Conditions: Pancreatic Cancer
Keywords: mFOLFIRINOX Ramucirumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 84
Healthy volunteers: no

Brief summary:
This is a phase II, multicenter, double-blinded, randomized, 2-arm trial evaluating the efficacy and safety of mFOLFIRINOX plus ramucirumab (Arm A) vs. mFOLFIRINOX plus placebo (Arm B) in 94 subjects with advanced pancreatic cancer, not amenable to curative treatment. Both arms will continue treatment until disease progression or unacceptable toxicity.

Detailed description:
OUTLINE: This is a multi-center study.

EXPERIMENTAL ARM A:

* Oxaliplatin 85 mg/m\^2 over 2-4 hours
* Irinotecan 165 mg/m\^2 over 90 minutes
* 5-FU 2,400 mg/m\^2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.
* Arm A will receive ramucirumab (RAM) administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.

CONTROL ARM B :

* Oxaliplatin 85 mg/m2 over 2-4 hours
* Irinotecan 165 mg/m2 over 90 minutes
* 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.
* Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were RAM.

In order to demonstrate adequate organ function, all screening labs must be obtained within 7 days prior to registration:

Hematological:

* Hemoglobin ≥ 9 g/dL
* Absolute Neutrophil Count (ANC) ≥ 1,500/mm\^3
* Platelet Count (PLT) ≥ 100,000/mm\^3

Renal:

* Creatinine ≤ 1.5 mg/dL or Creatinine clearance\^1 ≥ 40 mL/min
* Albumin ≥ 2.5 g/dL

Hepatic:

* Bilirubin ≤ 1.5 mg/dL
* Aspartate aminotransferase (AST) ≤ 3 × ULN or \< 5 xULN in the setting of liver metastases
* Alanine aminotransferase (ALT) ≤ 3 × ULN or \< 5 xULN in the setting of liver metastases

Coagulation:

* International Normalized Ratio (INR) (Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) \< 1.5 x ULN

Arms:
arm 1: mFOLFIRINOX will be administered every 2 weeks, and consist of:

* Oxaliplatin 85 mg/m2 over 2-4 hours
* Irinotecan 165 mg/m2 over 90 minutes
* 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.
* Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. arm 2: mFOLFIRINOX will be administered every 2 weeks, and consist of:

* Oxaliplatin 85 mg/m2 over 2-4 hours
* Irinotecan 165 mg/m2 over 90 minutes
* 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.
* Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab

Interventions: intervention 1: mFOLFIRINOX intervention 2: Ramucirumab intervention 3: Placebo
Intervention descriptions: intervention 1: mFOLFIRINOX:

* Oxaliplatin 85 mg/m2 over 2-4 hours
* Irinotecan 165 mg/m2 over 90 minutes
* 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. intervention 2: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. intervention 3: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
HCRN GI14-198 
Clinical Study Protocol 
Version Date: 13AUG2018 
Confidential 
Page 1 of 51 
 
 
Phase II Randomized, Double-Blind Study of mFOLFIRINOX plus Ramucirumab versus 
mFOLFIRINOX plus placebo in Advanced Pancreatic Cancer Patients 
HCRN GI14-198 
 
 
Sponsor-Investigator 
Walid Shaib, MD 
Emory University 
 
Site Principal Investigators 
 
Tanios Bekaii-Saab, MD 
Mayo Clinic Cancer Center; Phoenix 
Arizona 
 
Mohamed Kassar, MD 
Community Healthcare System 
(Muncie, IN) 
 
Bert O’Neil, MD 
Indiana University Simon Cancer Center 
 
Tina Khair, DO 
Gettysburg Cancer Center 
 
Timothy Huyk, MD 
Nebraska Methodist 
 
Stephen Cohen< MD 
Thomas Jefferson University 
 
Rebecca Redman, MD 
University of Louisville 
 
Co-Investigators 
Astrid Belalcazar, MD 
Alese Tunji, MD 
Natalyn Hawk, MD 
Bassel El-Rayes, MD 
 
Statistician 
Zhengjia Chen, PhD 
 
Trial Management Provided by  
Hoosier Cancer Research Network 
 
Trial Supported by 
Eli Lilly and Company 
 
IND EXEMPT: April 29, 2016 
 
Initial Protocol Version Date: 31MAR2016 
Protocol Amendment Version Date: 
09FEB2017 
21JUL2017 
13AUG2018 
 


 
 
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PROTOCOL SIGNATURE PAGE 
Phase II Randomized, Double-Blind, Study of mFOLFIRINOX plus Ramucirumab versus 
mFOLFIRINOX plus placebo in Advanced Pancreatic Cancer Patients 
GI14-198 
VERSION DATE: 13AUG2018 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable ethical review board(s). 
 
 
 
 
 
____________________________________ 
________________________ 
Signature of Site Investigator  
 
 
 
Date 
____________________________________ 
Site Investigator Name (printed) 
____________________________________ 
Site Investigator Title 
____________________________________ 
 Name of Facility 
____________________________________ 
 Location of Facility (City and State) 
____________________________________ 
❑ Not Submitting to IRB 
 Expected IRB Approval Date 
PLEASE COMPLETE AND EMAIL COPY TO HCRN 
Instructions to the site investigator:  Please SIGN and DATE this signature 
page.  PRINT your name and title, the name and location of the facility in 
which the study will be conducted, and the expected IRB approval date.  Scan 
and email the completed form to HCRN and keep a record for your files. 
 


 
 
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Page 3 of 51 
 
SYNOPSIS 
TITLE 
Phase II Randomized, Double-Blind Study of mFOLFIRINOX plus 
Ramucirumab versus mFOLFIRINOX plus placebo in Advanced 
Pancreatic Cancer Patients 
 
SHORT TITLE 
Phase II Randomized Trial of mFOLFIRINOX +/- Ramucirumab in 
Advanced Pancreatic Cancer 
 
PHASE  
II 
OBJECTIVES 
Primary Objective:  
Estimate and compare progression free survival (PFS) of mFOLFIRINOX 
plus Ramucirumab (RAM) versus mFOLFIRINOX plus placebo in 
subjects with recurrent or metastatic pancreas cancer (PCA) who present 
for first line chemotherapy treatment. 
 
Secondary Objectives: 
• Estimate and compare the median overall survival (mOS) 
in each arm. 
• Evaluate and compare the response rate (RR) in each arm. 
• Evaluate and compare the toxicities in each arm. 
 
STUDY DESIGN 
Phase II, multicenter, double-blinded, randomized, 2-arm trial evaluating 
efficacy and safety of mFOLFIRINOX plus ramucirumab (Arm A) vs. 
mFOLFIRINOX plus placebo (Arm B) in 85 subjects with advanced 
PCA, not amenable to curative treatment. Both arms will continue 
treatment until disease progression or unacceptable toxicity. 
  
ELIGIBILITY 
CRITERIA  
Each of the criteria in the checklist that follows must be met in order for a 
subject to be considered eligible for this study.  
Inclusion Criteria 
1. Written informed consent and HIPAA authorization for release of 
personal health information. NOTE:  HIPAA authorization may 
be included in the informed consent or obtained separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status of 0-1 within 7 days prior to 
registration. 
4. Histologic or cytological diagnosis of recurrent or metastatic 
pancreas adenocarcinoma (PCA) who present for first line 
chemotherapy treatment.  
5. No prior first line systemic treatment (prior adjuvant or 
neoadjuvant treatment is permitted). Subjects whose disease has 
progressed after 6 months of last systemic chemotherapy or 


 
 
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chemo-radiation in the adjuvant or neoadjuvant setting are 
eligible. 
6. Measurable disease determined using guidelines of RECIST 1.1. 
Baseline tumor assessment should be performed using high 
resolution CT scans or MRI. 
7. Urine protein < 1+ on dipstick test or routine urinalysis. If the 
proteinuria on these tests is ≥ 2+, then a 24-hour urine test must be 
collected and must demonstrate < 1 g protein in 24 hours to allow 
participation 
8. Estimated life expectancy of > 12 weeks, as assessed by the site 
investigator. 
9. If sexually active, must be postmenopausal, surgically sterile, or 
using effective contraception (hormonal or barrier methods) due to 
unknown risk of teratogenicity of ramucirumab  
10. Demonstrate adequate organ function as defined in Table 1 below; 
all screening labs to be obtained within 7 days prior to registration. 
 
Table 1: Organ Function Requirements 
1: If serum creatinine is >1.5 times the ULN, a 24-hour urine collection to 
calculate creatinine clearance must be performed 
 
System 
Laboratory Value 
Hematological 
Hemoglobin 
≥ 9 g/dL 
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count (PLT) 
≥ 100,000/mm3 
Renal 
Creatinine or 
Creatinine clearance1 
≤ 1.5 mg/dL 
≥ 40 mL/min 
Albumin 
≥ 2.5 g/dL 
Hepatic 
Bilirubin 
≤ 1.5 mg/dL 
Aspartate aminotransferase (AST) 
≤ 3 × ULN 
or <5 xULN in the setting 
of liver metastases 
Alanine aminotransferase (ALT) 
≤ 3 × ULN 
or <5 xULN in the setting 
of liver metastases 
Coagulation 
International Normalized Ratio (INR) 
Patients receiving warfarin must be 
switched to low molecular weight 
heparin and have achieved stable 
coagulation profile prior to first dose 
of protocol therapy. 
The subject has adequate 
coagulation function as 
defined by International 
Normalized Ratio (INR) 
≤1.5 and a partial 
thromboplastin time (PTT) 
(PTT/aPTT) < 1.5 x 
ULN.).  
 


 
 
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Exclusion Criteria 
11. Subjects with histology other than adenocarcinoma; Examples 
include: neuroendocrine tumors, acinar cell cancer, sarcoma or 
lymphoma of the pancreas 
12. Ongoing or active infection 
13. Symptomatic congestive heart failure, unstable angina pectoris, 
symptomatic or poorly controlled cardiac arrhythmia.  
Symptomatic heart failure (NYHA Class II-IV)  
14. Uncontrolled or poorly-controlled hypertension (>160 mmHg 
systolic or > 100 mmHg diastolic for >4 weeks) despite standard 
medical management. 
15. Acute or sub-acute intestinal obstruction 
16. Interstitial pneumonia or interstitial fibrosis of the lung, which in 
the opinion of the site investigator could compromise the subject 
or the study 
17. Pleural effusion or ascites that causes > grade 1 dyspnea 
18. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any 
degree) with a history of hepatic encephalopathy or clinical 
meaningful ascites resulting from cirrhosis; clinically meaningful 
ascites is defined as ascites resulting from cirrhosis and requiring 
ongoing treatment with diuretics and/or paracentesis 
19. Grade 3 or higher bleeding event ≤ 3 months prior to 
randomization. 
20. Experience of any arterial thrombotic or arterial thromboembolic 
events, including, but not limited to myocardial infarction, 
transient ischemic attack, or cerebrovascular accident, ≤ 6 months 
prior to randomization. 
21. History of deep vein thrombosis, pulmonary embolism, or any 
other significant thromboembolism (venous port or catheter 
thrombosis or superficial venous thrombosis are not considered 
“significant”) during the 3 months prior to randomization. 
22. GI perforation/fistula 
23. Documented and/or symptomatic or known brain or 
leptomeningeal metastases.  
24. Severely immune-compromised (other than being on steroids) 
including known HIV infection 
25. Concurrent active malignancy, other than adequately treated non-
melanoma skin cancer, other noninvasive carcinoma, or in situ 
neoplasm. A subject with previous history of malignancy is 
eligible, provided that he/she has been disease-free for > 3 years. 
26. Breast-feeding or pregnant.  Serum pregnancy test for women of 
child-bearing potential must be performed within 7 days prior to 
first dose of study treatment 
27. Prior autologous or allogeneic organ or tissue transplantation. 
28. Known allergy to any of the treatment components 
29. The patient has undergone major surgery within 28 days prior to 


 
 
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first dose of protocol therapy, or minor surgery/subcutaneous 
venous access device placement within 2 days prior to first dose of 
protocol therapy.  The patient has elective or planned major 
surgery to be performed during the course of the clinical trial. 
30. Have any condition that does not permit compliance with the study 
schedule including psychological, geographical, or medical. 
31. Receiving medications that can affect clotting ability: including 
warfarin, aspirin (once-daily aspirin use- maximum dose 325 
mg/day is permitted), nonsteroidal anti-inflammatory drugs 
(NSAIDs, including ibuprofen, naproxen, and others), 
dipyridamole or clopidogrel, or similar agents.  
32. Serious or non-healing wound, ulcer, or bone fracture within 28 
days prior to first dose of protocol therapy. 
STATISTICAL 
CONSIDERATIONS 
 
We aim to test the null hypothesis of PFS at 6 months. Using a one-sided 
log-rank test we have estimated a sample size of 85 patients (43 in one 
and 42 in another arm) which will provide 80% power under a type 1 
error of 20%. This is an estimation on 24 months accrual and 9 months 
follow up after accrual for the primary endpoint.  Sample size may 
increase to 95 to account for a 10% drop out rate. 
 
The primary endpoint of this clinical trial is PFS. PFS is defined as the 
time from enrollment to the time of progression or death. An interim 
analysis with Kaplan Meier method and Logrank test will be conducted 
after 23 subjects have been enrolled in each arm and followed up for 9 
months. The trial will stop if it detects a significant difference of 3 months 
in PFS between the study arm-mFOLFIRINOX/RAM, as compared to the 
standard arm-mFOLFIRINOX at the significance level of 0.0013 
according to the O’Brien-Fleming approach. Otherwise the trial will 
continue until the targeted sample size has been completed. 
 
RR, PFS and OS will be reported with 95% confidence intervals. 
Response is defined as a complete or partial response according to 
CT/MRI evaluations based on RECIST 1.1 criteria. Toxicity will be 
graded using CTCAE v4 
 
Early stopping: In the case of excessive toxicity, safety-stopping rules 
will be used. A grade ≥3 or adverse event that will lead to stop or 
termination of treatment is defined as suspected treatment related toxicity 
observed in the first 4 weeks of enrollment after dose modification, but 
excluding: nausea or vomiting and hematologic toxicities if not 
adequately treated. Ramucirumab will be held for drug related adverse 
events grade ≥ 3 until recovery to grade ≤ 1 and then resumed with a 
lower dose level -1 (6 mg/kg). If the grade ≥ 3 related adverse events does 
not resolve within 3 weeks of holding treatment, subject will be taken off 
the trial. In the case of prolonged or medically concerning grade 2 toxicity 
related to chemotherapy combination, treatment will be interrupted until 


 
 
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recovery to grade ≤ 1, at which time treatment will be resumed at the 
same dose. If the adverse event does not resolve in or within 2 weeks with 
medical intervention, then the subject will be taken off trial.  
 
In case of excessive toxicity, safety-stopping rules will be used. An 
acceptable toxicity rate will be assumed at 0.20. The study will be stopped 
based on an unacceptable excessive toxicity rate of 0.40. A sequential 
probability ratio test will be used where a likelihood ratio of 8 in favor of 
an excessive toxicity rate of 0.40 (vs. 0.20) provides sufficient evidence to 
stop the study due to excessive toxicity. Toxicity will be continuously 
reviewed for excessive toxicity and statistical analysis performed if 
excessive toxicity is suspected. 
 
In the interim safety analysis, the study will be closed to accrual after the 
first 20 subjects (10 in each arm) are analyzed, if within the first cycle of 
treatment n/10 subjects developed any of the following grade ≥ 3 toxicity: 
2/10 febrile neutropenia, 3/10 neuropathy, 3/10 hypertensive emergency 
or urgency, 3/10 life threatening thromboembolic event, 2/10 GI 
perforation or 2/10 bleeding or hemorrhage, the regimen mFOLFIRINOX 
RAM will be considered toxic and the trial will stop.  
 
TOTAL  
NUMBER OF 
SUBJECTS 
N = 85 to 95 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 24 months 
ESTIMATED STUDY 
DURATION  
Estimated 33 months 
 
 


 
 
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TABLE OF CONTENTS 
SCHEMA .............................................................................................................................................................................. 9 
1. 
BACKGROUND AND RATIONALE ................................................................................................................ 10 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................................................... 12 
3. 
ELIGIBILITY CRITERIA .................................................................................................................................... 12 
4. 
SUBJECT REGISTRATION ................................................................................................................................ 15 
5. 
TREATMENT PLAN ........................................................................................................................................... 15 
6. 
TOXICITY MONITORING AND DOSE MODIFICATIONS ...................................................................... 20 
7. 
STUDY CALENDAR & EVALUATIONS   Cycle = 28 days ..................................................................... 25 
8. 
CRITERIA FOR DISEASE EVALUATION..................................................................................................... 29 
9. 
DRUG INFORMATION ....................................................................................................................................... 33 
10 ADVERSE EVENTS ............................................................................................................................................. 38 
11. STATISTICAL METHODS ................................................................................................................................. 40 
12. TRIAL MANAGEMENT ..................................................................................................................................... 44 
13. DATA HANDLING AND RECORD KEEPING ............................................................................................. 46 
14. ETHICS .................................................................................................................................................................... 47 
15. REFERENCES ....................................................................................................................................................... 49 
 
 


 
 
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SCHEMA 
 
 
 
 
 
Chemotherapy Naive 
Advanced Pancreatic Cancer 
ECOG PS ≤1 
Arm A 
mFOLFIRINOX + Ramucirumab 
 
Arm B 
mFOLFIRINOX + Placebo 
 


 
 
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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
The prognosis of pancreas adenocarcinoma (PCA) remains poor with little progress made in 
the last few decades with the exception of FOLFIRINOX (PRODIGE 4/ACCORD 11) 1 and 
gemcitabine/nab-Paclitaxel (MPACT trial) 2 treatments in 2011 and 2013, respectively, 
changing the PCA management paradigm with a median overall survival (OS), at best, 
reaching 11.1 months. Despite these advances, there is a continuous need to improve 
survival through the investigation of molecularly targeted agents. 
  
Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)-mediated 
signaling and angiogenesis contribute to the pathogenesis and progression of PCA. 3,4 VEGF 
is expressed in all PCA tumors. 5 VEGF-A/VEGFR-2 signaling plays an important role in 
inducing invasion and migration of PCA cells. 6,7 VEGFR-2 and phosphorylated-VEGFR-2 
(pVEGFR-2) are expressed in 69% and 50% of 107 PCA. The pVEGFR-2 is significantly 
associated with invasion of the anterior capsule of pancreas and arteries. It is proposed that 
the expression of these receptors is an important predictive and prognostic factor in PCA 
treatment. 6,8 
 
Results from anti-angiogenic agents studied in advanced PCA failed to significantly improve 
primary outcomes. The use of bevacizumab was evaluated in the AViTA Trial (Addition of 
bevacizumab to gemcitabine and erlotinib) and the reported negative primary outcome (OS). 
9 Another phase III trial with gemcitabine and bevacizumab (10 mg/kg) combination 
compared to gemcitabine alone (CALGB 80303) proved same outcomes (P= 0.95). 10 
Axitinib, in a phase III trial, compared gemcitabine/Axitinib to gemcitabine alone in the 
same setting, and yielded no significant difference in overall survival (OS). 11 Interestingly, 
and challenging the findings from single agent backbone studies, the combination of 
gemcitabine and a fluoropyrimidine (5FU or capecitabine) with bevacizumab reached their 
primary endpoints in two separate single arm phase II trials. 4,12 Additionally, a pooled 
analysis of 300 subjects enrolled in all single arm phase II trials utilizing gemcitabine-based 
doublets with bevacizumab proved survival advantage compared to historical controls. 13 
These studies demonstrate the feasibility of building upon more intensive chemotherapy 
backbones, specifically those including a fluoropyrimidine with bevacizumab combinations 
in PCA.  
 
As suggested above, the choice of a chemotherapeutic backbone may impact the efficacy of 
anti-angiogenic therapy in PCA. In a preclinical study, the anti-tumor activity of 
fluoropyrimidines but not that of gemcitabine caused the release of bone marrow derived 
circulating endothelial progenitor cells (CEPs) and Tie-2 expressing monocytes (TEMs) as 
well as the induction of pro-angiogenic growth factors. Anti-angiogenic agents inhibit the 
CEP and TEM mobilization and pro-angiogenic signaling and thus enhance significantly the 
anti-tumor activity of fluoropyrimidines but not that of gemcitabine. 14 Additionally, 
gemcitabine-induced myelosuppression in subjects with PCA was found to interfere with the 
mobilization of pro-angiogenic cell types targeted by bevacizumab and may further 
counteract anti-angiogenic therapy by substantially reducing the angiogenesis inhibitor TSP-
1. 15 These findings may explain why gemcitabine does not elicit TEM and CEP recruitment 
and may therefore lack synergy with anti-VEGF agents. This phenomenon is not known to 


 
 
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occur with fluoropyrimidines. FOLFIRINOX, a combination of a fluoropyrimidine, 
oxaliplatin and irinotecan, proved to have a large and significant survival advantage over 
gemcitabine alone in advanced PCA, 1 thus the choice of FOLFIRINOX combination in our 
proposed trial. The AViTA Trial (Addition of bevacizumab to gemcitabine and erlotinib) 
suggests that a subset of PCA subjects with elevated VEGF-A or VEGFR-2 levels may 
benefit from bevacizumab. 9,16 
 
1.2 
Ramucirumab Clinical Experience 
Ramucirumab (RAM) (IMC-1121B, trade name Cyramza) is a fully human monoclonal 
antibody (IgG1) directed mainly against VEGFR-2. RAM also blocks binding of VEGFR 
ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, RAM inhibits ligand-stimulated 
activation of VEGFR-2, thereby inhibiting ligand-induced proliferation, and migration of 
human endothelial cells. RAM received its first global approval by the FDA on April 21, 
2014 as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-
esophageal junction (GEJ) adenocarcinoma subjects who experience disease progression on 
or after 5FU- or platinum-containing chemotherapy. This approval was granted following 
the results of the REGARD trial, which compared RAM, as a single agent, to placebo in 
second line treatment of gastric and GEJ adenocarcinomas. 17 RAM had significant OS 
benefit when combined to paclitaxel in advanced/metastatic gastric and GEJ 
adenocarcinoma in the second line setting (RAINBOW trial). 17,18 These results have shifted 
the treatment paradigm in the treatment of gastric and GEJ cancers despite the initial 
disappointments with phase II trials utilizing another anti-angiogenic agent, bevacizumab. 19-
22 These negative results were reflected in the international, randomized phase III 
AVAGAST (Avastin for Advanced Gastric Cancer) study, in which 774 subjects with 
advanced gastric or GEJ adenocarcinoma were randomized to a cisplatin/capecitabine with 
bevacizumab or placebo. 23 Given these opposing results between bevacizumab and RAM in 
gastric and GEJ cancers, it is becoming clearer that blocking VEGFR-2 (RAM) has a likely 
advantage over blocking VEGF-A (bevacizumab). More recently, the RAISE trial 
demonstrated the benefit of using ramucirumab in the setting of metastatic colorectal cancer. 
This trial compared ramucirumab versus placebo in combination with FOLFIRI in the 
second line setting for subjects with metastatic colorectal carcinoma. In this study, 536 
subjects were assigned to each arm and ramucirumab plus FOLFIRI significantly improved 
OS with a manageable side effect profile.24 
 
Currently there are no validated predictive biomarkers for selecting which cancer subjects 
will benefit from anti-angiogenic therapy.25 Albumin has shown to play a role as a 
prognostic factor in advanced stage bevacizumab treated PCA subjects. A pooled analysis of 
7 prospective trials showed that normal albumin levels (>3.4 g/dL) were associated with 
significantly improved median OS (10.2 months vs. 4.1 months; P=0.0001), median time to 
tumor progression (TTP) of 6.2 vs. 3.7 months (P=0.0488), and disease control rate (71% vs. 
46%; P=0.007) for subjects receiving bevacizumab, but not for those treated without 
bevacizumab. 26  
 
 
 
 
 


 
 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Estimate and compare PFS of mFOLFIRINOX plus ramucirumab (RAM) versus 
mFOLFIRINOX plus placebo in subjects with recurrent or metastatic pancreas cancer 
(PCA) who present for first line chemotherapy treatment. 
 
2.1.2 Secondary Objectives 
• Estimate and compare the median overall survival (mOS) in each arm. 
• Evaluate and compare the response rate (RR) in each arm. 
• Evaluate and compare the toxicities in each arm. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
Nine month PFS is based upon the time of registration until progression or death. Disease is 
evaluated by CT/MRI scans of the organ(s) with the target lesion(s) based on RECIST 1.1 
criteria. 
 
2.2.2 Secondary Endpoints 
• Median overall survival (mOS) will be measured using the Kaplan-Meier method. 
• Response rate (RR) will be evaluated per RECIST 1.1 
• Toxicity evaluation will be assessed per CTCAE v4 
 
3. 
ELIGIBILITY CRITERIA 
Each of the criteria in the checklist that follows must be met in order for a subject to be 
considered eligible for this study.  
 
3.1 
Inclusion Criteria 
1. Written informed consent and HIPAA authorization for release of personal health 
information. NOTE:  HIPAA authorization may be included in the informed consent 
or obtained separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status of 0-1 within 7 days prior to registration. 
4. Histologic or cytological diagnosis of recurrent or metastatic pancreas 
adenocarcinoma (PCA) who present for first line chemotherapy treatment.  
5. No prior first line systemic treatment (prior adjuvant or neoadjuvant treatment is 
permitted). Subjects whose disease has progressed after 6 months of last systemic 
chemotherapy or chemo-radiation in the adjuvant or neoadjuvant setting are eligible. 
6. Measurable disease determined using guidelines of RECIST 1.1. Baseline tumor 
assessment should be performed using high resolution CT scans or MRI. 
7. Urine protein < 1+ on dipstick test or routine urinalysis. If the proteinuria on these 
tests is ≥ 2+, then a 24-hour urine test must be collected and must demonstrate < 1 g 
protein in 24 hours to allow participation 


 
 
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8. Estimated life expectancy of > 12 weeks, as assessed by the site investigator. 
9. If sexually active, must be postmenopausal, surgically sterile, or using effective 
contraception (hormonal or barrier methods) due to unknown risk of teratogenicity of 
ramucirumab  
10. Demonstrate adequate organ function as defined in Table 1 below; all screening labs 
to be obtained within 7 days prior to registration. Include additional labs or remove 
as needed below and ensure they are included in the Study Calendar and Evaluations 
Section 
 
Table 1: Organ Function Requirements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1: If serum creatinine is >1.5 times the ULN, a 24-hour urine collection to 
calculate creatinine clearance must be performed. 
 
3.2 
Exclusion Criteria 
1. Subjects with histology other than adenocarcinoma; Examples include: 
neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas 
2. Ongoing or active infection 
3. Symptomatic congestive heart failure, unstable angina pectoris, symptomatic or 
poorly controlled cardiac arrhythmia.  Symptomatic heart failure (NYHA Class II-
IV)  
System 
Laboratory Value 
Hematological 
Hemoglobin 
≥ 9 g/dL 
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count (PLT) 
≥ 100,000/mm3 
Renal 
Creatinine or 
Creatinine clearance1 
≤ 1.5 mg/dL 
≥ 40 mL/min 
Albumin 
≥ 2.5 g/dL 
Hepatic 
Bilirubin 
≤ 1.5  mg/dL 
Aspartate aminotransferase (AST) 
≤ 3 × ULN 
or < 5 x ULN in the setting 
of liver metastases 
Alanine aminotransferase (ALT) 
≤ 3 × ULN 
or < 5 x ULN in the setting 
of liver metastases 
Coagulation 
International Normalized Ratio (INR)   
 
Patients receiving warfarin must be 
switched to low molecular weight 
heparin and have achieved stable 
coagulation profile prior to first dose 
of protocol therapy   
The subject has adequate 
coagulation function as 
defined by International 
Normalized Ratio (INR) 
≤1.5 and a partial 
thromboplastin time (PTT) 
(PTT/aPTT) < 1.5 x 
ULN.).  
 


 
 
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4. Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 
mmHg diastolic for >4 weeks) despite standard medical management. 
5. Acute or sub-acute intestinal obstruction 
6. Interstitial pneumonia or interstitial fibrosis of the lung, which in the opinion of the 
site investigator could compromise the subject or the study 
7. Pleural effusion or ascites that causes > grade 1 dyspnea 
8. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) with a 
history of hepatic encephalopathy or clinical meaningful ascites resulting from 
cirrhosis; clinically meaningful ascites is defined as ascites resulting from cirrhosis 
and requiring ongoing treatment with diuretics and/or paracentesis 
9. Grade 3 or higher bleeding event ≤ 3 months prior to randomization. 
10. Experience of any arterial thrombotic or arterial thromboembolic events, including, 
but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular 
accident, ≤ 6 months prior to randomization. 
11. History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous 
thrombosis are not considered “significant”) during the 3 months prior to 
randomization. 
12. GI perforation/fistula 
13. Documented and/or symptomatic or known brain or leptomeningeal metastases.  
14. Severely immune-compromised (other than being on steroids) including known HIV 
infection 
15. Concurrent active malignancy, other than adequately treated non-melanoma skin 
cancer, other noninvasive carcinoma, or in situ neoplasm. A subject with previous 
history of malignancy is eligible, provided that he/she has been disease-free for > 3 
years. 
16. Breast-feeding or pregnant.  Serum pregnancy test for women of child-bearing 
potential must be performed within 7 days prior to first dose of study treatment 
17. Prior autologous or allogeneic organ or tissue transplantation. 
18. Known allergy to any of the treatment components 
19. The patient has undergone major surgery within 28 days prior to first dose of 
protocol therapy, or minor surgery/subcutaneous venous access device placement 
within 2 days prior to first dose of protocol therapy.  The patient has elective or 
planned major surgery to be performed during the course of the clinical trial. 
20. Have any condition that does not permit compliance with the study schedule 
including psychological, geographical, or medical. 
21. Receiving medications that can effect clotting ability: warfarin, aspirin (once-daily 
aspirin use- maximum dose 325 mg/day is permitted), nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), 
dipyridamole or clopidogrel, or similar agents.  
22. The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 
days prior to first dose of protocol therapy. 
 
 
 


 
 
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4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN electronic data capture (EDC) system. A 
subject is considered registered when an “On Study” date is entered into the EDC system. 
 
Subjects must be registered and randomized prior to starting protocol therapy. Subjects must 
be randomized within one business day of registration and begin therapy within 5 business 
days of randomization.  
 
4.1 
Blinding 
Site pharmacy staff and HCRN EDC administrative team will be unblinded to the study 
treatment. Subjects, site investigators, site analysis teams, and other site personnel will be 
blinded to the study treatment.  
 
Unblinding of site personnel may occur for emergency purposes only. Site investigators 
should note that the occurrence of a serious adverse event or progressive disease should not 
routinely precipitate the immediate unblinding of the label.  The site investigator will 
contact HCRN to unblind a subject.  If this is not feasible, HCRN must be notified within 24 
hours of unblinding. 
 
In compliance with applicable regulations, in the event of a serious adverse event (SAE), the 
subject’s treatment assignment may be unblinded before reporting to the health authorities, 
ethic committees, and site investigators if the SAE was related (possibly, probably, 
definitely) to the blinded treatment. 
 
5. 
TREATMENT PLAN 
 
5.1 
Treatment Regimen 
One cycle will be equal to 28 days. The ramucirumab/placebo will be administered prior to 
the mFOLFIRINOX regimen.  Both arms will receive mFOLFIRINOX regimen given per 
institutional standards (suggested administration sequence below), which will be a 
modification of the previously published regimen. 27 mFOLFIRINOX will be administered 
every 2 weeks. Dose modifications for all medications are outlined in Section 6: 
• Arm A will receive ramucirumab administered as an intravenous infusion over 60 
minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg 
every 2 weeks.  
• Arm B will receive a placebo infusion. Due to the double-blinded nature of this study, 
the volume of placebo will be calculated as if it were ramucirumab.  
• Oxaliplatin 85 mg/m2 over 2-4 hours 
• Irinotecan 165 mg/m2 over 90 minutes 
• 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to 
decrease the risk of neutropenia.  
 
Leucovorin is not included in this regimen since the 5-FU is administered as a continuous 
infusion and not in bolus form. 
 


 
 
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5.2 
Pre-medications and Home Medications 
 
5.2.1 Pre-medications 
The following medications will be administered: 
• Palonosetron 250 mcg IV within 30 minutes prior to oxaliplatin and 5-FU 
• Dexamethasone 20 mg IV or PO within 30 minutes prior to oxaliplatin and 5-FU 
• Atropine 0.4 mg IV within 30 minutes prior to Irinotecan. May repeat 1 dose for 
cramping or diarrhea. 
• Diphenhydramine 50 mg IV within 30 minutes prior to ramucirumab/placebo. 
 
5.2.2 Home Medications 
The following are suggested medications to be provided to the subject to take home: 
• Prochlorperazine 10 mg PO every 6 hours PRN nausea/vomiting. 
• Loperamide PRN diarrhea. Subject will be instructed to take 4 mg PO at onset of 
diarrhea, followed by 2 mg PO every 2 hours (or 4 mg every 4 hours at night) until 
12 hours have passed without a bowel movement. 
 
5.3 
Drug Administration 
 
Table 2. Drug Administration 
Drug 
Dose 
Frequency of 
administration 
Route of administration 
Ramucirumab 
or Placebo 
8 mg/kg 
Every 2 weeks 
IV; infusion rate should 
not exceed 25 mg/min 
Oxaliplatin 
85 mg/m2 
Every 2 weeks 
IV over 2 to 4 hrs 
Irinotecan 
165 mg/m2 
Every 2 weeks 
IV over 90 min 
5-FU 
2,400 mg/m2 
Every 2 weeks 
IV 46-hour continuous 
infusion 
Body surface area and drug doses should be recalculated for subject’s whose weight changes by ≥ 
10% during the course of the study. 
 
Leucovorin is not included in this regimen since the 5-FU is administered as a continuous infusion 
and not in bolus form.   
 
5.3.1 Missed Doses 
All medications are given on Day 1. A missed dose implies delay of that cycle. Infusions 
may be given within 3 days for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc. It should be clearly documented in subject’s chart and case report 
forms. 
 
 
 


 
 
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5.4 
Supportive Care 
Subjects should receive full supportive care in accordance with ASCO or equivalent 
guidelines on supportive care for solid tumors, if necessary. Supportive care measures may 
include but are not limited to anti-diarrheal agents, anti-emetic agents, opiate and non-opiate 
analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors. Subjects 
will receive supportive care as judged by their treating physician. If it is unclear whether a 
therapy should be regarded as supportive care, the site investigator should consult with 
HCRN. Use of any supportive care therapy should be reported on the eCRFs.  
 
5.4.1 Analgesic agents 
The use of analgesic agents during the study is permitted at the discretion of the site 
investigator.  The subject is receiving chronic antiplatelet therapy, including aspirin, 
nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), 
dipyridamole or clopidogrel, or similar agents will be excluded. Once-daily aspirin use 
(maximum dose 325 mg/day) is permitted. Chronic use of analgesic agents with no or low 
bleeding risk (for example acetaminophen) is acceptable.  See exclusion criteria above for 
additional information. 
 
5.4.2 Antiemetic therapy 
The use of antiemetic agents is permitted during this study and at the discretion of the site 
investigator. However, it is recommended to follow the guidelines of the Multinational 
Association of Supportive Care in Cancer (MASCC) and ASCO.  
 
5.4.3 Appetite Stimulants 
 The use of appetite stimulants is permitted at the discretion of the site investigator. 
 
5.4.4 Blood Product Transfusions 
Transfusions of red blood cells, platelets or other blood products are permitted at the site 
investigators discretion during the conduct of the study. 
 
5.4.5 Treatment of Diarrhea 
In the event of diarrhea, the following supportive measures are strongly recommended: 
 
Subjects should be advised to drink at least 3 L of fluids per day. Frequent small meals are 
recommended. 
 
Upon the subject experiencing the first episode of a loose stool, the subject should take an 
initial dose of loperamide 2 capsules (4 mg) by mouth, then l capsule (2 mg) by mouth every 
2 hours or 2 capsules every 4 hours overnight for at least 12 hours after the first liquid stool 
and up to 12 hours after the last liquid stool without exceeding total treatment duration of 48 
hours. 
 
For uncomplicated Grade 1 or 2 diarrhea that does not resolve after 24 hours, start a broad 
spectrum antibiotic such as a fluoroquinolone for a 7-day course. After 48 hours of 
unresolved uncomplicated Grade 1 or 2 diarrhea the subject should stop loperamide and be 
evaluated in the out subject setting with a stool workup, complete blood count (CBC) and 


 
 
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replacement of fluids and electrolytes as clinically indicated. A second-line agent, such as 
octreotide, should then be considered. 
 
Octreotide has been shown to be effective in the control of diarrhea induced by 
fluoropyrimidine-based chemotherapy regimens when administered as an escalating dose by 
continuous infusion or subcutaneous injection. Octreotide can be administered at doses 
starting from 100 mcg 3 times daily and escalating to 500 mcg 3 times daily. 
 
Subjects should be admitted to the hospital whenever they present with Grade 3 or 4 
diarrhea, or when they have complicated Grade 1 or 2 diarrhea, defined as having diarrhea 
plus one or more of the following symptoms: cramping, nausea/vomiting grade ≥ 2, 
decreased performance status, fever, sepsis, neutropenia, frank bleeding or dehydration. If 
the subject is already on loperamide, it should be stopped, and the subject should be started 
on octreotide, intravenous fluids and undergo a stool workup CBC and electrolyte 
evaluation, with repletion as clinically indicated. In addition, if the subject is febrile or has 
an ANC < 500 a broad-spectrum antibiotic should be started for at least 7 days and until the 
resolution of fever and an ANC ≥ 1000. Events that require a subject to be hospitalized are 
considered SAEs. 
 
It is imperative that subjects have access to loperamide for home use prior to the start of 
each cycle. In addition, subjects should receive oral and written information about the risk 
for diarrhea, associated symptoms and instructions on how to manage diarrhea. This 
includes the need for oral hydration, when and how to take medications, when to notify the 
site physician and when to report to the hospital for further treatment. These 
recommendations have been adapted from the ASCO guidelines (Benson et al. 2004) 
 
5.4.6 Erythroid Growth Factors 
The use of erythroid-stimulating factors is permitted at the discretion of the site investigator 
based on ASCO and FDA guidelines (FDA 2009; Rizzo et al.2010) or according to local 
guidelines. 
 
5.4.7 Therapy for Febrile Neutropenia 
Subjects experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of 
intravenous antibiotic therapy.  
 
5.4.8 Granulocyte Colony-Stimulating Factors 
The use of granulocyte-colony stimulating factor (G-CSF) or similar agents is permitted 
during this study, at the discretion of the site investigator based on local guidelines or ASCO 
(Smith et al. 2006), European Society for Medical Oncology (Crawford et al. 2009). Note 
that prophylactic use of G-CSF or similar agents is also permitted. 
 
5.4.9 Hand-Foot Syndrome 
Also called palmar-plantar erythrodysesthesia is a side effect of some types of 
chemotherapy. Treatment with pyridoxine (B6) at a dose of 100 to 150 mg per day is 
allowed. 


 
 
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5.4.10 Hypersensitivity Reactions 
Premedication for ramucirumab/placebo administration: H1 antagonist (for example, 
diphenhydramine hydrochloride) intravenously. Additional premedication and treatment 
may be provided at site investigator discretion. All premedication administered must be 
adequately documented in the eCRF. 
 
Premedication after first episode of grade 1 or 2 infusion-related reaction: Subjects should 
be premedicated within 30 minutes prior to infusion with antihistamines, corticosteroids, 
acetaminophen, etc.   
 
Treatment for second episode of grade 1 or 2 infusion-related reaction: administer 
dexamethasone 8 to 10 mg I.V. (or equivalent). For subsequent infusions pre-medicate with 
diphenhydramine hydrochloride 50 mg I.V. (or equivalent), acetaminophen 650 mg orally 
and dexamethasone 8 to 10 mg I.V. (or equivalent).  Reduce the ramucirumab infusion rate 
by 50% for the duration of the infusion and all subsequent infusions if the patient 
experiences a Grade 1 or 2 IRR (per NCI-CTCAE). 
 
Treatment for grade 3 or 4 infusion-related reaction: Subjects should be treated with 
epinephrine, bronchodilators and/or glucocorticoids for symptomatic bronchospasm and I.V. 
fluids and/or pressors for hypotension.  Subjects with grade 3 or 4 infusion reaction must not 
receive further treatment with ramucirumab. 
 
5.4.11 Contraception 
Ramucirumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
ramucirumab has transient adverse effects on the composition of sperm. Subjects should 
start using birth control from time of consent throughout the study period up to 90 days after 
the last dose of study therapy. 
 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period. If there is any question that a subject 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
 
5.5 
Treatment Compliance 
Ramucirumab/placebo, 5-FU, Irinotecan, oxaliplatin will be administered only at HCRN 
sites by the authorized study personnel. As a result, treatment compliance is ensured. 
 


 
 
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5.6 
Concurrent Therapy 
Additional concurrent chemotherapy or radiation therapy, biologic response modifiers, or 
other investigational agents may not be administered to subjects on this study. However, 
palliative radiation during the study is allowed if clinically indicated. 
 
5.7 
Concomitant Medications 
Medications allowed:  
• Medications required for supportive care during the study (See Section 5.4)  
• Medications subject requires for treatment of previous comorbidities. 
 
6. 
Toxicity Monitoring and Dose Modifications  
The NCI Common Terminology Criteria for Adverse Events CTCAE v4 will be used to 
grade adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation at each study visit for the 
duration of their participation in the study.  
 
6.1 
Dose Modifications for Ramucirumab/placebo  
Ramucirumab/placebo will be held for Grade ≥ 3 study drug related adverse events until 
recovery to Grade ≤ 1 and then resume with a dose reduction (level -1; 6 mg/kg) if site 
investigator evaluation relates toxicity to ramucirumab/placebo. If a second Grade ≥ 3 drug 
related adverse event is experienced and does not resolve within 2 weeks of the initial dose 
reduction, an additional dose reduction (level -2; 5mg/kg) will be made.  If Grade ≥ 3 related 
adverse event does not resolve within 2 weeks of the second dose reduction, the subject will 
be taken off the trial.  
 
Table 3. Modified dose of ramucirumab 
Dose level 
Ramucirumab 
Starting dose 
8 mg/kg 
Level -1 dose reduction 
6 mg/kg 
Level -2 dose reduction 
5 mg/kg 
 
 
 


 
 
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Table 4. Dosing level of ramucirumab/placebo for treatment related adverse events 
Toxicity NCI 
Grade (value)  
Worst Interval Toxicity  
Day of Treatment  
1 
Maintain dose level 
Continue treatment per protocol 
schedule. 
2 
Maintain dose level 
Hold until resolved to grade 1 or 
less. 
3 
Reduce to dose level -1 
6 mg/kg 
Hold until resolved to grade 1 or 
less. 
4  
Reduce to dose level -2 
5 mg/kg 
Hold until resolved to grade 1 or 
less. 
 
6.1.1 Management of Hypertension  
Interrupt ramucirumab/placebo for severe hypertension until controlled with medical 
management. Permanently discontinue ramucirumab/placebo for severe hypertension that 
cannot be controlled with antihypertensive therapy.  The subject will continue to be 
followed per guidelines in Section 7. Subjects with grade 4 hypertension must not receive 
further treatment with ramucirumab 
 
6.1.2 Proteinuria  
Interrupt ramucirumab/placebo for urine protein levels ≥ 2 g/24 hours. Reinitiate treatment 
at a dose level -1 reduction (see Table 3) once the urine protein level returns to <2 g/24 
hours. If the protein level ≥ 2 g/24 hours reoccurs, interrupt ramucirumab/placebo and 
reduce the dose to dose level -2 (table 4) once the urine protein level returns to < 2 g/24 
hours.  Permanently discontinue ramucirumab if there is a third occurrence of > 2 g/24 
hours, or if the protein level does not return to < 2 g/24 hours within 2 weeks. Permanently 
discontinue ramucirumab/placebo for urine protein level >3 g/24 hours or in the setting of 
nephrotic syndrome  
 
6.1.3  Wound Healing Complications  
Interrupt ramucirumab/placebo prior to scheduled surgery until the wound is fully healed  
 
6.1.4  Thyroid Dysfunction 
Monitor thyroid function during treatment with ramucirumab. In Study 4, the incidence of 
hypothyroidism reported as an adverse event was 2.6% in the ramucirumab plus FOLFIRI 
treated subjects and 0.9% in the placebo plus FOLFIRI treated subjects.  
 
6.1.5 Venous Thromboembolic Events 
Ramucirumab therapy should be discontinued in the event of any Grade 3/4 VTE that is 
considered by the site investigator to be life threatening, or symptomatic and not adequately 
treated by anticoagulation therapy. Patients with unresected primary tumors (or local 
recurrence) who develop Grade 3 and 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. Ramucirumab should 


 
 
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also be discontinued in the setting of a deep vein thrombosis or pulmonary embolism that 
occurs or intensifies while the patient is receiving therapeutic anticoagulation therapy.  Any 
venous event leading to discontinuation of ramucirumab therapy will be considered serious 
and should be reported via the serious adverse event (SAE) mechanism. 
 
6.1.6 Conditions for permanent discontinuation of ramucirumab/placebo 
Listed below are clinical conditions in which ramucirumab/placebo should be permanently 
discontinued.   
• Grade 3 and 4 arterial thromboembolic events, or any PE/DVT occurring or 
worsening during anticoagulant therapy. Any arterial event leading to 
discontinuation of ramucirumab therapy will be considered serious and should be 
reported via the serious adverse event (SAE) mechanism. 
• Subjects with Grade 4 hypertension must not receive further treatment with 
ramucirumab 
• Gastrointestinal Perforation 
• Grade 3 or 4 Bleeding  
• Grade 3 or 4 Infusion Reaction  
• Hepatic encephalopathy or other serious signs of liver impairment such as 
hepatorenal syndrome  
• Fistula Formation  
• Reversible Posterior Leukoencephalopathy (RPLS); All cases of RPLS must be 
reported via the SAE reporting guidelines. 
 
6.2 
Dose Modification for mFOLFIRINOX 
Toxicities to 5-Fluorouracil (5-FU), oxaliplatin and irinotecan may include hematologic and 
non-hematologic events. The dose adjustment of 5-Fluorouracil, oxaliplatin, and irinotecan 
for hematologic toxicity is shown in Table 5. 
 
Table 5: Modified dosing of the mFOLFIRINOX combination 
Dose level 
Oxaliplatin 
Irinotecan 
5-FU Infusion 
Starting dose 
85 mg/m2 
165 mg/m2 
2400 mg/m2 
First dose 
reduction 
50 mg/m2 
150 mg/m2 
1800 mg/m2 
Second dose 
reduction 
40 mg/m2 
127 mg/m2 
1200 mg/m2 
 
6.2.1 Dose Modifications of mFOLFIRINOX for Hematologic Toxicity 
Dose adjustments of oxaliplatin, irinotecan and 5-FU on subsequent treatment cycles, will 
be based on the worst hematologic toxicity due to any of the chemotherapy agents on any 
day of the previous cycle. See Table 6. 
 
 
 


 
 
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Table 6: Dosing level of Oxaliplatin, Irinotecan and 5-FU for hematologic toxicity 
Toxicity NCI Grade (value) 
Worst Interval Toxicity 
Day of Treatment 
Neutropenia  
Grade 1 (ANC< LLN-1500/mm3) 
Grade 2 (ANC<1499-1000/ mm3) 
Grade 3 (ANC<999-500/ mm3) 
Grade 4 (ANC<500/ mm3)  
 
G1 Maintain dose level  
G2 Maintain dose level  
G3 Maintain dose level  
G4 Reduce 5-FU, oxaliplatin 
and irinotecan 1 dose level  
 
If ANC < 1000 mm3 on 
day of treatment, hold and 
check weekly until >1000 
mm3. Then treat based on 
interval toxicity  
Thrombocytopenia  
Grade 1 (PLT < 75,000/mm3)  
Grade 2 (PLT 74,999-50,000/mm3) 
Grade 3 (PLT 49,999-25,000/mm3)  
Grade 4 (PLT<25,000/ mm3)  
 
G1 Maintain dose level  
G2 Maintain dose level  
G3 Reduce 5-FU, oxaliplatin, 
irinotecan 1 dose level  
G4 Reduce 5-FU, oxaliplatin 
and irinotecan 1 dose level  
 
If PLT < 75,000 on day of 
treatment, hold and check 
weekly until > 75,000. 
Then treat based on 
interval toxicity  
Recommend red cell transfusion for hemoglobin < 8 g/dL, no dose adjustment required. 
 
6.2.2  Dose Modifications for Other Treatment Related Non-Hematological Toxicity 
Dose adjustments of oxaliplatin, irinotecan and 5-FU on subsequent treatment cycles will be 
based on the worst non-hematologic toxicity due to any of the chemotherapy agents on any 
day of the previous cycle. If neurologic toxicity appears, only oxaliplatin dose should be 
modified. See Table 7 for all non-hematologic toxicities except neurologic toxicity and 
Table 8 for neurologic toxicity.  
 
Table 7: Dosing level of Oxaliplatin, Irinotecan, and 5-FU for non-hematologic toxicity 
(except diarrhea and neurologic toxicity) 
Toxicity NCI Grade  
Worst Interval Toxicity 
Day of Treatment 
Non-Hematologic Toxicity 
(Except diarrhea and 
neurologic toxicity)  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
G1: Maintain dose level  
G2: Maintain dose level  
G3: Reduce irinotecan, 5-FU 
and/or oxaliplatin 1 dose 
level.  
G4: Reduce irinotecan, 5-FU 
and/or oxaliplatin 1 dose 
level.  
G1: Continue treatment per 
protocol schedule. 
G2: Hold until resolved to grade 
1 or less.  
G3: Hold until resolved to grade 
1 or less.  
G4: Hold until resolved to grade 
1 or less. 
Toxicity NCI Grade  
Worst Interval Toxicity 
Day of Treatment 
Diarrhea  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
G1: Maintain dose level  
G2: Reduce 5-FU, 
oxaliplatin, irinotecan 1 dose 
level  
G3: Reduce 5-FU, 
oxaliplatin, irinotecan 1 dose 
level  
G4: Reduce 5-FU, 
oxaliplatin, irinotecan 1 dose 
level  
Hold chemotherapy if any grade 
of diarrhea above baseline is 
present with the subject not 
taking anti-diarrheal agents 
within 24 hours of treatment. 
Decrease irinotecan and 
oxaliplatin 1 dose level upon 
resolution of diarrhea. If diarrhea 
has not resolved within 2 weeks 
of scheduled treatment day, 
discontinue therapy.  
 


 
 
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Table 8. Modified dosing of oxaliplatin for neurologic toxicity. 
Toxicity 
Duration of Toxicity 
Parasthesia/dysesthesia 
1-7 Days  
> 7 Days  
Persistent 
Between 
Doses  
Grade 1  
Short duration that 
resolves and does not 
interfere with function  
No change  
No change  
No change  
Grade 2  
Interferes with function 
but not activities of 
daily living (ADL)  
No change  
No change  
Reduce 
oxaliplatin  
1 dose level  
Grade 3  
With pain or with 
functional impairment 
that also interferes with 
ADL  
1st time: reduce 1 dose level 
2nd time: reduce another 
dose level  
1st time: reduce 1 dose level  
2nd time: reduce another 
dose level  
Discontinue 
oxaliplatin  
Grade 4  
Persistent symptoms 
that are disabling or 
life-threatening  
Discontinue oxaliplatin  
Discontinue oxaliplatin  
Discontinue 
oxaliplatin  
 
6.3 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities, a subject will also be 
discontinued from protocol therapy and followed up per protocol under the following 
circumstances: 
• Evidence of disease progression  
• The site physician thinks a change of therapy would be in the best interest of the subject 
• The subject requests to discontinue protocol therapy, whether due to unacceptable 
toxicity or for other reasons 
o In case a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if she or he may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
• 
A female subject becomes pregnant  
• If protocol therapy is interrupted for ≥ 30 days.  
 
6.4 
Study Withdrawal 
If a subject decides to withdraw from the study (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. 
The site investigator should contact the subject or a responsible relative by telephone or 
through a personal visit to establish as completely as possible the reason for the study 
withdrawal. A complete final evaluation at the time of the subject’s study withdrawal should 
be made with an explanation of why the subject is withdrawing from the study. If the reason 
for removal of a subject from the study is an adverse event, it will be recorded on the eCRF. 
 


 
 
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7. STUDY CALENDAR & EVALUATIONS 
 
CYCLE = 28 DAYS 
Examination 
 
Screening 
Cycle 1–2 
Cycle 3–4 
Cycle 5+ 
End of 
Treatment 
Visit 
Follow 
up 
Within 28 
days of 
registration 
Day 1 
(±7) 
Day 15 
(±3) 
Day 1 
(±3) 
Day 15 
(±3) 
Day 1 
(±3) 
Day 15 
(±3) 
30 days   
(± 7) 
after last dose 
of study drug 
 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Demographics and Medical History/Height 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and ECOG PS1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Metabolic Panel2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Magnesium and uric acid 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with Differential and platelet3 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT, PTT, INR11 
X 
 
 
 
 
 
 
 
 
CA19-94 
X 
X 
 
X 
 
X 
 
 
 
Pregnancy Test (Urine or Serum β-HCG)5 
X 
 
 
 
 
 
 
 
 
Urinalysis6 
X 
X 
 
X 
 
X 
 
 
 
AEs and Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function (TSH, total T3, free T4)10 
X 
 
X 
 
X 
 
X 
 
 
Diagnosis Confirmation7 
X 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
CT or MRI of Chest, Abdomen and Pelvis8 
X 
 
 
X 
 
X 
 
X 
X9 
TREATMENT 
 
 
 
 
 
 
 
 
 
mFOLFIRINOX every 2 weeks 
 
X 
X 
X 
X 
X 
X 
 
 
Ramucirumab/placebo every 2 weeks 
 
X 
X 
X 
X 
X 
X 
 
 
FOLLOW-UP 
 
 
 
 
 
 
 
 
 
For progression, start of additional cancer 
treatment, and survival9 
 
 
 
 
 
 
 
 
X9 
 
 
 


 
 
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1: Vital signs to include blood pressure, weight, height (screen only) and ECOG performance status. 
 
2: CMP to include Sodium, potassium, total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate  
aminotransferase (AST), blood urea nitrogen (BUN), creatinine, calcium, random glucose, albumin 
 
3: CBC to include Hemoglobin, hematocrit, erythrocyte count (RBC), mean cell volume, mean cell hemoglobin concentration, 
leukocytes (WBC), neutrophils, lymphocytes, monocytes, basophils, platelets 
 
4: CA19-9 at screening and every 2 cycles 
 
5: Serum pregnancy test for women of child-bearing potential must be performed within 7 days prior to first dose of study treatment 
 
6: Protein in the urine should be monitored prior to each cycle.  Urine dipstick may be used to quantify the amount if necessary. 
 
7: Confirmation of diagnosis must be obtained during screening.  A pathology report with staging information will be obtained from 
the institution that performed the diagnosis procedure. 
 
8: Scans to be repeated every 8 weeks (± 7 days) until progression of disease. Pre-treatment scans to be performed within 28 days 
prior to registration. 
 
9: For subjects who discontinue study treatment without radiographically documented PD, the investigative sites will continue to 
evaluate tumor response every 8 weeks (± 7 days) by the same method used at baseline and throughout the study until time of disease 
progression, death or until study completion, except when not feasible in the opinion of the site investigator due to subject's clinical 
status.  After the subject has documented PD, radiologic assessments are no longer required and the subject will be followed every 8 
weeks (± 7 days) until the subject's death or study completion, whichever is earlier. 
 
10: If the TSH is abnormal, a total T3 and free T4 should be ordered.  
 
11: Coagulation tests should be periodically repeated during the course of the study per site investigator discretion. 
 


 
 
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7.1 
Screening 
 
7.1.1 Within 28 Days Prior to Registration for Protocol Therapy: 
 
The following should be collected before registration for protocol therapy:  
• Prior to the subject being registered to the study, confirmation of diagnosis must 
be obtained via pathology report including staging information. 
• Medical history and Height 
• Physical examination 
• Vitals Signs (including blood pressure), Weight [kg] and ECOG PS 
• Laboratory Testing: 
o CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), 
mean cell volume, mean cell hemoglobin concentration, leukocytes (WBC), 
neutrophils, lymphocytes, monocytes, basophils, platelets. 
o CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen (BUN), creatinine, calcium, random glucose, albumin  
o Magnesium and uric acid 
o Coagulation tests: PT, INR and PTT; coagulation tests should be periodically 
repeated during the course of the study per site investigator discretion. 
o CA 19-9  
o Thyroid function (TSH, total T3, free T4).  If the TSH is abnormal, a total T3 
and free T4 should be ordered. 
o Serum pregnancy test for women of child-bearing potential must be 
performed within 7 days prior to first dose of study treatment  
o Urinalysis including a urine dipstick for protein if quantification needed 
• Radiological assessment (CT or MRI of chest, abdomen, and pelvis) with tumor 
measurements. Pre-treatment scans to be performed within 28 days prior to 
registration. 
 
7.1.2 On Treatment; Day 1 of each cycle 
 
Note: Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
• Physical examination 
• Vitals Signs (including blood pressure), Weight [kg] and ECOG PS 
• Laboratory Testing: 
o CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), 
mean cell volume, mean cell hemoglobin concentration, leukocytes (WBC), 
neutrophils, lymphocytes, monocytes, basophils, platelets. 
o CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen (BUN), creatinine, calcium, random glucose, albumin  
o Magnesium and uric acid 
o CA 19-9 every 2 cycles 
o Urinalysis including a urine dipstick for protein if quantification needed 
• CT or MRI of chest, abdomen/pelvis after every 2 cycles of treatment 
• mFOLFIRINOX and ramucirumab/placebo 


 
 
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7.1.3 On Treatment; Day 15 of each cycle 
• Physical examination 
• Vitals Signs (including blood pressure), Weight [kg] and ECOG PS 
• Laboratory Testing: 
o CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), 
mean cell volume, mean cell hemoglobin concentration, leukocytes (WBC), 
neutrophils, lymphocytes, monocytes, basophils, platelets. 
o CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen (BUN), creatinine, calcium, random glucose, albumin  
o Magnesium and uric acid 
o Thyroid function (TSH, total T3, free T4).  If the TSH is abnormal, a total T3 
and free T4 should be ordered. 
• mFOLFIRINOX and ramucirumab/placebo 
 
7.1.4 Protocol therapy discontinuation: 
A subject will be discontinued from the protocol therapy under the following circumstances: 
• 
Evidence of disease progression (per RECIST 1.1) 
• 
Site physician determines a change of therapy would be in the best interest of the 
subject 
• 
Subject requests to discontinue protocol therapy 
• 
Subject exhibits unacceptable toxicity 
• 
Female subject becomes pregnant  
• 
Protocol therapy is interrupted for ≥ 30 days.  
 
7.1.5 
Safety follow up visit 30 days (±7 days) after last dose of study treatment 
Subjects will be evaluated 30 days (± 7) after the last dose of study drug. Suggested testing 
includes: 
• Physical examination 
• Vitals Signs (including blood pressure), Weight [kg] and ECOG PS 
• Laboratory Testing: 
o CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), mean 
cell volume, mean cell hemoglobin concentration, leukocytes (WBC), 
neutrophils, lymphocytes, monocytes, basophils, platelets. 
o CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen 
(BUN), creatinine, calcium, random glucose, albumin  
o Magnesium and uric acid 
 
7.1.6 Follow-up 
For subjects who discontinue study treatment without radiographically documented PD, the 
investigative sites will continue to evaluate tumor response every 8 weeks by the same 
method used at baseline and throughout the study until time of disease progression, death or 
until study completion, except when not feasible in the opinion of the site investigator due to 
subject's clinical status.  
 


 
 
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After the subject has documented PD, radiologic assessments are no longer required and the 
subject will be followed up every 8 weeks (+/- 7 days) until the subject's death or study 
completion, whichever is earlier. 
 
8. 
CRITERIA FOR DISEASE EVALUATION 
 
8.1 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 28 
 
8.1.1 Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
8.1.2 Measurable lesions  
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). 
 
8.1.3 Non-measurable lesions  
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 subject, these are preferred for selection as target lesions. 
 
8.1.4 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. 
 
8.1.5 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 


 
 
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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. 
 
8.1.6 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. 
 
8.2 
Response Criteria 
 
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 
 
 
 


 
 
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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 
subject 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 
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 sponsor-investigator. 
 
 
Evaluation of best overall response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
 
Not evaluated 
No 
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated 
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


 
 
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In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
8.3 
Definitions for Response Evaluation – RECIST version 1.1 
 
8.3.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.3.2 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria 
are met for complete or partial response (whichever status is recorded first) until the date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since treatment started). 
 
8.3.3 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response 
until the first date that recurrent disease is objectively documented. 
 
8.3.4 Objective response rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR 
according to RECIST v1.1, from the start of treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the 
start of treatment). 
 
8.3.5 Disease Control Rate 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 
weeks, or partial response (PR), or complete response (CR) according to RECIST v1.1, 
from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 
 
8.3.6 Time to Progression 
A measurement from the date of randomization until the criteria for disease progression is 
met as defined by RECIST 1.1. Subjects who have not progressed or have died due to any 
cause will be right-censored at the date of the last disease evaluation or date of death. 
 
8.3.7 Progression Free Survival 
A measurement from the date of randomization until the criteria for disease progression is 
met as defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be 
right-censored at the date of the last disease evaluation. 
 
8.3.8 Overall Survival 
Overall survival is defined by the date of randomization to date of death from any cause. 
 
 
 


 
 
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9. 
DRUG INFORMATION 
 
9.1 
Ramucirumab (Cyramza) 
 
9.1.1 Formulation and Storage  
Ramucirumab is a sterile, preservative-free solution for infusion of ramucirumab formulated 
in an aqueous solution at a concentration of 10 mg/mL (500 mg/50-mL vial). The buffer 
contains 10 mM histidine, 75 mM sodium chloride, 133 mM glycine and 0.01% polysorbate 
80, pH 6.0. 
 
Vials of ramucirumab should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) until 
time of use. The vial should be kept in the outer carton in order to protect from light. For 
product diluted in 0.9% sodium chloride, the chemical and physical stability have been 
demonstrated for up to 24 hours at 2°C to 8°C (36°F to 46°F) or for 4 hours at room 
temperature (below 25°C [77°F]). The diluted product should not be frozen or shaken.  
 
9.1.2 Preparation and Administration  
Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the 
vial, if particulate matter or discolorations are identified. 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. 
• 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 RAM infusion via infusion pump over 60 minutes through a separate 
infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line 
with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.  
 
 
 


 
 
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9.1.3 Dosage Information  
Injection:  
100 mg/10 mL (10 mg per mL) solution, single-dose vial 
500 mg/50 mL (10 mg per mL) solution, single-dose vial  
 
9.1.4 Handling and Disposal 
The vial of ramucirumab should be kept in the outer carton in order to protect from light. 
Neither the vial nor the diluted solution should be frozen or shaken. 
 
9.1.5 Adverse Events 
For a comprehensive list of adverse events please refer to the package insert for 
ramucirumab. 
 
The following are adverse events that have been reported: 
• Cardiovascular: Hypertension, arterial thrombosis. 
• Hematologic: neutropenia, anemia, hemorrhage. 
• Respiratory: Epistaxis 
• Gastrointestinal: Diarrhea (14%), intestinal obstruction (2%) 
• Genitourinary: Proteinuria 
• Endocrine & metabolic: Hyponatremia 
• Central nervous system: Headache. 
• Immunologic: Antibody development. 
• Dermatologic: Skin rash. 
• Miscellaneous: Infusion related reaction 
• Thyroid Dysfunction: Hypothyroidism 2.6% 
 
9.2 
5-Fluorouracil/Adrucil 
 
9.2.1 Formulation and Storage 
Fluorouracil injection is a sterile, nonpyrogenic injectable solution for intravenous 
administration. Each 10 mL contains 500 mg fluorouracil; pH is adjusted to approximately 
9.2 with sodium hydroxide. 
 
Fluorouracil should be stored at room temperature 15° to 30°C (59° to 86°F). Protect from 
light. Retain in carton until time of use. 
 
NOTE: Although fluorouracil solution may discolor slightly during storage, the potency and 
safety are not adversely affected. 
 
9.2.2 Adverse Events 
For a comprehensive list of adverse events please refer to the package insert for 5- 
Fluorouracil.  The following are the adverse reactions most likely to occur on this study. 
Hematologic: Agranulocytosis, anemia, leukopenia (nadir: days 9-14; recovery by day 30), 
pancytopenia, thrombocytopenia 
• Central nervous system: Acute cerebellar syndrome, confusion, disorientation, 
euphoria, headache, nystagmus, stroke 


 
 
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• Cardiovascular: Angina, arrhythmia, heart failure, MI, myocardial ischemia, 
vasospasm, ventricular ectopy 
• Respiratory: Epistaxis 
• Gastrointestinal: Anorexia, bleeding, diarrhea, esophagopharyngitis, mesenteric 
ischemia (acute), nausea, sloughing, stomatitis, ulceration, vomiting 
• Dermatologic: Alopecia, dermatitis, dry skin, fissuring, nail changes (nail loss), 
palmar-plantar erythrodysesthesia syndrome, pruritic maculopapular rash, 
photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, vein 
pigmentation 
• Ocular: Lacrimation, lacrimal duct stenosis, photophobia, visual changes 
• Local: Thrombophlebitis 
• Miscellaneous: Anaphylaxis, generalized allergic reactions 
 
9.3 
Irinotecan/Camptosar 
 
9.3.1 Formulation and Storage 
Irinotecan is a sterile, pale yellow, clear, aqueous solution. Each milliliter of solution 
contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of 
sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of the solution has been adjusted to 3.5 
(range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan is intended for 
dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, 
prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP. 
 
Irinotecan should be stored at controlled room temperature 15° to 30°C (59° to 86°F) and 
protected from light. Keep the vial in the carton until the time of use.  
 
The solution is physically and chemically stable for up to 24 hours at room temperature and 
in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored 
at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light 
are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% 
Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence 
of visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may 
result in precipitation of the drug and should be avoided. 
 
9.3.2 Preparation and Administration 
Inspect vial contents for particulate matter and discoloration and repeat inspection when 
drug product is withdrawn from vial into syringe. 
 
Irinotecan injection 20 mg/mL is intended for single use only and any unused portion should 
be discarded. 
 
Irinotecan injection must be diluted prior to infusion. Irinotecan should be diluted in 5% 
Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final 
concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the 
infusion solution. 
 


 
 
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The CAMPTOSAR Injection solution should be used immediately after reconstitution as it 
contains no antibacterial preservative. Because of possible microbial contamination during 
dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, 
within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared 
with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should 
be used within 4 hours if kept at room temperature. If reconstitution and dilution are 
performed under strict aseptic conditions (e.g., on Laminar Air Flow bench), CAMPTOSAR 
Injection solution should be used (infusion completed) within 12 hours at room temperature 
or 24 hours if refrigerated (2° to 8°C, 36° to 46°F). 
 
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 CAMPTOSAR 
contacts the mucous membranes, flush thoroughly with water. 
 
9.3.3 Adverse Events 
For a comprehensive list of adverse events please refer to the package insert for irinotecan. 
 
The following are the adverse events most likely to occur with this medication  
• Cardiovascular: Vasodilation, edema, hypotension, thromboembolic events. 
• Central nervous system: Cholinergic toxicity, fever, pain, dizziness, insomnia, 
headache, chills, somnolence, confusion. 
• Dermatologic: Alopecia, rash 
• Endocrine & metabolic: Dehydration, 
• Gastrointestinal: Diarrhea, diarrhea, nausea, abdominal pain, vomiting, cramps, 
anorexia, constipation, mucositis, weight loss, flatulence, stomatitis, abdominal 
fullness, dyspepsia. 
• Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia, neutropenic 
fever, hemorrhage, neutropenic infection. 
• Hepatic: Bilirubin increased, alkaline phosphatase increased, AST increased, ascites, 
jaundice. 
• Neuromuscular & skeletal: Weakness, back pain 
• Respiratory: Dyspnea, cough, rhinitis, pneumonia. 
• Miscellaneous: Diaphoresis, infection 
 
9.4 
Oxaliplatin/Eloxatin 
 
9.4.1 Formulation and Storage 
Oxaliplatin is a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml. 
Water for Injection, USP is present as an inactive ingredient. 
 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect 
from light (keep in original outer carton). 
 
 
 


 
 
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9.4.2 Preparation and administration 
Do not freeze and protect from light the concentrated solution. A final dilution must never 
be performed with a sodium chloride solution or other chloride containing solutions. The 
solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose 
Injection, USP. After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf 
life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required. 
ELOXATIN is incompatible in solution with alkaline medications or media (such as basic 
solutions of 5-fluorouracil) and must not be mixed with these or administered 
simultaneously through the same infusion line. The infusion line should be flushed with 5% 
Dextrose Injection, USP prior to administration of any concomitant medication. Parenteral 
drug products should be inspected visually for particulate matter and discoloration prior to 
administration and discarded if present. Needles or intravenous administration sets 
containing aluminum parts that may come in contact with ELOXATIN should not be used 
for the preparation or mixing of the drug. Aluminum has been reported to cause degradation 
of platinum compounds. 
 
9.4.3 Handling and disposal 
As with other potentially toxic anticancer agents, care should be exercised in the handling 
and preparation of infusion solutions prepared from ELOXATIN. The use of gloves is 
recommended. If a solution of ELOXATIN contacts the skin, wash the skin immediately and 
thoroughly with soap and water. If ELOXATIN contacts the mucous membranes, flush 
thoroughly with water. Procedures for the handling and disposal of anticancer drugs should 
be considered.  
 
9.4.4 Adverse Events 
For a comprehensive list of adverse events please refer to the package insert for 
Oxaliplatin/Eloxatin 
 
• Central nervous system: Peripheral neuropathy, fatigue, pain, headache, insomnia, 
rigors, dizziness. 
• Cardiovascular: Edema, chest pain, peripheral edema, flushing, thromboembolism. 
• Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, constipation, anorexia, 
stomatitis, dyspepsia, dysgeusia, flatulence, hiccups, mucositis, gastroesophageal 
reflux disease, dysphagia. 
• Hematologic & oncologic: Anemia, thrombocytopenia, leukopenia, neutropenia. 
• Hepatic: Increased serum AST, increased serum ALT, increased serum bilirubin.  
• Endocrine & metabolic: Dehydration, hypokalemia. 
• Neuromuscular & skeletal: Back pain, arthralgia. 
• Respiratory: Dyspnea, cough, upper respiratory tract infection, rhinitis, epistaxis, 
pharyngitis, pharyngolaryngeal dysesthesia. 
• Renal: Increased serum creatinine  
• Dermatologic: Skin rash, alopecia, palmar-plantar erythrodysesthesia 
• Hypersensitivity: Hypersensitivity reaction (includes urticaria, pruritus, facial 
flushing, shortness of breath, bronchospasm, diaphoresis, hypotension, syncope) 
• Local: Injection site reaction  


 
 
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• Ocular: Abnormal lacrimation 
• Miscellaneous: Fever 
 
10 
ADVERSE EVENTS 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v4 will be utilized for AE reporting. A copy of the 
CTCAE v4 can be downloaded from the CTEP website at http://ctep.cancer.gov 
 
10.1 
Definitions  
 
10.1.1 Adverse Event  
An Adverse Event (AE) is any untoward medical occurrence whether or not considered 
related to the study drug that appears to change in intensity during the course of the study. 
The following are examples of AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an 
AE (e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
10.1.2 Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence resulting in one or more 
of the following: 
 
• Death- Death due to progression is not considered a SAE unless the site investigator 
feels the study drug contributed to disease progression. 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include, but are 
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bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or 
the development of drug dependency or drug abuse. 
 
10.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current IB, prescribing information or when it is 
not included in the informed consent document as a potential risk. Unexpected also refers to 
AEs that are mentioned in the IB as occurring with a class of drugs or are anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.   
 
10.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s) 
 
10.2 
Reporting adverse events 
 
10.2.1 Adverse Event (AE) 
• AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s).  
• AEs will be recorded regardless of whether or not they are considered related to the 
study drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within EDC system. 
• AEs considered related to study drug(s) will be followed until resolution to  
Grade ≤ 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
10.2.2 Serious Adverse Event (SAE)  
 
10.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
• SAEs will be reported from time of signed informed consent until 30 days after 
discontinuation of study drug(s).  
• SAEs will be reported on the SAE Submission Form within 24 hours of discovery 
of the event.   
• SAEs include events related and unrelated to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate 
study specific eCRF form within EDC system.   


 
 
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• All SAEs regardless of relation to study drug will be followed until resolution to ≤ 
Grade 1 or baseline and/or deemed clinically insignificant and/or until a new anti-
cancer treatment starts, whichever occurs first. 
 
The completed SAE Submission Form must be sent electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or 
the Regulatory Authority of the SAE as per local requirements.  The original copy of the 
SAE Submission Form and the email correspondence must be kept within the Trial Master 
File at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must submit a 
follow-up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
10.2.2.2 
HCRN Requirements for Reporting SAEs to Eli Lilly 
HCRN will report all SAEs to Eli Lilly at Global Patient Safety via fax within 24 hours of 
receipt of the SAE Submission Form from the site.  The fax number to send the form is   
866-644-1697 or 317-453-3402.  Follow-up information will be provided to Eli Lilly and 
Co. as reasonably requested.  
 
10.2.2.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 24 hours of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
10.2.2.4 
HCRN Requirements for Reporting to the Food and Drug Administration 
(FDA) 
This protocol was determined to be exempt from the requirements of an IND by the FDA. 
HCRN will continue to facilitate compliance of applicable requirements for the sponsor-
investigator in relation to this study. This includes but is not limited to 21 CFR 50.20 
informed consent, 21 CFR Part 56 IRB, and pertinent sections of the Public Health Service 
Act and FDAAA. 
 
11. 
STATISTICAL METHODS 
 
11.1 
Study Design 
This is a phase II, multicenter, double-blinded, randomized, 2-arm trial evaluating the 
efficacy and safety of mFOLFIRINOX + RAM (Arm A) vs. mFOLFIRINOX + placebo 
(Arm B) in 85 subjects with advanced PCA, not amenable to curative treatment. Subjects 
will be randomized in a 1:1 ratio (i.e., there will be 43 subjects in the control group and 42 
subjects in the treatment group). The primary objective of this trial is to estimate and 
compare PFS in Arm A versus Arm B. See section 11.10 for a description of the 
power/sample size analysis based on the logrank test. 
 
 
 
 


 
 
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11.2 
Definition of Primary Endpoint 
PFS is based upon the time of enrollment until progression or death. Disease is evaluated by 
CT/MRI scans of the organ(s) with the target lesion(s) based on RECIST 1.1 criteria. 
 
11.3 
Definitions of Secondary Endpoints 
Overall survival is defined as the time of enrollment to time of death. Response is defined as 
a complete or partial response according to CT/MRI evaluations based on RECIST 1.1 
criteria. CTCAE v4 is used to grade toxicities. 
 
11.4 
Analysis Plan for Primary Objective 
PFS will be estimated for each arm using the method of Kaplan and Meier. Nine month PFS 
will be reported along with a 95% confidence interval. PFS will be compared between Arm 
A and Arm B using a one-sided logrank test. The ITT analysis dataset will be used for this 
analysis. 
 
11.5 
Analysis Plan for Secondary Objectives 
OS will be estimated for each arm using the method of Kaplan and Meier. Median OS will 
be reported along with a 95% confidence interval. OS will be compared between the two 
arms using a logrank test. RR will be estimated for each arm and reported along with exact 
95% confidence intervals. A Fisher’s exact test will be used to compare RR between the two 
arms. Toxicities will be described for each arm using frequency tables. Fisher’s exact tests 
will be used compare toxicities between arms. The ITT analysis dataset will be used for 
secondary analyses related to OS and RR. The safety analysis dataset will be used for 
analyses related to toxicities. 
 
11.6 
Excessive Toxicity – Criteria for Stopping and Interim Safety Analysis 
In case of excessive toxicity, safety-stopping rules will be used. An acceptable toxicity rate 
will be assumed at 0.20. The study will be stopped based on an unacceptable excessive 
toxicity rate of 0.40. A sequential probability ratio test will be used where a likelihood ratio 
of 8 in favor of an excessive toxicity rate of 0.40 (vs. 0.20) provides sufficient evidence to 
stop the study due to excessive toxicity. Data will be continuously reviewed for excessive 
toxicity and statistical analysis performed if excessive toxicity is suspected. The table below 
provides the minimum number of patients exhibiting excessive toxicity that will trigger 
statistical analysis.  
 
Total number of treated patients 
Number of Patients observed with excessive toxicity 
3 
≥2 
4-5 
≥3 
6-7 
≥4 
8-9 
≥5 
10-11 
≥6 
12-13 
≥7 
14-16 
≥8 
17-18 
≥9 
19-20 
≥10 


 
 
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21-23 
≥11 
24-25 
≥12 
26-28 
≥13 
29-30 
≥14 
31-33 
≥15 
34-35 
≥16 
36-38 
≥17 
39-40 
≥18 
 
Ramucirumab will be held for drug related adverse events Grade ≥ 3 until recovery to Grade 
≤ 1 and then resumed with a lower dose level -1 (6 mg/kg). If the Grade ≥ 3 related adverse 
event does not resolve within 4 weeks of holding treatment, the subject will be taken off 
study treatment.   
 
In the case of prolonged or medically concerning Grade 2 toxicity related to the 
chemotherapy combination, treatment will be interrupted until recovery to Grade ≤ 1, at 
which time treatment will be resumed at the same dose. If the adverse event does not resolve 
in or within 2 weeks with medical intervention, then the subject will be taken off study 
treatment.  
 
11.6.1 Excessive Toxicity 
Excessive toxicity is defined as any adverse event that meets the following criteria: 
 
• Any grade 3 or higher adverse event or an adverse event that leads to discontinuation 
of study therapy.  
• The adverse event must be possibly, probably or definitely related to any of the study 
treatments (Ramucirumab, Oxaliplatin, Irinotecan, 5-FU) 
• The adverse event occurs in the first four weeks of treatment 
• The adverse event grade does not diminish to grade 1, four weeks after dose 
modification or dose delay. AE must have been adequately treated (e.g. nausea, 
vomiting, hematologic toxicities) 
 
11.6.2 Interim Safety Analysis 
The study will be closed to accrual and an interim safety analysis conducted after ten 
subjects are accrued to each arm. If the following rates of selected toxicities listed below are 
observed within the first cycle of treatment (four weeks), the regimen (Ramucirumab, 
Oxaliplatin, Irinotecan, 5-FU) will be considered toxic and the trial will be stopped. 
 
Adverse Event (> grade 3) 
Toxicity Rate (n/10 subjects) 
Febrile Neutropenia 
2/10 
Peripheral Motor or Sensory Neuropathy 
3/10 
Hypertension 
3/10 
Life Threatening Thromboembolic Event 
3/10 
GI Perforation 
2/10 
Hemorrhage, Bleeding 
2/10 
 
 


 
 
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11.7 
Interim Analysis for Efficacy 
An interim analysis with the Kaplan-Meier method and logrank test will be conducted after 
23 subjects have been enrolled in each arm and followed up for 9 months. The trial will stop 
if it detects a significant difference in PFS between the two arms at the significance level of 
0.0013 according to the O’Brien-Fleming approach. Otherwise the trial will continue until 
the targeted sample size has been completed. 
 
11.8 
Un-blinding Plan  
See section 4.1. 
 
11.9 
Analysis Datasets 
The intention-to-treat (ITT) analysis dataset includes all subjects who meet the eligibility 
criteria and are registered onto the study irrespective of their compliance to the planned 
course of treatment. The intention-to-treat principle asserts that the effect of a treatment 
policy can be best assessed by evaluating on the basis of the intention to treat a subject (i.e. 
the planned treatment regimen) rather than the actual treatment given. It has the 
consequence that subjects allocated to a treatment group should be followed up, assessed 
and analyzed as members of that group irrespective of their compliance to the planned 
course of treatment. 
 
The safety analysis dataset includes all subjects who are randomized and receive at least one 
dose of study treatment (on either arm). Subjects will be analyzed for safety according to the 
treatment actually received. 
 
11.10 Sample Size/Accrual/Study Duration  
We aim to test the null hypothesis of PFS at 6 months. Using a one-sided log-rank test we 
have estimated a sample size of 85 patients (43 in one and 42 in another arm) which will 
provide 80% power under a type 1 error of 20%. This is an estimation on 24 months accrual 
and 9 months follow up after accrual for the primary endpoint. Sample size may increase to 
95 to account for a 10% drop out rate. 
 
The expected progression free survival for mFOLFIRINOX in metastatic pancreatic cancer 
is 6 months. The addition of RAM to mFOLFIRINOX would be expected to increase the 
median PFS to at least 9 months. We assume a type 1 error (α) of 0.2 and a power (1-β) of 
80%.  
 
With an exact power of 0.8014, hazard ratio of 0.6667 and endpoint of detecting 3 months 
PFS advantage of the mFOLFIRINOX/ramucirumab combination over mFOLFIRINOX 
alone (from 6 to 9 months), the sample size on each arm was calculated to be 43 in the 
control arm and 42 in the treatment arm (total is 85). 29,30 
 
The estimated enrollment period for this study is 24 months and the estimated study duration 
is 33 months. 
 
 
 


 
 
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11.11 Subject Characteristics and Significant Protocol Violations 
Baseline, demographic, and medical history information will be summarized for each arm. 
Demographic and baseline data will also be provided in by-subject data listings.   
 
11.12 Concomitant Medications 
Concomitant medication use will be summarized for each arm and will be included in by-
subject data listings. 
 
11.13 Disposition 
A tabulation of subject disposition will be presented, including the number in each analysis 
dataset, the number who withdrew from treatment and the reasons for withdrawal, and the 
number who withdrew during the follow-up phase and the reasons for withdrawal.  
 
12. 
TRIAL MANAGEMENT 
 
12.1 
Data and Safety Monitoring Plan 
The study will be conducted in accord with the Winship Cancer Institute of Emory 
University’s Data and Safety Monitoring Plan (DSMP).  
 
In addition, HCRN data and safety activities include: 
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Notify participating sites of adverse events requiring expedited reporting  
• Provide data summary reports to the sponsor-investigator on a monthly basis 
• Submit data summary reports to the lead institution Data Safety Monitoring 
Committee for review as per their guidelines. 
 
12.2 
Winship Cancer Institute Data Safety Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study which has been deemed Moderate Risk.  The 
DSMC functions independently within Winship Cancer Institute to conduct internal 
monitoring functions to ensure that research being conducted produces high-quality 
scientific data in a manner consistent with good clinical practice (GCP) and appropriate 
regulations that govern clinical research.  Since this study is Moderate Risk, initial study 
monitoring will occur within 1 year from the date of the first subject accrued, with 2 of the 
first 5 subjects being reviewed.  Subsequent monitoring will occur in routine intervals per 
the Winship Data and Safety Monitoring Plan (DSMP).  
 
The DSMC will review the following: 
• Adverse event summary report 
• Monitoring and/or audit results if applicable 
• Summary of enrollment including number of subjects consented, enrolled, treated 
and active and discontinued  
• Any regulatory compliance findings from all active sites 
• Summary of investigational product accountability, handling, and dose delivery 
• Summary of protocol compliance relative to tumor response evaluation 
• Summary of data accuracy and timeliness of reporting 


 
 
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• Any site-specific concerns with elements above, with 
recommendation/documentation or corrective actions and re-monitoring as needed 
 
The Winship Cancer Institute DSMC will review aggregate AE data on an annual basis.  
Documentation of DSMC reviews will be provided to sponsor-investigator and HCRN.  
Issues of immediate concern by the DSMC will be brought to the attention of the sponsor-
investigator and other regulatory bodies as appropriate.  The sponsor-investigator will work 
with HCRN to address the DSMC’s concerns.   
 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance 
with the protocol, data collection, and risk-benefit ratio. Specifically, the HCRN Monitor 
assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and 
availability of source documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a preliminary report of monitoring 
findings to the PI and other pertinent individuals involved in the conduct of the study.  The 
PI is required to address and respond to all the deficiencies noted in the preliminary report.  
Prior to the completion of the final summary report, monitors will discuss the preliminary 
report responses with the PI and other team members (when appropriate).  A final 
monitoring summary report will then be prepared by the monitor.  Final DSMC review will 
include the final monitoring summary report with corresponding PI response, submitted 
CAPA (when applicable), PI Summary statement, and available aggregate toxicity and 
safety data.   
 
The DSMC will render a recommendation and rating based on the overall trial conduct.  The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB.  Continuing Review submissions will include the DSMC recommendation letter.  
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes.  The 
Committee reserves the right to conduct additional audits if necessary.  
 
12.3 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis 
throughout the life cycle of the study by HCRN.  A summary report (QC Report) of these 
checks together with any queries resulting from manual review of the eCRFs will be 
generated for each site and transmitted to the site and the site monitor. Corrections will be 
made by the study site personnel.  
 
On-site monitoring of the study and subjects will occur per section 13.2 of this protocol.  
Additional for-cause visits may occur as necessary. Source documents will be reviewed for 
verification of agreement with data entered into the EDC system.  It is important for the site 
investigator and their relevant personnel to be available for a sufficient amount of time 
during the monitoring visits or audit, if applicable. The site investigator and institution 
guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Eli Lilly and Co. or its 
designee as well as inspection by appropriate regulatory agencies. 


 
 
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12.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 
All results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering 
the trial and posting the results on clinicaltrials.gov. Information posted will allow subjects 
to identify potentially appropriate trials for their disease conditions and pursue participation 
by calling a central contact number for further information on appropriate trial locations and 
study site contact information.   
 
13. 
DATA HANDLING AND RECORD KEEPING 
 
13.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, OnCore, a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and 
entered into OnCore  by study site personnel from participating institutions.   
 
 
13.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative 
results will be captured in the EDC system or other secure database(s). If procedures on the 
study calendar are performed for standard of care, at minimum, that data will be captured in 
the source document. Select standard of care data will also be captured in the EDC system, 
according to study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and 
should not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and 
HCRN. 
 
13.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator 
agrees to keep records, including the identity of all subjects (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all 
source documents, and detailed records of drug disposition. All source documents are to 
remain in the subject’s file and retained by the site investigator in compliance with the site 
contract with HCRN.  No records will be destroyed until HCRN confirms destruction is 
permitted. 
 
13.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying 
the subjects will be kept confidential and, to the extent permitted by the applicable laws 
and/or regulations, will not be made publicly available.  


 
 
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Information collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure locations only 
accessible to the study team. Samples that are collected will be identified by a subject’s 
study number assigned at the time of registration to the trial. Any material issued to 
collaborating researchers will be anonymized and only identified by the subject’s study 
number. 
 
Subjects will be informed in writing that some organizations, including the sponsor-
investigator and his/her research associates, Emory University, HCRN, Eli Lilly and 
Company, IRB, or government agencies, like the FDA, may inspect their medical records to 
verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
 
If the results of the study are published, the subjects’ identity will remain confidential. 
 
13.5 
Changes to the Protocol and Informed Consent 
Study procedures will not be changed without the mutual agreement of the sponsor-
investigator, Emory University, HCRN, and Eli Lilly and Company. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of 
the study protocol (amended protocol) will be generated by HCRN and must be approved by 
the sponsor-investigator and Eli Lilly and Company in addition to each site’s IRB. Local 
requirements must be followed. 
 
If a protocol amendment requires a change to the informed consent form, then the IRB must 
be notified. Approval of the revised informed consent form by the IRB is required before the 
revised form is used.  
 
The site investigator is responsible for the distribution of these documents to his or her IRB, 
and to the staff at his or her center.  
 
Eli Lilly and Company’s willingness to supply study drug is predicated upon the review of 
the protocol. HCRN agrees to provide written notice to Eli Lilly and Company of any 
modifications to the protocol or informed consent. 
 
14. 
ETHICS 
 
14.1 
Ethics Review 
Each site must obtain approval of the final study protocol, including the final version of the 
informed consent form, from its IRB. The site investigator must submit written approval to 
the HCRN office before he or she can enroll any subjects into the study.  
 
The site investigator must inform the IRB of any amendment to the protocol in accordance 
with local requirements. In addition, the IRB must approve all advertising used to recruit 


 
 
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subjects for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Sites will provide progress reports and notifications of serious unexpected adverse drug 
reactions will be provided to the IRB as required by local regulations and guidelines. 
 
14.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles which are consistent with 
ICH/Good Clinical Practice E6 as adopted by the FDA, and applicable regulatory 
requirements. 
 
14.3 
Informed Consent Process 
The site investigator will ensure the subjects is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should 
be given the opportunity to ask questions and allowed time to consider the information 
provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
 
 


 
 
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capecitabine for advanced pancreatic cancer: a phase II study. British journal of cancer 
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13. Van Loon K, Espinoza AM, Fogelman DR, et al. Should combination chemotherapy 
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43:343-9. 


 
 
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