Conditions: Non-small Cell Lung Cancer
Keywords: ramucirumab docetaxel
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
The subjects who take part in this clinical research study have advanced non-small cell lung cancer (NSCLC) that has been previously treated with other drugs. If they join this study, they would receive ramucirumab (Cyramza ®) in combination with nab-paclitaxel (Abraxane®). Ramucirumab given with nab-paclitaxel is considered an investigational drug combination to use in this type of cancer because giving these two drugs together has not been approved by any regulatory authority like the US Food and Drug Administration (FDA) for NSCLC cancer. Ramucirumab works by slowing or stopping the growth of cancer cells. Nab-Paclitaxel works by blocking the ability of cancer cells to break down the internal 'skeleton' that allows them to divide and multiply. With the skeleton still in place, the cells cannot divide and they eventually die.

Detailed description:
Ramucirumab is a human IgG1 (Immunoglobulin G) monoclonal antibody that targets the extracellular domain of VEGFR-2 (vascular endothelial growth factor receptor). A recent double-blind, placebo-controlled clinical trial evaluated the addition of ramucirumab to docetaxel compared with docetaxel and placebo in patients with Stage IV squamous and non-squamous NSCLC in the 2nd-line treatment setting. This study demonstrated a superior overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with the combination therapy compared with docetaxel with placebo. This effect was seen across histologic subtypes, in the absence of excess toxicity in patients with squamous cell histology. This finding is intriguing, as prior study of bevacizumab in patients with NSCLC of squamous cell histology was associated with excess pulmonary hemorrhage. This provides the rationale for further investigation of ramucirumab in patients with squamous cell NSCLC.

nab-Paclitaxel is a formulation of paclitaxel complexed with albumin that is readily soluble in saline and allows administration of paclitaxel without the use of lipid-based solvents and the need for corticosteroid and antihistamine premedication. nab-Paclitaxel was approved for the 1st line treatment of NSCLC based on a trial which demonstrated a superior ORR with the addition of nab-paclitaxel to carboplatin compared with carboplatin/paclitaxel in patients with advanced and metastatic NSCLC, as well as prolonged PFS and OS without statistical significance. The subgroup analysis by tumor histology demonstrated a statistically significant advantage for nab-paclitaxel/carboplatin in terms of best overall response rate (41% vs 24%, p\<0.001), and numerically better PFS and OS in squamous NSCLC. \[3\]

This is a single-arm phase II clinical trial, in which patients with previously treated NSCLC will be treated with ramucirumab/nab-paclitaxel until disease progression, unacceptable treatment-related toxicity or withdrawal of consent with the primary endpoint of progression-free survival. A minimum of 40 patients with squamous cell histology will be required for determination of the co-primary endpoint. The investigators hypothesize that the addition of ramucirumab to nab-paclitaxel is well-tolerated and associated with a superior PFS compared with single agent taxane-based therapy.

Arms:
arm 1: Ramucirumab will be administered through a vein in the arm as a 60 minute infusion at a dose of 8 mg/kg on days 1 and 15 of a 28-day cycle.

The nab-paclitaxel will be administered through a vein in the arm as a 30 minute infusion at a dose of 100 mg/m2 on days 1, 8 and 15 of a 28 day cycle.

Interventions: intervention 1: ramucirumab intervention 2: nab-paclitaxel
Intervention descriptions: intervention 1: it is administered through a vein in the arm as a 60 minute infusion at a dose of 8 mg/kg on days 1 and 15 of a 28-day cycle. intervention 2: it is administered through a vein in the arm as a 30 minute infusion at a dose of 100 mg/m2 on days 1, 8 and 15 of a 28 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
HCC 15-169 
Version Date 09 July 2018 
 
1 
 
TITLE: A phase II clinical trial of the safety and efficacy of the addition of ramucirumab to 
nab-paclitaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) 
 
HCC #: 
15-169 
BB-IND#: 
N/A 
Phase: 
Phase II 
Version: 
 5 
Version Date: 
 July 9, 2018 
Commercial Agents: 
Ramucirumab; nab-Paclitaxel 
 
Sponsor-Investigator: 
Liza C. Villaruz  
 
5150 Centre Avenue, 5th Floor 
 
T: 412-648-6577 
 
F: 412-648-6579 
 
villaruzl@upmc.edu 
 
Biostatistician: 
Brenda Kurland, PhD 
 
T 412-383-1128 
 
bfk10@pitt.edu 
 
Source(s) of Support: 
Lilly  
 
Study Monitor: 
Education and Compliance Office for Human Subject 
Research 
Research Conduct and Compliance Office 
University of Pittsburgh 
3500 Fifth Avenue, Suite 205 
Pittsburgh, PA 15213 
 
 
 
 


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SCHEMA 
Ramucirumab is a human IgG1 (Immunoglobulin G) monoclonal antibody that targets the 
extracellular domain of VEGFR-2 (vascular endothelial growth factor receptor).  A recent 
double-blind, placebo-controlled phase III clinical trial (REVEL) evaluated the addition of 
ramucirumab to docetaxel compared with docetaxel and placebo in patients with Stage IV 
squamous and non-squamous NSCLC in the 2nd-line treatment setting. [2] This study 
demonstrated a superior overall survival (OS), progression-free survival (PFS), and overall 
response rate (ORR) with the combination therapy compared with docetaxel with placebo.  This 
effect was seen across histologic subtypes, in the absence of excess toxicity in patients with 
squamous cell histology.  This finding is intriguing, as prior study of bevacizumab in patients 
with NSCLC of squamous cell histology was associated with excess pulmonary hemorrhage.  
This provides the rationale for further investigation of ramucirumab in patients with squamous 
cell NSCLC.   
 
nab-Paclitaxel is a formulation of paclitaxel complexed with albumin that is readily soluble in 
saline and allows administration of paclitaxel without the use of lipid-based solvents and the 
need for corticosteroid and antihistamine premedication.   nab-Paclitaxel was approved for the 
1st line treatment of NSCLC based on a trial by Socinski et al. which demonstrated a superior 
ORR with the addition of nab-paclitaxel to carboplatin compared with carboplatin/paclitaxel in 
patients with advanced and metastatic NSCLC, as well as prolonged PFS and OS without 
statistical significance.  The subgroup analysis by tumor histology demonstrated a statistically 
significant advantage for nab-paclitaxel/carboplatin in terms of best overall response rate (41% 
vs 24%, p<0.001), and numerically better PFS and OS in squamous NSCLC. [3]  
 
This is a single-arm phase II clinical trial, in which patients with previously treated NSCLC will 
be treated with ramucirumab/nab-paclitaxel until disease progression, unacceptable treatment-
related toxicity or withdrawal of consent with the primary endpoint of progression-free survival.  
A minimum of 40 patients with squamous cell histology will be required for determination of the 
co-primary endpoint.  We hypothesize that the addition of ramucirumab to nab-paclitaxel is well-
tolerated and associated with a superior PFS compared with single agent taxane-based therapy.   
 
Primary objectives:  
• 
To evaluate the safety of the addition of ramucirumab to nab-paclitaxel 
• 
To evaluate the efficacy of ramucirumab/nab-paclitaxel as determined by PFS in 
the histologically unselected population 
Stage IV NSCLC with disease 
progression after at least one 
prior platinum-based 
chemotherapy for advanced 
disease
N=80
(Minimum 40 patients with 
squamous cell histology will be 
accrued.)
nab-Paclitaxel 100 mg/m2 IV 
Day 1, 8 and 15 
Ramucirumab 8 mg/kg IV 
Day 1 and day 15 and 
28 day cycle


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• 
To evaluate the efficacy of ramucirumab/nab-paclitaxel as determined by PFS in 
patients with squamous cell histology 
 
Secondary objectives: 
• 
To evaluate the efficacy of ramucirumab/nab-paclitaxel as determined by ORR 
and OS in all patients and in patients with squamous cell histology 
• 
To evaluate patient-reported symptoms and quality-of-life using the EuroQoL 
Five Dimensions questionnaire (EQ-5D-5L) [1]. 
 
Interim analysis: 
• 
Ramucirumab/nab-paclitaxel is a novel combination, but a dose finding study is 
not planned since prior addition of monoclonal antibodies to cytotoxic therapies 
has been safe and tolerable, in the absence of overlapping toxicities.  However, 
enrollment will be halted for a safety review after C2D21 for the 6th patient with 
squamous cell histology, and separately for the first 6 patients without squamous 
cell histology.  Dose delivered and adverse events for those patients will be 
examined, and the decision to continue as planned or modify the protocol in any 
way will be made by the disease center Data and Safety Monitoring Board 
(DSMB) and the University of Pittsburgh Cancer Institute (UPCI) Data and 
Safety Monitoring Committee (DSMC).   
 
Statistical Methods: 
• 
For the unselected population (squamous and non-squamous) and for the 
subgroup of squamous NSCLC only, the PFS curve and a 90% confidence 
interval for the median PFS will be estimated by standard methods (the Kaplan-
Meier method for survival, and the Greenwood variance formula applied to log-
transformed survival).  Sampling weights will be used to approximate PFS for the 
unselected population, in which about 25% of the study population has disease 
with squamous histology [2].  
• 
Power calculations assume accrual of 80 patients at a uniform rate over 2 years, 
with 10 months of additional follow-up. A minimum of 40 patients with NSCLC 
of squamous cell histology will be accrued, e.g. after 40 patients with non-
squamous histology have been enrolled, the remaining patients must have 
squamous cell histology.  Simulating data with median 5 months PFS 
(exponential distribution), the lower bound of the 90% confidence interval for 
median PFS was greater than 3 months for 93% of 10,000 simulated datasets of 
size n=80 and 75% for size n=40.  Therefore, we conclude that with two-sided 
alpha=0.1, the study has 93% power to conclude that the median PFS is unlikely 
to be 3 months or less in an unselected population, and 75% power for the 
squamous histology subgroup.   The average width of the confidence interval for 
median PFS for squamous histology is expected to be about 3.8 months (ie, 90% 
confidence interval 3.6-7.4 months).  The null rate of 3 months is from the median 
TTP of 2.7 months (median OS of 7 months) in previously treated advanced stage 
NSCLC patients treated with single agent docetaxel [4].   
• 
Patient-reported symptoms and quality-of-life will be assessed using the EuroQoL 
Five Dimensions questionnaire[1]. 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives...................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Non-Small Cell Lung Cancer...................................................................................8 
2.2 
Agents ....................................................................................................................10 
2.3 
Rationale ................................................................................................................17 
3. 
PATIENT SELECTION ....................................................................................................17 
3.1 
Inclusion Criteria ...................................................................................................17 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4. 
REGISTRATION PROCEDURES ...................................................................................21 
4.1 
General Guidelines.................................................................................................21 
4.2 
Registration Process ...............................................................................................21 
5. 
TREATMENT PLAN ........................................................................................................22 
5.1 
Agent Administration.............................................................................................22 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................24 
5.3 
Patient Reported Outcomes for EQ-5D-5L............................................................24 
5.4 
Duration of Therapy ...............................................................................................25 
5.5 
Duration of Follow Up ...........................................................................................25 
5.6 
Criteria for Removal from Study ...........................................................................25 
6. 
DOSING DELAYS/DOSE MODIFICATIONS/Treatment Discontinuation ...................25 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................28 
7.1 
Adverse Events and Risks Lists .............................................................................29 
7.2 
Definitions..............................................................................................................30 
7.3 
Reporting of Suspected Adverse Reactions ...........................................................31 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................32 
8.1 
Ramucirumab .........................................................................................................32 
8.2 
nab-Paclitaxel ........................................................................................................32 
9. 
STUDY CALENDAR .......................................................................................................34 
10. 
MEASUREMENT OF EFFECT........................................................................................36 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................36 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................42 


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11.1 
Data Safety Monitoring Plan .................................................................................42 
11.2 
Quality Control and Quality Assurance .................................................................43 
11.3 
Data Handling and Record-Keeping ......................................................................43 
11.4 
Institutional Review Board (IRB) Approval ..........................................................43 
11.5 
Ethical and Scientific Conduct of the Clinical Study ............................................44 
11.6 
Informed Consent...................................................................................................44 
12. 
STATISTICAL CONSIDERATIONS...............................................................................45 
12.1 
Study Design/Endpoints.........................................................................................45 
12.2 
Reporting and Exclusions ......................................................................................46 
REFERENCES ..............................................................................................................................48 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................54 
APPENDIX B 
EuroQoL EQ-5D-5L Questionnaire [1, 69-76] ..........................................55 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration time curve 
AUC0-last 
AUC from time zero to the last quantifiable time point 
AUC0-∞ 
AUC from time zero to infinity 
AUC0-inf 
AUC from time zero to infinity 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Cmax 
maximum plasma concentration 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DVT 
deep vein thrombosis 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
EQ-5D-5L 
EuroQoL Five Dimensions questionnaire 
FDA 
Food and Drug Administration 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
HCC 
hepatocellular carcinoma 
HR 
hazard ratio 
ICH 
International Conference on Harmonisation 
IgG1 
Immunoglobulin G 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
MI 
myocardial infarction 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NRP-1 
Neuropilin-1 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small-cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PE 
pulmonary embolism 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetic 
PR 
partial response 
PT 
prothrombin time 


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PTT 
partial thromboplastin time 
QTc 
corrected QT 
RPLS 
reversible posterior leukoencephalopathy syndrome 
RR 
response rate 
SAE 
serious adverse event 
SD 
stable disease 
TK 
toxicokinetic 
TKI 
tyrosine kinase inhibitor 
TIA 
transient ischemic attack 
ULN 
upper limit of normal 
VEGF(R) 
vascular endothelial growth factor (receptor) 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• To evaluate the safety of the addition of ramucirumab to nab-paclitaxel 
• To evaluate the efficacy of ramucirumab/nab-paclitaxel as determined by PFS in the 
histologically unselected population 
• To evaluate the efficacy of ramucirumab/nab-paclitaxel as determined by PFS in patients 
with squamous cell histology 
 
1.2 
Secondary Objectives 
 
• To evaluate the efficacy of ramucirumab/nab-paclitaxel as determined by ORR and OS in 
all patients and in patients with squamous cell histology 
• To evaluate patient-reported symptoms and quality-of-life using the EuroQoL Five 
Dimensions questionnaire (EQ-5D-5L) 
 
2. BACKGROUND 
 
2.1 
Non-Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer mortality in the United States and worldwide[5]. An 
estimated 224,210 new cases of lung cancer will be diagnosed in 2014 in the United States alone, 
and 159,260 lung cancer deaths are estimated to occur[4]. Historically, palliative chemotherapy 
in the metastatic non–small cell lung cancer (NSCLC) setting resulted in modest survival 
prolongation and preservation of quality of life.[6-10] A series of large randomized controlled 
phase 3 clinical trials established platinum-based doublets as the standard of care in the  1st line 
treatment of metastatic NSCLC with response rates (RR) of 20 to 30% and a median survival of 
8 to 11 months.[11-15]  Currently approved 2nd line therapies for advanced NSCLC include 
docetaxel, erlotinib and pemetrexed[4, 16-18].  Treatment in the 2nd line setting is associated 
with a limited ORR of less than 10%, a median PFS of less than 4 months and a median OS of 7-
9 months[19]. Treatment of patients with squamous cell histology NSCLC in particular is an 
unmet need because of lack of driver mutations associated with response to currently approved 
agents and significant risk of hemoptysis associated with treatment of monoclonal antibodies 
targeting vascular endothelial growth factor (VEGF). 
 
Overexpression VEGF has been found in most human tumors, including NSCLC, and is 
associated with increased tumor recurrence, metastasis and death [20-24].  The angiogenic 
phenotype is considered a hallmark of the malignant process whereby proangiogenic 
mechanisms overwhelm or circumvent the negative regulators of angiogenesis[25].  The 
VEGF/VEGF-receptor (VEGFR) pathway plays a pivotal role in normal and pathologic 
angiogenesis[26].  VEGF pathway activation leads to endothelial cell survival, mitogenesis, 
migration and differentiation and mobilization of endothelial progenitor cells from the bone 
marrow into the peripheral circulation [26].   
 
The VEGF-related gene family is composed of six secreted glycoproteins referred to as VEGF-


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A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placenta growth factor (PlGF) -1 and -2[27-29].  
VEGF-A (commonly referred to as VEGF) is an endothelial specific mitogen with a diverse 
range of angiogenic activities[30].  VEGF-A undergoes alternate splicing to yield isoforms of 
121, 165, 189 and 206 amino acids, which have distinct tissue specific expression patterns, 
suggesting defined roles in vasculogenesis and tumor angiogenesis[28, 29, 31-33].  The VEGF 
ligands mediate their effect through several receptor tyrosine kinases [26].  All isoforms of 
VEGF bind to VEGFR-1 and VEGFR-2, whereas PlGF-1 and -2 and VEGF-B specifically bind 
and activate VEGFR-1[34-36].  While VEGFR-1 is critical for physiologic and developmental 
angiogenesis, the precise function of VEGFR-1 in angiogenesis is unclear [26].  The majority of 
the effects of VEGF are mediated through binding of VEGFR-2, which leads to microvascular 
permeability, invasion, migration and survival [37-39].  Other mediators of the VEGF ligands 
include VEGFR-3, which may be involved in cardiovascular development and vascular 
remodeling during embryogenesis and lymphangiogenesis in the adult, and Neuropilin-1 (NRP-
1) and NRP-2, which are likely to serve as co-receptors for VEGF[26].   
 
Recognition of the VEGF pathway as a key mediator of angiogenesis has led to the clinical study 
of several VEGF targeted therapies in lung cancer.  These targeted therapies include neutralizing 
antibodies to VEGF (bevacizumab and aflibercept) and VEGFR-2 (ramucirumab) and receptor 
tyrosine kinase inhibitors (TKIs) with preferential selectivity for the VEGFRs.   
 
Ramucirumab is a fully human IgG1 monoclonal antibody that specifically binds to the VEGFR-
2 extracellular domain with high affinity, preventing binding of all VEGF ligands and receptor 
activation and signaling[52].  Two phase II clinical trials have assessed the addition of 
ramucirumab to platinum doublet chemotherapy in the 1st line setting.  Camidge et al. enrolled 
squamous and non-squamous patients on a single arm trial of carboplatin/paclitaxel/ramucirumab 
and demonstrated tolerability of this regimen, a RR of 55%, a median PFS of 7.9 months and OS 
of 17.9 months[53].  Of interest in this single-arm trial, the single-nucleotide polymorphism 
(SNP) rs2981582 on the FGFR-2 gene had significant associations with improved overall 
survival, PFS, and best overall response.  Doebele et al. randomized patients with non-squamous 
NSCLC to either platinum/pemetrexed or platinum/pemetrexed/ramucirumab and demonstrated 
no statistically significant improvements in PFS (5.6 versus 7.2 months, respectively, HR 0.75, P 
= 0.132), OS (10.4 versus 13.9 months, HR 1.03, P = 0.892), and RR (38.0% and 49.3%, 
respectively, P = 0.180) and no new or unexpected safety findings[40].  
 
The REVEL clinical trial is a randomized phase III clinical trial which assessed the addition of 
ramucirumab to docetaxel compared with docetaxel/placebo in patients with squamous or non-
squamous advanced NSCLC after platinum based chemotherapy.  This trial met its primary 
endpoint demonstrating an OS advantage with the addition of ramucirumab (9.1 months with 
docetaxel/ramucirumab versus 10.5 months with docetaxel/placebo, HR 0.86, P = 0.023), in 
addition to a PFS prolongation (4.5 versus 3.0 months, respectively, HR 0.76, p<0·0001; Table 
1; Figure 2b) and improvement in RR (23% versus 14%, respectively, OR 1.89, p<0.0001; Table 
1[2]).  Although this study was not powered for subgroup analyses, most subgroups of patients 
had numerically longer survival with the addition of ramucirumab compared with 
docetaxel/placebo, including patients with non-squamous disease (11.1 versus 9.7 months, 
respectively, HR 0.83, 95% CI 0.71–0.97), patients with squamous disease (9.5 versus 8.2 
months, HR 0.88, 95% CI 0.69–1.13), and responders to first-line platinum therapy (11.2 versus 


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10.3 months, HR 0.84, 95% CI 0.71–0.99).  The most common grade 3 or worse adverse events 
were neutropenia (49% patients in the ramucirumab group versus 40% in the placebo group), 
febrile neutropenia (16% versus 10%), fatigue (14% versus 10%), leukopenia (14% versus 12%), 
and hypertension (6% versus 2%). The numbers of deaths from adverse events (5% versus 6%) 
and grade 3 or worse pulmonary hemorrhage (1% versus 1%) did not differ between the 
treatment groups. The efficacy of ramucirumab in combination with docetaxel across NSCLC 
histologies and the safety with regard to the risk of pulmonary hemorrhage make ramucirumab of 
particular interest in patients with squamous cell NSCLC. 
 
nab-Paclitaxel is a formulation of paclitaxel complexed with albumin that is readily soluble in 
saline and allows administration of paclitaxel without the use of lipid-based solvents and the 
need for corticosteroid and antihistamine premedication.   nab-Paclitaxel was approved for the 
1st line treatment of NSCLC based on a trial by Socinski et al. which demonstrated a superior 
ORR with the addition of nab-paclitaxel to carboplatin compared with carboplatin/paclitaxel in 
patients with advanced and metastatic NSCLC, as well as numerically longer PFS and OS 
without statistical significance.  The subgroup analysis by tumor histology demonstrated a 
statistically significant advantage for nab-paclitaxel/carboplatin in terms of best overall response 
rate (41% vs 24%, p<0.001), and numerically better PFS and OS in squamous NSCLC [2].  
More importantly, the overall toxicity profile, with the exception of anemia and 
thrombocytopenia favor nab-paclitaxel over paclitaxel.   
 
 
 
2.2 
Agents 
 
2.2.1 Ramucirumab 
 
Mechanism of Action 
Ramucirumab (IMC-1121B [LY3009806]) drug substance 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 2 
and its downstream intracellular signaling components, including Erk1/Erk2, neutralizing ligand 
induced proliferation and migration of human endothelial cells[41-46]. 
 


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Potent antiangiogenic and antitumor effects have been demonstrated in murine models with the 
administration of DC101, a rat antibody to murine ortholog of VEGF Receptor 2 (ramucirumab 
does not cross-react with the murine VEGF Receptor 2; therefore, DC101 was used in murine 
models as a proof-of-principle surrogate antibody)[47-49].  DC101 administration resulted in a 
reduced rate of tumor growth and in lower tumor microvessel density characteristic of 
antiangiogenic agents. Thus, the primary mechanism of action of DC101 appropriately models 
the expected primary mechanism of the antitumor effect of ramucirumab [26, 50, 51]. The 
efficacy of DC101 has been demonstrated in numerous mouse xenograft solid tumor models, 
providing a rationale for evaluation of ramucirumab in clinical studies in patients with multiple 
malignancies. 
 
Clinical Data 
 
A comprehensive clinical development program to evaluate ramucirumab focusing on tumors 
where VEGF ligands (including VEGF-A) and VEGF Receptor 2 are overexpressed and/or 
where the unmet medical need is high was initiated following Phase 1 studies evaluating dose, 
schedule, and toxicity.  As of 31 December 2013, ramucirumab DP or ramucirumab DP/placebo 
has been administered either as a single agent or in combination with various antineoplastic 
agents to approximately 7000 patients with different oncologic conditions in Phase 1/1b, Phase 
2, and Phase 3 clinical trials. Based upon actual exposure data from completed clinical trials and 
the enrollment/ randomization schemes for ongoing trials (for which the development program 
team remains blinded), an estimated 4002 patients have received ramucirumab with 932 patients 
receiving single-agent ramucirumab and 3070 patients receiving ramucirumab in combination 
with antineoplastic agents. 
 
Ramucirumab has shown clinical efficacy in patients with gastric cancer in 2 randomized Phase 
3 trials: REGARD (I4T-IE-JVBD; IMCL CP12-0715) (ramucirumab monotherapy with best 
supportive care [BSC]) and RAINBOW (I4T-IE-JVBE; IMCL CP12-0922) (ramucirumab in 
combination with paclitaxel). A Phase 3 trial (ROSE [I4T-IE-JVBC; IMCL CP12-0606]) 
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. 
 
Safety 
 
The nonclinical toxicity of ramucirumab DP was investigated in cynomolgus monkeys. This 
toxicology evaluation involved a 5-week study (administration of 4 ramucirumab DP doses over 
5 weeks [dose range, 4-40 mg/kg]) and a 39-week study (weekly ramucirumab DP for up to 
39 weeks [dose range, 5-50 mg/kg]). Clinically observable, ramucirumab DP-related adverse 
events (AEs) were infrequent and mild in these evaluations. The most notable AEs were renal 
toxicity (observed in the 39-week study at 16- and 50-mg/kg/week doses), manifested by 
elevations in blood urea nitrogen, serum creatinine, and urinary protein, and diffuse 
glomerulonephritis at necropsy. Thickening and osteochondropathy of the epiphyseal growth 
plates (observed in the 39-week study at 5-mg/kg/week doses and greater) were also noted. 
 


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As of 31 December 2013, AE information was available for 2485 patients receiving 
ramucirumab 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) is available in Section 6.2.1 and Section 7.3.8 of the ramucirumab 
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. 
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 (See 
Section 7.3.7 of the ramucirumab Investigator Brochure for details on use during pregnancy and 
lactation). No formal studies have been performed to evaluate the safety and efficacy of 
ramucirumab DP in the treatment of children or elderly patients. 
 
Pharmacokinetics 
 
The pharmacokinetics (PK) and toxicokinetics (TK) of ramucirumab in cynomolgus monkeys 
were obtained in the 5-week and 39-week repeat-dose toxicology studies, and after a single dose 
in a wound-healing study. In the 5-week study, animals were administered intravenous (I.V.) 
doses of 0, 4, 12, or 40 mg/kg ramucirumab DP weekly and blood samples for ramucirumab 
concentration analysis in serum were obtained after the first dose. In the 39-week study, animals 
were administered I.V. doses of 0, 5, 16, or 50 mg/kg ramucirumab DP weekly and blood 
samples were obtained after the first, 12th, and 39th doses. 
 
Noncompartmental analysis of the concentration-vs-time data from the monkey toxicology 
studies indicated that the PK behavior of ramucirumab was nonlinear over the 4- to 50-mg/kg 


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dose range. Area under the concentration-vs-time curve extrapolated to infinity (AUC0-inf) and 
maximum concentration (Cmax) increased in a greater than dose-proportional manner. 
Ramucirumab half-life increased and clearance decreased with increasing dose. The steady-state 
volume of distribution was approximately equal to the vascular space at each dose level. Mean 
ramucirumab AUC0-inf in the 50-mg/kg group increased between the first and 39th doses, 
indicating that drug accumulation occurred. Antibodies against ramucirumab were detected in 
the 4-, 12-, and 40-mg/kg dose groups in the 5-week study, and in the 5- and 16- mg/kg dose 
groups in the 39-week study. In summary, the PK behavior of ramucirumab in monkeys was 
nonlinear and typical of monoclonal antibodies. 
 
The PK of ramucirumab were determined after a single 10-minute I.V. infusion dose of 5, 15, or 
50 mg/kg in a wound-healing study. Similar to previous studies in monkeys, the systemic 
exposure to ramucirumab as indicated by Cmax and area under the concentration-vs-time curve 
(AUC) increased with increasing dose and the apparent volume of distribution was in the range 
of plasma volume for monkeys, indicating that ramucirumab did not substantially distribute 
beyond the vasculature. 
 
Rationale for Starting Dose 
 
The REVEL clinical trial evaluated ramucirumab at a dose of 10 mg/kg IV on day 1 in 
combination with docetaxel given IV at 60 to 75 mg/m2 on day 1 of a 21 day cycle.  
Ramucirumab has been approved in gastric and gastroesophageal cancer at 8 mg/kg IV every 2 
weeks.  The dosing schedule of ramucirumab in the proposed study has been selected to coincide 
with weekly dosing of nab-paclitaxel.    
 
2.2.2 nab-Paclitaxel 
 
Mechanism of Action 
 
Paclitaxel is an anti-microtubule agent that has a broad spectrum of activity against human 
cancers. It was first authorized in the proprietary product Taxol® (paclitaxel) Injection, 
manufactured by Bristol-Myers Squibb, New York, New York, which is now available as 
generic equivalents. Taxol consists of paclitaxel dissolved in a proprietary solvent, Cremophor® 
ELb (BASF, Ludwigshafen, Germany) and ethanol. 
 
nab-Paclitaxel (ABRAXANE® for Injectable Suspension [Abraxis BioScience, LLC, a wholly 
owned subsidiary of Celgene Corporation, Summit, New Jersey, United States; hereafter referred 
to as “Celgene”], ABI-007) is a proprietary solvent-free, protein-stabilized formulation of 
paclitaxel comprised of paclitaxel in a noncrystalline amorphous state and human albumin with 
mean particle size of approximately 130 nanometers. nab-Paclitaxel has been developed to 
improve the therapeutic index of paclitaxel, also reducing the toxicities associated with Taxol 
and the CrEL and ethanol vehicle. This may be achieved in part by taking advantage of 
endogenous transport pathways to deliver higher doses of paclitaxel to the tumor. Because     
nab-paclitaxel does not contain a solvent vehicle, micellar entrapment observed with Taxol does 
not occur[52-54].  nab-Paclitaxel displays linear pharmacokinetic (PK) characteristics. The novel 
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achieve a higher maximum tolerated dose (MTD) based on every 3-weeks dosing: 300 mg/m2 
for nab-paclitaxel (Study DM97-123) versus 175 mg/m2 for Taxol [55]. The use of albumin-
bound paclitaxel also enables nab-paclitaxel to be given in a shorter, more convenient infusion 
time of 30 - 40 minutes compared with 3 hours to 24 hours with Taxol. Due to its distinct 
pharmacological and PK properties and therapeutic index, nab-paclitaxel has been approved by 
regulatory authorities worldwide in over 40 countries/regions as a new product, rather than as a 
generic formulation of Taxol. 
 
nab-Paclitaxel may be given without steroid and anti-histamine premedication, which is required 
for Taxol to prevent solvent-related HSRs (Taxol US prescribing information). Cremophor EL 
has been shown to leach plasticizers, specifically di(2-ethylhexyl)phthalate (DEHP), from 
polyvinyl chloride (PVC) bags and polyethylene-lined tubing [56-61].  Although no controlled 
epidemiologic toxicity studies have been conducted in humans exposed to DEHP, severe effects 
(eg, carcinogenicity, cardiopulmonary toxicity, hepatotoxicity, and nephrotoxicity) have been 
observed in experimental models. The Taxol prescribing information instructs users to prepare, 
store, and administer solutions in glass, polypropylene, or polyolefin containers; non-PVC-
containing infusion sets (eg, those with polyethylene lining) should be used (Taxol US 
prescribing information). By comparison, standard tubing and intravenous (IV) bags may be used 
for the IV administration of nab-paclitaxel [52, 55]. 
 
Clinical Data and Safety 
 
As of October 2014, nab-paclitaxel is approved under the trade name of ABRAXANE in 
51 countries worldwide for the treatment of patients with metastatic breast cancer. ABRAXANE 
is also approved in 8 countries worldwide for the first-line treatment of locally advanced or 
metastatic non-small cell lung cancer (NSCLC), and in 40 countries for the first-line treatment of 
metastatic adenocarcinoma of the pancreas, and it is approved in Japan for treatment of advanced 
gastric cancer. 
 
Nonclinical toxicity studies revealed no evidence for unique and previously unseen risks with 
nab-paclitaxel and the results were similar to the nonclinical toxicology profile of solvent-based 
paclitaxel. The known adverse effects for paclitaxel were not masked by its formulation with 
albumin, but were generally not exacerbated in comparison to Taxol. The primary toxicities 
based on the results of animal studies and the known toxicities of paclitaxel when administered 
as Taxol include myelosuppression, testicular degeneration, and neuropathy. In nonclinical 
studies with mice-bearing adult and pediatric tumor xenografts, repeat-dose administration of 
nab-paclitaxel was generally well-tolerated. In in vitro studies with human liver microsomes and 
tissue slices, it has been shown that paclitaxel is metabolized primarily to 6α-hydroxypaclitaxel 
by CYP-2C8 and to two minor metabolites, 3′-p-hydroxypaclitaxel and 6α, 3′-p-
dihydroxypaclitaxel, by CYP-3A4. 
 
A Phase 3 randomized, controlled study (Study CA012-0) conducted in patients with metastatic 
breast cancer compared nab-paclitaxel (260 mg/m2) with solvent-based paclitaxel (175 mg/m2) 
both given on Day 1 of a 21-day cycle. nab-Paclitaxel demonstrated greater efficacy (higher 
response rates, longer times to tumor progression [TTP], and longer progression-free survival 
[PFS] in patients previously treated for metastatic disease) with toxicity similar to that of 


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solvent-based paclitaxel, despite the higher dose of active agent achieved with nab-paclitaxel. 
Grade 4 neutropenia occurred less frequently in the nab-paclitaxel group, and did not appear to 
be related to cumulative dose. Instances of neutropenia were clinically asymptomatic and 
transient. Grade 3 sensory neuropathy (National Cancer Institute Common Terminology Criteria 
for Adverse Events [NCI CTCAE v 2.0]) occurred more often in the nab-paclitaxel group 
compared with solvent-based paclitaxel; however, these events were manageable with therapy 
interruption followed by dose reduction. 
 
A Phase 3 randomized, controlled study (Study CA031) conducted in patients with advanced 
NSCLC compared nab-paclitaxel (100 mg/m2) and carboplatin (Arm A) with Taxol (200 
mg/m2) and carboplatin (Arm B). Patients in Arm A received IV nab-paclitaxel on Days 1, 8, 
and 15 of a 21-day cycle and carboplatin administered on Day 1 of each 21-day cycle. Patients in 
Arm B received Taxol IV over 3 hours followed by carboplatin on Day 1 of each 21-day cycle. 
Administration of nab-paclitaxel/carboplatin as a first-line therapy resulted in significantly 
improved overall response rates (ORR) versus Taxol/carboplatin. Statistically nonsignificant 
trends in favor of the nab-paclitaxel/carboplatin arm were observed for PFS and overall survival 
(OS), meeting non-inferiority criteria. The nab-paclitaxel/carboplatin regimen was better 
tolerated, with significant reduction in severe peripheral neuropathy, arthralgias, and myalgia. A 
higher percentage of patients in the nab-paclitaxel treatment arm developed anemia and 
thrombocytopenia. The anemia was readily corrected with a single blood transfusion in the 
majority of cases. The thrombocytopenia did not lead to increased rates of hemorrhages. 
 
A Phase 3 randomized, controlled study (Study CA046) in patients with metastatic 
adenocarcinoma of the pancreas evaluated nab-paclitaxel 125 mg/m2 in combination with 
gemcitabine 1000 mg/m2 on Days 1, 8, 15, 29, 36, and 43 of a 56-day cycle in Cycle 1 only, 
followed by Days 1, 8, and 15 of a 28-day cycle in Cycle 2 and onwards, compared with 
standardtherapy of gemcitabine 1000 mg/m2 on Days 1, 8, 15, 22, 29, 36, and 43 of a 56-day 
cycle in Cycle 1 followed by Days 1, 8, and 15 of a 28-day cycle in Cycle 2 and onward. The 
study met its primary endpoint with an improvement in OS. Median OS was 8.5 months in the 
nab-paclitaxel/gemcitabine arm compared with 6.7 months in the gemcitabine arm. The 1-year 
survival rate was 35% in the nab-paclitaxel/gemcitabine arm compared with 22% in the 
gemcitabine arm. The treatment effect consistently favored the nab-paclitaxel/gemcitabine arm 
across the majority of pre-specified subgroups. Key secondary efficacy endpoints of PFS and 
ORR were also met. The rate of febrile neutropenia was low in the 2 treatment arms, 3% in 
nab-paclitaxel/gemcitabine arm and 1% in the gemcitabine arm. The rates of Grade 3/4 anemia 
and thrombocytopenia by central laboratory were comparable between the 2 treatment arms. 
Grade 3 or higher events of sepsis were reported for 5% of patients in the nab-
paclitaxel/gemcitabine arm and 2% of patients in the gemcitabine arm. The most common 
adverse event (AE) leading to drug discontinuation in a greater percentage of patients in the 
combination arm was peripheral neuropathy. 
 
Post-hoc analyses completed approximately 1 year after the final formal study analyses showed 
the following results: median OS increased to 8.7 months in the nab-paclitaxel/gemcitabine arm 
compared with a decrease to 6.6 months in the gemcitabine arm. The 1-year survival rate 
remained the same in both treatment arms. No new safety signals were observed for either 
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Pharmacokinetics 
 
Clinical pharmacology of paclitaxel has been evaluated over the nab-paclitaxel dose range of 80 
to 375 mg/m2 in patients with solid tumors. Systemic exposure (Cmax [maximum concentration] 
and AUC∞ [area under the time curve to infinity]) of paclitaxel is approximately proportional to 
nab-paclitaxel doses from 80 to 300 mg/m2; however, at doses from 300 to 375 mg/m2, the 
exposure appears more than dose proportional. Paclitaxel AUC in plasma was independent of the 
nab-paclitaxel infusion duration. Following nab-paclitaxel administration, paclitaxel is highly 
bound to plasma proteins (94%). However, the mean fraction unbound of paclitaxel is 
approximately 2.6-fold higher with nab-paclitaxel as compared to Taxol. The whole blood and 
plasma exposure levels are comparable, suggesting similar distribution between plasma and 
blood cells. Distribution of paclitaxel to extravascular tissue is more rapid and more extensive 
with nab-paclitaxel versus Taxol. The faster distribution to peripheral tissues, the larger volume 
of distribution, the 2.6-fold higher fraction of unbound drug in circulation, the higher dose, and 
the shorter infusion time of nab-paclitaxel over Taxol may all contribute to the better responses 
to nab-paclitaxel over Taxol in clinical studies. 
 
Hepatic metabolism and biliary excretion are likely routes of paclitaxel elimination in humans. 
Patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x upper limit of normal 
[ULN]) have no clinically important changes in pharmacokinetics (PK) of paclitaxel while 
patients with moderate (total bilirubin > 1.5 to ≤ 3 x ULN) or severe (total bilirubin > 3 to ≤ 5 x 
ULN) hepatic impairment have a 22% to 26% decrease in the maximum elimination rate of 
paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with 
normal hepatic function. Mild to moderate renal impairment (creatinine clearance ≥ 30 and 
< 90 mL/min) has no clinically important effect on the maximum elimination rate and systemic 
exposure (AUC and Cmax) of paclitaxel. 
 
In pharmacokinetic/pharmacodynamic (PK/PD) modeling, neutropenia development was driven 
by systemic exposure to paclitaxel, positively correlated with increasing age at a given exposure 
level, but was not significantly influenced by the type of solid tumors, sex, hepatic function (as 
indicated by albumin or total bilirubin level), and dosing schedule (every 3 weeks [q3w] versus 
every week [qw]). 
 
Rationale for Starting Dose 
 
Data suggest that weekly taxane administration improves tolerability over an every 3 week 
schedule, and does not appear to compromise clinical effectiveness. Taxanes have been 
extensively studied as weekly regimens in the breast and lung cancer literature. A phase III study 
compared carboplatin plus paclitaxel on a standard every three week regimen (with both drugs 
given on day one) to a four week cycle (with carboplatin given on day 1 and paclitaxel given 
weekly for weeks one to three [62]). Survival was similar between the two arms, but non-
hematologic toxicity favored the weekly taxane arm. A dose finding study showed a favorable 
benefit to risk ratio with weekly nab-paclitaxel at a dose of 100mg/m2 when administered in 
combination with carboplatin [63].  Weekly dosing of nab-paclitaxel administered at 100 mg/m2 
on days 1, 8 and 15 of a 28 day cycle was selected to coincide with q2 weekly ramucirumab 


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dosing.     
 
2.3 
Rationale 
 
Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of 
VEGFR-2.  A recent double-blind, placebo-controlled phase III clinical trial (REVEL) evaluated 
the addition of ramucirumab to docetaxel compared with docetaxel and placebo in patients with 
Stage IV squamous and non-squamous NSCLC in the 2nd-line treatment setting (Lancet 
2014;384:665-73.)  This study demonstrated a superior overall survival (OS), progression-free 
survival (PFS), and overall response rate (ORR) with the combination therapy compared with 
docetaxel with placebo.  This effect was seen across histologic subtypes, in the absence of excess 
toxicity in patients with squamous cell histology.  This finding is intriguing, as prior study of 
bevacizumab in patients with NSCLC of squamous cell histology was associated with excess 
pulmonary hemorrhage.  This provides the rationale for further investigation of ramucirumab in 
patients with squamous histology NSCLC.   
 
nab-Paclitaxel is a formulation of paclitaxel complexed with albumin that is readily soluble in 
saline and allows administration of paclitaxel without the use of lipid-based solvents and the 
need for corticosteroid and antihistamine premedication.   nab-Paclitaxel was approved for the 
1st line treatment of NSCLC based on a trial by Socinski et al. which demonstrated a superior 
ORR with the addition of nab-paclitaxel to carboplatin compared with carboplatin/paclitaxel in 
patients with advanced and metastatic NSCLC, as well as prolonged PFS and OS without 
statistical significance.  The subgroup analysis by tumor histology demonstrated a statistically 
significant advantage for nab-paclitaxel/carboplatin in terms of best overall response rate (41% 
vs 24%, p<0.001), and numerically better PFS and OS in squamous NSCLC. [3]  
 
We now propose a phase II clinical trial evaluating the safety and efficacy of the addition of 
ramucirumab to nab-paclitaxel in patients with previously treated NSCLC, and in particularly 
patients with squamous cell histology.  We hypothesize that the addition of ramucirumab to nab-
paclitaxel is well-tolerated and associated with a superior PFS compared with single agent 
taxane-based therapy.   
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Patients must have histologically or cytologically confirmed Stage IV (AJCC 7) non-
small cell lung cancer. 
 


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2. Patients 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. Patients must have received at least one prior platinum-based chemotherapy for locally 
advanced or metastatic disease.  Prior bevacizumab as 1st line and/or maintenance 
therapy is allowed.  Prior nivolumab is allowed.   
 
4. Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of ramucirumab in combination with nab-paclitaxel in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
 
5. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
6. Life expectancy of greater than 12 weeks. 
 
7. Patients must have adequate liver function: total bilirubin ≤1.5 times the upper limit 
normal (ULN), AST and ALT ≤ 3.0 x ULN or 5.0 x ULN in the setting of liver 
metastases. 
 
8. The patient has adequate hematologic function, as evidenced by an absolute neutrophil 
count (ANC) ≥1500/µL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/µL 
(transfusion independent, defined as not receiving platelet transfusions within 7 days 
prior to laboratory sample.) 
 
9. The patient does not 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. Clinically meaningful ascites is defined as ascites from cirrhosis requiring 
diuretics or paracentesis. 
 
10. The patient has adequate renal function as defined by a serum creatinine ≤1.5 times the 
ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute 
(that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate 
creatinine clearance must be performed). 
 
11. The patient’s urinary protein is ≤1+ on dipstick or routine urinalysis (UA; if urine 
dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must 
demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol). 
 
12. The patient must have adequate coagulation function as defined by International 
Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds 
above the ULN (unless receiving anticoagulation therapy).  Patients receiving warfarin 
must be switched to low molecular weight heparin and have achieved stable coagulation 
profile prior to first dose of protocol therapy.  


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13. Patients with treated and clinically stable brain metastases are allowed.   
 
14. 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. Females 
of child-bearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy 
[the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at 
least 24 consecutive months [i.e., has had menses at any time during the preceding 24 
consecutive months]) must: 
 
a. Either commit to true abstinence* from heterosexual contact (which must be 
reviewed on a monthly basis), or agree to use, and be able to comply with, 
effective contraception without interruption [such as use of an appropriate 
“double barrier” method of birth control (female use of a diaphragm, intrauterine 
device (IUD), or contraceptive sponge, in addition to male use of a condom) or 
the female should be using prescribed “birth control” pills, injections, or 
implants], 28 days prior to starting IP therapy (including dose interruptions), and 
while on study medication or for a longer period if required by local regulations  
following the last dose of IP; and 
 
b. Have a negative serum pregnancy test (β -hCG) result within 7 days of starting 
study treatment.  This applies even if the subject practices true abstinence* from 
heterosexual contact. 
 
* True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception]. 
 
15. Male subjects must practice true abstinence* or agree to use a condom during sexual 
contact with a pregnant female or a female of childbearing potential while participating in 
the study, during dose interruptions and for 6 months following IP discontinuation, even 
if he has undergone a successful vasectomy. 
 
16. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE). 
 
17. Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
1. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier. 
 
2. Patients with previous intolerance to ramucirumab. 


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3. Patients who are receiving any other investigational agents. 
 
4. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ramucirumab or nab-paclitaxel.  
 
5. Patients with untreated CNS metastases. Patients with treated brain metastases are 
eligible if they are clinically stable with regard to neurologic function, off steroids after 
cranial irradiation (whole brain radiotherapy, focal radiotherapy, and stereotactic 
radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection 
performed at least 28 days prior to randomization. The patient may have no evidence of 
Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan 
(performed within 21 days before randomization). 
 
6. The patient has significant bleeding disorders, vasculitis, or experienced Grade 3/4 
gastrointestinal (GI) bleeding within 3 months prior to enrollment.   
 
7. The patient has 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 randomization. 
 
8. The patient has 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. 
 
9. The patient has a history of uncontrolled hereditary or acquired thrombotic disorder. 
 
10. The patient has uncontrolled or poorly-controlled hypertension (>160 / >100 mm Hg for 
>4 weeks) despite standard medical management. 
 
11. The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28 days 
prior to enrollment. 
 
12. The patient has undergone major surgery within 28 days prior to enrollment, or 
subcutaneous venous access device placement within 7 days prior to enrollment. 
 
13. The patient is 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. 
 
14. The patient has elective or planned major surgery to be performed during the course of 
the clinical trial. 
 


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15. Patients with hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months 
prior to enrollment, or with central or cavitating lesions, will be excluded. 
. 
16. The patient has radiologically documented evidence of major blood vessel invasion or 
encasement by cancer. 
 
17. The patient has a history of GI perforation and/or fistulae within 6 months prior to 
enrollment, or has risk factors for perforation.  
 
18. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
19. Pregnant women are excluded from this study because ramucirumab is pregnancy 
category C agent 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. 
 
20. HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions ramucirumab. In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy. 
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally by the Study Coordinator.  
Following registration, patients should begin protocol treatment within 5 days.   
Issues that would cause treatment delays should be discussed with the Investigator. The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
 
4.2 
Registration Process 
 
Once the signed informed consent has been obtained, all pretreatment evaluations have been 
performed, and patient’s eligibility has been confirmed by the coordination team and the treating 
physician investigator, a patient will be entered on study. To register a patient, the research nurse 
or data manager must complete the eligibility/registration form and review the signed Informed 


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Consent, and HIPAA authorization form. 
To complete the registration process, the research nurse or data manager will: 
• Verify the eligibility 
• Register the patient on study 
• Assign a patient accession number 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 7. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Agent 
Premedication 
Dose 
Route 
Schedule 
Cycle 
Length 
Ramucirumab 
Diphenhydramine 
50 mg IV* 
 
8 mg/kg 
IV before 
nab-paclitaxel 
Day 1, 15 
28 days  
(4 weeks) 
 
 
 
nab-Paclitaxel None* 
100 mg/m2 IV after 
ramucirumab 
Days 1, 8, 15 
*For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with 
dexamethasone 10 mg IV (or equivalent) and acetaminophen 500 mg po prior to each 
ramucirumab infusion.  Additional premedications, such as antiemetics, may be used at the 
discretion of the treating investigator. 
 
 
5.1.1 Ramucirumab 
 
Preparation for Administration: Inspect vial contents for particulate matter and discoloration 
prior to dilution. Discard the vial, if particulate matter or discolorations are identified. Store vials 
in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton 
in order to protect from light. Calculate the dose and the required volume of ramucirumab 
needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at 
a concentration of 10 mg/mL solution of ramucirumab. Withdraw the required volume of 
ramucirumab and further dilute with only 0.9% Sodium Chloride Injection in an intravenous 
infusion container to a final volume of 250 mL. Do not use dextrose containing solutions. Gently 
invert the container to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion 
solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications. 
Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room 
temperature (below 25°C [77°F]). Discard vial with any unused portion of ramucirumab. 


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Administration: Visually inspect the diluted solution for particulate matter and discoloration 
prior to administration. If particulate matter or discolorations are identified, discard the solution. 
Administer diluted ramucirumab infusion via infusion pump over 60 minutes, ±5 minutes, 
through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. 
 
5.1.2 nab-Paclitaxel 
 
nab-Paclitaxel is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, 
caution should be exercised in handling nab-paclitaxel. The use of gloves is recommended. If 
nab-paclitaxel (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin 
immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, 
events may include tingling, burning and redness. If nab-paclitaxel contacts mucous membranes, 
the membranes should be flushed thoroughly with water. Given the possibility of extravasation, 
it is advisable to closely monitor the infusion site for possible infiltration during drug 
administration. Limiting the infusion of nab-paclitaxel to 30 minutes (-5 minutes or +10 
minutes), as directed, reduces the likelihood of infusion-related reaction. 
 
Premedication to prevent hypersensitivity reactions is generally not needed prior to the 
administration of nab-paclitaxel. Premedication may be needed in patients who have had prior 
hypersensitivity reactions to nab-paclitaxel. Patients who experience a severe hypersensitivity 
reaction to nab-paclitaxel should not be re-challenged with this drug.  
 
Preparation for Administration: nab-paclitaxel is supplied as a sterile lyophilized powder for 
reconstitution before use. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium 
Chloride Injection, USP. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over 
a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE 
WALL OF THE VIAL. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly 
onto the lyophilized cake as this will result in foaming. Once the injection is complete, allow the 
vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. 
Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any 
cake/powder occurs. Avoid generation of foam. If foaming or clumping occurs, stand solution 
for at least 15 minutes until foam subsides. Each mL of the reconstituted formulation will contain 
5 mg/mL paclitaxel. Calculate the exact total dosing volume of 5 mg/mL suspension required for 
the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL). 
 
The reconstituted suspension should be milky and homogenous without visible particulates. If 
particulates or settling are visible, the vial should be gently inverted again to ensure complete 
resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. 
Discard any unused portion.  
 
Administration: Inject the appropriate amount of reconstituted nab-paclitaxel into an empty, 
sterile intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type 
intravenous bag]. The use of specialized DEHP-free solution containers or administration sets is 
not necessary to prepare or administer nab-paclitaxel infusions. The use of an in-line filter is not 
recommended. Parenteral drug products should be inspected visually for particulate matter and 


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discoloration prior to administration whenever solution and container permit. 
 
nab-Paclitaxel is injected into a vein [intravenous (I.V.) infusion] over 30 minutes, -5 minutes or 
+10 minutes. The ideal infusion time is between 30-40 minutes, and no less than 25 minutes to 
avoid the safety concern of potential overdose through increase of the Cmax by approximately 
20% if infused too quickly.  The use of an in-line liter is not recommended.  Following 
administration, the intravenous line should be flushed with sodium chloride 9 mg/ml (0.9%) 
solution for injection to ensure complete administration of the complete dose, according to local 
practice. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were 
observed when ramucirumab 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients 
with solid tumors. No clinically meaningful changes in docetaxel exposure were observed when 
ramucirumab 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid 
tumors. Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel 
based on cross study comparisons in patients with solid tumors. 
 
The metabolism of paclitaxel is catalyzed, in part, by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4. Therefore, caution should be exercised when administering nab-paclitaxel 
concomitantly with medicines known to inhibit (e.g., ketoconazole, erythromycin, fluoxetine, 
imidazole antifungals, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or 
induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or 
CYP3A4.  Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information. As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new medications need 
to be prescribed or if the patient is considering a new over-the-counter medicine or herbal 
product.  
 
Because there is a potential for interaction of nab-paclitaxel with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. 
 
5.3 
Patient Reported Outcomes for EQ-5D-5L 
 
To ensure completion of the EQ-5D-5L questionnaires at the appropriate time-points, assigned 
research staff must adhere to the instructions in this section. The patient should complete the EQ-
5D-5L questionnaires in clinic at the following times: at baseline, prior to the start of each cycle, 
and at the end of therapy.  
 
Research staff should instruct the patient how to properly fill in the EQ-5D-5L questionnaire per 


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the following instructions: 
• All questionnaires must be completed prior to any other study procedures (baseline 
following informed consent) and before discussion of current disease status to avoid 
biasing the patient’s responses to the questions. 
• Provide a private environment for the patient to answer the questions. 
• Provide sufficient time for the patient to complete the questionnaire at their own pace. 
• Avoid assistance from relatives, friends or clinic staff to help the patient answer the 
questionnaires. However, if the patient is unable to read the questionnaire (due to vision 
impairment such as blindness or uncorrected vision, illiteracy), the questionnaires may be 
read out loud by trained clinic staff and responses recorded. 
• When the patient completes the questionnaire, it should be handed back to the person 
responsible for the questionnaires, checking for completeness prior to initiating any other 
procedures. 
• Only one answer should be recorded for each question. 
 
5.4 
Duration of Therapy 
 
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), 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
5.5 
Duration of Follow Up 
 
Patients will be followed via medical records review for survival for12 months after removal 
from study or until death, whichever occurs first. Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 
At the discretion of the sponsor-investigator (or sponsor/investigator) the study may be closed 
prematurely. 
 
5.6 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies. The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS/TREATMENT DISCONTINUATION 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 


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the NCI Common Toxicity Criteria version 4.The following criteria should be met prior to the 
administration of treatment at the start of each new cycle:  
 
• Patients must have the following clinical laboratory values: 
a. ANC count ≥ 1,500/ µL. 
b. Platelets ≥ 100,000/ µL. 
• Evidence of adequate hepatic function : 
a. Total Bilirubin ≤ 1.5 times the upper limit normal (ULN) 
b. AST(SGOT)/ALT(SGPT) ≤  3.0 × ULN or 5.0 x ULN in the setting of liver 
metastases. 
• Serum creatinine ≤ 1.5 times the ULN or creatinine clearance ≥ 40 mL/minutes; if serum 
creatinine is >1.5 times ULN, a 24-hour urine collection to calculate creatinine clearance 
must be performed. 
 
If any of the above conditions are not met, treatment will be delayed for up to 4 weeks from the 
planned date, to permit resolution of toxicity.  
 
Dose modifications of ramucirumab and nab-paclitaxel will be based on toxicity occurring 
anytime between day 1 of the previous cycle and day 1 of the new cycle. Dose re-escalation is 
not allowed.   
 
Ramucirumab 
 
Permanent Dose Reductions for Hematologic and Other Adverse Drug Reactions 
Adverse Drug Reaction 
Dose modification or discontinuation 
Infusion-Related Reactions (IRR) 
 
Reduce the infusion rate of ramucirumab by 50% for 
Grade 1 or 2 IRRs.  
 
For patients who have experienced a Grade 1 or 2 
IRR, also premedicate with dexamethasone (or 
equivalent) and acetaminophen prior to each 
subsequent ramucirumab infusion 
 
Permanently discontinue ramucirumab for Grade 3 or 
4 IRR 
Hypertension 
Interrupt ramucirumab for severe hypertension (180 
mm Hg or greater systolic or 110 mm Hg or greater 
diastolic) until controlled with medical management. 
 
Permanently discontinue ramucirumab for severe 
hypertension that cannot be controlled with 
antihypertensive therapy. 
Patients with grade 4 hypertension must not receive 
further treatment with ramucirumab. 
Proteinuria 
Interrupt ramucirumab for urine protein levels ≥2 g/24 
hours.  


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Reinitiate treatment at a reduced dose once the urine 
protein level returns to <2 g/24 hours as follows: 
 
1st Occurrence: 6 mg/kg  
 
2nd Occurrence: 5 mg/kg 
 
3rd Occurrence: Discontinue Treatment 
 
If the protein level does not return to <2 g/24 hours 
within 2 weeks: Discontinue Treatment 
 
Permanently discontinue ramucirumab for urine 
protein level >3 g/24 hours or in the setting of 
nephrotic 
syndrome 
 
Other criteria for dose modification/discontinuation of ramucirumab are as follows: 
• Grade 3 and 4 arterial thromboembolic events, or any pulmonary embolism/ deep vein 
thrombosis (PE/DVT) occurring or worsening during anticoagulant therapy, require 
permanent discontinuation of ramucirumab therapy. Any venous or arterial event leading 
to discontinuation of ramucirumab therapy will be considered serious and should be 
reported via the SAE mechanism. 
• Patients with unresected primary tumors (or local recurrence) who develop Grade 3 or 4 
venous thromboembolism may also receive anticoagulation and continue ramucirumab 
therapy provided that the tumor does not confer an excessive bleeding risk, in the opinion 
of the patient’s physician. 
• Ramucirumab should be permanently discontinued in the event of a gastrointestinal 
perforation or fistula formation. 
• If Reversible Posterior Leukoencephalopathy (RPLS) is diagnosed, ramucirumab must be 
permanently discontinued. All cases of RPLS must be reported via the SAE mechanism. 
• Any patient who experiences signs of hepatic encephalopathy or other serious signs of 
liver impairment such as hepatorenal syndrome must be permanently discontinued from 
ramucirumab therapy. 
• Patients with Grade 3/4 bleeding or hemorrhagic event (any cause) must not receive 
further treatment with ramucirumab. 
 
Patients who meet criteria for discontinuation of ramucirumab may continue on single 
agent nab-paclitaxel until criteria for removal from the study in Section 5.3 are met.   
 
nab-Paclitaxel 
 
Do not administer nab-paclitaxel on Day 1 of a cycle until absolute neutrophil count (ANC) is at 
least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. In patients who develop 
severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute 


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neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on 
Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 
50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce 
nab-paclitaxel as outlined below. Withhold nab-paclitaxel for Grade 3-4 peripheral neuropathy. 
Resume nab-paclitaxel at reduced doses when peripheral neuropathy improves to Grade 1 or 
completely resolves (see below). 
 
Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions 
Adverse Drug Reaction 
Occurrence 
nab-Paclitaxel 
 weekly dose 
(mg/m2) 
Neutropenic Fever (ANC less than 
500/mm3 with fever>38°C) 
OR 
Delay of next cycle by more than 7 
days for ANC less than 1500/mm3 
OR 
ANC less than 500/mm3 for more 
than 7 days 
1st 
 
75 
2nd 
 
50 
3rd 
 
Discontinue Treatment 
Platelet count less than 50,000/mm3 1st 
 
75 
2nd 
 
50 
3rd 
 
Discontinue Treatment 
Severe sensory Neuropathy – Grade 
3 or 4 
1st 
 
75 
2nd 
 
50 
3rd 
 
Discontinue Treatment 
 
Hypersensitivity reactions to nab-paclitaxel rarely occur. If they do occur, minor symptoms such 
as flushing, skin reactions, dyspnea, lower back pain, hypotension, or tachycardia may require 
temporary interruption of the infusion. However, severe reactions, such as hypotension requiring 
treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria require 
immediate discontinuation of nab-paclitaxel administration and aggressive symptomatic therapy. 
Patients who experience a severe hypersensitivity reaction to nab-paclitaxel should not be re-
challenged. 
 
Other dose modification and/or treatment discontinuation of either ramucirumab or nab-
paclitaxel may be made at the discretion of the treating investigator.  
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 


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Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of 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 
Adverse Events and Risks Lists 
 
7.1.1 Adverse Event Lists for Ramucirumab and nab-Paclitaxel 
 
For this study, the applicable reference document is the most current version of the investigator’s 
brochure (IB) for each commercial agent.  
 
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. The sponsor/sponsor-investigator will routinely review any new 
distributions of the IB for relevant new safety information and incorporate into the informed 
consent form document as appropriate. 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events.  IP is to be discontinued 
immediately. The female subject may be referred to an obstetrician-gynecologist (not necessarily 
one with reproductive toxicity experience) or another appropriate healthcare professional for 
further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy.  
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE immediately by facsimile, or other 
appropriate method, within 24 hours of the investigator’s knowledge of the event using the SAE 
report form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form. 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. Male patients treated with nab-paclitaxel 
are advised not to father a child during and up to 6 months after treatment. 
 
Overdose, as defined for this protocol, refers to nab-paclitaxel dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of nab-paclitaxel assigned to a given patient, regardless of any associated adverse events or 


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sequelae. 
PO any amount over the protocol-specified dose 
IV 10% over the protocol-specified dose  
 
SC 10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate.  For nab-paclitaxel, an infusion completed in less than 25 minutes may increase Cmax by 
approximately 20%, therefore a nab-paclitaxel infusion completed in less than 25 minutes will 
meet the infusion rate criterion for an overdose. 
 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.    
 
7.2 
Definitions 
 
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction is considered "life-
threatening" if, in the view of the sponsor-investigator, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction is considered "serious" if, in the 
view of the sponsor-investigator, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Unexpected adverse event or unexpected suspected adverse reaction is considered "unexpected" 
if it is not listed in the investigator brochure or is not listed at the specificity or severity that has 


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31 
 
been observed; or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the investigator brochure listed only 
cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to 
adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular 
drug under investigation. 
 
7.3 
Reporting of Suspected Adverse Reactions 
 
In the event of a serious adverse event, the PI, the institutional review board (per institutional reporting 
requirements), and supporting entities per contract will be notified using the CRS Internal SAE Form. An 
FDA Form 3500 MedWatch report will be completed in the event FDA reporting is required.   
 
All events meeting the definition of a serious adverse event should be recorded on the CRS 
Interal SAE Form and submitted to 
 
1. PI: Liza C. Villaruz, MD 
a. Phone: 412-648-6577 
b. Fax:   412-648-6579 
c. Email: villaruzl@upmc.edu 
2. Clinical Research Manager: Carrie Muňiz 
a. Phone: 412-623-6121 
b. Fax: 412-648-6650 
c. Email: munizca@upmc.edu 
3. crssafetysubmissions@upmc.edu 
4. Local Institutional Review Board per institutional reporting requirements 
 
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32. 
 
Serious adverse events (SAE) are defined above.  The investigator must inform Lilly in 
writing using the CRS Internal SAE Form of any SAE within 24 hours of being aware of 
the event.  The written report must be completed and supplied to Lilly by facsimile within 
24 hours.  The initial report must be as complete as possible, including an assessment of 
the causal relationship between the event and the investigational product(s).  Information 
not available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a follow-up report.  A 
final report to document resolution of the SAE is required.  The Lilly tracking number (I4T-
US-X001) and the institutional protocol number should be included on SAE reports (or on 


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the fax cover letter).  A copy of the fax transmission confirmation of the SAE report to 
Lilly should be attached to the SAE and retained with the patient records. 
 
5. Lilly Drug Safety Contact Information: 
Lilly Global Patient Safety  
Fax: (866) 644-1697 or (317) 453-3402 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Section B and/or Section C – Narrative of the CRS Internal SAE Form: 
 
• CTCAE term(s) and grade(s) 
• Current status of study drug 
• All interventions to address the AE (testing and result, treatment and response) 
• Hospitalization and/or discharge dates 
• Event relationship to study drug 
 
Follow-up reports: 
Additional information may be added to a previously submitted report by updating the original 
CRS Internal SAE Form and submitting it as follow-up or creating supplemental summary 
information and submitting it as follow-up with the original CRS Internal SAE Form. 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 
Ramucirumab 
 
Ramucirumab is a recombinant human IgG1 monoclonal antibody that specifically binds to 
vascularendothelial growth factor receptor 2. Ramucirumab has an approximate molecular 
weight of 147 kDa. Ramucirumab is produced in genetically engineered mammalian NS0 cells. 
Ramucirumab is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly 
yellow solution for intravenous infusion following dilution and preparation. Ramucirumab is 
supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-
dose vials. CYRAMZA is formulated in glycine (9.98 mg/mL), histidine (0.65 mg/mL), histidine 
monohydrochloride (1.22 mg/mL), polysorbate 80 (0.1 mg/mL), sodium chloride (4.383 
mg/mL), and Water for Injection, USP, pH 6.0. 
 
8.2 
nab-Paclitaxel 
 
nab-Paclitaxel for Injectable Suspension (paclitaxel protein-bound particles for injectable 
suspension) (albumin-bound) is paclitaxel formulated as albumin-bound nanoparticles with a 
mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-
crystalline, amorphous state. nab-Paclitaxel is supplied as a white to yellow, sterile, lyophilized 
powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to 
intravenous infusion. Each single-use vial contains 100 mg of paclitaxel (bound to human 
albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium 
acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel 


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formulated as albumin-bound particles. nab-Paclitaxel is free of solvents. The active agent in 
nab-paclitaxel is paclitaxel, a microtubule inhibitor. The chemical name for paclitaxel is 5β,20-
Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with 
(2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel is a white to off-white crystalline powder with 
the empirical formula C47H51NO14 and a molecular weight of 853.91. It is highly lipophilic, 
insoluble in water, and melts at approximately 216°C to 217°C. 
 
 


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9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy. Scans 
and x-rays must be done <21 days prior to enrollment. In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy. 
 
 
Pre- 
Study 
Cycle 1 
 
Cycle 2 
 
Cycle 3 (and subsequent 28-
day cycles) 
Off Studye 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Ramucirumab 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
 
nab-Paclitaxel 
 
B 
B 
B 
 
B 
B 
B 
 
B 
B 
B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signsa 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Serum chemistryb 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
PT/PTT/INR 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 8 weeks. Documentation (radiologic) must 
be provided for patients removed from study for progressive disease. 
X 
Radiologic evaluation f 
X 
Radiologic measurements with CT or MRI of all sites of disease should be performed 
every 8 weeks. 
X 
B-HCG 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary protein  
Xd 
Xd 
 
 
 
Xd 
 
 
 
Xd 
 
 
 
Xd 
EQ-5D-5L 
questionnaire g 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
A: 
Ramucirumab 8 mg/kg IV Day 1 and day 15 and  28 day cycle 
B: 
nab-Paclitaxel 100 mg/m2 IV Day 1, 8 and 15 
a: 
Vital signs include pulse, breathing rate, blood pressure, and temperature 
b:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. If serum creatinine is >1.5 times ULN, a 24-hour urine 
collection to calculate creatinine clearance must be performed – see Section 6. 
c: 
Serum pregnancy test (women of childbearing potential) within 7 days of starting study treatment. 
d: 
Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during 
ramucirumab treatment. The patient’s urinary protein must demonstrate a urine protein level <2 g/24 hours to allow ramucirumab 
treatment. Perform proteinuria testing only if subject was removed from ramucirumab treatment within 30 days of end of treatment visit. 
e:      Off-study evaluation completed within 30 days of being removed from treatment. Patients will be followed via medical records review for 
survival for12 months after removal from study or until death, whichever occurs first. Patients removed from study for unacceptable 


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adverse event(s) will be followed until resolution or stabilization of the adverse event.  
f.      CT or MRI scan should include at minimum chest and abdomen (including adrenals). Other scan area imaging should include all sites of 
disease as appropriate for each subject. 
g.      See Appendix B [1], and section 5.3 for instructions.  
Note: There is a window of ± 1 week available for rescheduling treatment and/or procedures at 
the discretion of the Sub-investigator, and as discussed with the Investigator if a course is missed 
or a subject's treatment and/or testing day(s) need to be rescheduled due to the subject’s inability 
to comply with the study calendar (i.e., hospitalizations, business, vacation plans, travel from 
long distances for study treatment, in advance of the scheduled date to allow ready access to the 
result(s), reduce financial burden on the subject [i.e. non-UPMC insurance coverage] or reduce 
travel inconvenience, illness, transportation issues, holidays, family emergencies, etc.). 
 
 


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10. MEASUREMENT OF EFFECT 
 
10.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks with 
CT or MRI to evaluate all sites of disease. In addition to a baseline scan, confirmatory scans 
should also be obtained not less than 4 weeks following initial documentation of objective 
response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)[64]. 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 toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment. 
 
Evaluable for objective response. Only those patients 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 response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response. Patients 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 as ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area may 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 


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the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


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evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 


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Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [65-
67]. 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[68]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
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 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. 


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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. 
 
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 Investigator). 
 
10.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 


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until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 


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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). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
10.1.6 Progression-Free Survival and Overall Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. Overall survival is defined as the duration of time from the 
start of treatment to death. 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
11.1 
Data Safety Monitoring Plan 
 
Sponsor/Investigator, Sub-investigators, regulatory, CRS management, clinical research 
coordinators, clinical research associates, data managers, and clinic staff meet monthly in disease 
center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but 
not limited to, the following: 
 
• serious adverse events 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 4. All study treatment associated adverse events that 
are serious, at least possibly related and unexpected will be reported to the IRB. Any 
modifications necessary to ensure subject safety and decisions to continue, or close the trial to 
accrual are also discussed during these meetings. If any literature becomes available which 
changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB 
will be notified in the form of an Unanticipated Problem submission and the study may be 
terminated. 
 


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All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPCI DSMC which 
also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, 
and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to 
suspend accrual or further investigate treatment on any trial based on information discussed at 
these meetings.  See Section 12.1.1. for details of the planned interim analysis of dose delivery 
and adverse events. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
11.2 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and Guidelines on Good Clinical 
Practice compliance will be conducted periodically (i.e., at a minimum of annually) by qualified 
staff of the Education and Compliance Office – Human Subject Research, Research Conduct and 
Compliance Office, University of Pittsburgh. 
 
The Investigator (i.e., the study site principal investigator) and the University of Pittsburgh and 
University of Pittsburgh Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
11.3 
Data Handling and Record-Keeping 
 
The Investigator (i.e., the study site principal investigator) will maintain records in accordance 
with Good Clinical Practice. 
 
The investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not 
submitted or approved for the investigational drug, until 2 years after investigations under the 
IND have been discontinued and the FDA so notified. 
 
11.4 
Institutional Review Board (IRB) Approval 
 


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The investigator (i.e., the study site principal investigator) will obtain, from the University of 
Pittsburgh Institutional Review Board (IRB), prospective approval of the clinical protocol and 
corresponding informed consent form(s); modifications to the clinical protocol and 
corresponding informed consent forms, and advertisements (i.e., directed at potential research 
subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
investigator will promptly notify the University of Pittsburgh IRB of the deviation. 
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice. 
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event 
of an sponsor’s decision to modify the previously accepted clinical protocol, the sponsor will 
submit (i.e., in advance of implementing the change) a Protocol Amendment to the IND 
describing any change that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Examples of protocol changes requiring the 
submission of a Protocol Amendment include: 
 
• Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
• Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
• The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or AE; or the dropping of a test intended to monitor the 
safety of the investigational drug. 
 
11.5 
Ethical and Scientific Conduct of the Clinical Study 
 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and relevant policies, 
requirements, and regulations of the University of Pittsburgh IRB, University of Pittsburgh and 
University of Pittsburgh Medical Center, Commonwealth of Pennsylvania, and applicable federal 
agencies. 
 
11.6 
Informed Consent 
 
The investigator (i.e., the study site principal investigator) will make certain that an appropriate 
informed consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the 
potential risks and benefits of study participation, and their rights as research subjects. The 


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investigator, or a sub-investigator(s) designated by the sponsor, will obtain the written, signed 
informed consent of each subject, or the subject’s authorized representative, prior to performing 
any study-specific procedures on the subject. The date and time that the subject, or the subject’s 
authorized representative, signs the informed consent form and a narrative of the issues discussed 
during the informed consent process will be documented in the subject’s case history. The 
investigator or sub-investigator will retain the original copy of the signed informed consent form, 
and a copy will be provided to the subject, or to the subject’s authorized representative. 
 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator will obtain the informed consent of 
enrolled subjects for continued participation in the clinical study. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
12.1.1 Interim analysis 
Enrollment will be halted for a safety review after C2D21 for the 6th patient with 
squamous cell histology, and separately after C2D21 for 6th patient without 
squamous cell histology.  Patients who withdraw prior to C2D21 for reasons other 
than toxicity (disease progression, consent withdrawn) will not count toward these 
first 6 patients.  Dose delivered and adverse events for those patients will be 
examined, and the decision to continue as planned or modify the protocol in any way 
will be made by the study investigators, the disease center Data and Safety 
Monitoring Board (DSMB), and the University of Pittsburgh Cancer Institute (UPCI) 
Data and Safety Monitoring Committee (DSMC).   
 
 
12.1.2 Primary objective (safety)   
Safety and systemic toxicity will be summarized for all patients who receive at least 
one dose of study drug.  All adverse events that are determined to be possibly, 
probably or definitely related to treatment will be tabulated according to grade and 
type, in order of frequency, separately for patients with disease of squamous and non-
squamous histology. Each adverse event will be counted only once per patient, with 
the highest grade recorded. Serious adverse events will also be tabulated by 
frequency, separately for patients with disease of squamous and non-squamous 
histology. Listings will be provided for all on-study deaths and adverse events that 
lead to withdrawal from study. 
 


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12.1.3 Primary objective (PFS)  
For the unselected population (squamous and non-squamous) and for the subgroup of 
squamous NSCLC only, the PFS curve and a 90% confidence interval for the median 
PFS will be estimated by standard methods (the Kaplan-Meier method for survival, 
and the Greenwood variance formula applied to log-transformed survival).  Sampling 
weights will be used to approximate PFS for the unselected population, in which 
about 25% of study population has disease with squamous histology [2].  
 
12.1.4 Power calculations assume accrual of 80 patients at a uniform rate over 2 years, with 
10 months of additional follow-up. A minimum of 40 patients with NSCLC of 
squamous cell histology will be accrued, e.g. if 40 patients with non-squamous 
histology are enrolled initially, the remaining patients must have squamous cell 
histology.  Simulating data with median 5 months PFS (exponential distribution), the 
lower bound of the 90% confidence interval for median PFS was greater than 3 
months for 93% of 10,000 simulated datasets of size n=80 and 75% for size n=40.  
Therefore, we conclude that with two-sided alpha=0.1, the study has 93% power to 
conclude that the median PFS is unlikely to be 3 months or less in an unselected 
population, and 75% power for the squamous histology subgroup.   The average 
width of the confidence interval for median PFS for squamous histology is expected 
to be about 3.8 months (ie, 90% confidence interval 3.6-7.4 months). The null rate of 
3 months is from the median TTP of 2.7 months (median OS of 7 months) in 
previously treated advanced stage NSCLC patients treated with single agent docetaxel 
[4].   
 
12.1.5 Secondary objectives  
OS will be evaluated using the same methodology as for PFS.  The ORR will be 
estimated with a 90% Wilson (Score confidence interval), for the unselected 
population (with sampling weights) and for the squamous histology group. Patient-
reported symptoms and quality-of-life (QOL) at baseline, the end of each cycle, and 
at the end of therapy will be assessed using the EuroQoL Five Dimensions 
questionnaire[1].  Total scores and subscales will be summarized for each patient and 
by histology, and analyzed using standard linear mixed models methods.   The 
primary analysis will be specified once EuroQoL results are published for the REVEL 
trial, which is large enough to provide precise benchmarks.  In the absence of 
guidance from REVEL analysis, the primary analysis will summarize baseline QOL, 
average decreases over the first two cycles of treatment, and average QOL in 
survivors at approximately 6 months and 12 months. 
 
12.2 
Reporting and Exclusions 
 
12.2.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment. 
 
12.2.2 Evaluation of Response 
 


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All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). [Note: By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate. Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, 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 patients from the analysis should be clearly reported. The 95% 
confidence intervals should also be provided.  
 
 


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


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APPENDIX B 
EuroQoL EQ-5D-5L Questionnaire [1, 69-76]   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


UPCI #:15-169 
Version Date: 06/17/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Assessment Date: _ _/_ _ /_ _ _ _  
                                                                                                        
                                mm/dd/yyyy 
 
EQ-5D-5L Worksheet           Protocol:  15-169         
Patient Initials: _ _ _                         Patient number: _ _ _ 
 
2 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 


Assessment Date: _ _/_ _ /_ _ _ _  
                                                                                                        
                                mm/dd/yyyy 
 
EQ-5D-5L Worksheet           Protocol:  15-169         
Patient Initials: _ _ _                         Patient number: _ _ _ 
 
3 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
The worst health 
you can imagine 
 
 
 
 
 
 
 
 
  
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below. 
The best health 
you can imagine 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100 
5
15
25
35
45
55
75
65
85
95