including the purpose and nature of the study, the expected efficacy and possible side effects of 
the treatment(s), and specifying that refusal to participate will not influence further options for 
therapy. Any additional information that is applicable to the study must also be included. 
Additional national or institutionally mandated requirements for informed consent must also be 
adhered to. The participant should also be made aware that by signing the consent form, 
processing of sensitive clinical trial data and transfer to other countries for further processing is 
allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
15 STUDY RESPONSIBILITIES
15.1 Data Collection
Data entry into the database is to be completed in a timely fashion (within 30 days) after the 
participant’s clinic visit. If an AE is considered serious it is captured on both the Adverse Event 
page and the Serious Adverse Event Source Form (as well as the BI SEA form), which is 
handled in an expedited fashion.
Data management activities will be performed using eClinical. eClinical is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
eClinical Information Technology team. Once the database design is approved by the Principal 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs (via the EXPeRT Module). eClinical is compliant with all relevant 
technical aspects of relevant GCP guidelines.

The system can generate accurate copies of stored data and audit trail information in 
human readable form.

System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.

The system is designed to periodically force users to change their passwords and verifies 
that user ID and password combinations remain unique.

The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
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Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
15.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI.
16 ADMINISTRATIVE RULES
16.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
16.2 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or NCCN or Boehringer 
Ingelheim, may terminate this study, provided a written notice is submitted within the time 
period provided for in the Clinical Trial Agreement. In addition, RPCI may terminate the study 
at any time upon immediate notice if it believes termination is necessary for the safety of 
participants enrolled in the study.
16.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
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17 APPENDICES
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Appendix A
Instructions for Network Sites
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 8: 00 AM to 4: 30 PM EST
716-845-3870 or 716-845-1205
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
E-mail: CRSNetworkcoordinators@roswellpark.org 
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any 
participants wishing to participate, prior to any research procedures or treatment.

An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.

All consent changes must be reviewed by RPCI Network Office prior to submission to 
the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being used.

Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be faxed to the RPCI Network Office within 
1 business day of the date the participant is consented. Once the Investigator has determined that 
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eligibility has been met, complete the Subject Registration Form and fax it to the RPCI 
Network Monitor at 716-845-8743.
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.

If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.
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
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have its 
own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. A preliminary written report must follow within 1 business day of the first 
notification using the following forms:

RPCI SAE Source form

MedWatch 3500 A will be required only if it is necessary to report to the FDA.

See Section 10.4 of protocol for information on notifying the drug sponsor, Boehringer 
Ingelheim Pharmaceuticals.

SAE reports are to be submitted to the NCCN: email ORPReports@NCCN.org or fax 
SAE’s to 215-358-7699.

SAE reports are to be submitted to BI as well. 
A complete follow-up report must be sent to the RPCI Network Monitor when new information 
becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
criteria in Section 10.6.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff 
from each site will notify their local IRB in accordance with their local institutional 
guidelines. The site must also notify the RPCI Network Monitor within 1 business day of being 
made aware of the Unanticipated Problem by completing the RPCI Unanticipated Problem 
Report Form and faxing or emailing it to the RPCI Network Monitor.
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Appendix B
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix C
New York Heart Association Classification
New York Heart Association (NYHA)
Congestive Heart Failure (CHF)
Functional Classification Systema
Class
Functional Description
NYHA Class I
Cardiac disease, but no symptoms and no 
limitation in ordinary physical activity (e.g., 
shortness of breath when walking, climbing 
stairs, etc.).
NYHA Class II
Mild symptoms (mild shortness of breath 
and/or angina) and slight limitation during 
ordinary activity.
NYHA Class III
Marked limitations in activity due to 
symptoms, even during less-than-ordinary 
activity [e.g., walking short distance (20-100 
m)]. Comfortable only at rest.
NYHA Class IV
Severe limitations. Experiences symptoms 
even while at rest. Mostly bedbound patients.
a The Criteria Committee of the New York Heart Association. (1994). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, 
Brown & Co. pp. 253–256.
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Appendix D
IMPACT Assay (MSKCC)
MSK-IMPACT is a NGS platform that was recently developed at MSKCC and uses massively 
parallel sequencing and solution-phase exon capture to perform NGS.(33-35) The platform screens 
341 oncogenes and tumor suppressor genes commonly altered across tumor types, and provides a 
comprehensive analysis of multiple genes in the PI3K/Akt/mTOR pathway, including PIK3CA, 
AKT1/2/3, PTEN, TSC1/2, and mTOR, as well as SMAD family genes, AURKA, EGFR, 
HSP90, and PDGFR that were identified in the small bowel sequencing project.  The platform 
successfully identifies sequence variants, small insertions and deletions, copy number alterations, 
loss of heterozygosity, and select rearrangements. We will use MSK-IMPACT to perform NGS 
in pre-treatment and drug-resistant tumor with germ-line DNA (whole blood) as a reference.
After MSK-IMPACT sequencing has been performed in both pre-treatment and drug-resistant 
tumor, Dr Raj and Dr. Reidy will work with the genetics experts in the MSKCC Center for 
Molecular Oncology to clinically translate our findings, reviewing and interpreting the results for 
biologic and clinical significance. In particular, they will look at changes in the mTOR pathway 
(AKT) to investigate if any observed mutations may confer resistance to nintedanib. All 
IMPACT Assay Samples can be sent to the following address below along with site name and 
tracking number and copies of specimen and shipping log:
Diane Reidy-Lagunes
MSKCC
300 East 66th street room 1039
NY, NY 10065
Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples

Any target tumor tissue can be collected per discretion of the PI, providing physician, 
and/or surgical/ radiology team members.

At minimum, adequate tissue should be collected for 20 unstained and one (1)H&E 
stained slide that are 4-5µm thick and on positively charged slides. Tissue should be 
formalin fixed paraffin embedded (FPPE). 

Ideally, biopsy should be performed prior to introduction of new chemo/radiation; 
however, this is not required.
Blood Sample Collection and Processing
Germline DNA is required for comparison with tumor tissue. Patients will be asked to provide 
whole blood samples via venipuncture using one (1) 10 mL lavender top EDTA collection tubes. 
Samples will be labeled as “Post Treatment IMPACT Assay Blood Samples” along with date of 
collection, protocol number, and study participant identification number. Sample will be kept in 
ambient temperature and shipped overnight to MSK.
Ideally, the blood sample should be obtained on the same day and prior to the IMPACT biopsy. 
However, this blood sample can be collected any time after the patient is taken off nintedanib. 
Results of the IMPACT assay will not be made available to the patient. 
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Appendix E
Drug-Induced Liver Injury Follow-Up Procedures
Procedures for the follow-up of a potential DILI case 
(Hy`s Law case) in IIS with nintedanib (BIBF 1120)
______________________________________________________________________________
Introduction
Drug-induced liver injury
Drug-induced liver injury (DILI) has been the most frequent single cause of safety-related drug 
marketing withdrawals for the past 50 years (e.g., iproniazid), continuing to the present (e.g., 
ticrynafen, benoxaprofen, bromfenac, troglitazone, nefazodone). Accordingly, detection of drug-
induced liver injury of an investigational compound has become an important aspect of patient´s 
safety guarding in drug development.
The US-FDA has published a Guidance for Industry entitled, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation” 
(http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf ) which outlines the 
detection, evaluation, follow-up and reporting of drug-induced liver injury in clinical trials. 
Drugs that have the potential for inducing severe liver injury may be identified by marked peak 
aminotransferase elevations (10x-, 15xULN), or the combination of hepatocellular injury 
(aminotransferase elevation ≥3xULN) and altered liver function (hyperbilirubinemia ≥2xULN) 
which is defined as potential “Hy´s law case” if not explained by other causes including evidence 
of biliary obstruction (i.e., significant elevation of alkaline phosphatase, ALP, >2X ULN) or some 
other explanation of the injury (e.g., viral hepatitis, alcohol hepatitis, concomitant use of other known 
hepatotoxic drugs). This constellation predicts a poor outcome and although very rare, these 
potential cases have to be well characterized as soon as being identified as other confounding 
conditions may be the cause.
In further consideration of this FDA Guidance, any potential “Hy’s Law case” has to be reported 
in an expedited manner to the FDA (i.e., even before all other possible causes of liver injury have 
been excluded) and be followed-up appropriately. The follow-up includes a detailed clinical 
evaluation and identification of possible alternative etiologies for the “Hy´s Law case” 
constellation such as concomitant diseases (e.g. Hepatitis B) and/or other concomitant therapies 
that might potentially be hepatotoxic.
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and follow-
up of laboratory alterations of selected liver laboratory parameters to ensure patients´ safety.
The concept below has been worked out by Boehringer Ingelheim (BI) in order to guard patient´s 
safety and to respond to regulatory requirements. It is the basis for all clinical studies and should 
be applied as appropriate.
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Definition
The following changes in the laboratory values are considered to be a protocol-specific 
significant adverse event for all 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
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.
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The investigator will report all SAEs and non-serious AEs which are relevant to reported SAEs 
and AESIs by fax using BI IIS SAE form or MedWatch 3500A form, and completed BI SAE Fax 
Cover sheet to BI Unique Entry Point as detailed below:
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road
Ridgefield, CT  06877
Fax: 1-203-837-4329
3. An evaluation of the patient within 48 hours with respect to but not limited to:

Abdominal ultrasound or clinically appropriate other imaging and investigations 
adequate to rule out biliary tract, pancreatic,  intra- or extrahepatic pathology, e.g. bile 
duct stones,  neoplasm, hepatic tumour involvement, biliary tract, pancreatic or 
intrahepatic pathology, vascular hepatic conditions such as portal vein thrombosis or 
right heart failure. These data need to be collected, documented in the respective field 
of the eCRF / CRF / additional documentation form, and the respective SAE form has 
to be updated and forwarded to BI.

Detailed history of current symptoms and concurrent diagnoses and medical history.

Detailed history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations and e.g., steroids as concomitant 
supportive treatment), alcohol use, recreational drug use, and special diets detailed 
history of exposure to environmental chemical agents.
4. In case that both imaging and laboratory value did not unequivocally confirm cholestasis 
as the reason of ALT / AST increase, in particular if AP < 2x ULN, then please complete 
the following laboratory tests:

Clinical chemistry:

Alkaline phosphatase, cholinesterase (either plasma or red blood cell), albumin, PT or 
INR, CK, CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin, ferritin, amylase*, 
lipase*, fasting glucose*, cholesterol, triglycerides

Serology:

Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HBsAg, Anti-HBs, DNA), Hepatitis 
C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG)*, 
Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive)*, Anti-
Smooth Muscle antibody (titer)*, Anti-nuclear antibody (titer)*, Anti-LKM (liver-
kidney microsomes) antibody*, Anti-mitochondrial antibody*, Epstein Barr Virus 
(VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, 
IgM), varicella (IgG, IgM), parvovirus (IgG, IgM)

Hormones, tumor marker:

TSH*
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
Hematology:

Thrombocytes*, eosinophils*
*If clinically indicated and, in case that additional investigations are needed (e.g., 
immunocompromised patients).
5. Initiate close observation of all patients with elevated liver enzyme and bilirubin 
elevations by repeat testing of ALT, AST,  bilirubin (with fractionation into total and 
direct) and AP at least weekly until the laboratory values return to normal or to the values 
as defined in the protocol.
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
Study Medication Diary for Nintedanib
Protocol No.: ________________
Patient Name: ______________________________
Cycle ________ ID# ___________
Medical Record No.: _________________________
Please complete this calendar on a daily basis. Take the AM and PM doses approximately 12 hours apart.  Take with 
water within 30 minutes after the end of a meal. If a dose is missed write “0” in the # taken box. If your dose changes, 
record the new dose.
Start Date: ____________ 
Nintedanib per dose #100mg: _______ #150mg: _________
Cycle Day
Day 1
Day 2
Day 3 
Day 4
Day 5
Day 6 
Day 7
Date
Nintedanib
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Dose:
100mg  #
150mg  #
Cycle Day
Day 8
Day 9
Day 10 
Day 11
Day 12
Day 13 
Day 14
Date
Nintedanib
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Dose:
100mg  #
150mg  #
Cycle Day
Day 15
Day 16
Day 17 
Day 18
Day 19
Day 20 
Day 21
Date
Nintedanib
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Dose:
100mg  #
150mg  #
Cycle Day
Day 22
Day 23
Day 24 
Day 25
Day 26
Day 27 
Day 28
Date
Nintedanib
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Dose:
100mg  #
150mg  #
Please remember to bring this calendar and your capsule bottle (including any unused capsules) with you to your 
next study appointment.
Coordinator use only
Date of return: __________________
Patient signature: _________________________________________
____Date: _____________
Investigator signature: _____________________________________
____Date: _____________
Clinical Research Services
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Appendix G
Procedure for Obtaining a Urine Protein/ Creatinine Ratio
1. Obtain at least 4 ml of a random urine sample (does not have to be a 24-hour urine)
2. Determine protein concentration (mg/dL)
3. Determine creatinine concentration (mg/dL)
4. Divide #2 by #3 above: urine protein / creatinine ratio = protein concentration (mg /dL) /
Creatinine concentration (mg/dL)
The UPC directly correlates with the amount of protein excreted in the urine per 24 hr (i.e., a 
UPC of 1 should be equivalent to 1 g protein in a 24 hr urine collection)
Protein and creatinine concentrations should be available on standard reports of urinalyses, not 
dipsticks. If protein and creatinine concentrations are not routinely reported at an Institution, 
their measurements and reports may need to be requested.
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Appendix H
Isolation of Mononuclear Cells
Protocol for Isolation of Mononuclear cells by Density Gradient Separation
Principle
This procedure describes a method for isolation of mononuclear cells from circulating blood.  
Histopaque®-1077 is a solution of polysucrose and sodium diatrizoate, adjusted to a density of 
1.077+0.001 g/mL. This medium facilitates rapid recovery of viable mononuclear cells from 
small volumes of blood.
Anticoagulated blood is layered onto Histopaque®-1077.  During centrifugation, erythrocytes 
and granulocytes are aggregated by polysucrose and rapidly sediment; whereas, lymphocytes and 
other mononuclear cells remain at the plasma-Histopaque®-1077 interface.  
Erythrocyte 
contamination is negligible.  Most extraneous platelets are removed by low speed centrifugation 
during the washing steps.
Reagents and Supplies
Histopaque®-1077”Ficoll” (Sigma Aldrich cat#10771)
RPMI 1640
Hanks balanced salt Solution (HBSS)
Phosphate Buffered Solution (PBS)
Fetal calf serum (FCS)
15 or 50mL polypropylene tubes
Procedure
1
Dilute blood in a 1:1 dilution with either HBSS or PBS. Calculate the amount of Ficoll to 
be used; it will be half of the volume of diluted blood (e.g., for 8ml diluted blood you will 
need 4ml of Ficoll).
2
Place the Ficoll in the bottom of the polypropylene tube.
3
Carefully layer sample over the tube of Ficoll. Do not pipette the sample too quickly as 
mixing will occur.
4
Centrifuge the sample for 30 minutes at 400g, 25˚C and most importantly without the 
brake.
5
After the centrifuge has stopped, the cells need to be removed from the Ficoll 
immediately and washed because the Ficoll solution is toxic to cells. The mononuclear 
layer should be visible as a cloudy white disk at the interface of the plasma-Ficoll layers, 
roughly in the middle of the tube.  Carefully remove and discard the top layer of plasma 
and media until there is only a small amount left above the cell layer.
6
Next, remove the mononuclear layer (the cloudy disk) taking care not to disturb the red 
cell layer below, and place in a sterile tube.
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7
Dilute the mononuclear cells 3-6 times their volume in RPMI media containing 10% FCS 
and centrifuge for 5 min at 400g, 25˚C with the brake on.
8
Aspirate supernatant, resuspend the pellet in residual volume and add up to 5mls of 
RPMI 1640w 10% FCS.
9
Perform a cell count. Cells are now ready to be assayed. 
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Appendix I
Protocol for Cryopreserving PBMCs
Materials and Reagents
RPMI 1640 media
Fetal Calf Serum
Dimethyl Sulfoxide (DMSO), Hybri- Max (Sigma Aldrich #D2650)
100% Isopropanol
Nalgene Cryo 1 freezing container (aka Mr. Frosty) (Catalogue #5100-0001)
Phosphate Buffered Saline Solution (PBS)
Method
1
Following Ficoll Histopaque (Sigma Aldrich #10771) density gradient separation, 
resuspend PBMC’s in cold RPMI1640 and perform a cell count.
2
Adjust cell density to no more than 2x107 cells/ml
3
Make up 2x cryopreservation solution fresh as needed, to contain 100% FCS, 20% 
DMSO.  Add DMSO slowly to FCS on ice (it generates heat).
4
Add an equal amount of ice-cold 2x cryopreservation solution drop-wise to the ice-cold 
cell suspension while vortexing, making sure to slowly increase the DMSO concentration 
from 0 to 10% 
5
Aliquot 1ml of cell mixture into labelled 1.5ml cryo vials.
6
Add room temperature 100% Isopropanol to the fill line of a Mr. Frosty Cryo container 
(source) and place vials in the insert. 
7
Place the Mr. Frosty in a -80 degree freezer, for at least 4h then transfer the frozen vials 
to liquid N2 for long term storage.
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Appendix J
In vivo P-gp Transporter Inhibitors and Inducers
Examples of in vivo P-gp transporter inhibitors and inducers a
P-gp Inhibitors
P-gp Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin
Conivaptan
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir And Ritonavir,
Quercetin,
Quinidine
Ranolazine
Verapamil
Avasimibe
Carbamazepine
Phenytoin
Rifampin
St John’s wort
Tipranavir/Ritonavir
aadapted from Table 12: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm
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Appendix K
EORTC QLQ – GI.NET21
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