Clinical trial NCT02795858
Conditions: Carcinoid Tumors
Keywords: Carcinoid Tumors
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-06-14; Completion date: 2023-12-31
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is evaluating the drug Ramucirumab as a possible treatment for Advanced, Progressive Carcinoid Tumors.

Detailed description:
This research study is a Phase II clinical trial. The purpose of this study is to test the safety and effectiveness of ramucirumab in advanced, progressive carcinoid tumors.

Cancer cells can make growth factors that cause the abnormal growth of new blood vessels. Ramucirumab is an investigational drug which works by blocking a receptor for a vascular growth factor, thereby preventing new blood vessels from forming. This may stop the cancer from growing or spreading and the tumor cells may die.

The FDA (the U.S. Food and Drug Administration) has not approved Ramucirumab for treatment of Carcinoid Tumors.

Arms: arm 1: Patients will receive treatment with ramucirumab starting at a dose of 8 mg/kg intravenously every 14 days of a 28-day treatment cycle. Patients already receiving a somatostatin analog continued somatostatin analog therapy at their current dose. Patients not already receiving a somatostatin analog initiated treatment at an approved dose, according to institutional guidelines.

Toxicity and adverse events will be examined in the first 10 patients who complete one cycle of therapy before expanding enrollment.
Interventions: intervention 1: Ramucirumab intervention 2: Somatostatin Analog
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #:
NCT02795858
DF/HCC Protocol #: 16-072
TITLE:  A Phase II Study of Ramucirumab with Somatostatin Analog Therapy in Patients 
with Advanced, Progressive Carcinoid Tumors
Coordinating Center:
Dana-Farber Cancer Institute
*Principal Investigator (PI):
Jennifer Chan, MD, MPH
Dana-Farber Cancer Institute
jang@partners.org
Statistician:
Study Coordinator: 
Hui Zheng, Ph.D.
      Sofia von Fedak
Massachusetts General Hospital
      Dana-Farber Cancer Institute
HZheng1@partners.org
      Sofia_VonFedak@dfci.harvard.edu 
Agent: Ramucirumab (Eli Lilly)
Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Type / Version # / Version Date:
Original / Version #3 /February 1, 2021


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SCHEMA
Patients with advanced carcinoid tumors and 
documented disease progression within 12 months
Ramucirumab, IV every 2 weeks 
Patients will continue current dose of somatostatin analog therapy.
Restaging scans every 12 weeks
Primary Endpoint: Progression-Free Survival


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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objectives...................................................................................................5
1.3
Secondary Objectives...............................................................................................5
2.
BACKGROUND .................................................................................................................5
2.1
Overview of Neuroendocrine Tumors .....................................................................5
2.2
IND Agent................................................................................................................7
2.3
Rationale ................................................................................................................10
3.
PARTICIPANT SELECTION...........................................................................................10
3.1
Eligibility Criteria..................................................................................................10
3.2
Exclusion Criteria ..................................................................................................12
4.
REGISTRATION PROCEDURES ...................................................................................14
4.1
General Guidelines for DF/HCC Institutions ........................................................14
4.2
Registration Process for DF/HCC Institutions.......................................................14
4.3
General Guidelines for Other Investigative Sites ..................................................14
4.4
Registration Process for Other Investigative Sites.................................................14
5.
TREATMENT PLAN........................................................................................................14
5.1
Treatment Regimen................................................................................................14
5.2
Pre-Treatment Criteria ...........................................................................................15
5.3
Agent Administration.............................................................................................15
5.4
General Concomitant Medication and Supportive Care Guidelines......................15
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................16
5.6
Duration of Follow Up...........................................................................................16
5.7
Criteria for Taking a Participant Off Study ...........................................................17
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................17
6.1
Dose Adjustment and Delays.................................................................................17
6.2
Dose levels.............................................................................................................17
6.3
Dose Modification Guidelines...............................................................................17
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................25
7.1
Expected Toxicities................................................................................................25
7.2
Definitions..............................................................................................................27
7.3
Adverse Event Characteristics...............................................................................27
7.4
Expedited Adverse Event Reporting......................................................................28
8.
PHARMACEUTICAL INFORMATION..........................................................................29
8.1
Ramucirumab.........................................................................................................30


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9.
STUDY CALENDAR .......................................................................................................34
10.
MEASUREMENT OF EFFECT .......................................................................................35
10.1
Antitumor Effect – Solid Tumors ..........................................................................35
11.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................41
11.1
Data Reporting.......................................................................................................41
11.2
Data Safety Monitoring..........................................................................................42
12.
STATISTICAL CONSIDERATIONS...............................................................................42
12.1
Study Design/Endpoints ........................................................................................42
12.2
Sample Size, Accrual Rate and Study Duration ....................................................42
12.3
Analysis of Primary Endpoints..............................................................................43
12.4
Analysis of Secondary Endpoints..........................................................................43
12.5
Reporting and Exclusions ......................................................................................44
13.
PUBLICATION PLAN .....................................................................................................44
REFERENCES ..............................................................................................................................45
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................47


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1. OBJECTIVES
1.1
Study Design
This is an open-label phase II study to evaluate the safety and efficacy of ramucirumab in 
patients with advanced carcinoid tumors.
1.2
Primary Objectives

To assess the progression-free survival duration of patients with advanced, progressive 
carcinoid tumors treated with ramucirumab in combination with somatostatin analog 
therapy.
1.3
Secondary Objectives

To determine the safety and tolerability of ramucirumab in combination with 
somatostatin analog therapy in patients with advanced carcinoid tumors.

To assess the overall radiographic and biochemical response rate associated with 
ramucirumab in combination with somatostatin analog therapy in patients with advanced 
carcinoid tumors

To assess the overall survival duration of  patients with advanced, progressive carcinoid 
tumors treated with ramucirumab in combination with somatostatin analog therapy. 
2. BACKGROUND
2.1
Overview of Neuroendocrine Tumors
Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by 
variable but most often indolent biologic behavior.  Well-differentiated NETs can be broadly 
classified as either carcinoid or pancreatic NET. 
The treatment of advanced NET has undergone a rapid evolution in recent years.  In addition to 
controlling symptoms related to hormone hypersecretion, somatostatin analogs have also been 
shown to control tumor growth.  In the PROMID trial, patients with advanced small bowel 
carcinoid tumors receiving octreotide had a longer median time to tumor progression compared 
with those receiving placebo (14.3 vs. 6 months).(Rinke, Muller et al. 2009)  Further support for 
the antiproliferative effect of somatostatin analogs in patients NET was demonstrated in the 
CLARINET trial, a randomized, placebo-controlled phase III trial evaluating the antiproliferative 
effects of lanreotide in patients with advanced well- or moderately-differentiated, non-
functioning gastroenteropancreatic NETs, including both gastrointestinal NET and pancreatic 
NET.  Patients receiving lanreotide had improved progression-free survival (PFS) compared to 
those receiving placebo (median not reached vs. median of 18 months).(Caplin, Pavel et al. 


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2014) 
Agents targeting the VEGF- and mTOR-pathway signaling pathways are also active in the 
treatment of NET.  In advanced pancreatic NET, independent randomized, placebo-controlled 
studies of everolimus and sunitinib demonstrated clear improvements in progression-free 
survival (PFS), leading to the approval of both agents for this indication.(Raymond, Dahan et al. 
2011, Yao, Shah et al. 2011)  In advanced carcinoid tumors, however, there remains no approved 
drug for tumor control, and the development of effective systemic therapy for this patient 
population represents a clear and unmet medical need.
VEGF Inhibition in Carcinoid Tumors
Several studies suggest that vascular endothelial growth factor (VEGF) pathway inhibition is a 
promising approach in treating patients with advanced carcinoid tumors.   A key role for 
angiogenesis and VEGF pathway signaling in NET has been suggested by clinical observations 
that NET are vascular tumors.  Additionally, pre-clinical studies have demonstrated that NET 
have increased expression of VEGF, VEGF receptor-2 (VEGFR-2), and other growth factor 
receptors including platelet-derived growth factor receptors (PDGFRs) α and β, stem-cell factor 
receptor (c-kit).(Fjallskog, Lejonklou et al. 2003, Hansel, Rahman et al. 2003, Fjallskog, 
Hessman et al. 2007, Bowen, Silva et al. 2009, Silva, Bowen et al. 2011)
The VEGF pathway inhibitors bevacizumab, sunitinib, sorafenib, and pazopanib have been 
evaluated in advanced carcinoid tumors in the phase II setting.(Hobday, Rubin et al. 2007, 
Kulke, Lenz et al. 2008, Yao, Phan et al. 2008, Phan, Yao et al. 2010) These drugs have shown 
low radiographic response rates, but a relatively high rate of disease stabilization and 
encouraging median progression-free survival durations (8-14 months). 
We have evaluated the prognostic significance of expression of VEGF pathway components, 
including VEGF-A, VEGFR-1, and VEFGR-2, in NET (Fig 1) and found that expression of 
VEGFR-2 appears to be an adverse prognostic factor associated with shorter overall survival 
(Fig 2). 
Figure 1: Expression of VEGF-A, VEGFR-1 and VEGFR-2 by immunohistochemistry.


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Figure 2: Overall survival of patients with NET according to VEGFR2 expression. 
2.2
IND Agent
Ramucirumab has been previously evaluated as monotherapy in separate clinical studies, and a 
recommended schedule and dose range for monotherapy has been determined. Detailed 
information about the characteristics of ramucirumab is provided in the Investigator’s Brochure 
(IB).  The following sections provide a summary of the information most relevant to this phase II 
study.
2.2.1
Ramucirumab
Mechanism of action:
Ramucirumab (IMC-1121B [LY3009806]) is a human receptor-targeted monoclonal antibody 
that specifically binds VEGF Receptor 2. The binding of ramucirumab to VEGF Receptor 2 
prevents its interaction with activating ligands (VEGF-A, VEGF-C, and VEGF-D).  As a result, 
ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2and its downstream 
intracellular signaling components, including Erk1/Erk2, neutralizing ligand induced 
proliferation and migration of human endothelial cells.
Pharmacokinetics:
Trough concentrations (or minimum concentrations [Cmin]) were collected in two Phase 3 
studies (REGARD and RAINBOW) in patients with gastric cancer. Following the recommended 
clinical dose regimen, 8 mg/kg every 2 weeks, observed Cmin values were similar between


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REGARD and RAINBOW, as noted in the table below (Investigator’s Brochure, Table 6.1). The 
geometric mean observed trough values were approximately 50 ug/mL and approximately 60 to 
70 ug/mL before the fourth and seventh doses, respectively.
Pharmacokinetic data were from pooled from 8 studies including 497 patients with various 
malignancies for a population pharmacokinetic (PopPK) analysis. In these studies, ramucirumab 
was administered as a 1-hour I.V. infusion, at either 8 mg/kg once every 2 weeks on a 14- or 28-
day cycle, or 10 mg/kg every 3 weeks on a 21-day cycle. The geometric mean (percentage 
coefficient of variation [CV%]) of PopPK model-derived estimates of ramucirumab clearance 
(CL), volume of distribution at steady state (Vss) and terminal half-life (t1/2) were 0.0140 L/h 
(29.8%), 5.5 L (14.4%), and 15 days (24.1%), respectively. These parameter estimates were 
consistent with those observed with other human monoclonal IgG1 (Keizer et al. 2010) 
antibodies. Results from the PopPK analyses indicate that the PK of ramucirumab following 8- 
and 10-mg/kg dose administrations were dose linear (absolute dose range: 169 to 1234 mg) and 
time independent.
Weekly doses of ramucirumab ranging from 2 to 16 mg/kg were evaluated in a Phase 1 study: 
I4TIE- JVBM [IMCL CP12-0401]. A maximum tolerated dose (MTD) for weekly dosing was 
identified as 13 mg/kg (2 dose-limiting toxicities [DLTs] were observed in patients receiving the
16-mg/kg weekly dose: Grade 3 deep vein thrombosis and Grade 3 hypertension). Preliminary 
activity was observed across a range of doses, including the 2-mg/kg dose. Pharmacokinetic 
results from this study suggested that, as with other recombinant human IgG1 monoclonal 
antibodies targeting cell membrane-expressed antigens, ramucirumab exhibited nonlinear PK 
characteristics. 
Apparent nonlinear PK profiles were observed between 2 and 8 mg/kg; PK profiles appeared to 
be linear at and above 8 mg/kg, suggesting saturation of the target mediated (VEGF Receptor 2) 
clearance pathway. Every-2-week (6 to 10 mg/kg) and every-3- week (15 to 20 mg/kg) dose 
regimens were evaluated in an additional dose-ranging study (Study I4T-IE-JVBN [IMCL CP12-
0402]). No MTD was identified for every-2-week or every-3-week dosing; all dose regimens 
were well tolerated, and preliminary evidence of clinical efficacy was observed across a range of 
dose/schedule cohorts.


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Clinical Experience and Activity:
Ramucirumab has been studied and/or continues to be investigated in ongoing clinical studies for 
the indications as indicated in the Investigator’s Brochure.  As of 31 December 2013, 
ramucirumab or ramucirumab/placebo has been administered either as a single agent or in 
combination with various antineoplastic agents to approximately7000 patients with different 
oncologic conditions in Phase 1/1b, Phase 2, and Phase 3 clinical trials. 
Ramucirumab demonstrated significant and clinically meaningful benefit in overall survival (OS) 
as a single agent at a dose of 8 mg/kg every 14 days in patients with advanced gastric cancer in 
the REGARD study, a randomized Phase 3 trial of ramucirumab monotherapy with best 
supportive care [BSC] versus placebo with best supportive care.(Fuchs, Tomasek et al. 2014)  
Ramucirumab also has shown clinical efficacy in patients with gastric cancer in combination 
with paclitaxel in a phase III study of paclitaxel with ramucirumab compared with paclitaxel 
with placebo (RAINBOW).(Wilke, Muro et al. 2014)  A Phase 3 trial (ROSE) examining the 
combination of ramucirumab with docetaxel in previously untreated metastatic breast cancer 
failed to meet its primary endpoint of investigator-assessed progression-free survival (PFS). In 
ROSE, while investigator-assessed PFS numerically favored ramucirumab, this difference was 
not statistically significant.(Mackey, Ramos-Vazquez et al. 2015)
Please refer to the current version of the Investigator’s Brochure for updated information 
regarding the clinical experience and activity of ramucirumab.
Adverse Events:  
As of 31 December 2013, AE information was available for 2485 patients receiving 
ramucirumab drug product (DP) on 7 Phase 1/1b studies, 18 open-label or unblinded Phase 2 
studies, and 3 completed Phase 3 studies, including monotherapy and combination therapy with 
cytotoxic chemotherapy agents. Placebo-controlled blinded clinical trials are ongoing (1 Phase 2 
study, 3 Phase 3 studies); unblinded safety data for these studies are not available. Detailed AE 
information based on a review of Phase 1/1b, Phase 2, and completed Phase 3 clinical studies of 
ramucirumab DP (N=2485) are available in the Investigator Brochure.
Adverse drug reactions (ADRs; AEs for which a causal relationship to the investigational drug 
was considered at least possible) of special interest include AEs which have been associated with
antiangiogenic agents and therapeutic monoclonal antibodies and include the following 
categories: infusion-related reaction (IRR), hypertension, proteinuria, arterial thromboembolic 
events (ATEs), venous thromboembolic events (VTEs), bleeding/hemorrhagic events, 
gastrointestinal (GI) perforation, and congestive heart failure (CHF) when used in combination 
with mitoxantrone or following prior anthracycline therapy.
Infusion-related reaction is considered an adverse event of special interest (AESI), as it has been 
observed in association with other approved and investigational therapeutic monoclonal 
antibodies. With the exception of liver injury/liver failure, the AESIs discussed are potentially 
associated with other agents that inhibit VEGF- or VEGF Receptor 2-mediated angiogenesis.


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Some AESIs also have been reported in clinical trials of ramucirumab DP, although in some 
instances a causal association with ramucirumab DP could not be clearly established. Liver 
failure and/or other significant liver injury events were included as an AESI in August 2012, 
following the independent data monitoring committee (IDMC) recommendations in an ongoing
Phase 3 study in patients with advanced hepatocellular carcinoma (HCC; Study I4T-IE-JVBF
[IMCL CP12-0919; REACH]). 
Animal studies have not been specifically conducted to evaluate the effect of ramucirumab on 
female reproduction and fetal development, and there are no studies in pregnant women.
Please refer to Section 7 or the protocol and the current version of the Investigator’s Brochure for 
updated information regarding the adverse events associated with ramucirumab.
2.3
Rationale
Ramucirumab is a fully human monoclonal antibody targeting VEGFR-2 that prevents ligand 
binding and receptor-mediated pathway activation.  In light of pre-clinical data demonstrating 
prognostic significance for VEGFR-2 expression in NET and preliminary evidence of activity of 
VEGF pathway inhibitors in carcinoid, we propose a 43 patient single-arm phase II study of 
ramucirumab in advanced carcinoid tumors. Because somatostatin analogs also have antitumor 
activity, concurrent treatment with a somatostatin analog will be required in all patients.  
A future randomized, placebo-controlled phase II study or phase III study could be planned if 
ramucirumab demonstrates efficacy in this study.
Because prior studies of targeted agents have demonstrated low RECIST-defined tumor response 
rates in advanced carcinoid, we propose enrolling patients with documented disease progression 
and will use progression-free survival (PFS) as a primary endpoint. Assessment of efficacy will 
be made by comparing our results to the PFS of patients in the placebo arm of the RADIANT-2 
study, a randomized phase III study of everolimus plus octreotide LAR vs. placebo plus 
octreotide LAR in patients with progressive carcinoid tumors with carcinoid syndrome.
We hypothesize that ramucirumab in combination with a somatostatin analog will be active in 
the treatment of advanced carcinoid tumors and will be associated with a median PFS duration of 
12 months or greater.
3. PARTICIPANT SELECTION
3.1
Eligibility Criteria 
3.1.1
Participants must have histologically or cytologically confirmed low- to intermediate-
grade neuroendocrine tumor (carcinoid tumor).


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3.1.2
Carcinoid tumors of any site are eligible. Patients with pancreatic neuroendocrine tumors 
are excluded.
3.1.3
Participants must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques 
or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.  See Section 10 for 
the evaluation of measurable disease.
3.1.4
Locally advanced, unresectable or metastatic disease.
3.1.5
Patients must have evidence of radiographic disease progression within the past 12 
months.  Progressive disease by RECIST criteria is not required.
3.1.6
Age ≥ 18 years.  
3.1.7
ECOG performance status 0-1 (see Appendix A).
3.1.8
Participants must have normal organ and marrow function as defined below:

absolute neutrophil count
≥1,000/ mm3

platelets
≥100,000/ mm3

hemoglobin 
≥ 9 g/dL

total bilirubin
≤ 1.5 × institutional upper limit of normal

AST(SGOT)/ALT(SGPT)
≤ 3 × institutional upper limit of normal, or ≤ 5× 
institutional upper limit of normal in the setting of liver 
metastases

creatinine
≤ 1.5 × upper limit of normal

urinary protein
≤ 1+ on dipstick or routine urinalysis (if urine dipstick 
or routine urinalysis is 2+, a 24-hour urine collection 
for protein must demonstrate <1000 mg of protein in 24 
hours)

coagulation function
Adequate coagulation function as defined by 
International Normalized Ratio (INR) ≤ 1.5 and a 
partial thromboplastin time (PTT) < 1.5 x institutional 
upper limit of normal. Patients on full-dose 
anticoagulation must be on a stable dose (minimum 
duration 14 days) of oral anticoagulant or low 
molecular weight heparin.


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3.1.9
The effects of ramucirumab on the developing human fetus are unknown.  For this reason 
and because anti-antiangiogenic agents are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months 
after completion of ramucirumab administration.
3.1.10 Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents administered 
more than 4 weeks earlier.
3.2.2
Patients who have undergone major surgery within 28 days or subcutaneous venous 
access device placement within 7 days prior to study enrollment.  
3.2.3
Patients with elective or planned major surgery to be performed during the course of the 
clinical trial.
3.2.4
Patients who are receiving any other investigational agents.
3.2.5
Patients with any Grade 3-4 gastrointestinal bleeding within 3 months prior to 
enrollment.
3.2.6
Patients with a 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 registration.
3.2.7
Patients who have experienced any arterial thromboembolic events, including but not 
limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or 
unstable angina, within 6 months prior to enrollment.
3.2.8
Patients with uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 
100 mmHg diastolic for >4 weeks) despite standard medical management.
3.2.9
Patients who have congestive heart failure (NYHA Class III or IV), sustained ventricular 
tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart 
block within the six months preceding enrollment.


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3.2.10 Patients who have cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any 
degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting 
from cirrhosis.
3.2.11 Patients with a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior 
to enrollment.
 
3.2.12 Patients receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole 
or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is 
permitted.
3.2.13 Patients  with uncontrolled brain or leptomeningeal metastases, including patients who 
continue to require glucocorticoids for brain or leptomeningeal metastases.
3.2.14 Patients with prior or concurrent malignancy except for the following: adequately treated 
basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any 
other cancer from which the patient has been disease free for five years.
3.2.15 Patients with symptomatic cholelithiasis.
3.2.16 Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as:

Severely impaired lung function

Any active (acute or chronic) or uncontrolled infection/ disorders.

Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy

Psychiatric illness/social situations that would limit compliance with study 
requirement
3.2.17 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ramucirumab .
3.2.18 Pregnant and breastfeeding women are excluded from this study because ramucirumab is 
associated with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with ramucirumab, breastfeeding should be discontinued if the mother is 
treated with ramucirumab.  These potential risks may also apply to other agents used in 
this study.


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4. REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
N/A
4.4
Registration Process for Other Investigative Sites
N/A
5. TREATMENT PLAN
5.1
Treatment Regimen
Patients will receive treatment with ramucirumab at a dose of 8 mg/kg intravenously every 
14 days of a 28-day treatment cycle.  
Patients already receiving a somatostatin analog may continue at their current dose. 
Patients not already receiving a somatostatin analog should initiate treatment at an 
approved dose, according to institutional guidelines.
No other investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the participant's malignancy.


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Patients will continue treatment until progression, unacceptable toxicity, or withdrawal of 
consent. 
Because adverse events associated with the combination of ramucirumab and a 
somatostatin analog have not examined previously, toxicity and adverse events will be 
examined in the first 10 patients who complete one cycle of therapy before expanding 
enrollment.
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1: Participants must meet eligibility criteria on the first day of treatment and 
have completed all of the required activities by the first day of treatment (Section 9).
5.2.2
Subsequent Cycles: Participants must complete all required assessments (Section 9).  Any 
treatment-related adverse events must meet parameters for re-treatment with required 
dose adjustment as specified in Section 6.3.
5.3
Agent Administration
5.3.1
Ramucirumab
Ramucirumab will be administered as a 1-hour IV infusion on Days 1 and 15 of a 28-day cycle.  
The infusion rate of ramucirumab should not exceed 25 mg/min.
Premedication: Prior to each infusion of ramucirumab, premedicate all patients with an 
intravenous histamine H1 antagonist, such as diphenhydramine hydrochloride.  Additional 
premedication may be provided at investigator discretion.
If a patient experiences a Grade 1 or 2 infusion-related reaction (IRR), premedication must be 
given for all subsequent infusions, as outlined in Section 6 of the protocol.
5.4
General Concomitant Medication and Supportive Care Guidelines
5.4.1
Use of other cancer treatments 
Other than a somatostatin analog, no other antineoplastic agents will be permitted during this 
study. No concurrent radiation treatment will be permitted, except for palliation or symptom 
relief after completion of Cycle 2.
The use of erythropoietin or other specific red blood cell growth factors and red blood cell 
transfusions will be permitted as clinically indicated during the study. The use of bone marrow 
colony stimulating factors (such as granulocyte colony-stimulating factor or granulocyte-
macrophage colony-stimulating factor) is not permitted.


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5.4.2
Supportive medications
Other concomitant medications may be given as clinically indicated, including supportive 
medications for diarrhea, nausea/vomiting, or other supportive medications.
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s) or adverse event(s) requiring discontinuation of 
therapy as specified in the dose modification section of this protocol

Participant demonstrates an inability or unwillingness to comply with the treatment 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Jennifer Chan, MD at 617-632-6315. 
5.6
Duration of Follow Up
Subject survival and subsequent therapy information will be collected, preferably via office visit 
or telephone contact, every 6 months +/- 1 week from the date of last dose of study drug until the 
subject’s death or until the subject is lost to follow-up, or until study closure. For patients who 
discontinue therapy prior to disease progression, a physical exam, performance status, 
Chromogranin A, and radiographic imaging will be assessed every 12 weeks +/- 1 week until 
tumor progression or start of new anticancer therapy. 


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Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
6. DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
6.1
Dose Adjustment and Delays
Beginning with cycle 1, if a patient experiences a toxicity warranting a dosing delay, 
ramucirumab may be held for up to 28 days to allow sufficient time for recovery from toxicity.  
6.2
Dose levels
Dose Level
Ramucirumab Dose, IV
-2
5 mg/kg, every 14 days
-1
6 mg/kg, every 14 days
0
8  mg/kg, every 14 days
6.3
Dose Modification Guidelines


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6.3.1
Hematologic toxicity
If the ANC is <1,000 or the platelet count is <50,000 during study therapy, therapy with 
ramucirumab will be delayed. If therapy cannot be administered on the scheduled day of dosing, 
the CBC will be repeated weekly for up to and including 4 weeks until the ANC is  1000/mm3 
and the platelet count  50,000mm3. At that time, ramucirumab will be reinitiated at one reduced 
dose level.
Growth factors cannot be used to induce elevations in neutrophil count for the purposes of 
administration of treatment on the scheduled dosing OR to allow treatment.  
Neutropenia
Management for Ramucirumab
≤ Grade 1 
(<LLN - 1500/mm3)
No change in dose
Grade 2 
(<1500 - 1000/mm3)
No change in dose
Grade 3 
(<1000 - 500/mm3)
Hold* until  1000/mm3.  Resume at one dose level lower.**
Grade 4
Discontinue ramucirumab
* Participants requiring a delay of >4 weeks should go off protocol therapy.
**Participants requiring > two dose reductions should go off protocol therapy.
Thrombocytopenia
Management for Ramucirumab
≤ Grade 1 
(<LLN - 75,000/mm3)
No change in dose
Grade 2 
(<75,000 - 50,000/mm3)
No change in dose
Grade 3 
(<50,000 - 25,000/mm3)
Hold* until  50,000 mm3.  Resume at one dose level lower.**
Grade 4 (<25,000/mm3)
Discontinue ramucirumab
*Participants requiring a delay of >4 weeks must go off protocol therapy.
**Participants requiring > two dose reductions must go off protocol therapy.
6.3.2
Infusion-related reaction
As with other monoclonal antibodies, infusion-related reactions may occur during or following 
ramucirumab. The NCI CTCAE Version 4 description and grade of Infusion-Related Reactions 
are described in the following table:
Adverse 
Event
Grade 1
Grade 2
Grade 3
Grade 4 
Grade 5
Infusion-
related
A disorder characterized by adverse reaction to the infusion of 
pharmacological or biological substances.


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reaction
Mild 
transient
reaction; 
infusion
interruption 
not
indicated;
intervention 
not
indicated
Therapy or 
infusion
interruption 
indicated but
responds 
promptly to
symptomatic 
treatment
(eg, 
antihistamines,
NSAIDs, 
narcotics, IV
fluids); 
prophylactic
medications 
indicated for
≤24 hours
Prolonged (eg, not
rapidly responsive 
to
symptomatic
medication and/or 
brief
interruption of
infusion); 
recurrence of
symptoms 
following
initial 
improvement;
hospitalization
indicated for 
clinical
sequelae
Life-
threatening
consequenc
es;
urgent 
intervention
indicated
Death
Allergic
Reaction
A disorder characterized by an adverse local or general response from 
exposure to an allergen.
Transient 
flushing
or rash, 
drug fever
<38°C 
(<100.4°F);
intervention 
not
indicated
Intervention or 
infusion
interruption 
indicated;
responds 
promptly to
symptomatic 
treatment
(eg, 
antihistamines,
NSAIDs, 
narcotics);
prophylactic 
medications
indicated for ≤24 
hours
Prolonged (eg, not
rapidly responsive 
to
symptomatic
medication and/or 
brief
interruption of
infusion); 
recurrence of
symptoms 
following
initial 
improvement;
hospitalization
indicated for 
clinical
sequelae (eg, renal
impairment, 
pulmonary
infiltrates)
Life-
threatening
consequenc
es;
urgent 
intervention
indicated
Death
Anaphylaxis
A disorder characterized by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, causing a 


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hypersensitivity immune response.  Clinically, it presents with breathing 
difficulty, dizziness, hypotension, cyanosis, and loss of consciousness and 
may lead to death
-
-
Symptomatic
bronchospasm, 
with or
without urticaria;
parenteral 
intervention
indicated; allergy 
related
edema/angioedem
a;
hypotension
Life-
threatening
consequenc
es;
urgent 
intervention
indicated
Death
A disorder characterized by nausea, headache, tachycardia, hypotension, rash, 
and shortness of breath; it is caused by the release of cytokines from the cells.
Cytokine
release
syndrome
Mild 
reaction;
infusion 
interruption
not 
indicated;
intervention 
not
indicated
Therapy or 
infusion
interruption 
indicated
but responds 
promptly
to symptomatic
treatment (eg,
antihistamines,
NSAIDs, 
narcotics, IV
fluids); 
prophylactic
medications 
indicated
for ≤24 hours
Prolonged (eg, not
rapidly responsive 
to
symptomatic 
medication
and/or brief 
interruption
of infusion); 
recurrence
of symptoms 
following
initial 
improvement;
hospitalization 
indicated
for clinical 
sequelae (eg,
renal impairment,
pulmonary 
infiltrates)
Life-
threatening
consequenc
es;
urgent 
intervention
indicated
Death
Patients should be closely monitored for signs and symptoms indicative of an infusion-related 
reaction, starting with the initiation of the infusion until at least 30 minutes after the infusion. 
Monitoring should be performed in an area where resuscitation equipment and other agents (eg, 
epinephrine, corticosteroids) are readily available.
The following are treatment guidelines for infusion-related reactions due to ramucirumab:
Grade 1


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
Slow the infusion rate by 50%.

Monitor the patient for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV; 
additional premedication may be administered at the investigator’s discretion.
Grade 2

Stop the infusion.

Administer diphenhydramine hydrochloride 50 mg IV and oxygen.  Other medications, 
including methylprednisolone 50 mg IV, ranitidine 50 mg IV, acetaminophen 650 mg 
orally for fever,  and meperidine 12.5 mg-25 mg IV for rigors can be administered as 
medically indicated.

Resume the infusion at 50% of the prior rate once the infusion-related reaction has 
resolved or decreased to Grade 1; the infusion duration should not exceed 2 hours.

Monitor for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV; 
additional premedication may be administered at the investigator’s discretion.

For a second Grade 1 or 2 infusion-related reaction, administer diphenhydramine 50 mg 
IV, methylprednisolone 50 mg IV.  Other medications, including ranitidine 50 mg IV, 
acetaminophen 650 mg orally for fever, and meperidine 12.5 mg-25 mg IV for rigors can 
be administered as medically indicated.  For subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg IV and methylprednisolone 50 mg IV.  Additional 
premedication may be administered at the investigator’s discretion.
Grade 3

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV, methylprednisolone 50  mg IV, 
ranitidine 50 mg IV, oxygen.  Other medications/treatment, including acetaminophen 650 
mg orally for fever, meperidine 12.5 mg-25 mg IV for rigors, and bronchodilators for 
bronchospasm can be administered as medically indicated.

Patients who have a Grade 3 infusion-related reaction will not receive further 
ramucirumab
Grade 4

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV, methylprednisolone 50 mg IV, 
ranitidine 50 mg IV and other medications/treatment as medically indicated.

Give epinephrine or bronchodilators as indicated.

Hospital admission for observation may be indicated.

Patients who have a Grade 4 infusion-related reaction will not receive further 
ramucirumab
6.3.3
Hypertension
Hypertension
Definition
Recommended 


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CTCAE 
version:4.0
management
Grade 1
Prehypertension: 
systolic 120-139 mm Hg or diastolic 
80-89 mm Hg
No dose modification or 
delay
Grade 2
Stage 1 hypertension:
systolic: 140-159 mm Hg 
or 
diastolic: 90-99 mm Hg

Medical intervention indicated

Recurrent or persistent (≥24 
hours)

Symptomatic increase by >20 
mmHg (diastolic)

>140/90 mm Hg if previously 
normal

Monotherapy indicated
No dose modification or 
delay.  Medical management 
of hypertension.
Grade 3
Stage 2 hypertension:
Systolic ≥160 mm Hg or
Diastolic ≥100

Medical intervention indicated

More than one antihypertensive 
drug 

or more intensive therapy than 
previously indicated
Delay treatment with 
ramucirumab for a maximum 
of 4 weeks.  
First occurrence:
When BP is controlled to < 
140/90, resume ramucirumab 
at same dose.
Second occurrence: When BP 
is controlled to < 140/90 
resume ramucirumab at one 
reduced dose level.
 
Third occurrence: A second 
dose reduction of 
ramucirumab should be 
undertaken if additional 
postponement of 
ramucirumab is required.


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Grade 4
Life threatening consequences (e.g., 
malignant hypertension, transient or 
permanent neurological deficit, 
hypertensive crisis); urgent 
intervention indicated
Discontinue ramucirumab.  
6.3.4
Proteinuria
For proteinuria ≥2+ per a dipstick or routine urinalysis: Confirm total urine protein with a 24-hr 
urine collection.
24 hour urine protein
Management
<2 g/24 hours
Continue on ramucirumab at the same dose without 
interruption. 
2 to 3 g/24 hours
Ramucirumab will be held for 2 weeks and a 24- hour urine 
collection will be repeated. 
Treatment with ramucirumab will resume at 1 lower dose 
level once the protein level returns to <2 g/24 hours. 

A dose reduction of ramucirumab to 5 mg/kg every 2 
weeks is permitted if proteinuria >2 g/24 hours recurs.

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.  
>3 g/24 hours
Discontinue ramucirumab. 
6.3.5
Venous Thromboembolic Events
Grade 3 or asymptomatic Grade 4: 
Interrupt ramucirumab.  If the planned duration of full-dose anticoagulation is <2 weeks, 
protocol treatment should be held until the full-dose anticoagulation period is over.  If the 
planned duration of full-dose anticoagulation is >2 weeks, protocol treatment may be resumed 
during the period of full-dose anticoagulation if all of the following criteria are met:

The patient must have an in-range INR (usually between 2-3) on a stable dose of warfarin 
(or other anticoagulant) prior to restarting therapy;

The patient must not have had a grade 3 or 4 hemorrhagic event while on study; and

The patient must not have had evidence of a tumor involving major blood vessels on any 
prior CT scan.
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.


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For recurrent/worsening venous thromboembolic events after resumption of treatment: 
Discontinue ramucirumab.  
For symptomatic grade 4: 
Discontinue ramucirumab.  
Any venous thrombotic event leading to discontinuation of ramucirumab therapy will be 
considered serious and should be reported via the SAE mechanism.
6.3.6
Arterial thrombotic event
Discontinue ramucirumab for any grade 3 and 4 arterial thromboembolic events.  
Any arterial thrombotic event leading to discontinuation of ramucirumab therapy will be 
considered serious and should be reported via the SAE mechanism.
6.3.7
Bleeding (Hemorrhagic) Events
For Grade 3 or 4 bleeding (hemorrhagic) event bleeding:  Discontinue ramucirumab.  
6.3.8
Gastrointestinal Perforations or Fistula
Ramucirumab should be discontinued in the event of a GI perforation or fistula formation.  
6.3.9
Congestive Heart Failure 
Ramucirumab should be discontinued in the event of any Grade 3-4 events consistent with CHF.
6.3.10 Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome should be identified and treated promptly in 
order to minimize potential for permanent neurological damage. Treatment encompasses careful 
control of BP, withdrawal of potentially causative medication, and administration of 
anticonvulsant agents to those experiencing seizures. If the diagnosis of RPLS is confirmed, 
ramucirumab should be permanently discontinued. All cases of RPLS must be reported via the 
SAE mechanism.
6.3.11 Liver Impairment 
Any patient who experiences signs of hepatic encephalopathy or other serious signs of liver 
impairment such as hepatorenal syndrome must permanently discontinue ramucirumab.
6.3.12 Other non-hematologic toxicity 
Management for Ramucirumab
≤ Grade 1
No change in dose


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Management for Ramucirumab
Grade 2
Hold* until ≤ Grade 1.  
Resume at same dose level.
Grade 3
Hold* until ≤ Grade 1.  
Resume at one lower dose level.
If the same toxicity recurs at grade ≥ 3, protocol therapy will 
be stopped.
Grade 4
Discontinue ramucirumab
*Participants requiring a delay of >4 weeks should go off protocol therapy.
Standard supportive measures for the treatment of nausea, vomiting, fatigue are encouraged, at 
the discretion of the treating provider.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
7.1
Expected Toxicities
7.1.1
Adverse Event List(s) for ramucirumab
Please refer to the Investigator’s Brochure for up to date information regarding adverse events 
associated with ramucirumab.
The most frequently observed, possibly related treatment-emergent adverse events (TEAEs) 
associated with ramucirumab include adverse events (AEs) which have been associated with 
antiangiogenic agents and therapeutic mAbs, and include the following categories: infusion-
related reactions, hypertension, proteinuria, arterial thromboembolic events (ATEs), venous 
thromboembolic events (VTEs), bleeding/hemorrhagic events, gastrointestinal (GI) perforation, 
impaired wound healing, reversible posterior leukoencephalopathy syndrome (RPLS), and 
congestive heart failure (CHF) in patients who received ramucirumab following prior 
anthracycline therapy.
Table 7.2 of the Investigator’s Brochure, summarized below, provides the frequency and severity 
of adverse drug reactions (ADRs) reported in ≥5% of ramucirumab-treated patients in the 
REGARD study, a single-agent, placebo-controlled Phase 3 gastric cancer study.  The list below 
presents the frequency category of ADRs reported in the pooled safety analysis.  ADRs are listed 
according to MedDRA system organ class. Within each system organ class, the adverse reactions 
are ranked by frequency, with the most frequent reactions first. In addition, the corresponding 
frequency category using the following convention (CIOMS III) is also provided for each 


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adverse reaction: very common (≥1/10); common (≥1/100 to <1/10);uncommon (≥1/1,000 to 
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000)
Gastrointestinal Disorders
Very common: abdominal pain, diarrhea
Nervous System Disorders
Common: headache
Metabolism and Nutrition Disorders
Common: hypokalemia, hyponatremia
Vascular Disorders
Very common: hypertension
Clinically relevant ADRs reported in ≥1% and <5% of ramucirumab-treated patients in
REGARD were: neutropenia, ATEs, intestinal obstruction, epistaxis, and rash.
Clinically relevant reactions (including Grade ≥3) associated with antiangiogenic therapy 
observed in ramucirumab-treated patients across clinical trials were proteinuria, infusion-related 
reactions, and GI perforations.
Table 7.3 of the Investigator’s Brochure, summarized below, provides the frequency and severity 
of ADRs reported in ≥5% of ramucirumab-treated patients in the RAINBOW study, a phase III 
study of paclitaxel in combination with ramucirumab compared with paclitaxel with placebo in 
patients with advanced gastric cancer.
Blood and Lymphatic System Disorders
Very common: leukopenia, neutropenia, 
thrombocytopenia
Renal and Urinary Disorders
Very common: proteinuria
Gastrointestinal Disorders
Very common: diarrhea, gastrointestinal 
hemorrhage, stomatitis
Respiratory, Thoracic, Mediastinal 
Disorders
Very common: epistaxis
General Disorders
Very common: fatigue, peripheral edema
Vascular Disorder
Very common: hypertension
Metabolism and Nutrition Disorders
Very common: hypoalbuminemia
Clinically relevant ADRs reported in ≥1% and <5% of the ramucirumab plus paclitaxel treated 
patients in RAINBOW were GI perforations (1.2% for ramucirumab plus paclitaxel versus 0.3% 
for placebo plus paclitaxel) and sepsis (3.1% for ramucirumab plus paclitaxel versus 1.8% for 
placebo plus paclitaxel).
The most frequent (≥5%) ADRs observed in the open-label Phase 2 Study I4T-IE-JVBL (IMCL
CP12-0917) for the nonsquamous population receiving ramucirumab plus platinum-based 
chemotherapy (pemetrexed plus carboplatin or cisplatin) are listed below.
Blood and Lymphatic System Disorders
Very Common: anemia, neutropenia
Common: thrombocytopenia, leukopenia
Nervous System Disorders
Very Common: headache
Common: dysgeusia, neuropathy
Gastrointestinal Disorders
Very Common: nausea, vomiting
Common: constipation, diarrhea, stomatitis
Respiratory, Thoracic  Disorders
Very Common: epistaxis
Common: dyspnea


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General Disorders 
Very Common: fatigued
Common: peripheral edema
Skin and Subcutaneous Tissue Disorders
Common: rash
Investigations
Common: weight decrease
Vascular Disorders
Very Common: hypertension
Metabolism and Nutrition Disorders
Very Common: decreased appetite
Common: hypomagnesemia
7.2
Definitions
7.2.1
Adverse event
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
the treatment.  
Abnormal laboratory values or diagnostic test results constitute adverse events only if they are 
determined to be of clinical significance or require treatment or further diagnostic tests. 
7.2.2
Serious adverse event
A serious adverse event (SAE) is an undesirable sign, symptom or medical condition 
which:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the 
patient’s general condition

is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above.
7.3
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 


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4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.4
Expedited Adverse Event Reporting 
7.4.1
Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form. 
7.4.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
The DFCI IRB requires the following Adverse Events (AE) be reported for all subjects enrolled 
and actively participating in the trial or when the AE occurs within 30 days of the last study 
intervention (e.g. drug administration): 

Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are Unexpected and 
Possibly, Probably or Definitely Related / Associated with the Intervention. 

ALL Grade 4 (life threatening or disabling) Events – Unless expected AND specifically 
listed in protocol as not requiring reporting. 

ALL Grade 5 (fatal) Events 
Notes: 

If subject is in Long Term Follow Up, death is reported at continuing review. 

Grade 2 and Grade 3 laboratory abnormalities that are considered by the investigator to 
be clinically insignificant and do not require therapy, or adjustment in prior therapy, do 
not need to be reported to the DFCI IRB. 
The DFCI IRB AE Reporting Form must be used to report AEs experienced by DF/HCC 
participants enrolled in a DF/HCC study.  The full written AE report must be submitted to OHRS 


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within 10 working days from notification of the event. All AE Reports must be submitted via 
OHRS Submit. No interoffice submissions, faxes or e-mail notifications of AEs will be accepted. 
For follow Up AE Reports: When submitting follow up reports to previously reported AEs, 
please include the prior OHRS AE # in the reporting form.
7.4.3
Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.4.4
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.4.5
Expedited Reporting to Eli Lilly and Company
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method. If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms. This 24- 
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
The Global Product Safety Fax Number for all SAEs for ramucirumab studies is 866-644-1697 
or 317-453-3402
A copy of all submissions to Lilly must be sent to the DF/HCC Overall Principal Investigator.
7.4.6
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1.


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8.1
Ramucirumab
Ramucirumab is a recombinant human monoclonal antibody of the immunoglobulin G 
subclass 1 (IgG1) subclass. It is composed of 4 polypeptide chains, 2 identical heavy (γ) 
chains consisting of 446 amino acids each, and 2 identical light (κ) chains consisting of 
214 amino acids each. The antibody contains 1 conserved N-linked glycosylation site at 
each heavy chain, in the Fc region.
Molecular weight: The ramucirumab molecular masses, determined by mass 
spectrometry, of the light chain and the heavy chain are 23.2 kDa and 50.1 kDa, 
respectively, resulting in a relative molecular mass for the ramucirumab monoclonal 
antibody of 146.8 kDa. The theoretical molecular weights predicted by complementary 
deoxyribonucleic acid (cDNA) of the light chain and the heavy chain are 23.2 kDa and 
48.7 kDa, respectively, resulting in a theoretical relative molecular mass for the 
ramucirumab monoclonal antibody of 143.8 kDa. The difference between the observed 
and theoretical molecular weights, approximately 3 kDa, is attributed to posttranslational 
glycosylation.
Pharmacokinetic data from the 8 studies involving 497 patients were pooled together for 
a population pharmacokinetic (PopPK) analysis. In these studies, ramucirumab was 
administered as a 1-hour I.V. infusion, at either 8 mg/kg once every 2 weeks on a 14- or 
28-day cycle, or 10 mg/kg every 3 weeks on a 21-day cycle. The studies included patients 
with varying cancer indications: gastric cancer (80.5% of patients), non-small cell lung 
cancer (NSCLC; 8.2%), breast cancer (2.2%), colorectal cancer (CRC; 1.6%), and other 
tumor types (7.4%). The geometric mean (percentage coefficient of variation [CV%]) of 
PopPK model-derived estimates of ramucirumab clearance (CL), volume of distribution 
at steady state (Vss) and terminal half-life (t1/2) were 0.0140 L/h (29.8%), 5.5 L (14.4%), 
and 15 days (24.1%), respectively. 
8.1.1
Form
Ramucirumab DP 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 or 
100mg/10mL vial). The buffer contains 10mM histidine, 75mM sodium chloride, 
133mM glycine, and 0.01% polysorbate 80.  Ramucirumab DP is a clear to slightly 
opalescent and colorless to slightly yellow liquid without visible particles. The pH is 6.0. 
The osmolality is 285 mmol/kg. All excipients used for the manufacture of ramucirumab 
DP are of pharmacopeial grade.  No animal-derived components are used in the 
manufacture of ramucirumab DP excipients.
8.1.2
Storage and Stability
PREPARED RAMUCIRUMAB DOSING SOLUTION FOR INFUSION: Chemical and 
physical in-use stability for the prepared ramucirumab dosing solution has been 
demonstrated for up to 24 hours below 25°C (77°F). However, it is recommended that the 
prepared dosing solution be used immediately in order to minimize the risk of microbial 


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contamination. If not used immediately, the prepared ramucirumab dosing solution 
should be stored under refrigeration at 2°C to 8°C (36°F to 46°F), for a duration not to 
exceed 24 hours. If the prepared solution is held at room temperature (below 25°C 
[77°F]), it must be used within 4 hours. This recommendation supersedes the room 
temperature storage recommendation of up to 24 hours specified in some study protocols. 
Store protected from light. Brief exposure to ambient light is acceptable while 
preparation and administration is taking place. DO NOT FREEZE AND/OR SHAKE 
PREPARED RAMUCIRUMAB
8.1.3
Compatibility
DO NOT dilute with other solutions or co-infuse with other electrolytes or medication.
8.1.4
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
8.1.5
Availability
Ramucirumab will be provided by Eli Lilly and Company from investigational supply.
8.1.6
Preparation
1. Prepare the infusion solution using aseptic technique to ensure the sterility of the 
prepared solution.
2. Each vial is intended for single use only. Inspect the content of the vials for particulate 
matter and discoloration prior to dilution. If particulate matter or discolorations are 
identified, discard the vial.
3. Calculate the dose and volume of ramucirumab needed to prepare the infusion 
solution. Vials contain either 100 mg or 500 mg as a 10 mg/mL solution of ramucirumab. 
Only use sterile sodium chloride (0.9%) solution for injection as a diluent. DF/HCC sites 
will use their own practices with regards to calculating doses based on body weight (kg).
In case of prefilled I.V. infusion container usage:
Based on the calculated volume of ramucirumab, remove the corresponding volume of 
sterile sodium chloride (0.9%) solution for injection from the prefilled 250 mL I.V. 
container. Aseptically transfer the calculated volume of ramucirumab to the I.V. 
container. The final total volume in the container should be 250 mL. The container 
should be gently inverted 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.


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In case of empty I.V. infusion container usage: 
Aseptically transfer the calculated volume of ramucirumab into an empty I.V. container. 
Add a sufficient quantity of sterile sodium chloride (0.9%) solution for injection to the 
container to make the total volume 250 mL. The container should be gently inverted 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 medication.
4. Parenteral drug products should be inspected visually for particulate matter prior to 
administration. If particulate matter is identified, discard the infusion solution.
5. Discard any unused portion of ramucirumab left in a vial, as the product contains no 
preservatives.
8.1.7
Administration
Ramucirumab will be administered as a 1-hour IV infusion on Days 1 and 15 of a 28-day 
cycle.  The infusion rate of ramucirumab should not exceed 25 mg/min. DF/HCC sites 
will use their own practices with regards to calculating doses based on body weight (kg).
Administer via infusion pump. A separate infusion line with a protein-sparing 0.22 
micron filter must be used for the infusion and the line must be flushed with sterile 
sodium chloride (0.9%) solution for injection at the end of the infusion.
If a patient experiences a Grade 1 or 2 infusion-related reaction (IRR), premedication 
must be given for all subsequent infusions.   If a patient has a second Grade 1 or 2 IRR, 
administer dexamethasone; for subsequent infusions, premedicate with the following or 
equivalent medications: diphenhydramine hydrochloride (I.V.), acetaminophen, and 
dexamethasone, as outlined in Section 6 of the protocol.
8.1.8
Ordering
Eli Lilly and Company provides commercially packaged material for investigator-
initiated studies and provides labeling for the material to be limited to investigational use 
only. For Investigational Product Reorders, please send a completed form to both:
data_account_usmail-sdc@lilly.com and iits_usmail-oncology@lilly.com  
Allow 5-7 business days for shipment to arrive.
If a Reorder Form is not available, please send an email request to iits_usmail-
oncology@lilly.com including the following in the request:

Lilly Trial Alias –I4T-US-I005

Principal Investigator’s Name

Institute’s shipping address

Name of the person receiving product in the pharmacy


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
Email address for pharmacy contact

Phone & Fax Number

Name of Compound
o
Ramucirumab (Cyramza) 500 mg vials
o
Ramucirumab (Cyramza) 100 mg vials

Number of vials needed

Date product needed to arrive at site
8.1.9
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.10 Destruction and Return
At the end of the study, unused supplies of ramucirumab will be either destroyed per 
institutional policy or returned to Eli Lilly as directed.


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9. STUDY CALENDAR
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 2 days of the protocol-specified date, unless 
otherwise noted.
REQUIRED 
INFORMATION/EXAMS
Pre-
Studya
Day 1 
of each 
cyclea
Day 15 
of each 
cycle
Restagingb
Off-
Treatmentc
Follow-Up 
(Overall 
Survival)
Informed consent
X
Medical and Oncologic 
History
X
X
X
X
Concurrent meds
X
X
X
X
Physical exam (including 
height, weight, blood 
pressure, pulse)
X
X
X
X
Xc
ECOG Performance Status
X
X
X
X
Xc
Adverse event evaluation
X
X
X
CBC with differential
X
X
X
X
PT/PTT
X
Bilirubin, ALT, AST, 
Albumin, Alkaline 
Phosphatase
X
X
X
X
BUN, Cr, electrolytes, 
including Na, K, Cl, 
HCO3, Ca, Phosphate, Mg
X
X
X
X
Urinalysis with assessment 
of urine protein
X
X
X
β-HCGd
X
EKGf
X
X
Radiographic evaluationb
X
X
X
Xc
Chromogranin A, 24-hr 
urine 5-HIAAe
X
X
X
Xc
a. Screening assessments must occur within 14 days of start of ramucirumab administration. Pre-registration labs 
may be used for Day#1 of Cycle#1 if obtained within 7 days of starting treatment. For subsequent cycles, labs must 
be obtained within 48 hours of start of treatment
b. Baseline scans must be performed within 28 days of start of study therapy.  Restaging scans will be performed 
every 12 weeks until disease progression, or end of study treatment. All patients will receive an arterial and venous 
phase Chest/Abdomen/Pelvic CT. A liver MRI with gadolinium may be included at the discretion of the treating 
physician. Please note, Multiphase CT scan (chest/abdomen/pelvis) is the preferred modality for imaging. 
Equivalent modalities (e.g., CXR and MRI scan of abdomen and chest) may be used at the discretion of the 
investigator.


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c. For patients who discontinue study treatment prior to tumor progression, physical examination, performance 
status, chromogranin A, and radiologic imaging studies should be performed every 12 +/-1  weeks until tumor 
progression or the start of a new anticancer therapy.  Patients who discontinue treatment at the time of tumor 
progression should be followed every 6 months +/- 1 week for survival, with chromogranin A and imaging studies at 
the discretion of the investigator. 
d. Serum pregnancy test (women of childbearing potential)
e. Chromogranin A will be assessed every 12 weeks.  24-hour urine 5-HIAA will be assessed and followed as 
clinically indicated every 12 weeks.
f. EKG assessments will be performed with standard 12-lead EKG equipment according to standard procedures. 
Abnormalities in the EKG that lead to a change in subject management (eg, dose reduced or withheld, requirement 
for additional medication or monitoring) or result in clinical signs and symptoms are considered clinically 
significant for the purposes of this study and will be recorded on the AE CRF. If values meet criteria defining them 
as serious, they must be reported as SAEs.
10. MEASUREMENT OF EFFECT
10.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 12 weeks.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
10.1.1 Definitions
Evaluable for Target Disease Response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
10.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 


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measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
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 participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 


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10.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 


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progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD.
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].


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Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease
10.1.4 Response Criteria
10.1.4.1
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
10.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
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.    


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Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
10.1.4.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
10.1.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target Lesions
New Lesions
Overall 
Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-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

See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion.
Note:  Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at 


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that time should be reported as “symptomatic deterioration.”  Every effort should 
be made to document the objective progression even after discontinuation of 
treatment.
10.1.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
10.1.6 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from registration to death 
due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation.
11. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
11.1
Data Reporting
11.1.1 Method
The ODQ will collect, manage, and perform quality checks on the data for this study.
11.1.2 Responsibility for Data Submission


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Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ.
11.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
12. STATISTICAL CONSIDERATIONS
12.1
Study Design/Endpoints
The primary objective of this study is to assess the progression-free survival duration of patients 
with advanced, progressive carcinoid tumors treated with ramucirumab in combination with 
somatostatin analog therapy.  Patients will be accrued in one stage.
Progression-Free Survival (PFS) is defined as the time from registration to the earlier of 
progression as defined by RECIST criteria or death due to any cause. Patients will be censored in 
the analysis of PFS at the time they begin a new anti-cancer therapy if disease has not met the 
criteria for progression at the time the new treatment is started.  Participants alive without disease 
progression are censored at date of last disease evaluation.  
We will use the Kaplan-Meier method to estimate the distribution of progression-free survival.   
12.2
Sample Size, Accrual Rate and Study Duration
Recent studies of targeted agents in neuroendocrine tumors suggest that while many of these 
agents are associated with low RECIST-defined response rates, they may be associated with 
significant improvements in progression-free survival. In the registration studies of sunitinib and 
everolimus in pancreatic neuroendocrine tumors, for example, PFS durations more than doubled 
while overall response rates were only 9% and 4%, respectively.(Raymond, Dahan et al. 2011, 
Yao, Shah et al. 2011)


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In this study, we propose using PFS as the primary outcome measure. We note that all patients in 
our study will receive a somatostatin analog. The RADIANT 2 study provides a reasonable 
estimate of PFS duration in a large cohort of carcinoid tumor patients treated with either a 
somatostatin analog or somatostatin analog and an investigational agent.(Pavel, Hainsworth et al. 
2011) RADIANT 2 randomized 429 patients with a history of symptoms attributed to carcinoid 
syndrome and evidence for radiographic progression within 12 months of enrollment to receive 
everolimus plus octreotide LAR, or placebo plus octreotide LAR. A significant PFS benefit in 
favor of everolimus was demonstrated based on investigator radiology review (12 vs. 8.6 
months, p<0.01). However, the primary endpoint of the study was based on adjudicated central 
review, and while this analysis also favored the everolimus arm over placebo, the predefined 
threshold for statistical significance was not met. 
Investigator radiology review will be used to determine the primary endpoint in our study. We 
assume that an inactive agent will be associated with a PFS of 8 months, and that an agent 
worthy of further investigation will be associated with a PFS of 12 months or greater. A sample 
size of 43 achieves 80% power to detect the difference between the null hypothesis median PFS 
of 8 months and the alternative hypothesis median PFS of 12 months at a 0.05 significance level 
(alpha) using a one-sided test. The length of follow up is 2 years.
The expected accrual rate is 6 patients per quarter with an accrual period of 2 years.  
The end of the study will be defined as the time at which all protocol specified time points have 
passed and/or follow-up data are sufficiently mature for analysis. 
12.3
Analysis of Primary Endpoints
Analysis of endpoints of this study is described in Section 12.1.
12.4
Analysis of Secondary Endpoints
Secondary objectives of this study are to:

To determine the safety and tolerability of ramucirumab in combination with 
somatostatin analog therapy in patients with advanced carcinoid tumors.  We will assess 
the rate of adverse events (as defined by Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0), associated with treatment.
Because adverse events associated with the combination of ramucirumab and a somatostatin 
analog have not examined previously, toxicity and adverse events will be examined in the 
first 10 patients who complete one cycle of therapy before expanding enrollment.

To assess the overall radiographic and biochemical response rate associated with 
ramucirumab in patients with advanced carcinoid tumors.  We will estimate the response 
rate and provide the associated 95% confidence interval.


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
To assess the overall survival duration of patients with advanced carcinoid tumors treated 
with ramucirumab.  We will use the Kaplan-Meier method to estimate the distribution of 
overall survival.
12.5
Reporting and Exclusions
12.5.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment.
12.5.2 Evaluation of the Primary Efficacy Endpoint
Analyses will be conducted on an intent-to-treat basis.  Specifically, all eligible 
participants included in the study must be assessed for response/outcome to therapy, even 
if there are major protocol therapy deviations.  
Subanalyses may then be performed on the basis of a subset of participants, excluding 
those for whom major protocol deviations have been identified (e.g., early death due to 
other reasons, early discontinuation of treatment, major protocol violations, etc.).  
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding participants from the 
analysis should be clearly reported.  If applicable to the endpoint, the 95% confidence 
intervals should also be provided. 
13. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 


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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.