Ramucirumab Plus Irinotecan in Patients With Previously Treated Advanced Gastric or Gastro-esophageal Junction Adenocarcinoma
Phase: PHASE2
Conditions: Gastric Adenocarcinoma, Gastro-esophageal Junction Adenocarcinoma
Sponsor: Washington University School of Medicine

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Ramucirumab plus irinotecan in patients with previously treated advanced gastric or 
gastro-esophageal junction adenocarcinoma 
 
Washington University School of Medicine, Division of Oncology 
660 South Euclid Avenue, Campus Box 8056, St. Louis, MO  63110 
 
Protocol #: 201704082 
Version Date: 06/10/2022 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
Kian-Huat Lim, M.D., Ph.D. 
Phone: (314) 362-6157 
E-mail: kian-huat.lim@wustl.edu   
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Ryan Fields, M.D. 
 
 
Washington University 
Surgery 
Jason Mills, M.D., Ph.D. 
 
Washington University 
Pathology 
Katrina Pederson, M.D. 
 
Washington University 
Medical Oncology 
Caron Rigden, M.D.  
 
Washington University 
Medical Oncology 
Rama Suresh, M.D. 
 
 
Washington University 
Medical Oncology 
Benjamin Tan, M.D.  
 
Washington University 
Medical Oncology 
Nikolaos Trikalinos, M.D. 
 
Washington University 
Medical Oncology 
Esther Lu, M.S., Ph.D. 
 
Washington University 
Biostatistics 
Peter Joel Hosein, MBBS 
 
University of Miami  
Medical Oncology 
Aravind Sanjeevaiah, MD 
 
UT Southwestern 
 
Medical Oncology 
Rutika Mehta, M.D.  
 
Moffitt Cancer Center  
Medical Oncology  
 
Study Drug(s): 
 
Ramucirumab (Cyramza) 
Irinotecan (Camptosar) 
 
ClinicalTrials.gov #: 
NCT03141034 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 

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Ramucirumab plus irinotecan in patients with previously treated advanced gastric or 
gastro-esophageal junction adenocarcinoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
04/19/2017 
Amendment #1 Version 
 
 
 
 
 
 
05/01/2018 
Amendment #2 Version 
 
 
 
 
 
 
05/16/2019 
Amendment #3 Version 
 
 
 
 
 
 
08/23/2019 
Amendment #4 Version 
 
 
 
 
 
 
03/27/2020 
Amendment #5 Version 
 
 
 
 
 
 
09/23/2021 
Amendment #6 Version 
 
 
 
 
 
 
06/10/2022 

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Ramucirumab plus irinotecan in patients with previously treated advanced gastric or 
gastro-esophageal junction adenocarcinoma 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
Kian Huat-Lim, M.D., Ph.D. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 
 

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Ramucirumab plus irinotecan in patients with previously treated advanced gastric or 
gastro-esophageal junction adenocarcinoma 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent, Screening and Register 
Treatment Plan 
Irinotecan plus ramucirumab 
 
Ramucirumab 8 mg/kg IV with Irinotecan 180 mg/m2 IV 
 
Day 1 of each 14-day cycle. 
 
Patients to continue on treatment as long as the regimen is 
tolerated and the patient does not meet discontinuation 
criteria. Patient will be assessed with CT scans after every 4 
cycles. 
Eligible Patients 
• Metastatic gastric or gastro-esophageal adenocarcinoma. 
• Age ≥ 18 years, ECOG performance status 0 or 1. 
• Disease progression after first-line of therapy with fluoropyrimidine/ 
platinum or taxane based regimen. 
• Patients with ≥grade 2 peripheral neuropathy are eligible 
(Details - see protocol Section 3.0) 
Generate patient-derived 
xenografts/organoids 
Tumor biopsy* (Wash U only) 
*at least 7 days prior to planned C1D1 

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Glossary of Abbreviations 
 
5-FU 
5-fluorouracil 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BOR 
Best overall response 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CFR 
Code of Federal Regulations 
CR 
Complete response 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
DVT 
Deep vein thrombosis 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FWA 
Federal wide assurance 
GEJ 
Gastro-esophageal junction 
GI 
Gastrointestinal 
HGF 
Hepatocyte growth factor 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
IV 
Intravenous 
LV 
Leucovorin 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OHRP 
Office of Human Research Protections  

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ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PE 
Pulmonary embolism 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
PTT 
Partial thromboplastin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RPLS 
Reversible posterior leukoencephalopathy syndrome 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TTP 
Time to progression 
UA 
Urinalysis 
UPN 
Unique patient number 
VEGF 
Vascular endothelial growth factor 
WUSM 
Washington University School of Medicine 
 
 

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Table of Contents 
SCHEMA ........................................................................................................................................ 4 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 9 
1.1 
Gastric Cancer .................................................................................................................. 9 
1.2 
VEGF in Gastric Cancer .................................................................................................. 9 
1.3 
Chemotherapy for Metastatic Gastric Cancer .................................................................. 9 
1.4 
Irinotecan (Camptosar) ................................................................................................... 10 
1.5 
Ramucirumab (Cyramza) ............................................................................................... 10 
1.6 
Study Rationale .............................................................................................................. 10 
1.7 
Correlative Studies ......................................................................................................... 11 
2.0 
OBJECTIVES .................................................................................................................... 13 
2.1 
Primary Objective .......................................................................................................... 13 
2.2 
Secondary Objectives ..................................................................................................... 13 
2.3 
Exploratory Objectives ................................................................................................... 14 
3.0 
PATIENT SELECTION .................................................................................................... 14 
3.1 
Inclusion Criteria ............................................................................................................ 14 
3.2 
Exclusion Criteria ........................................................................................................... 16 
3.3 
Inclusion of Women and Minorities............................................................................... 18 
4.0 
REGISTRATION PROCEDURES ................................................................................... 18 
4.1 
Confirmation of Patient Eligibility ................................................................................. 18 
4.2 
Patient Registration in the Siteman Cancer Center Database ........................................ 18 
4.3 
Assignment of UPN ....................................................................................................... 19 
5.0 
TREATMENT PLAN ........................................................................................................ 19 
5.1 
Premedication Administration........................................................................................ 19 
5.2 
Agent Administration ..................................................................................................... 19 
5.3 
Evaluability .................................................................................................................... 19 
5.4 
General Concomitant Medication and Supportive Care Guidelines .............................. 19 
5.5 
Women of Childbearing Potential .................................................................................. 20 
5.6 
Duration of Therapy ....................................................................................................... 20 
5.7 
Duration of Follow-up .................................................................................................... 21 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 22 
6.1 
Dose Modifications for Ramucirumab ........................................................................... 22 
6.2 
Dose Modifications for Irinotecan ................................................................................. 23 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 24 
7.1 
Definitions ....................................................................... Error! Bookmark not defined. 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
24 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 25 
7.4 
Reporting Requirements for Secondary Sites ................................................................ 25 
7.5 
Reporting to Secondary Sites ......................................................................................... 26 
7.6 
Reporting to Eli Lilly ..................................................................................................... 26 
7.7 
Timeframe for Reporting Required Events .................................................................... 27 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 28 
8.1 
Ramucirumab (Cyramza) ............................................................................................... 28 
8.2 
Irinotecan (Camptosar) ................................................................................................... 29 

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9.0 
CORRELATIVE STUDIES .............................................................................................. 32 
9.1 
Rationale for patient-derived xenograft and organoid generation ................................. 32 
9.2 
Rationale for assessment of circulating angiogenic factors ........................................... 34 
9.3 
Blood-based Angiome profiling using multiplex technology ........................................ 35 
9.4 
Blood for Cell-Free DNA ............................................................................................... 37 
9.5 
HER-2 Status Collection ................................................................................................ 38 
10.0 STUDY CALENDAR ....................................................................................................... 39 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 40 
12.0 MEASUREMENT OF EFFECT........................................................................................ 40 
12.1 Antitumor Effect – Solid Tumors................................................................................... 40 
12.2 Disease Parameters ......................................................................................................... 42 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 43 
12.4 Response Criteria ........................................................................................................... 45 
13.0 DATA AND SAFETY MONITORING ............................................................................ 48 
14.0 AUDITING ........................................................................................................................ 49 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 49 
15.1 Design and Sample Size ................................................................................................. 49 
15.2 Primary Efficacy Measure .............................................................................................. 50 
15.3 Secondary Efficacy Measures ........................................................................................ 50 
15.4 Anticipated Findings ...................................................................................................... 51 
15.5 Exploratory Analyses ..................................................................................................... 51 
16.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 52 
17.0 REFERENCES .................................................................................................................. 53 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 57 
APPENDIX B: CYP3A4 Strong Inhibitors and Inducers............................................................. 58 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Gastric Cancer 
 
Gastric cancer is the fifth most common malignancy, and the third leading cause of cancer 
mortality 
worldwide.1 
Currently, 
platinum-based 
and 
fluoropyrimidine-based 
combinations are accepted worldwide as established first-line drug regimens for advanced 
gastric adenocarcinoma, with a median survival ranging from 8 months to 10 months.2 
Selected second-line chemotherapy including docetaxel and irinotecan improved overall 
survival compared with best supportive care in randomized trials, however median survival 
remained dismally poor at less than 6 months.3-5 Newer, more active second line systemic 
therapy options are needed. 
 
1.2 
VEGF in Gastric Cancer 
 
Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated 
signaling and angiogenesis contribute to the pathogenesis of gastric cancer. In patients with 
gastric cancer, circulating VEGF levels are associated with increased tumor aggressiveness 
and reduced survival.6,7 In animal models of gastric adenocarcinoma, VEGFR-2 inhibition 
reduced tumor growth and vascularity.8 Ramucirumab, a human IgG1 monoclonal antibody 
VEGFR-2 antagonist, prevents ligand binding and receptor-mediated pathway activation in 
endothelial cells.9  
 
1.3 
Chemotherapy for Metastatic Gastric Cancer 
 
Ramucirumab monotherapy has shown overall survival benefit after first-line chemotherapy 
in advanced gastric cancer.10 Second-line treatment with ramucirumab plus paclitaxel after 
progression on frontline chemotherapy (platinum plus fluoropyrimidine with or without an 
anthracycline) showed an improvement in overall survival to more than 9 months in patients 
with metastatic gastric or gastro-esophageal junction cancer.11 This is now being regarded 
as a new standard in second-line treatment for patients with advanced gastric cancer.  
 
Despite these advances, many patients may be unable to receive this combination due to 
prior taxane exposure, as taxane containing regimens are a standard option as first line 
therapy.12 Additionally, peripheral neuropathy after frontline platinum-based chemotherapy, 
may preclude patients from receiving paclitaxel in the second line setting, or can 
significantly worsen with paclitaxel leading to early discontinuation. Most platinum 
containing gastric cancer regimens have reported very high rates of peripheral neuropathy. 
In the REAL-2 (Randomized ECF for Advanced and Locally Advanced Esophagogastric 
Cancer 2) phase III trial, peripheral neuropathy (all grades) was seen in 30-36% patients in 
cisplatin arms and 80-84% patients in oxaliplatin arms.13 Similarly, neurosensory toxicity 
was fairly common (all grades: 62.5%, grade 3 or 4: 14.3%) with oxaliplatin and 5-
fluorouracil/leucovorin use in the first line setting.14 In a large meta-analysis, platinum based 
therapy compared to non-platinum based therapy containing S-1, taxanes or irinotecan was 
associated with two-fold risk of neurotoxicity (RR = 2.01, 95%CI, 1.05–3.86, p = 0.03).15 

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Furthermore, in the RAINBOW trial, peripheral neuropathy was more common in the 
ramucirumab plus paclitaxel arm (all grades: 46%) compared with paclitaxel alone (all 
grades: 37%) and was associated with a higher cumulative paclitaxel dose.11 Therefore, there 
is a need to evaluate newer chemotherapy combinations with ramucirumab for advanced 
gastric cancer.  
 
1.4 
Irinotecan (Camptosar) 
 
Irinotecan is an antineoplastic agent of the topoisomerase I inhibitor class.  Irinotecan is an 
active drug for gastric cancer, and is not neurotoxic. Irinotecan based combinations have 
shown survival benefit in first-line,16,17 second-line4,5,18 and third-line19 treatment of 
advanced gastric cancer.  Common adverse reactions observed in single agent therapy 
clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, 
neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body 
weight decreasing, and alopecia. 
 
Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU) and 
leucovorin (LV) and as a single agent.  When given as a component of combination-agent 
treatment, irinotecan was either given with a weekly schedule of bolus 5-FU/LV or with 
an every-2-week schedule of infusional 5-FU/LV.  Weekly and once-every-3-week dosage 
schedules were used for the single-agent irinotecan studies. 
 
1.5 
Ramucirumab (Cyramza) 
 
Ramucirumab is a human vascular endothelial growth factor receptor 2 antagonist 
indicated: as a single agent or in combination with paclitaxel for treatment of advanced 
gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after 
prior fluoropyrimidine- or platinum-containing chemotherapy; in combination with 
docetaxel for treatment of metastatic non-small cell lung cancer with disease progression 
on or after platinum-based chemotherapy; and in combination with FOLFIRI for the 
treatment of metastatic colorectal cancer with disease progression on or after prior therapy 
with bevacizumab, oxaliplatin, and a fluoropyrimidine.  Ramucirumab alone and 
ramucirumab in combination with chemotherapy (paclitaxel) has shown prolonged 
survival in the REGARD and RAINBOW trial. 
 
The most common adverse reactions observed in single-agent ramucirumab-treated 
patients were hypertension and diarrhea.  Ramucirumab increases the risk of: hemorrhage 
and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events; 
gastrointestinal perforation; and impaired wound healing. 
 
1.6 
Study Rationale 
 
Ramucirumab monotherapy as well as combination of paclitaxel plus ramucirumab has 
shown overall survival benefit after first-line chemotherapy (platinum plus 
fluoropyrimidine with or without an anthracycline) in advanced gastric or gastro-
esophageal junction cancer.10,11 Irinotecan is active in gastric cancer and has shown 

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survival benefit, that is similar to taxanes in second-line setting.4,5,18  Safety of 5-
fluorouracil/Irinotecan (FOLFIRI with irinotecan at a dose of 180 mg/m2 – similar to 
present study) and ramucirumab combination has been studied in second-line treatment for 
metastatic colon cancer, where this combination is safe and provides survival benefit.20 
Therefore, studying irinotecan plus ramucirumab in the second-line setting for gastric 
cancer after fluoropyrimidine and platinum based therapy is prudent. If active, this would 
offer a non-neurotoxic treatment combination of chemotherapy and ramucirumab for 
patients with advanced gastric cancer and GEJ cancers. 
 
We hypothesize that this combination regimen of irinotecan plus ramucirumab administered 
as second line treatment will be tolerated and lead to improved outcomes similar to paclitaxel 
plus ramucirumab in patients with advanced gastric and GEJ cancers. This study proposes a 
phase II clinical trial with irinotecan plus ramucirumab for treatment of patients with 
metastatic gastric and GEJ adenocarcinoma who have progressed after first line 
chemotherapy. To our knowledge, this regimen has not been previously administered to this 
patient population, so safety and tolerability will be monitored and reported. 
 
1.7 
Correlative Studies 
 
1.7.1 Patient-derived xenograft and organoid in gastroesophageal cancer 
 
The use of biomarkers to predict response to novel targeted therapies have ushered 
in an ever- expanding era of precision oncology.  However, development of targeted 
treatments in upper gastrointestinal cancers has been met with, at best, modest 
success.  HER2 and VEGF-targeting agents are the only approved targeted therapy 
for metastatic gastric and GEJ cancers. Several targeted therapy agents have been 
tested in clinical trials, but did not show significant improvement over traditional 
chemotherapy, in part due to limitations in patient selection. The advent of patient-
derived xenograft and organoid modeling systems has enabled novel approaches to 
truly personalize and improve cancer treatment.   
 
Patient-derived xenograft (PDX) models are generated by growing cells or tissue 
from a patient’s cancer in an immunodeficient mouse.  These PDXs have been shown 
to recapitulate many key aspects of the original tumor biology, and, more 
importantly, allow predictions of clinical efficacy for new targeted treatments in that 
patient whose cell or tissue is derived from. 21,22 Therefore, PDXs derived from 
gastric and GEJ cancers are used to screen novel agents23-26 (Figure 1A).   
Patient-derived organoid (PDO) models are generated by culturing epithelial tumor 
cells or tissue in 3D matrigel.  Novel “biobanks” have been established in many tumor 
types for use in genomic analyses, transcriptome studies, large scale drug screens, 
and the development of personalized medicine allowing predictions of future drug 
response.27 Gastric and esophageal cancer have been shown to amenable to these 
culture techniques with high concordance between primary tissue and organoid 
histology, genomic landscape, and transcriptomic expression profiles28,29 with the 
ability to carry out large scale drug screens as shown in Figure 1B.   
 

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Figure 1.  Applications for PDX and PDO models in cancer biology.  A) Five GC 
PDX models were generated and tested for tumor volume response after treatment 
with trastuzumab, pertuzumab and 1A12 (a novel HER2 antibody).  B) Nine GC PDO 
models were used to screen drug sensitivities (IC50) for 37 compounds.   
 
Both techniques have certain advantages and disadvantages as pre-clinical models 
summarized in Table 1.  But despite the advancement in PDX and PDO technology, 
there have been few studies that have utilized both in direct comparison.  PDX models 
require less amount of patient tissue than PDO, but takes longer time to generate. 
Therefore, PDO models are likely better suited for rapid drug screen, and potentially 
can be used for real-time treatment decision making. Furthermore, prospective 
studies demonstrating the ability of either of these models to predict or recapitulate 
individual patient treatment response are lacking.  This correlative study would be 
wholly novel in utilizing both techniques in the context of a clinical trial allowing 
prospective investigation of both models and actual patient response to the same 
treatments.   
 
We plan to generate PDX and PDO models from enrolled patient derived samples.  
Using these models, we will specifically assay efficacy of ramucirumab and 
irinotecan and compare with prospective clinical data regarding actual patient 
treatment response.   This will serve as a pilot study for future clinical trials that may 

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integrate PDX/PDO models to provide truly personalized cancer therapy options to 
patients with gastroesophageal cancer. 
 
Table 1.  Comparison of PDO and PDX models.  Features were determined as best 
(+++), suitable (++), possible (+), not very suitable (+/-) or unsuitable (−). 
 
1.7.2 Circulating blood biomarkers including angiome profiles and cell-free 
DNA 
 
Accumulating preclinical and clinical evidence suggests antiangiogenic therapy 
affects the level of several factors, and that changes in these factors with therapy may 
have predictive value. This trial provides an excellent correlative opportunity to 
assess markers that may predict response to angiogenesis inhibition. 
 
For this trial, blood will be collected to measure alterations in circulating angiogenic 
factors (plasma angiome profile) during therapy and to assess correlations with 
outcome, and to identify relevant pharmacogenetic markers, mechanisms of 
resistance and correlate with response. 
 
Further rationale for correlative studies is described later in the protocol (Section 9.0).  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the progression-free survival (PFS) with irinotecan plus ramucirumab in 
patients with metastatic gastric and gastro-esophageal junction cancer who have progressed 
after first line chemotherapy. 
 
2.2 
Secondary Objectives 
 
1. To determine the overall survival (OS) of patients treated with irinotecan plus 
ramucirumab. 
2. To determine time to progressive disease (TTP) in patients treated with irinotecan plus 
ramucirumab. 

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3. To determine the best overall response (BOR) of confirmed Complete Response (CR), 
confirmed Partial Response (PR), Stable Disease (SD) or Progressive disease (PD) in 
patients treated with irinotecan plus ramucirumab. 
4. To determine the objective response rate (ORR) (defined as confirmed CR + confirmed 
PR) in patients treated with irinotecan plus ramucirumab. 
5. To determine clinical benefit rate (CBR) (percentage of combined patients who have 
achieved confirmed CR, confirmed PR and SD) in patients treated with irinotecan plus 
ramucirumab. 
6. To evaluate toxicity and tolerability of irinotecan plus ramucirumab as measured by 
NCI-CTCAE version 4.03. 
 
2.3 
Exploratory Objectives 
 
1. To determine the success rate of PDX/PDO generation from patients with metastatic 
gastroesophageal cancer. 
2. To evaluate the responses to treatment with ramucirumab and irinotecan in PDX/PDO 
models 
3. To characterize molecular changes in PDX/PDO models along with corresponding 
patients’ clinical courses to identify potential predictors of response and mechanism of 
resistance 
4. To investigate changes blood based angiome profile and cell free DNA in patients 
following treatment with ramucirumab and irinotecan to identify potential mechanism 
of response and resistance 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histopathologically 
or 
cytologically 
confirmed 
diagnosis 
of 
gastric 
or 
gastroesophageal junction (GEJ) adenocarcinoma that is metastatic or locally advanced 
and unresectable. 
 
2. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan (or MRI at the 
discretion of the PI), as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical 
exam. 
 
3. Either primary or non-osseous metastatic site amenable for research biopsy for patients 
enrolled at Washington University, if safe and feasible, as confirmed by scheduling of 
biopsy procedure. Other methods to obtain appropriate cancer cells such as large-
volume paracentesis or thoracentesis can be allowed at PI discretion. Biopsy or other 
procedures should be performed at least 7 days prior to C1D1. 
 
 
 

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4. Experienced documented objective radiographic or clinical disease progression during 
first-line therapy or within 4 months after the last dose of first-line therapy with any 
platinum/fluoropyrimidine doublet with or without anthracycline (epirubicin or 
doxorubicin) or taxane (docetaxel) for unresectable or metastatic disease. 
 
NOTE: This is not intended to be an exclusive list of allowed agents. The targeted 
therapies such as Herceptin and ADC, or immunotherapies without cytotoxic 
chemotherapy, are permitted. 
 
5. At least 18 years of age. 
 
6. ECOG performance status ≤ 1 (see Appendix A). 
 
7. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count (ANC) ≥ 1,500/µL 
b. Hemoglobin ≥ 9.0 g/dL (5.58 mmol/L) 
c. Platelets ≥ 100,000/µL 
d. Total bilirubin ≤ 1.5 mg/dL (25.65 µmol/L) 
e. AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN (or ≤ 5.0 x IULN in the setting of liver 
metastases) 
f. Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 40 mL/min/1.73 m2 for patients 
with creatinine levels > 1.5 x IULN (that is, if serum creatinine is > 1.5 x IULN, a 
24-hour urine collection to calculate creatinine clearance must be performed)  
g. Urinary protein ≤ 1+ on dipstick or routine UA; if dipstick or routine UA is ≥ 2+, a 
24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 
hours 
h. Adequate coagulation function as defined by INR ≤ 1.5 and PTT ≤ 5 seconds above 
the ULN (unless receiving anticoagulation therapy).  Patients receiving warfarin 
must be switched to low molecular weight heparin and have achieved stable 
coagulation profile prior to first dose of protocol therapy. 
 
8. All clinically significant toxic effects (except peripheral neuropathy) of prior 
locoregional therapy, surgery, or other anticancer therapy have resolved to ≤ CTCAE 
grade 1. 
 
9. Women of childbearing potential and men must agree to use two forms of adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to study 
entry and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she must inform her treating 
physician immediately. Women of childbearing potential must have a negative serum 
pregnancy test within 7 days of study entry. 
 
10. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 

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3.2 
Exclusion Criteria 
 
1. Squamous cell or undifferentiated gastric cancer. 
 
2. Received any chemotherapy (including irinotecan) other than platinum and 
fluoropyrimidine with or without anthracycline or taxane for advanced gastric or GEJ 
adenocarcinoma. 
 
3. Received previous systemic chemotherapy with a cumulative dose of > 900 mg/m2 of 
epirubicin or > 400 mg/m2 of doxorubicin. 
 
4. Received any previously systemic therapy (including investigational agents) targeting 
VEGF or the VEGFR signaling pathways.  Other previous targeted therapies are 
permitted if stopped at least 28 days prior to start of treatment. 
 
5. A history of other malignancy ≤ 3 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix or other solid tumors treated curatively and without 
evidence of recurrence. 
 
6. Currently receiving any other investigational agents. 
 
7. History or evidence of known brain metastases or carcinomatous meningitis.  Patients 
with known brain metastases must be excluded from this clinical trial because of their 
poor prognosis and because they often develop progressive neurologic dysfunction that 
would confound the evaluation of neurologic and other adverse events. 
 
8. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to monoclonal antibody treatment, any components used in the 
ramucirumab DP preparation, irinotecan, or other agents used in the study. 
 
9. Any grade 3-4 GI bleeding within 3 months prior to enrollment. 
 
10. History of gastrointestinal perforation and/or fistulae within 6 months prior to 
enrollment. 
 
11. History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port of catheter thrombosis or superficial venous 
thrombosis are not considered “significant”) during the 3 months prior to enrollment. 
 
12. History of any arterial thromboembolic event, including but not limited to myocardial 
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina 
within 6 months prior to enrollment. 
 
13. Diagnosis of symptomatic congestive heart failure (NYHA II-IV) or symptomatic or 

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poorly controlled cardiac arrhythmia. 
 
14. Uncontrolled or poorly controlled hypertension (> 160 mmHg systolic or > 100 mmHg 
diastolic for > 4 weeks) despite standard medical management. 
 
15. Presence of serious or nonhealing wound, ulcer, or bone fracture within 28 days prior 
to enrollment. 
 
16. Major surgery within 28 days prior to first dose of protocol therapy. 
 
17. Minor surgery/subcutaneous venous access device placement within 7 days prior to 
first dose of protocol therapy. 
 
18. Receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), 
dipyridamole or clopidogrel, or similar agents.  Once-daily aspirin use (maximum dose 
325 mg/day) is permitted. 
 
19. The patient has elective or planned major surgery to be performed during the course of 
the clinical trial. 
 
20. Bowel obstruction, history or presence of inflammatory enteropathy or extensive 
intestinal resection (hemicolectomy or extensive small intestine resection with chronic 
diarrhea), Crohn’s disease, ulcerative colitis, or chronic diarrhea. 
 
21. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history 
of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis (i.e. 
ascites from cirrhosis requiring diuretics or paracentesis). Patients with ascites not 
related to cirrhosis, such as malignant ascites, are allowed.  
 
22. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, metabolic disorders or other nonmalignant organ or systemic disease or 
secondary effects of cancer that induce a high medical risk and make assessment of 
survival uncertain, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
23. Pregnant and/or breastfeeding.   
 
24. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with ramucirumab and irinotecan.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
 
 

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3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within one business day. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center database at 

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Washington University. 
 
 
 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Premedication Administration 
 
Consider prophylactic or therapeutic administration of 0.25 to 1 mg of IV or SC atropine 
to prevent early diarrhea (occurring during or shortly after infusion of irinotecan). 
 
It is recommended that patients receive premedication with antiemetic agents on the day 
of treatment, starting at least 30 minutes before administration of irinotecan.  Suggested 
antiemetic agents are 10 mg of dexamethasone given with a 5HT3 blocker (e.g. 
ondansetron or granisetron). 
Prior to each ramucirumab infusion, premedicate all patients with an intravenous histamine 
H1 antagonist (e.g., diphenhydramine).  For patients who have experienced a grade 1 or 2 
infusion-related reaction, also premedicate with dexamethasone (or equivalent) and 
acetaminophen prior to each ramucirumab infusion. 
 
5.2 
Agent Administration 
 
Patients will receive ramucirumab intravenously on an outpatient basis at a dose of 8 mg/kg 
over the course of 60 minutes on Day 1 of each 14-day cycle.  They will then receive 
irinotecan intravenously at a dose of 180 mg/m2 over the course of 90 minutes on Day 1 of 
each 14-day cycle. With approval by the Washington University PI, the agents may be 
given on different days within the protocol specified window. 
 
5.3 
Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 4 and have not had any disease assessment.  
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 

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Patients receiving warfarin must be switched to low molecular weight heparin and have 
achieved stable coagulation profile prior to the first dose of protocol therapy. 
 
Do not administer strong CYP3A4 inducers or inhibitors while patients are receiving 
irinotecan (refer to Appendix B). 
 
UGT1A1 inhibitors (atazanavir, gemfibrozil, indinavir) are prohibited. 
 
Late diarrhea associated with irinotecan can be life-threatening since it may be prolonged 
and may lead to dehydration, electrolyte imbalance, or sepsis.  Patients should have 
loperamide readily available to begin treatment for late diarrhea.  Begin loperamide at the 
first episode of poorly formed or loose stools or the earliest onset of bowel movements 
more frequent than normal.  One dosage regimen for loperamide is 4 mg at the first onset 
of later diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 
12 hours.  Loperamide is not recommended to be used for more than 48 consecutive hours 
at these doses because of the risk of paralytic ileus. 
 
Patients with unresected primary tumors (or local recurrence) who develop grade 3 or 4 
venous thromboembolism may also receive anticoagulation and continue ramucirumab 
therapy provided that the tumor does not confer an excessive bleeding risk, in the opinion 
of the patient’s physician. 
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 7 days prior to the first day of treatment.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 3 months following the last dose of either study drug.  
 
If a patient is suspected to be pregnant, ramucirumab and irinotecan should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of either study drug, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 

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in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug, including: 
o Grade 3 or 4 infusion reaction 
o Grade 4 hypertension 
o Grade 3 or 4 arterial thromboembolic event, or any PE/DVT occurring or 
worsening during anticoagulant therapy 
o One occurrence of urine protein level > 3 g/24 hours, three occurrences of 
urine protein level > 2 g/24, or urine protein level > 2 g/24 hours for more 
than 2 weeks 
o Gastrointestinal perforation or fistula formation 
o RPLS 
o Hepatic encephalopathy or other serious signs of liver impairment such as 
hepatorenal syndrome  
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.7 
Duration of Follow-up 
 
Patients will be followed every 2 months after discontinuation of treatment for progression 
and survival for 30 months.  Patients removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event. 
 
 
 
 
 
 
 
 
 

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6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications for Ramucirumab 
 
Treatment modifications for toxicities not listed below will be made at the discretion of the 
PI.  Treatment may be held for a maximum of 4 weeks before a patient must be removed 
from study treatment. Treatment may be held beyond 4 weeks at the discretion of the PI. 
 
6.1.1 Infusion-Related Reactions 
 
Reduce the infusion rate of ramucirumab by 50% for grade 1 or 2 infusion-related 
reactions.  Permanently discontinue ramucirumab for grade 3 or 4 infusion-related 
reactions. 
 
6.1.2 Hypertension 
 
Interrupt ramucirumab for severe hypertension until controlled with medical 
management.  Permanently discontinue ramucirumab for severe hypertension that 
cannot be controlled with antihypertensive therapy or any grade 4 hypertension. 
 
6.1.3 Proteinuria 
 
If urinalysis or dipstick shows protein ≥ 2+, a 24-hour urine collection must be 
collected and ramucirumab cannot be dosed until the below criteria are met. 
Interrupt ramucirumab for urine protein levels ≥ 2 g/24 hours.  Reinitiate treatment 
at a reduced dose once the urine protein level returns to < 2 g/24 hours.  If the 
protein level ≥ 2 g/24 hours reoccurs, interrupt ramucirumab and reduce the dose 
again once the urine protein level returns to < 2 g/24 hours.  Permanently 
discontinue ramucirumab for urine protein level > 3 g/24 hours, if there is a third 
occurrence of > 2 g/24 hours, if the protein level does not return to < 2 g/24 hours 
within 2 weeks, or in the setting of nephrotic syndrome. If it is anticipated that the 
urine protein will be elevated, a 24-hour urine collection can be collected and 
evaluated for dosing criteria independent of the urinalysis or urine dipstick. 
 
Initial dose 
8 mg/kg 
First dose reduction 
6 mg/kg 
Second dose reduction 5 mg/kg 
 
6.1.4 Venous and Arterial Thromboembolic Events, Gastrointestinal 
Perforation, Fistula, or Bleeding 
 

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Ramucirumab should be permanently discontinued in the event of a gastrointestinal 
perforation or fistula formation.   
 
Patients with unresected primary tumors (or local recurrence) who develop grade 3 
or 4 venous thromboembolism may receive anticoagulation and continue 
ramucirumab therapy provided that the tumor does not confer an excessive bleeding 
risk, in the opinion of the patient’s physician. 
 
Grade 3 or 4 arterial thromboembolic events, or any PE/DVT occurring or 
worsening during anticoagulant therapy, require permanent discontinuation of 
ramucirumab therapy.  Any venous or arterial event leading to discontinuation of 
ramucirumab therapy will be considered serious and should be reported via the SAE 
mechanism. 
 
For any clinically significant bleeding events deemed at least possibly related to 
Ramucirumab, patients must be discontinued from further treatment unless 
permission is granted from the Washington University PI to continue study therapy. 
 
6.1.5 Hepatic Encephalopathy or Other Serious Signs of Liver Impairment 
 
Permanently discontinue ramucirumab.  Signs of serious liver impairment include 
hepatorenal syndrome or other signs as determined by the treating physician. 
 
6.1.6 Reversible Posterior Leukoencephalopathy Syndrome 
 
If RPLS is diagnosed, ramucirumab must be permanently discontinued.  All cases 
of RPLS must be reported via the SAE mechanism. 
 
6.2 
Dose Modifications for Irinotecan 
 
Treatment modifications for toxicities not listed below will be made at the discretion of the 
PI.  Patients requiring a dose reduction beyond that outlined in the study protocol will have 
the agent discontinued. The other agent may be continued independently in keeping with 
the applicable dose modifications for that agent.  Treatment may be held for a maximum 
of 4 weeks before a patient must be removed from study treatment. Treatment may be held 
beyond 4 weeks at the discretion of the PI.  
 
Initial Dose 
180mg/m2 
First Dose Reduction 
150 mg/m2 
Second Dose Reduction 
120 mg/m2 
 
6.2.1 Late Diarrhea 
 
Treatment should be delayed until the return of pre-treatment bowel function for at 
least 24 hours without anti-diarrhea medication.  Patients must not be treated with 

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irinotecan until resolution of any bowel obstruction.  If grade 2, 3, or 4 late diarrhea 
recurs, subsequent doses of irinotecan should be decreased to 150 mg/m2. 
 
 
 
 
6.2.2 Myelosuppression 
 
Hold irinotecan if neutropenic fever occurs or if ANC < 1000/mm3.  After recovery 
to an ANC ≥ 1000/mm3, subsequent doses of irinotecan should be reduced by one 
level. 
 
6.2.3 Hypersensitivity 
 
Discontinue irinotecan if anaphylactic reaction occurs. 
 
6.2.4 Pulmonary Toxicity 
 
If Interstitial Pulmonary Disease is diagnosed, irinotecan and other chemotherapy 
should be discontinued and appropriate treatment instituted as needed. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
Please refer to Appendix C for definitions and Appendix D for a grid of reporting timelines. 
 
Adverse events will be tracked from start of treatment through 30 days following the last day of 
study treatment.  All adverse events must be recorded on the toxicity tracking case report form.  
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may be found in Section 7.2. 
Eli Lilly requires that all events be reported as outlined in Section 7.6. 
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 

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Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Washington University Sponsor-Investigator (or designee) is required to notify 
the QASMC of any unanticipated problems involving risks to participants or others 
occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to a qasmc@wustl.edu.  Submission to QASMC must include the myIRB 
form and any supporting documentation sent with the form. 
 
For events that occur at secondary sites, the Washington University Sponsor 
Investigator (or designee) is required to notify the QASMC within 10 days of 
Washington University notification via email to qasmc@wustl.edu.  Submission to 
QASMC must include either the myIRB form and supporting documentation or (if 
not submitted to myIRB) the date of occurrence, description of the event, whether 
the event is described in the currently IRB approved materials, the event outcome, 
determination of relatedness, whether currently enrolled participants will be 
notified, and whether the informed consent document and/or any study procedures 
will be modified as a result of this event. 
 
7.1.3 Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the 
Washington University Sponsor-Investigator and designee of all serious adverse 
events (Appendix C, Section D) within 1 working day of the occurrence of the 
event or notification of the secondary site’s PI of the event.  This notification may 
take place via email if there is not yet enough information for a formal written report 
(using either an FDA 3500a MedWatch form and the Washington University 
Serious cover sheet (Appendix E).  A formal written report must be sent to the 
Washington University Sponsor-Investigator and designee4 calendar days (for 
fatal of life-threatening suspected adverse reactions) or 11 calendar days (for 
serious unexpected suspected adverse reactions) of the occurrence of the event or 
notification of the secondary site’s PI of the event.  The death of a research 
participant that qualifies as a reportable event should be reported within 1 working 
day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 

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The research team at a secondary site is responsible for following its site’s 
guidelines for reporting applicable events to its site’s IRB according to its own 
institutional guidelines.  .  The research team at Washington University is 
responsible for reporting all applicable events to the FDA, IBC, and as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained 
prior to implementing the change.  Local IRB approval must be obtained as per 
local guidelines.  Washington University IRB approval is not required for protocol 
exceptions occurring at secondary sites. 
 
7.1.4 Reporting to Secondary Sites 
 
The Washington University Sponsor-Investigator (or designee) will notify the 
research team at each secondary site of all unanticipated problems involving risks 
to participants or others that have occurred at other sites within 10 working days 
of the occurrence of the event or notification of the Sponsor-Investigator (or 
designee) of the event.  This includes events that take place both at Washington 
University and at other secondary sites, if applicable.  Refer to Section 16.0 
(Multicenter Management) for more information. 
 
7.1.5 Reporting to Eli Lilly  
 
Any venous or arterial event leading to discontinuation of ramucirumab therapy 
will be considered serious and should be reported via the SAE mechanism. 
 
Lilly will be notified within twenty-four (24) hours of Investigator and/or 
Institution receiving notification of any “serious” adverse event experienced by a 
patient participating in the Study and receiving Study Drug. For purposes of this 
requirement, “serious” means: (1) death; (2) in-patient hospitalization or prolonged 
hospitalization; (3) life-threatening; (4) persistent or significant disability or 
incapacity; (5) congenital anomaly or birth defect; or (6) other serious events that 
may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the other five listed outcomes. Serious adverse events should be 
reported to Lilly using a CIOMS Form or other form acceptable to Lilly. Institution 
further agrees to make available promptly to Lilly such records as may be necessary 
and pertinent for Lilly to further investigate an adverse event in the Study that is 
possibly associated with the Study Drug. 
  
Lilly will be notified within twenty-four (24) hours of Investigator and/or 
Institution receiving notification or becoming aware of any product complaint 
related to the Study Drug. For purposes of this requirement, a product complaint is 
any written, electronic, or oral communication that alleges deficiencies of a drug or 
drug delivery systems related to: (1) identity, (2) performance, (3) reliability, (4) 
safety, (5) quality, (6) durability, (7) purity, or (8) effectiveness. 
  

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The Lilly Global Patient Safety Fax Number for all SAEs is 866-644-1697 or 317-
453-3402. 
 
7.1.6 Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment. 
With the exception of progressive disease, all adverse events that occur between 
the first treatment on study and 30 days after the last day of study treatment will be 
recorded on the case report forms. This includes all adverse events that are CTCAE 
version 4.03 gradable laboratory values, regardless of attribution or clinical 
significance. Progressive disease should not be reported as an AE. 
 
In addition to the planned revision to the protocol detailed above, please find 
guidance below for tracking of abnormal labs in the study EDC: 
• For patients currently on treatment at the time this clarification is released, 
enter the highest occurrence of each gradable abnormal lab to date with drug 
attribution and the highest gradable abnormal labs with drug attribution per 
cycle moving forward (regardless of clinical significance) on the AE case 
report form. 
• For patients off study at the time this clarification is released, enter the 
highest grade of each abnormal lab with drug attribution for the duration of 
the patient’s time on study treatment on the AE case report form. 
• Please note that medical history data is not required to be entered on the AE 
case reporting form. 
 
 
 
 

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8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Ramucirumab (Cyramza) 
 
8.1.1 Ramucirumab Description 
 
Ramucirumab is a recombinant human IgG1 monoclonal antibody that specifically 
binds to vascular endothelial growth factor receptor 2. Ramucirumab has an 
approximate molecular weight of 147 kDa. Ramucirumab is produced in 
genetically engineered mammalian NS0 cells. 
 
8.1.2 Clinical Pharmacology 
 
Ramucirumab is a vascular endothelial growth factor receptor 2 antagonist that 
specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-
A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated 
activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, 
and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in 
an in vivo animal model. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetic (PK) characteristics of ramucirumab are similar for patients 
with gastric cancer, NSCLC, and mCRC based on a population PK analysis. The 
mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 
L/hour (30%) and the mean terminal half-life was 14 days (20%). 
 
8.1.4 Supplier(s) 
 
Ramucirumab will be provided free of charge by Eli Lilly and Company. 
 
8.1.5 Dosage Form and Preparation 
 
Ramucirumab is available in two dose strengths: 
• 100 mg/10 mL (10 mg per mL) solution, single dose vial 
• 500 mg/50 mL (10 mg per mL) solution, single dose vial 
 
8.1.6 Storage and Stability 
 
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the 
vial in the outer carton in order to protect from light. 
 
 
 

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8.1.7 Administration 
 
Calculate the dose and the required volume of ramucirumab needed to prepare the 
infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a 
concentration of 10 mg/mL solution of ramucirumab.  
 
Withdraw the required volume of ramucirumab and further dilute with only 0.9% 
Sodium Chloride Injection in an intravenous infusion container to a final volume 
of 250 mL. Do not use dextrose containing solutions.  
 
Gently invert the container to ensure adequate mixing.  
 
DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other 
solutions or co-infuse with other electrolytes or medications.  
 
Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 
hours at room temperature (below 25°C [77°F]).  
 
Discard vial with any unused portion of ramucirumab.  
 
Visually inspect the diluted solution for particulate matter and discoloration prior 
to administration. If particulate matter or discolorations are identified, discard the 
solution.  
 
Administer diluted ramucirumab infusion via infusion pump over 60 minutes 
through a separate infusion line. Use of a protein sparing 0.22micron filter is 
recommended. Flush the line with sterile sodium chloride (0.9%) solution for 
injection at the end of the infusion.  
 
8.2 
Irinotecan (Camptosar) 
 
8.2.1 Irinotecan Description 
 
Irinotecan is an antineoplastic agent of the topoisomerase I inhibitor class.  It is a 
semisynthetic derivative of camptothecin, an alkaloid extract from plants such as 
Camptotheca acuminata or is chemically synthesized. 
 
The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-
dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]-1’-
carboxylate, monohydrochloride, trihydrate. 
 
Its empirical formula is C33H38N4O6·HCl·3H2O.  Its molecular weight is 677.19. 
 
 
 

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8.2.2 Clinical Pharmacology 
 
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with 
the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing 
reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to 
the topoisomerase I-DNA complex and prevent relegation of these single-strand 
breaks. Current research suggests that the cytotoxicity of irinotecan is due to 
double-strand DNA damage produced during DNA synthesis when replication 
enzymes interact with the ternary complex formed by topoisomerase I, DNA, and 
either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-
strand breaks. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
After intravenous infusion of irinotecan in humans, irinotecan plasma 
concentrations decline in a multiexponential manner, with a mean terminal 
elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life 
of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone 
(active) forms of irinotecan and SN-38 are similar to those of total irinotecan and 
SN-38, as the lactone and hydroxy acid forms are in equilibrium. 
 
Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 
is highly bound to human plasma proteins (approximately 95% bound). The plasma 
protein to which irinotecan and SN-38 predominantly binds is albumin. 
 
Irinotecan is subject to extensive metabolic conversion by various enzyme systems, 
including esterases to form the active metabolite SN-38, and UGT1A1 mediating 
glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. 
Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several 
inactive oxidation products, one of which can be hydrolyzed by carboxylesterase 
to release SN-38. In vitro studies indicate that irinotecan, SN-38 and another 
metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 
isozymes. UGT1A1 activity is reduced in individuals with genetic polymorphisms 
that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. 
Approximately 10% of the North American population is homozygous for the 
UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). 
 
The disposition of irinotecan has not been fully elucidated in humans. The urinary 
excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. 
The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-
38 and SN-38 glucuronide) over a period of 48 hours following administration of 
irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% 
(300 mg/m2). 
 
 
 

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8.2.4 Supplier(s) 
 
Irinotecan is commercially available and will be billed to insurance. 
 
8.2.5 Dosage Form and Preparation 
 
Irinotecan is available in three single-dose sizes: 
• 2 mL via containing 40 mg irinotecan hydrochloride injection 
• 5 mL via containing 100 mg irinotecan hydrochloride injection 
• 15 mL via containing 300 mg irinotecan hydrochloride injection 
 
8.2.6 Storage and Stability 
 
Store at controlled room temperature (15° to 30°C / 59° to 86°F).  Protect form 
light. 
 
8.2.7 Administration 
 
See Section 5.2. 
 
8.2.8 Special Handling Instructions 
 
Care should be exercised in the handling and preparation of infusion solutions 
prepared from irinotecan injection. The use of gloves is recommended. If a solution 
of irinotecan contacts the skin, wash the skin immediately and thoroughly with soap 
and water. If irinotecan contacts the mucous membranes, flush thoroughly with 
water. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.0 
CORRELATIVE STUDIES 
 
9.1 
Rationale for patient-derived xenograft and organoid generation 
 
Patient-derived xenograft (PDX) and patient-derived organoid (PDO) models have been 
shown to be important emerging preclinical models in oncology.  Recent work has focused 
on developing these models for application in gastric and GEJ cancers to screen novel 
agents.23-26,28,29 Despite the advancement in PDX and PDO technology, there have been few 
studies that have utilized both in direct comparison.  Furthermore, studies are also lacking 
demonstrating the prospective ability of either of these models to predict or recapitulate 
individual patient treatment response.  We propose to generate PDXs and PDOs from patient 
derived biopsy samples prior to initiation of trial treatment when the biopsy procedure is both 
safe and feasible.  We plan a prospective comparison between both models and actual patient 
response to the same trial treatments of ramucirumab and irinotecan.   
 
9.1.1 Collection of Specimens 
 
For patients enrolled at Washington University School of Medicine, prior to study 
treatment, fresh tissue samples will be obtained either by surgical laparoscopic 
sampling (preferred), endoscopic biopsy, or image-guided core biopsy.  If safe and 
feasible, biopsy will be done at least 7 days prior to planned C1D1.  Additional 
methods to obtain adequate samples for PDX/PDO generation, including large-
volume paracentesis or thoracentesis, will be allowed at PI discretion. 
 
9.1.2 Handling of Specimens 
 
Samples will be stored in ice cold PBS prior to downstream processing. Samples will 
be immediately delivered to the Mills Laboratory (Washington University School of 
Medicine, Division of Gastroenterology, Bldg: CSRB-NTA, Rm 927, 425 S Euclid 
Ave, St Louis, MO 62110 United States) and stored until processed. All samples will 
be processed by Mills Lab and Fields Lab for PDX/PDO related experiments. 
 
 
9.1.3 PDX generation 
 
To generate gastric cancer PDX models, typical procedures are as follows; however, 
standard procedures at the Fields Laboratory and PDXNet will be followed (HRPO 
#201803010).  
 
Primary patient tumor tissue will be implanted subcutaneously into the flank of 6-
week-old NODSCID mice (Charles River Laboratories, Wilmington, MA, USA) for 
the first passage. When the tumor size reaches 500 mm3 (approximately 3months), 
the mice will be sacrificed, tumors will be surgically removed, and implanted into 
male athymic nude mice (BALB/c-nude; 6 weeks old; Japan SLC, Hamamatsu, 
Japan) for amplification. After four consecutive passages, the xenografts will be 
amenable to drug treatment. 

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9.1.4 PDO generation 
 
To generate gastric cancer PDO models, typical procedures are as follows; however, 
standard procedures at the Mills Laboratory will be followed if there is any 
discrepancy.  
 
Primary patient tumor tissues will be rinsed with advanced DMEM/F12 containing 1 
x P/S twice, and then incubated at 37 C with digestion buffer (advanced DMEM/F12 
containing 1x P/S, 1mg/ml primocin, 2.5% FBS, 0.6mg/mL collagenase, 20mg/mL 
hyaluronidase and 10mM Y-27632). Tissue debris will be removed by passing the 
mixture through a 100 µm cell strainer. Cell clusters will be washed twice using 
AdDMEM medium followed by centrifugation at 1000 g for 5 min, and resuspension 
in Matrigel, and plated in a 24-well plate.  500 ml of standard gastric organoid 
medium (advanced DMEM/F12, 1x GlutaMax, 1x HEPES, 1x P/S, 50% Wnt3a, 10% 
RSPO-1, 10% Noggin, 1xB27, 50ng/mL EGF, 200ng/mL FGF10, 1mM N-
Acetylcystenine, 1nM Gastrin, 2mM A83-01), 10mM Y-27632 and 1mg/ul primocin 
were added to each well. Fresh medium was changed every 2-3 days and passage of 
the organoid cultures will be performed every two weeks.   
 
9.1.5 PDX and PDO treatment 
 
For treatment of PDX models, after maturation of xenografts, athymic nude mice 
will be treated with ramucirumab (27 mg/kg) every 3 days for 3 weeks and 
irinotecan (40 mg/kg according to previous studies30,31).  Tumors will be measured 
twice weekly with calipers, and tumor volumes will be calculated.   
 
For treatment of PDO models, one day after splitting, tumor organoids will be 
treated with ramucirumab and irinotecan diluted according to a seven-point half-
log scale, with a concentration range spanning patients’ therapeutic levels28. For 
each biological run, raw data from three technical replicates across three plates will 
be averaged and compared with the mean of the positive control (10mM MG132) 
and negative control (DMSO).  The effect of the drugs on the tumor organoids, in 
terms of cell viability, will be quantitated using a Cell titer-Glo 2.0 assay 
(Promega).  Dose response curves, absolute IC50 and AUC will be calculated.  
 
Based on further molecular characterization as noted below, additional therapeutic 
agents may be used to treat these models.  
 
9.1.6 PDX and PDO characterization 
 
For our PDX and PDO models, we plan for additional characterization experiments 
to be performed before and after drug treatment.  These important additional 
experiments will assess concordance between PDX and PDO models through 
histology, transcriptome, and whole genome analyses.  In addition, pre and post 

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treatment data will allow further exploratory analyses to be made between treatment 
response and molecular characteristics to generate hypotheses regarding 
resistance/sensitivity mechanisms.  First we will process a portion of xenograft 
tumors and organoids by standard formalin fixation and paraffin embedding for 
H&E pathohistological analyses and further serial unstained sectioning.  Additional 
samples from xenograft tumors and organoids will be processed for high quality 
RNA and DNA isolation using Qiagen isolation kits.   
 
Dr. Mills is a human pathologist who will analyze morphological and cytological 
features of PDO and PDX samples analyzed for histology. Specifically, he will be 
interested in whether PDOs and PDXs and original tumor resection/biopsy 
specimens are concordant with level of differentiation (well, moderate, poor), 
pattern of invasion (single-cell, clusters, glands), morphology of tumor as a whole 
(single-cells with signet ring features vs. “intestinal”-type), cellular morphology 
(degree of atypia, N:C ratio, nuclear/nucleolar features). 
 
A portion may be sent to the Washington University Genome Technology Access 
Core (GTAC) for library preparation and RNA and DNA sequencing (e.g., on an 
Illumina HiSeq-3000).  Downstream analyses will be performed on Partek 
Genomics Suite. Additional analyses including comparison between PDX and PDO 
models, and pre- and posttreatment molecular responses using exome sequencing 
and transcriptomics via RNA seq may be performed. We are cognizant that the 
tumor organoids are an epithelial-biased system. Methods, such as single-cell 
RNAseq or epithelial cell enrichment through flow cytometry, may be used to 
distinguish and analyze the contribution of non-epithelial, non-tumor tissue in our 
PDX models. 
 
9.2 
Rationale for assessment of circulating angiogenic factors 
 
Circulating levels of angiogenic factors have been increasingly evaluated in cancer patients 
receiving antiangiogenesis therapy. The results of such correlative studies are well 
documented.32 Overall, correlations have been inconsistent and have not identified clear 
predictive markers. Such data in patients with gastroesophageal cancer is sparse, given the 
lack of Phase 2 experience in delivering antiangiogenic therapy in this disease. However, 
certain candidate factors warrant further investigation in ways which account for our 
growing appreciation of the complexity of interwoven pathways. Angiogenesis appears to 
be important in the progression of this disease and, therefore, correlative studies to improve 
our understanding of drug mechanisms and improve patient selection are warranted. 
 
The association between circulating angiogenesis factors in gastroesophageal cancer has 
been explored. Gastric cancer cells have been shown to generate high VEGF levels.33 
Circulating VEGF levels have correlated with microvessel density in primary gastric 
tumors34 and with higher stage.35,36 In esophageal cancer, serum VEGF levels have been 
found to be raised in patients with cancer, compared with controls.37,38 Serum VEGF has 
been associated with tumor size, tumor depth, lymph node metastasis, distant metastasis, 
response to chemotherapy, and survival.37,39 

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9.3 
Blood-based Angiome profiling using multiplex technology 
 
In the past, the gold standard for detection of growth factors and cytokines in blood was 
the use of ELISAs; however, multiplex technology offers an attractive alternative approach 
for cytokine and growth factor analysis. This novel technology allows for the measurement 
of multiple analytes simultaneously from a single sample.  The advantages of multiplex 
technology compared to traditional ELISA assays are conservation of patient sample, 
increased sensitivity, and significant savings in cost, time and labor.  Furthermore, all plate 
designs have been validated in order to 1) limit cross-reactivity of the antibodies 2) 
optimize sensitivity and specificity and 3) maximize the linearity of the assay’s dynamic 
range. 
 
Several systems exist, the plate-based platforms being the Meso Scale Discovery (MSD) 
multiplex system and the SearchLight system, produced by Aushon Biosystems. The assay 
design in both cases is similar to a sandwich ELISA, except multiple capture antibodies 
are pre-spotted into individual wells of a 96-well plate. Samples or standards are added 
which bind to the specific capture antibodies and are detected using various outputs.  Over 
the past 7 years, the design of customized multiplex ELISA plates has been optimized via 
extensive collaborations with Aushon Biosystems.  This has led to the development of an 
appropriately designed panel for the simultaneous evaluation of 28 regulators of tumor and 
normal angiogenesis.   
 
The table below lists the panel of markers currently optimized; that would be analyzed for 
this study. This will be performed in collaboration with Duke Molecular Reference 
Laboratory at Duke University Medical Center (Dr. Andrew Nixon).  
Table:  Plasma-based marker identification 
Soluble 
Angiogenic 
Factors 
Matrix-
Derived  
Factors 
Markers of Vascular 
Activation and 
Inflammation 
ANG-2 
PDGF-BB 
sEndoglin 
CRP 
bFGF 
PlGF 
Osteopontin 
ICAM-1 
HGF 
VEGF-A 
TGFβ1 
IL-6 
IGFBP1 
VEGF-D 
TGFβ2 
PAI-1 Active 
IGFBP2 
sVEGFR1 
TGFβRIII 
PAI-1 Total 
IGFBP3 
sVEGFR2 
TIMP1 
SDF-1 
PDGF-AA 
sVEGFR3 
TSP2 
VCAM-1 
 
 
 
 
 
 

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9.3.1 Collection of Specimens 
 
Ten mL of blood will be collected into one lavender top (K2EDTA) tube at each of 
the following time points: 
• Cycle 1 Day 1 (prior to start of study treatment) 
• Cycle 5 Day 1 (at the time of first restaging evaluation, prior to treatment) 
• Cycle 9 Day 1 (at the time of second restaging evaluation, prior to 
treatment) 
• End of treatment 
 
9.3.2 Handling of Specimens 
 
For plasma samples: 
 
1. Invert tubes 10 times to mix blood 
2. Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with 
centrifuge manufacturer’s instructions) 
3. Remove plasma from each tube and transfer equally into two separate 
clean 15ml polypropylene tubes 
4. Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance 
with centrifuge manufacturer’s instructions) 
5. Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml 
cryovial.  For the EDTA, aliquot into pink capped cryovial.  Total of 4 
pink capped cryovials needed for EDTA plasma.  
6. Label and freeze at -80°C* (see labeling instructions below) 
 
• If the participating site does not have a -80°C freezer, samples should 
be shipped on dry ice on the day of collection.  If unable to ship 
samples on the day of collection, please place the samples on dry ice 
until they can be shipped.  Samples can be stored on dry ice for no 
more than 48 hours prior to shipping.  Please replenish dry ice as 
needed to ensure samples stay frozen and there is enough to last 
throughout shipment. 
• Biomarker assays are time sensitive.  Samples must be processed 
within one hour of collection.  Complete the Biomarker Flowsheet, 
insert a copy of the flowsheet with shipment, and fax to ATTN: 
BIOMARKER LABORATORY at 919-668-3925.  
• Any questions regarding biomarker processing, supplies and shipping, 
should be directed to 919-681-2239 
 
All samples have appropriate chain-of-custody documentation to ensure 
compliance with FDA and IRB regulations.  Systems are in place detailing the 
location, transfer, and use of any and all human research subject samples. Any 
discrepancies or omissions in flow sheets and/or sample labels are resolved upon 

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receipt of the sample in the lab.  All sample and data handling procedures will be 
fully compliant with the Health Insurance Portability and Accountability Act of 
1996 (HIPAA). 
 
9.3.3 Shipping of Specimens 
 
Plasma samples will be stored for future translational studies with blood based 
angiome-profiling.  
 
Plasma-containing tubes need to be labeled with the following information (using 
a Sharpie or Cryopen): 
• Protocol Name  
• Subject Study Number 
• Subject Initials 
• Sample Date and Time 
• Sample Type (ie. whole blood, EDTA plasma, citrate plasma, serum, 
urine) 
 
Biomarker samples will be shipped within 48 to 72 hours of completed processing 
with a completed Biomarker Flowsheet with shipment.  
 
All biomarker samples (whole blood, plasma, serum and urine) must be shipped 
on dry ice by overnight delivery Monday through Thursday (no holidays) to the 
following address: 
 
Phase I Biomarker Laboratory 
ATTN:  Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
 
9.4 
Blood for Cell-Free DNA 
 
The analysis of cell free or circulating tumor DNA is a promising area of investigation that 
allows for interrogation of tumor-specific molecular alterations in the circulation. One of 
the key advantages of cfDNA analyses is the high degree of specificity offered, because 
mutations found in cfDNA are in essence integral agents of an individual's cancer and are 
defined by their presence in tumor DNA and absence in matched normal DNA. In terms of 
sensitivity, levels of cfDNA are abundant in most patients with advanced cancer, allowing 
for the assessment of molecular heterogeneity, monitoring of tumor dynamics, 
identification of genetic determinants for therapy, tracking of genomic evolution, and 
development of acquired resistance.40  
 
 
 
 

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9.4.1 Collection of Specimens 
 
Ten mL of blood will be collected into EDTA tubes prior to treatment at each of 
the following time points: 
• Cycle 1 Day 1 
• Cycle 3 Day 1 
• Cycle 5 Day 1 
• Cycle 7 Day 1 
• Cycle 9 Day 1 
• End of treatment 
 
9.4.2 Handling of Specimens 
 
See Section 9.3.2 
 
9.4.3 Shipping of Specimens 
 
Plasma samples will be stored for future translational studies using circulating 
cell-free DNA.  
 
See Section 9.3.3  
 
9.5 
HER-2 Status Collection 
 
Because of its involvement in the development of different types of cancer, HER-2 
gene/protein status information will be collected for all patients during the study. No formal 
testing will take place but information will be obtained from prior testing available in 
medical records or tests that have occurred for other medical reasons during the trial as a 
part of routine medical care. 
 
 
 

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10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 28 days prior to start of protocol 
therapy.  Cycles are 14 days long but may be extended to up to 21 days at physician discretion.  
 
 
Screening 
Day 1 of each 
cycle (+/- 3 
days) 
Every 8 weeks 
(+/- 3 days 
EOT 
(+/- 3 
days) 
F/U1 
Informed consent 
X 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
ECOG PS, Vitals, weight 
X 
X 
 
 
 
Height 
X 
 
 
X 
 
Physical exam 
X 
X 
 
X 
X5 
EKG 
X 
 
 
 
 
CBC 
X 
X 
 
X 
 
CMP 
X 
X 
 
X 
 
PTT/INR 
X 
 
 
 
 
Urinalysis or Urine 
Dipstick6 
X 
X 
 
X 
 
β-hCG2 
X 
 
 
 
 
Imaging3 and RECIST 
1.1 time point response 
X 
 
X 
X4 
 
Ramucirumab 
 
X 
 
 
 
Irinotecan 
 
X 
 
 
 
Tumor Biopsy (Wash U only) 
X7 
 
 
 
 
Blood for angiome 
profiling 
 
Before treatment on C1D1, C5D1, 
and C9D1 
X 
 
Blood for cfDNA 
 
Before treatment on C1D1, C3D1, 
C5D1, C7D1, and C9D1 
X 
 
Collection of HER2 
status 
At some point during the study 
 
Adverse event 
assessment 
X --------------------------------------------------------------- X 
X 
Survival information 
 
 
 
 
X 
1. 30 days after EOT visit, then every 2 months. AEs only collected for 30 days after treatment discontinuation. 
2. Women of childbearing potential only 
3. Imaging (CT or MRI) will be performed every 8 weeks, +/- 7days, regardless of dosing/cycle delays up to 1 year. 
After 1 year, the imaging frequency is at the discretion of the treating physician. Information from lesion 
evaluation by imaging done as part of routine care will be collected until progressive disease has been objectively 
determined if the patient discontinued treatment due to any other reason than progressive disease. 
4. EOT imaging not required if most recent scan has been performed within 21 days prior to EOT.  
5. Physical exam will only be done if the follow-up visit involves an in-person office visit. 
6. A urine dipstick may be performed in lieu of a full urinalysis, however, if the dipstick is abnormal, confirm urine 
protein with a full urinalysis. If urinalysis or dipstick shows protein ≥ 2+, a 24-hour urine collection must be 
collected. 
7. If safe and feasible, biopsies are to be performed at least 7 days prior to the planned C1D1. See Section 9.1 for 
additional information. 

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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Correlative Form 
Per protocol 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 2 months 
Tumor Measurement Form 
 Submit at imaging time points. See section 10.0 for 
imaging time points. 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
11.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Toxicity Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks 
regardless of dosing/cycle delays.  In addition to a baseline scan, confirmatory scans should 
also be obtained not less than 4 weeks following initial documentation of objective 
response. 
 

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Information from lesion evaluation by imaging done as part of routine care will be collected 
until progressive disease has been objectively determined if the patient discontinued 
treatment due to any other reason than progressive disease. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).41  Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria. 
 
 
 

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12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 

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12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice 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.   

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Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 

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corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 

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Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
                                      

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 For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. For those who are alive and do not experience 
progression, we censor them at the time of loss to follow-up (very few) or at 12 
months from the study entry, which come first. 
 
12.4.6 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) 
independent of the study at the study’s completion.  Simultaneous review of the 
patients’ files and radiological images is the best approach.  
 
 
 

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13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are 
subject to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 
be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC) semi-annually beginning 6 months after study activation at Washington 
University (if at least one patient has been enrolled) or one year after study activation (if no patients 
have been enrolled at the 6-month mark). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee.  The 
DSMB must meet beginning six months after enrollment of the first patient at a secondary site, no 
more than one month prior to the due date of the DSM report to QASMC.  This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date, accrual by site, and accrual by arm 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities at all participating sites and separated by arm 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 

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Further DSMB responsibilities are described in the DSMB charter.   
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (Please refer to 
section 7.0). 
 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/. 
 
 
14.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by 
Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing 
mechanism in place and can provide a report. The outside sites will be asked to send copies of all 
audit materials, including source documentation.  The audit notification will be sent to the 
Washington University Research Patient Coordinator, who will obtain the audit materials from the 
participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Additional details regarding the Auditing Policies and procedures can be found at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMC%20Policies%20and%20Procedures%2
05-3-13.pdf  
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Design and Sample Size 
 
This is a multi-institutional, open-labeled, Phase II study. The study will be conducted at 
five institutions (including Washington University). Patients with previously treated, 
metastatic esophagogastric adenocarcinomas will be assigned to treatment with irinotecan 
plus ramucirumab.  
 
Target sample size for this single arm, phase II study would be 40 patients. A sample size 
of 40 has 85% power at a 0.050 significance level to detect a median progression-free 
survival time of 4 months in the treatment group when the median survival time of the 

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historic control group is 2.5 months. These estimations are based on historical data from 
irinotecan studies and a PFS improvement of 1.5 months seen in the RAINBOW study 
(PFS for paclitaxel alone = 2.9 months, paclitaxel plus ramucirumab = 4.4 months). 
Calculation is based on one-sided, one-sample log-rank test and assumes that subjects will 
be accrued for a period of 12 months, and follow-up continues for a period of 12 months 
after the last subject is enrolled.42,43 The survival time distributions of both groups are 
assumed to follow an exponential distribution. 
 
15.2 
Primary Efficacy Measure  
 
Progression-Free Survival (PFS): 
PFS will be measured from date of study entry to first radiographic progression or death due 
to any cause. Radiographic progressive disease (PD) will be defined using Response 
Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1).41 For those who are alive and do 
not experience progression, we censor them at the time of loss to follow-up (very few) or at 
12 months from the study entry, which come first. 
 
15.3 
Secondary Efficacy Measures 
 
• Overall Survival Time (OS): 
OS time will be measured from date of study entry to date of death from any cause. For 
those who are alive, we censor them at the time of loss to follow-up (very few) or at 30 
months from the date of treatment discontinuation, which come first. 
• Time to Progressive Disease (TTP): 
TTP is defined as the time from study entry until date of radiographic PD using RECIST 
v1.1 criteria. For those who are alive and do not experience progression, we censor them 
at the time of loss to follow-up (very few) or at 12 months from the study entry, which 
come first. For those who are dead before progression, we will consider death as the 
competing risk. If the number of death are very small, we will censor them at time of 
death. 
• Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable 
Disease (SD) or PD: 
BOR is defined as the best response across all time points from randomization until 
radiologically confirmed PD using RECIST, v1.1 criteria. CR is defined as the 
disappearance of all target and non-target lesions and any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm and 
normalization of tumor marker level of non-target lesions. PR is defined as having a 
≥30% decrease in sum of longest diameter (LD) of target lesions. PD was defined as 
having a ≥20% increase in sum of LD of target lesions and ≥5 mm increase above nadir. 
SD was defined as small changes that did not meet above criteria. 
• Objective Response Rate (ORR): 
ORR is defined as the percentage of participants with confirmed CR or confirmed PR. 
• Clinical Benefit Rate (CBR): 
CBR is defined as percentage of combined patients who have achieved confirmed CR, 
PR and SD.  
 

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15.4 
Anticipated Findings 
 
We anticipate prolongation of PFS with combination of irinotecan and ramucirumab. This 
may provide an early signal of activity of this combination in second line treatment of 
esophagogastric adenocarcinomas, and would lay the foundation for future phase III 
studies.  
 
15.5 
Exploratory Analyses 
For PDX/PDO models, successful generation would be defined by growth in size/number 
ability to expand, and ability to passage. Treatment response will be assessed by cell death 
by counting or using a cell death assay. The correlation coefficient from the PDX and PDO 
models will be compared with the clinical outcome from the patients (progression vs no 
progressive disease) using a point biserial model which will give us a measure on the 
strength of the relationship between the two variables. Paired analyses for correlation will 
be underpowered (67% power to detect effect size of 0.6 and 10% significance level under 
null hypothesis of a medium effect size of 0.3 with 10 paired samples). Therefore, all 
analyses will be descriptive and hypothesis generating in nature, and it will be used to guide 
future clinical trial development incorporating PDX/PDO models.  
 
For circulating biomarkers, levels of plasma-based biomarkers will be presented in 
descriptive summary. Spearman correlations among analytes may be calculated and 
illustrated. The prognostic value of each analyte as a continuous measure may be assessed 
by a univariate Cox proportional hazards model for PFS with corresponding hazard ratios 
and 95% confidence intervals. Cox regression analyses with each analyte adjusting for 
clinical variables, including age, race, gender and performance status may be performed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Each participating institution must have the following documents on file at Washington University 
prior to first subject enrollment: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including the 
Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572, and signed and dated CVs of all 
participating investigators. 
• Documentation of training in protection of human subjects by all participating 
investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The Principal Investigator is responsible for disseminating to the participating sites all study 
updates, amendments, reportable adverse events, etc.  There will be one current version of the 
protocol document at any given time and each participating institution will utilize that document.  
Protocol/consent modifications and IB updates will be forwarded electronically to the secondary 
sites within 2 weeks of obtaining Washington University IRB approval with acknowledgement of 
receipt requested.  Secondary sites are to submit protocol/consent/IB modifications to their local 
IRBs within 4 weeks of receipt, and confirmation of submission must be forwarded to the 
appropriate contact person on the Washington University study team at the time of submission.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the 
Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 
 

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17.0 
REFERENCES 
 
 
1. 
Ferlay J SI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman 
D, Bray, F.: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC 
CancerBase No. 11 Lyon, France: International Agency for Research on Cancer, 2013 
 
2. 
Wagner AD, Grothe W, Haerting J, et al: Chemotherapy in advanced gastric cancer: 
a systematic review and meta-analysis based on aggregate data. J Clin Oncol 24:2903-9, 2006 
 
3. 
Ford HE, Marshall A, Bridgewater JA, et al: Docetaxel versus active symptom 
control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 
randomised controlled trial. Lancet Oncol 15:78-86, 2014 
 
4. 
Kang JH, Lee SI, Lim do H, et al: Salvage chemotherapy for pretreated gastric 
cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best 
supportive care alone. J Clin Oncol 30:1513-8, 2012 
 
5. 
Thuss-Patience PC, Kretzschmar A, Bichev D, et al: Survival advantage for 
irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a 
randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J 
Cancer 47:2306-14, 2011 
 
6. 
Juttner S, Wissmann C, Jons T, et al: Vascular endothelial growth factor-D and its 
receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin 
Oncol 24:228-40, 2006 
 
7. 
Suzuki S, Dobashi Y, Hatakeyama Y, et al: Clinicopathological significance of 
platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, 
PDGF receptor-beta phosphorylation, and microvessel density in gastric cancer. BMC Cancer 
10:659, 2010 
 
8. 
Jung YD, Mansfield PF, Akagi M, et al: Effects of combination anti-vascular 
endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the 
growth of gastric cancer in a nude mouse model. Eur J Cancer 38:1133-40, 2002 
 
9. 
Spratlin JL, Cohen RB, Eadens M, et al: Phase I pharmacologic and biologic study 
of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting 
the vascular endothelial growth factor receptor-2. J Clin Oncol 28:780-7, 2010 
 
10. 
Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously 
treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31-9, 2014 
 
11. 
Wilke H, Muro K, Van Cutsem E, et al: Ramucirumab plus paclitaxel versus 
placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal 
junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 
15:1224-35, 2014 
 
12. 
Van Cutsem E, Moiseyenko VM, Tjulandin S, et al: Phase III study of docetaxel 
and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for 
advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991-7, 2006 

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Page 54 of 64 
 
13. 
Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced 
esophagogastric cancer. N Engl J Med 358:36-46, 2008 
 
14. 
Al-Batran SE, Hartmann JT, Probst S, et al: Phase III trial in metastatic 
gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: 
a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 26:1435-42, 2008 
 
15. 
Petrelli F, Zaniboni A, Coinu A, et al: Cisplatin or not in advanced gastric cancer: 
a systematic review and meta-analysis. PLoS One 8:e83022, 2013 
 
16. 
Guimbaud R, Louvet C, Ries P, et al: Prospective, randomized, multicenter, phase 
III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine 
in advanced gastric adenocarcinoma: a French intergroup (Federation Francophone de 
Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe 
Cooperateur Multidisciplinaire en Oncologie) study. J Clin Oncol 32:3520-6, 2014 
 
17. 
Dank M, Zaluski J, Barone C, et al: Randomized phase III study comparing 
irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil 
in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric 
junction. Ann Oncol 19:1450-7, 2008 
 
18. 
Sym SJ, Hong J, Park J, et al: A randomized phase II study of biweekly irinotecan 
monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in 
patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line 
chemotherapy. Cancer Chemother Pharmacol 71:481-8, 2013 
 
19. 
Kang EJ, Im SA, Oh DY, et al: Irinotecan combined with 5-fluorouracil and 
leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in 
gastric cancer: treatment outcomes and a prognostic model to predict survival. Gastric Cancer 
16:581-9, 2013 
 
20. 
Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in 
combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that 
progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine 
(RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499-508, 2015 
 
21. 
Tentler JJ, Tan AC, Weekes CD, et al: Patient-derived tumour xenografts as models 
for oncology drug development. Nat Rev Clin Oncol 9:338-50, 2012 
 
22. 
Gao H, Korn JM, Ferretti S, et al: High-throughput screening using patient-derived 
tumor xenografts to predict clinical trial drug response. Nat Med 21:1318-25, 2015 
 
23. 
Kuwata T, Yanagihara K, Iino Y, et al: Establishment of Novel Gastric Cancer 
Patient-Derived Xenografts and Cell Lines: Pathological Comparison between Primary Tumor, 
Patient-Derived, and Cell-Line Derived Xenografts. Cells 8, 2019 
 
24. 
Zhu Y, Tian T, Li Z, et al: Establishment and characterization of patient-derived 
tumor xenograft using gastroscopic biopsies in gastric cancer. Sci Rep 5:8542, 2015 
 
25. 
Shin SH, Park SS, Ju EJ, et al: Establishment of a Patient-derived Xenograft for 
Development of Personalized HER2-targeting Therapy in Gastric Cancer. Anticancer Res 38:287-
293, 2018 
 
26. 
Ryu WJ, Lee JE, Cho YH, et al: A Therapeutic Strategy for Chemotherapy-
Resistant Gastric Cancer via Destabilization of Both beta-Catenin and RAS. Cancers (Basel) 11, 
2019 
 
27. 
Clevers H: Modeling Development and Disease with Organoids. Cell 165:1586-
1597, 2016 

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Page 55 of 64 
 
28. 
Yan HHN, Siu HC, Law S, et al: A Comprehensive Human Gastric Cancer 
Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening. 
Cell Stem Cell 23:882-897 e11, 2018 
 
29. 
Li X, Francies HE, Secrier M, et al: Organoid cultures recapitulate esophageal 
adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics. 
Nat Commun 9:2983, 2018 
 
30. 
Prewett M, Huber J, Li Y, et al: Antivascular endothelial growth factor receptor 
(fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several 
mouse and human tumors. Cancer Res 59:5209-18, 1999 
 
31. 
Nukatsuka M, Nakagawa F, Saito H, et al: Efficacy of combination chemotherapy 
using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human 
colorectal and gastric cancer xenografts. Anticancer Res 35:1437-45, 2015 
 
32. 
Jain RK, Duda DG, Willett CG, et al: Biomarkers of response and resistance to 
antiangiogenic therapy. Nat Rev Clin Oncol 6:327-38, 2009 
 
33. 
Keyes KA, Mann L, Cox K, et al: Circulating angiogenic growth factor levels in 
mice bearing human tumors using Luminex Multiplex technology. Cancer Chemother Pharmacol 
51:321-7, 2003 
 
34. 
Mangia A, Chiriatti A, Ranieri G, et al: H pylori status and angiogenesis factors in 
human gastric carcinoma. World J Gastroenterol 12:5465-72, 2006 
 
35. 
Eroglu A, Demirci S, Ayyildiz A, et al: Serum concentrations of vascular 
endothelial growth factor and nitrite as an estimate of in vivo nitric oxide in patients with gastric 
cancer. Br J Cancer 80:1630-4, 1999 
 
36. 
Kim HK, Song KS, Park YS, et al: Elevated levels of circulating platelet 
microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a 
metastasis predictor. Eur J Cancer 39:184-91, 2003 
 
37. 
Shimada H, Takeda A, Nabeya Y, et al: Clinical significance of serum vascular 
endothelial growth factor in esophageal squamous cell carcinoma. Cancer 92:663-9, 2001 
 
38. 
McDonnell CO, Harmey JH, Bouchier-Hayes DJ, et al: Effect of multimodality 
therapy on circulating vascular endothelial growth factor levels in patients with oesophageal 
cancer. Br J Surg 88:1105-9, 2001 
 
39. 
Dreilich M, Wagenius G, Bergstrom S, et al: The role of cystatin C and the 
angiogenic cytokines VEGF and bFGF in patients with esophageal carcinoma. Med Oncol 22:29-
38, 2005 
 
40. 
Diaz LA, Jr., Bardelli A: Liquid biopsies: genotyping circulating tumor DNA. J 
Clin Oncol 32:579-86, 2014 
 
41. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
42. 
Lawless JF: Statistical Models and Methods for Lifetime Data, Wiley, 2011  
 
43. 
Wu J: Sample size calculation for the one-sample log-rank test. Pharmaceutical 
Statistics 14:26-33, 2015 
 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 

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Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 

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

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APPENDIX B: CYP3A4 Strong Inhibitors and Inducers 
 
Strong CYP3A4 Inhibitors 
Indinavir 
Nelfinavir 
Ritonavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Saquinavir 
Suboxone 
Telithromycin 
Lopinavir 
Telaprevir 
Voriconazole 
Strong CYP3A4 Inducers 
Efavirenz 
Nevirapine 
Barbiturates 
Carbamazepine 
Glucocorticoids 
Modafinil 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
Troglitazone 
 
http://medicine.iupui.edu/clinpharm/ddis/main-table 
 
 
 
 
 

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APPENDIX C: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting.  
A copy of the CTCAE version 4.03 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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Page 60 of 64 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, 
based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 
 

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APPENDIX D: Reporting Timelines 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Eli Lilly 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 calendar 
days after it is determined that the 
information qualifies for 
reporting 
Report to Eli Lilly within 24 hours of 
Sponsor-Investigator notification. 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 calendar 
days after initial receipt of the 
information 
Report to Eli Lilly within 24 hours of 
Sponsor-Investigator notification. 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  If the 
event results in the death of a 
participant enrolled at WU/BJH/SLCH, 
report within 1 working day. 
Report via email 
after IRB 
acknowledgment 
 
Report to Eli Lilly within 24 hours of 
Sponsor-Investigator notification. 
Pregnancy 
 
 
 
Notify Eli Lilly as they occur. 
Overdose 
 
 
 
Notify Eli Lilly as they occur. 
Major deviation 
Report within 10 working days.  If the 
event results in the death of a 
participant enrolled at WU/BJH/SLCH, 
report within 1 working day. 
 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.   
 
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
that list in the protocol 
or IB 
 
 
Report no later than 15 calendar 
days after it is determined that the 
information qualifies for 
reporting 
 
Complaints 
If the complaint reveals an 
unanticipated problem involving risks 
 
 
 

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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Eli Lilly 
to participants or others OR 
noncompliance, report within 10 
working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the 
time of continuing review. 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Eli Lilly 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
Notify monthly via AE 
notification or cross-reporting 
reports/documents. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
 

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Page 3 of 64 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Eli Lilly 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 
Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Eli Lilly 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional guidelines. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to the 
FDA as needed. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to Eli  as 
needed. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 

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APPENDIX E: Washington University Serious Adverse Event Reporting Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Event Start Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date