A Phase II Study of Hepatic Arterial Infusion With Floxuridine and Dexamethasone in Combination With Intravenous Bevacizumab (A Monoclonal Antibody to Vascular Endothelial Growth Factor-A), in Patients With Unresectable Primary Hepatic Malignancy
Phase: PHASE2
Conditions: Liver Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 1 of 59 
 
 
 
 
 
A PHASE II STUDY OF HEPATIC ARTERIAL INFUSION WITH FLOXURIDINE AND 
DEXAMETHASONE IN COMBINATION WITH INTRAVENOUS BEVACIZUMAB (A 
MONOCLONAL ANTIBODY TO VASCULAR ENDOTHELIAL GROWTH FACTOR- 
A), IN PATIENTS WITH UNRESECTABLE PRIMARY HEPATIC MALIGNANCY 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator: 
William Jarnagin, MD, Hepatopancreatobiliary Surgery Service 
Co-Principal Investigator(s): 
Nancy Kemeny, MD, Gastrointestinal Oncology Service 
Kinh Gian Do, MD, Department of Radiology 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 2 of 59 
 
 
 
Investigator(s): 
Ghassan Abou-Alfa, MD, Gastrointestinal Oncology Service 
Peter Allen, MD, Hepatopancreatobiliary Surgery Service 
Ki-Young Chung, MD, Gastrointestinal Oncology Service 
David D’Adamo, MD, Melanoma/Sarcoma Service 
David Ilson, MD, Gastrointestinal Oncology Service 
David Kelsen, MD, Gastrointestinal Oncology Service 
Mary Keohan, MD, Melanoma/Sarcoma Service 
Robert Maki, MD, Melanoma/Sarcoma Service 
Diane Riedy, MD, Gastrointestinal Oncology Service 
Eileen O’Reilly, MD, Gastrointestinal Oncology Service 
Leonard B. Saltz, MD, Gastrointestinal Oncology Service 
Gary Schwartz, MD, Melanoma/Sarcoma Service 
Neil Segal, MD, Gastrointestinal Oncology Service 
Manish Shah, MD, Gastrointestinal Oncology Service 
Archie Tse, MD, Gastrointestinal Oncology Service 
Yuman Fong, MD, Gastric/Mixed Tumor Surgery Service 
Leslie Blumgart, MD, Hepatopancreatobiliary Surgery Service 
Michael D’Angelica, MD, Hepatopancreatobiliary Surgery 
Service 
Ronald DeMatteo, MD, Hepatopancreatobiliary Surgery Service 
Mithat Gönen, PhD, Department of Epidemiology and 
Biostatistics 
Jinru Shia, MD, Department of Pathology 
David Klimstra, MD, Department of Pathology 
David H. Gultekin, PhD, Department of Medical Physics 
Ioannis Konstantinidis, MD, Department of Surgery 
Laura Tang MD, Department of Pathology 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 3 of 59 
 
 
 
Consenting Professional(s): 
William Jarnagin, MD, Hepapancreatotobiliary Surgery Service 
Nancy Kemeny, MD, Gastrointestinal Oncology Service 
Peter Allen, MD, Hepatopancreatobiliary Surgery Service 
Ghassan Abou-Alfa, MD, Gastrointestinal Oncology Service 
Ki-Young Chung, MD, Gastrointestinal Oncology Service 
David D’Adamo, MD, Melanoma/Sarcoma Service 
David Ilson, MD, Gastrointestinal Oncology Service 
David Kelsen, MD, Gastrointestinal Oncology Service 
Mary Keohan, MD, Melanoma/Sarcoma Service 
Robert Maki, MD, Melanoma/Sarcoma Service 
Diane Reidy, MD, Gastrointestinal Oncology Service 
Eileen O’Reilly, MD, Gastrointestinal Oncology Service 
Leonard B. Saltz, MD, Gastrointestinal Oncology Service 
Gary Schwartz, MD, Melanoma/Sarcoma Service 
Neil Segal, MD, Gastrointestinal Oncology Service 
Manish Shah, MD, Gastrointestinal Oncology Service 
Archie Tse, MD, Gastrointestinal Oncology Service 
Yuman Fong, MD, Gastric/Mixed Tumor Surgery Service 
Leslie Blumgart, MD, Hepatopancreatobiliary Surgery Service 
Michael D’Angelica, MD, Hepatopancreatobiliary Surgery 
Service 
Ronald DeMatteo, MD, Hepatopancreatobiliary Surgery Service 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
Collaborating Institution (s): 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 4 of 59 
 
 
Table of Contents 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL ............................................................... 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ............................................................................... 6 
3.5 DYNAMIC MRI ......................................................................................................... 14 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................... 17 
4.1 
DESIGN ................................................................................................................ 17 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................... 18 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 20 
6.1 SUBJECT INCLUSION CRITERIA .......................................................................... 20 
6.2 
SUBJECT EXCLUSION CRITERIA ................................................................... 22 
7.0 
RECRUITMENT PLAN ................................................................................................... 24 
8.0 PRETREATMENT EVALUATION ..................................................................................... 24 
9.0 
TREATMENT/INTERVENTION PLAN ......................................................................... 26 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ......................................... 29 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................ 30 
12.1 
FUDR DOSE MODIFICATIONS .................................................................................... 32 
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............... 37 
14.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 38 
16.0 
BIOSTATISTICS .............................................................................................................. 45 
17.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES ..................... 46 
17.1 SUBJECT REGISTRATION .................................................................................. 46 
17.2 RANDOMIZATION ............................................................................................... 47 
18.0 
DATA MANAGEMENT ISSUES .................................................................................. 47 
18.1 
QUALITY ASSURANCE .................................................................................... 48 
18.2 
DATA AND SAFETY MONITORING ............................................................... 48 
19.0 
PROTECTION OF HUMAN SUBJECTS ........................................................................ 48 
19.9 PRIVACY ................................................................................................................ 50 
19.10 SERIOUS ADVERSE EVENT (SAE) REPORTING ............................................ 50 
ALL SAES MUST BE ENTERED INTO THE CRDB SAE FORM PAGE .................... 50 
20.0 
INFORMED CONSENT PROCEDURES ........................................................................ 52 
20.1 
RESEARCH AUTHORIZATION ........................................................................ 52 
21.0 
REFERENCES .................................................................................................................. 54 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 5 of 59 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This phase II study evaluates the efficacy of regional chemotherapy plus Bevacizumab in 
patients with unresectable primary hepatic malignancy. Specifically, eligible patients with 
unresectable hepatocellular carcinoma (HCC) and intrahepatic or peripheral 
cholangiocarcinoma (ICC) will undergo hepatic artery pump placement for continuous 
infusion of floxuridine (FUDR) combined with systemic IV Bevacizumab. A recent phase II 
study at MSKCC evaluated hepatic arterial FUDR alone in this same group of patients and 
found an overall response rate of 39% with a median time to progression (TTP) of 7.3 
months. At 1 year, 84.6% of patients were alive, with a median follow up of 8.8 months. The 
current protocol seeks to improve on these initial encouraging results by enhancing FUDR 
delivery to liver tumors. 
Emerging data suggest that ‘normalization’ of tumor vasculature with subsequent 
improvement in oxygenation and delivery of cytotoxic agents is a major mechanism of action 
of Bevacizumab. We hypothesize that such changes in liver tumor vasculature will increase 
the response rate and prolong the time to progression in patients undergoing concomitant 
treatment with regional FUDR. We further speculate that the addition of Bevacizumab will 
result in measurable changes in tumor perfusion kinetics compared to baseline data with 
FUDR treatment alone. The protocol includes radiological and biological correlative studies. 
All patients enrolled in the study will begin continuous HAI FUDR at 0.16 mg/kg/day. A 
total of 55 patients with unresectable HCC or ICC will be treated with HAI FUDR plus 
systemic Bevacizumab. All patients will receive HAI FUDR (0.16 mg/kg X pump volume / 
pump flow rate), Dexamethasone (Dex) (1 mg/day X pump volume / pump flow rate) and IV 
Bevacizumab 5 mg/kg every other week. 
 
The primary objective of the study is to assess the median time to progression of HAI 
FUDR/Dex + Bevacizumab. The calculated sample size will provide 90% power to detect a 
50% improvement in TTP using HAI FUDR + BEV, over that observed using HAI FUDR 
alone. Improved TTP will be considered indicative of improved efficacy and will serve as the 
baseline for a future comparative study. 
 
The secondary objective is to further investigate the utility of dynamic contract enhanced MRI 
(DCE-MRI) for assessing initial tumor perfusion prior to treatment, monitoring changes in 
tumor perfusion during treatment, and correlating these findings with radiographic tumor 
response. 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 6 of 59 
 
 
2.1 
PRIMARY 
To assess the median time to progression of continuous (HAI) of FUDR/Dex plus 
Bevacizumab in patients with unresectable hepatocellular carcinoma (HCC) and 
intrahepatic cholangiocarcinoma (ICC). 
 
2.2 
SECONDARY 
To investigate further the utility of dynamic contrast enhanced MRI (DCE-MRI) 
for assessing initial tumor perfusion prior to treatment, monitoring changes in 
tumor perfusion during treatment and in correlating these findings with 
radiographic tumor response. 
 
2.3 
EXPLORATORY 
2.3.1 To assess the expression pattern of VEGFR1, VEGFR2, and VEGFR3 and their 
cognate ligands (including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and P1GF), 
and correlate with patient progression and survival following therapy. 
 
2.3.2 To assess the pro-angiogenic activity of peripheral blood before and during 
treatment. 
2.3.3 To assess tumors for immunohistochemical markers of hypoxia (hypoxia 
inducible factor [HIF-1, carbonic anhydrase IX [CA IX], and the glucose 
transporters Glut-1 and Glut-3) for correlation with initial and treatment-related 
changes in perfusion and permeability, as determined by DCE-MRI. 
 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
INTRODUCTION 
Hepatocellular carcinoma (HCC) and primary intrahepatic cholangiocarcinoma (ICC) 
account for nearly all primary hepatic malignancies. HCC is among the most common 
cancers in the world, responsible for nearly 1 million annual deaths. Previously 
considered uncommon in Western countries, HCC incidence and mortality have both 
increased substantially in the United States over the past several years. ICC is much less 
common than HCC but its incidence and associated mortality have likewise increased. A 
recent analysis of Surveillance, Epidemiology and End Results (SEER) data showed a 
9% annual percentage increase in incidence of ICC and a 10-fold increase in ICC-related 
mortality since 1973. 
 
Complete resection remains the most effective therapy for both tumors. Resection is 
associated with 25-40% 5-year survival but is not possible in many patients. In most 
reported series, one-third of patients or fewer with HCC are amenable to a potentially 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 7 of 59 
 
 
curative resection. The rarity with which ICC is encountered makes it difficult to 
accurately assess overall resectability, since most studies only report patients submitted to 
operation. A report from MSKCC found a 62% resectability rate for ICC but did not 
include patients with unresectable disease at presentation. For both tumors, locally 
advanced disease confined to the liver is the predominant cause of unresectability. In 
addition, underlying hepatic parenchymal disease (ie, chronic hepatitis, cirrhosis) is also a 
potentially treatment-limiting factor in patients with HCC, less so for those with ICC. 
 
Patients with unresectable primary liver cancer (HCC or ICC) have a median survival of 
12 months or less, and non-resectional therapies have had generally disappointing results. 
For both tumors, multiple systemic regimens have been evaluated and shown to have 
limited efficacy. Modest activity (response rate of approximately 20%) of irinotecan- 
based regimens has been reported for both HCC and cholangiocarcinoma, although no 
complete responses. More recent studies using gemcitabine and oxaliplatin have not 
resulted in much improvement in response rates. Ablative approaches (cryoablation, 
ethanol injection, radiofrequency ablation) are often used in patients with unresectable 
HCC but their impact on disease natural history is unclear. Furthermore, most patients 
present with large tumors (> 5 cm) or multifocal disease, neither of which can be 
effectively ablated. Hepatic artery embolization or chemoembolization may have some 
utility in patients with HCC but there are conflicting data regarding the survival benefit of 
this approach. In contrast to HCC, experience with ablative techniques for ICC is 
extremely limited. ICC are typically firm tumors, making them unsuitable for ethanol 
injection, and most patients present with very large lesions that are inappropriate for other 
ablative approaches. 
 
Thus, for many patients with HCC and ICC, effective treatment options are limited. 
Liver directed chemotherapy (HAI), delivered through a surgically implanted hepatic 
artery infusion pump, has been evaluated in several small series and appears to have 
greater efficacy than systemic therapy alone. Although used predominantly in patients 
with hepatic colorectal metastases, HAI chemotherapy has been shown to have efficacy 
in patients with primary liver cancer. In an initial study from MSKCC, 10 patients with 
primary hepatic malignancy (8 HCC, 2 ICC) were treated with continuous intrahepatic 
FUDR (0.3mg/kg/day over 14 days, alternating with heparinized saline for 14 days) 
combined with Mitomycin C 10 mg/m2 given through a side port injection every 4 weeks. 
Four of 9 evaluable patients had a partial response (> 50% tumor reduction) and 2 had a 
minor response (25 – 50% tumor reduction). The median overall survival was 14.5 
months after initiation of HAI therapy. In patients without cirrhosis, median survival was 
27 months, compared to 5.2 months for those with cirrhosis. Additionally, 2 of 3 patients 
previously treated with systemic chemotherapy had a partial response. In this study, the 
treatment was well tolerated, with only 1 patient incurring any significant liver related 
toxicity (biliary sclerosis after 18 months of treatment). Furthermore, there was no 
evidence from this initial experience that patients with cirrhosis were less tolerant of 
liver-directed therapy than were patients with normal parenchyma.  More recently, 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 8 of 59 
 
 
investigators at MD Anderson Cancer Center reported results of 25 patients with 
unresectable HCC treated with a variety of continuous infusion regimens. In four 
patients (16%), tumor response was sufficient to allow for subsequent resection or 
radiofrequency ablation. Pathological analysis of resected specimens showed no viable 
tumor in one case and >90% necrosis in another. As in the study from MSKCC, these 
investigators did not find significant toxicity associated with this treatment approach. 
Additionally, Clavien et al recently reported their results using liver-directed plus 
systemic chemotherapy in patients with unresectable HCC. Using intrahepatic FUDR 
(0.2mg/kg/day) combined with bolus injection of cisplatin and adriamycin, the authors 
found that 5 patients with initially unresectable disease subsequently underwent a 
complete resection. 
 
Experience with liver-directed chemotherapy in patients with biliary tract cancer is more 
limited, although results of small series have been reported. Smith et al reported 1 
complete response (11%) and 6 partial responses (55%) out of 11 patients with 
cholangiocarcinoma and gallbladder carcinoma treated with bolus injection of hepatic 
arterial 5-FU and mitomycin C. Using continuous HAI FUDR through an implantable 
pump, Seeger et al. treated 3 patients with cholangiocarcinoma, 1 of whom had a 
complete pathological response. 
 
A recent phase II study at MSKCC (IRB# 02-120) evaluated the efficacy of HAI FUDR 
with no systemic component in patients with disease confined to the liver, 18 with ICC 
and 5 with HCC. The overall response rate was 39% and the median TTP was 7.3 
months. Partial responses appeared to be more common with ICC than HCC (45% vs. 
20%), although the number of HCC patients was much lower (Figure 1). To date, 12 
patients have developed disease progression, 6 (50%) of which were initially within the 
liver. Furthermore, the therapy was well tolerated, with only one grade 2 elevation in 
AST. The response rate and TTP observed in this study are higher than those reported 
for any systemic chemotherapeutic regimen and suggest that regional chemotherapeutic 
strategies have a potentially important role in the treatment of ICC and HCC. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 9 of 59 
 
 
 
 
3.2 
INTRAHEPATIC FUDR 
Several studies have shown that hepatic parenchymal tumors larger than a few 
millimeters in diameter derive most of their blood supply from the hepatic artery. Direct 
infusion of chemotherapeutic agents into the hepatic arterial system therefore exposes the 
tumor to higher drug concentrations than can be achieved with systemic administration. 
Several studies have shown that tumor response rates are higher with HAI therapy than 
with systemic treatment. In a prospective study of patients with metastatic colorectal 
cancer, patients were randomized to receive intrahepatic FUDR versus systemic FUDR. 
The partial response rate in the intrahepatic arm was 50% compared to 20% in the 
systemic arm. Furthermore, in a subsequent study, approximately one-third of patients 
with hepatic metastases that progressed on systemic therapy responded to intrahepatic 
FUDR. In this study, hepatic toxicity was dose-limiting. The addition of dexamethasone 
(20mg total dose for 14/28 days) has been shown to reduce hepatic toxicity, allowing 
administration of higher doses of FUDR and resulting in a higher response rate. 
 
Patients with 1o hepatic malignancies appear to tolerate intrahepatic FUDR well. In the 
initial study from MSKCC, the median duration of treatment was 11.2 months; one 
patient experienced a transient rise in bilirubin and one patient developed biliary 
sclerosis. Transient, reversible elevations of liver enzymes occurred in 9 patients. It 
should be noted that 4/10 patients had cirrhosis and 3/10 had serologic evidence of 
chronic hepatitis. It should further be noted that the dose of FUDR used in this study was 
0.3mg/kg/day, nearly twice that used in the more recent phase II study (0.16mg/kg/day). 
In the latter study, there was only one grade 2 elevation of liver enzymes noted. 
 
 
 
3.3 SYSTEMIC BEVACIZUMAB 
PR = 1 (20%) 
SD = 2 (40%) 
PD = 2 (40%) 
PR = 8 (45%) 
SD =
9 (50%) 
PD =  1 (5%) 
HCC 
 
5 Patients 
ICC 
 
18 Patients 
Unresectable 1o Liver 
Cancer 
23 Patients 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 10 of 59 
 
 
It is well established that tumor growth is critically dependent on the development of 
neovasculature for delivery of oxygen, nutrients, growth factors and other agents that 
promote proliferation. New blood vessel formation, or angiogenesis, is a complex 
process regulated by several pro- and anti-angiogenic factors. Growth of malignant solid 
tumors is associated with predominance of pro-angiogenic mediators, the so-called 
angiogenesis switch that promotes new blood vessel formation. This switch to a pro- 
angiogenic phenotype is a hallmark of malignant disease, and the extent to which it 
occurs is prognostic for some tumor types. 
 
Of the known pro-angiogenic mediators, vascular endothelial growth factor (VEGF) is 
the most important. Binding of VEGF to its receptor(s) (VEGFR) activates several 
signaling pathways that promote multiple pro-angiogenic events, including survival and 
proliferation of endothelial cells, mobilization of endothelial progenitor cells from bone 
marrow, and increased vascular permeability. VEGF’s ability to increase permeability of 
vascular beds led to its initial discovery (as vascular permeability factor) and results in 
deposition of several plasma proteins into the extra-vascular space that transform the 
normally anti-angiogenic stromal tissue into pro-angiogenic microenvironment. Over- 
expression of VEGF has been associated with poor prognosis in a number of different 
tumor types, and the VEGF/VEGFR pathway is now a major focus of anti-cancer 
research and drug development. 
 
There are several secreted glycoproteins that comprise the VEGF family of angiogenic 
and lymphangiogenic growth factors: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E 
and placenta growth factor (PlGF) -1 and -2. Of these proteins, VEGF-A (commonly 
referred to as VEGF) appears to be the most critical. The dominant isoform of VEGF-A 
is a 45-kDa homodimeric glycoprotein with a broad range of pro-angiogenic functions, 
both normal and pathologic. Alternative splicing of the VEGF-A gene gives rise to 
several mature isoforms, all of which are capable of binding to VEGFR (see below). The 
roles of VEGF-B, -C, -D and PlGF in tumor angiogenesis and vasculogenesis are less 
clear; VEGF-C and VEGF-D appear to be more important in lymphangiogenesis, 
although they may have some role in the development of new blood vessels in pathologic 
states. VEGF-E is a viral protein and not a mammalian VEGF homologue. 
 
The VEGF ligands mediate their effects through 3 different VEGFR: VEGFR-1 (or Flt- 
1), VEGFR-2 (or Flt-1/KDR) and VEGFR-3 (or Flt-4). Expression of VEGFR is largely 
confined to endothelial cells, although VEGFR-1 and VEGFR-2 have been identified on 
some adult hematopoietic cells. Certain tumor cells have also been recently shown to 
express VEGFR, the significance of which is unclear. The various VEGF ligands have 
different receptor binding specificities: VEGF-A isoforms bind to VEGFR-1 and 
VEGFR-2; VEGF-B and PlGF bind only to VEGFR-1; VEGF-C and VEGF-D can bind 
to both VEGFR-2 and VEGFR-3. Most of the downstream angiogenesis- related events 
orchestrated by VEGF-A are mediated through VEGFR-2, and this interaction is among 
the most critical. VEGFR-1 plays an important role in fetal development but its role in 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 11 of 59 
 
 
tumor angiogenesis is less clear. In adults, VEGFR-3 expression is limited to lymphatic 
endothelial cells, and through its interactions with VEGF-C and VEGF-D, mediates 
lymphangiogenesis. Increased expression of VEGF-C and VEGF-D, combined with 
activation of VEGFR-3, have been documented in several tumor types and are associated 
with lymph node metastases and may promote development of abnormal, tumor-related 
blood vessels. While tumor cells have the capacity of simultaneous expression of 
multiple VEGF ligands, VEGFR expression is more specific: VEGFR-2 is expressed by 
nearly all endothelial cells but expression of VEGFR-1 and VEGFR-3 is limited to 
distinct vascular beds. 
 
VEGF expression is regulated by several different factors, including hypoxia (hypoxia 
inducible factor or HIF-1), several different cytokines and growth factors, oncogenes and 
tumor suppressor genes (including p53). 
 
Substantial direct evidence for a role of VEGF in tumorigenesis has been provided by 
numerous studies showing that a murine anti-VEGF neutralizing antibody, alone or in 
combination with cytotoxic chemotherapy (see below), inhibits the growth of several 
different tumor types. 
 
Bevacizumab (rhuMAb VEGF) 
Bevacizumab is a recombinant humanized anti-VEGF-A monoclonal antibody composed 
of human IgG1 framework and antigen-binding complementarity-determining regions 
from a murine monoclonal antibody (rhuMAb VEGF A.4.6.1) that blocks binding of 
human VEGF-A to its receptors. Approximately 93% of the amino acid sequence, 
including most of the antibody framework, is derived from human IgG1. 
 
Pre-clinical Studies: 
This antibody has been shown to recognize all isoforms of VEGF. It fails to recognize 
other peptide growth factors tested (fibroblast growth factor, epidermal growth factor, 
hepatocyte growth factor, platelet-derived growth factor, and nerve growth factor). The 
binding affinity and specificity of rhuMAb VEGF (Bevacizumab) are essentially 
equivalent to those of its murine counterpart. 
 
 
a. In vitro and in vivo VEGF studies: 
 
A correlation has been noted between the degree of tumor vascularization and the 
level of VEGF mRNA expression. In virtually all specimens examined, VEGF 
mRNA is expressed in tumor cells but not in endothelial cells. In contrast, as 
previously noted, mRNAs for VEGFR are up-regulated in tumor-associated 
endothelial cells. These findings are consistent with the hypothesis that VEGF is 
primarily a paracrine mediator. Freeman et al. suggested that lymphocytes 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 12 of 59 
 
 
infiltrating the tumor might constitute an additional source of VEGF that 
contributes to tumor angiogenesis 
b. In vivo efficacy studies: 
 
In agreement with the hypothesis that inhibition of neovascularization is the 
mechanism of tumor suppression, the density of blood vessels is significantly 
lower in sections of tumors from antibody-treated animals compared with control. 
These findings provided a direct demonstration that inhibition of endogenous 
VEGF can suppress the growth of established tumors in vivo. Furthermore, 
substantial evidence has emerged showing improved anti-tumor activity when 
anti-VEGF therapy is combined with other chemotherapeutic agents (see below). 
Clinical Experience 
Phase I/II Efficacy Results: 
Antitumor activity has been demonstrated in multiple tumor types and with both 
single-agent Bevacizumab and combination therapy. Objective responses have 
been reported in a breast cancer trial (AVF0776g), including a complete response 
of supraclavicular nodal disease and partial responses of cervical node, liver, and 
skin-subcutaneous disease. In a NSCLC trial (AVF0757g), the data showed that 
Bevacizumab at a dose of 15 mg/kg every 3 weeks and in combination with 
Carboplatin/Paclitaxel chemotherapy, increased response rates and prolonged 
time to disease progression compared with chemotherapy alone. 
 
In a separate trial of patients with colorectal cancer (AVF0780g), based on 
blinded assessments by an independent review facility, the hazard of experiencing 
disease progression was reduced by 57% in subjects receiving 5 mg/kg 
Bevacizumab plus 5-FU/Leucovorin alone (p=0.005). Improvements in response 
rate and median survival were also seen for subjects treated with 5 mg/kg 
Bevacizumab plus 5-FU/Leucovorin versus 5-FU/Leucovorin alone. 
 
In a randomized, open-label, Phase III study (AVF2119g, metastatic breast 
cancer), the results of the primary efficacy analysis showed that treatment with 
the combination of Bevacizumab plus Capecitabine did not result in a statistically 
significant prolongation in progression-free survival compared with Capecitabine 
alone. There was a statistically significant increase in objective response rate 
(secondary endpoint); however, this did not result in an improvement in 
progression-free survival. 
 
In a randomized, double-blind, placebo-controlled phase III study, AVF2107g, 
the addition of Bevacizumab (5mg/kg IV q2 weeks) to first line therapy for 
metastatic colorectal cancer (Irinotecan/5-Fluorouracil/Leucovorin (IFL)) resulted 
in a statistically and clinically significant improvement in median survival as 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 13 of 59 
 
 
compared to the IFL + placebo control arm (15.6 vs 20.3 months, HR 0.65, 
p=0.00003). Improvements in median progression-free survival (6.2 vs 10.6 
months, p=0.00001), objective response rate (34.7% vs 44.9%, p=0.0029) and 
response duration (7.1 vs 10.4 months, p=0.0014) were also achieved with the 
addition of Bevacizumab to IFL chemotherapy. 
 
Safety of Bevacizumab: 
In the initial Phase I and II clinical trials, four potential Bevacizumabd-associated 
safety signals were identified: hypertension, proteinuria, thromboembolic events, 
and hemorrhage. Additional completed Phase II and III studies of Bevacizumab as 
well as spontaneous reports have further defined the safety profile of this agent. 
Bevacizumab-associated adverse events identified in Phase III trials include 
congestive heart failure (CHF), gastrointestinal perforations, wound healing 
complications, and arterial thromboembolic events (ATE). These and other safety 
signals are described in further detail in section 11.2. For further information 
regarding safety and adverse event rates, please refer to the Bevacizumab 
investigator’s brochure. 
 
3.4 
Rationale for HAI FUDR/Dex and Systemic Bevacizumab: 
 
It was initially postulated that anti-angiogenic therapy would essentially starve tumors of 
blood, thereby preventing growth beyond that sustainable with a rudimentary vascular 
supply. While pre-clinical studies showed that anti-angiogenic therapy alone can cause 
substantial regression of solid tumors, the objective response rates of such an approach in 
human trials have been disappointingly low. Subsequent studies have shown that anti- 
angiogenic therapy combined with cytotoxic agents significantly enhances disease 
control and survival. A recent landmark report from Hurwitz et al (NEJM, 350;2335-42, 
2004) showed that when IFL (irinotecan, 5-FU, leucovorin) chemotherapy was combined 
with Bevacizumab, progression-free survival increased from 6.2 months to 10.6 months 
and overall survival increased from 15.6 months to 20.3 months compare to IFL alone. 
From this and other observations, the concept of vascular normalization through the use 
of anti-angiogenic agents has been put forward and has data support from human studies. 
The concept of enhanced efficacy as combination therapy would initially seem 
paradoxical, since anti-angiogenic agents would be expected to reduce rather than 
augment the delivery of other anti-tumor drugs. Although new blood vessel formation is 
critical for tumor growth, tumor vasculature is grossly abnormal, both structurally and 
functionally. Tumor vasculature lacks the organized arrangement of normal vascular 
beds – vessels are tortuous and dilated, the system lacks defined arterioles, venules and 
capillaries, and connections between blood vessels are often incomplete. The 
arrangement of endothelial cells is also irregular, with wide gaps in some areas, which 
contributes to hyperpermeability. In addition, the lymphatic system within tumors is also 
abnormal. All of these features contribute to interstitial hypertension and poor intra- 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 14 of 59 
 
 
tumoral blood flow, which result in relative hypoxia and acidosis. In short, pathologic 
tumor vasculature creates a microenvironment that protects tumors from cytotoxic 
chemotherapy. Transient reversal of these abnormalities should therefore improve 
delivery of chemotherapeutic agents and make them more effective. 
By combining Bevacizumab with HAI FUDR, we seek to improve control of the primary 
liver disease, extend the time to hepatic and extrahepatic progression, and improve 
patient survival. Increased expression of VEGF mRNA is common in both ICC and 
HCC, and there is some suggestion of correlation with survival. The current study is 
based on the hypothesis that the growth and progression of primary liver cancer are 
dependent on the factors that promote angiogenesis and lymphangiogenesis. As signaling 
molecules regulating these two processes are driven by three different tyrosine kinase 
receptors – namely VEGFR1, VEGFR2 and VEGFR3 – we propose to assess the 
expression pattern of these receptors and their cognate ligands including VEGF-A, 
VEGF-B, VEGF-C, VEGF-D and P1GF, in primary liver tumors. Since Bevacizumab 
selectively blocks the activity of VEGF-A, but not VEGF-C and VEGF-D or P1GF, these 
studies will provide important information as to whether inhibition of the VEGF- 
A/VEGFR-2 signaling pathway is sufficient to block tumor angiogenesis and 
lymphangiogenesis within the primary liver lesions. 
 
3.5 Dynamic MRI 
The emergence and increasing use of therapeutic agents targeting tumor vasculature has 
made it necessary to develop imaging modalities that assess changes in tumor perfusion 
in order to determine treatment efficacy. Many techniques have been used and reported 
for evaluating tumor angiogenesis. Radiographic techniques are based on the fact that 
angiogenesis increases both the perfusion and permeability of tumors with respect to the 
surrounding normal tissue. 
 
Standard bi-dimensional tumor measurements may underestimate response to agents that 
target the tumor vasculature. Conventional MRI is useful for assessing tumor size and 
burden. Signal intensity changes may be assessed, but are not reliable for demonstrating 
possible responses to treatment. T1 weighted images alone cannot differentiate viable 
tumor from nonviable tissue or edema. Furthermore, standard T2 weighted images 
cannot adequately distinguish tumor from necrosis and frequently overestimate lesion 
boundaries due to the presence of edema and hemorrhage. While tumor shrinkage is 
useful and is the gold standard for response assessment, tumor measurements alone may 
underestimate tumor necrosis and do not consider changes in tumor vascularity. By 
contrast, DCE-MRI can document changes in tumor perfusion kinetics. 
 
DCE-MRI has been used to study a variety of tumors, including sarcoma, breast, brain 
and colorectal tumors. Injection of gadopentetate dimeglumine (Gd-DTPA) 
intravenously is followed by the agent passing from the intravascular space to the 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 15 of 59 
 
 
interstitial space at a rate that depends on perfusion and tissue permeability. This 
perfusion and tissue permeability within tumors can be visualized and measured using 
dynamic contrast-enhanced MRI. The same area of the tumor can be imaged before and 
several times after the administration of contrast medium, prior to and following a 
therapeutic intervention. In this way, it is possible to depict the change in MRI signal 
intensity due to the perfusion of the contrast medium over time. In malignancy, the 
number of blood vessels and the trans-endothelial permeability of the vessels are often 
higher than in normal tissue 
 
DCE-MRI has been shown to be useful for detecting viable tumor and differentiating it 
from necrosis in patients undergoing chemotherapy (Verstraete et al., Dyke et al.). 
Necrotic tumor, viable tumor, normal hepatic parenchyma, and blood vessels display 
distinct time intensity curves in dynamic contrast enhanced studies. Determining tumor 
necrotic fraction on static MRI during or after treatment is severely limited. On the 
other hand, the rapid acquisition sequences used in the dynamic studies may provide 
more information on vascular uptake than either static MRI or static post contrast 
images. Dynamic contrast enhanced images have the potential to provide quantitative 
estimates of necrotic fraction through an analysis of the entire time course of contrast 
agent uptake. 
 
More recent studies have suggested that dynamic contrast enhanced MRI (DCE-MRI) 
can be used to assess tumor oxygen levels, which in turn correlate with response to 
treatment and outcome. In studies on HCC, MRI findings have been shown to correlate 
with the degree of VEGF expression, which is also correlated with the degree of tumor 
hypoxia. Additionally, in a recent study of 7 patients with HCC treated with the anti- 
angiogenic drug thalidomide, changes in the time-intensity curve-related parameters 
from tumor regions of interest correlated with response to therapy. Additionally, in a 
recent MSKCC phase II study of HAI FUDR in patients with unresectable primary liver 
cancer, changes in the tumor perfusion kinetics on the first post-treatment DCE-MRI (2 
months) correlated with response as measured conventionally. In this study, the post- 
treatment changes in tumor perfusion, as measured by the time intensity curve slope 
(TIC) at an early (2 months) time point, were a significantly better predictor of treatment 
response compared to bi-dimensional tumor measurements at the same time point. In 
addition, the pre-treatment baseline (BL) slope values were found to be >300 (% 
increase/min) in all responders, and below this empirical value in non-responders. 
Similar trends were observed with the estimated compartmental model parameter AKep 
 
In the present study, unidimensional tumor measurements on standard MRI sequences 
will be used to assess response to therapy. The purpose of the dynamic component is to 
further assess for changes in tumor perfusion during treatment. Standard tumor 
measurements on conventional imaging may underestimate treatment response, and the 
dynamic component may offer a more complete assessment in that regard. In addition, 
early changes in tumor perfusion may signify a greater likelihood of a response as 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 16 of 59 
 
 
determined by reduction in tumor volume, which typically take longer to manifest. Data 
from the dynamic MRI will be correlated with conventionally measured tumor response, 
as determined on standard MRI sequences. Data from the dynamic portion of the MRI 
will be used experimentally, as described above, and will not be used to make clinical 
decisions. 
 
There is very little data derived from direct measurements of tumor perfusion changes 
during or after anti-angiogenic therapy. Most human studies use surrogate markers to 
detect improvement in the perfusion characteristics, such as increased pO2 and reduction 
in interstitial pressure. A recent study using DCE-MRI to monitor anti-angiogenesis 
treatment (PTK/ZK) of liver metastases demonstrated measurable differences in tumor 
perfusion kinetics as early as 2 days after the first dose. It is uncertain, however, how 
tumor perfusion and permeability, as measured by DCE-MRI will be altered by a 
treatment regimen that combines angiogenesis inhibition with direct cytotoxicity. In order 
to eliminate the risk of post-operative bleeding complications, Bevacizumab will not be 
given until 4 weeks after pump placement (see section 9.0, Treatment Intervention 
below). As in the previous protocol, patients will begin HAI FUDR at two weeks after 
pump placement, followed by pump emptying and refilling with heparinized saline for 
two weeks. It is during this latter time period that systemic Bevacizumab will begin. 
Patients will undergo an initial postoperative baseline DCE-MRI followed by a repeat 
study after the first two weeks of FUDR alone, and a third study following the initial 
treatment with Bevacizumab alone. In this way, we will obtain DCE-MRI data regarding 
changes in tumor perfusion kinetics as a result of antiangiogenesis treatment alone. We 
expect that DCE-MRI studies at this early time will reveal changes in tumor permeability 
and overall perfusion, indicating treatment effect of Bevacizumab. Subsequent MRI scans 
will be obtained at two-month intervals. We expect that the addition of Bevacizumab will 
improve the overall delivery of HAI FUDR to liver tumors, thereby resulting in greater 
tumor killing, and that this will ultimately be reflected in later DCE-MRI studies as 
greater reduction in tumor perfusion compared to our baseline data with HAI FUDR 
alone. 
 
3.6 
Tumor Hypoxia 
Tumor oxygenation is well recognized as an important determinant of treatment response 
and survival. For a number of different solid malignancies, hypoxia correlates with a 
more malignant phenotype, greater metastatic potential and resistance to chemotherapy 
and radiation therapy. As discussed above, the pro-angiogenic malignant phenotype is 
characterized by grossly abnormal vasculature, leading to poor tumor perfusion, hypoxia 
and acidosis. 
 
Hypoxic conditions regulate expression of several different genes with diverse functions 
that are important in promoting tumor cell survival. These include VEGF, hypoxia 
inducible transcription factor (HIF-1), carbonic anhydrase-IX (CA IX) and the glucose 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 17 of 59 
 
 
transporters Glut-1 and Glut-3, among others. HIF-1 is a central regulatory gene that 
controls expression of many downstream target genes with diverse function, including 
glucose transporters, angiogenesis and transmembrane carbonic anhydrases. CA IX, 
Glut-1 and Glut-3 are both regulated through the HIF-1 pathway and are more specific 
endogenous hypoxia-associated markers. CA IX is one of several CA’s that catalyzes the 
conversion of C02 to carbonic acid and help maintain normal intracellular pH under 
hypoxic conditions. Glut-1 and Glut-3 mediate cellular glucose uptake, thereby 
facilitating anaerobic glycolysis. Increased expression of both proteins has been 
correlated with poor outcome for several different human cancers. CA IX, in particular, 
appears to be among the most sensitive of the hypoxic markers. HIF-1, the nuclear 
protein product of the HIF-1 gene, has also been shown to be a useful intrinsic marker of 
hypoxia with prognostic relevance. 
 
Direct measurements of tumor oxygen levels have been shown to correlate with 
immunohistochemical markers of hypoxia; however there is limited data pertaining to the 
results of DCE-MRI. We expect that these studies will yield important data that will not 
only improve our understanding of the biology of primary liver cancers but that will also 
improve our ability to interpret the DCE-MRI assessment of tumor perfusion and 
permeability. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
A total of 55 patients whose liver lesions have been deemed unresectable will be treated 
with HAI FUDR plus systemic Bevacizumab. Unidimensional tumor measurements on 
standard MRI sequences will be used to assess response to therapy. Patients will remain 
on study as long as they show continued response as defined in section 13.0, and do not 
experience significant toxicity as defined in Sections 11.0 and 14.0. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 18 of 59 
 
 
4.2 
Intervention 
All patients enrolled in the study will receive HAI FUDR (0.16 mg/kg X pump volume / 
pump flow rate), Dexamethasone (1 mg/m2/day) and IV Bevacizumab at 5mg/kg. 
Chemotherapy with HAI FUDR/Dex will commence no sooner than 14 days post surgical 
placement of HAI pump; patients will receive their first treatment with Bevacizumab no 
sooner than 28 days post surgical placement of HAI pump. 
 
 
Cycle Schema q4 weeks 
Day 1 
Day 15 
Systemic chemotherapy 
IV Bevacizumab* 
Systemic chemotherapy 
IV Bevacizumab 
HAI with FUDR+Dexamethasone 
(continuous 14-day infusion) 
Pump emptied and refilled with heparinized 
saline (recycle with FUDR in 2 weeks) 
* The exception will be Cycle 1, Day 1, on which the patient will receive only HAI with 
FUDR/Dex. Systemic treatment with Bevacizumab will commence no sooner than Cycle 1, Day 
15, and patient will receive Bevacizumab every 2 weeks thereafter. 
 
The following doses will be used: 
 
FUDR 
(mg/kg x pump 
vol / flow rate) 
over 14 days 
Dexamethasone 
(mg) 
Given 
concurrent with 
pump 
Bevacizumab 
(mg/kg) 
IV, over 
10 min 
0.16 
25 
5 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 FUDR 
5.1.1 Floxuridine (FUDR) is an antimetabolite that blocks the methylation of 
deoxyuridylic acid interfering with the synthesis of DNA. It is also incorporated 
into RNA and interferes with its function. The drug is metabolized in the liver. 
5.1.2 FUDR is commercially available from Roche and Adria Laboratories in 500 
mg/10 cc ampules. It is stable (protected from light) and is a colorless aqueous 
solution. Store at room temperature. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 19 of 59 
 
 
5.1.3 Toxicities associated with the intrahepatic administration of FUDR include biliary 
sclerosis, chemical hepatitis, gastric ulcers. 
 
5.2 Dexamethasone 
5.2.1 Dexamethasone is an adrenocortical steroid, used for chronic inflammation, 
neoplastic and autoimmune diseases; used in HAI treatment as an agent to prevent 
liver damage. 
5.2.2 Common potential side effects include anxiety, mood alteration/lability, 
hyperglycemia, insomnia, peripheral edema, myopathy (with chronic use), acne, 
hirsutism. 
 
5.3 Bevacizumab (rhuMab VEGF) 
Description: 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid 
concentrate for solution for intravenous (IV) infusion. Bevacizumab may be supplied in 5-cc 
(100 mg), 20-cc (400 mg), and 50-cc (1000 mg) glass vials containing 4 mL, 16 mL, or 40 
mL of Bevacizumab, respectively (all at 25 mg/mL). Vials contain Bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection (SWFI), USP. Vials 
contain no preservative and are suitable for single use only. 
 
The monoclonal antibody (Bevacizumab) being administered is intended for use only in 
clinical trials. It is expected to be very similar in safety and activity to the commercially 
marketed drug (Avastin), but it is possible that some differences exist. 
 
For further details and molecule characterization, see the Bevacizumab Investigator 
Brochure. 
Administration: 
Bevacizumab will be administered as per MSKCC guidelines. 
 
Storage: 
Upon receipt of the study drug, vials are to be refrigerated at 2ºC - 8ºC (36ºF - 46ºF) and 
should remain refrigerated until just prior to use. DO NOT FREEZE. DO NOT SHAKE. 
Vials should be protected from light. 
Opened vials must be used within 8 hours. VIALS ARE FOR SINGLE USE ONLY. Vials 
used for 1 subject may not be used for any other subject. Once study drug has been added to 
a bag of sterile saline, the solution must be administered within 8 hours. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 20 of 59 
 
 
Bevacizumab Dose Modification and Toxicity Management: 
There are no reductions in the Bevacizumab dose. If adverse events occur that require 
holding Bevacizumab, the dose will remain the same once treatment resumes. 
Any toxicities associated or possibly associated with Bevacizumab treatment should be 
managed according to standard medical practice. Bevacizumab has a terminal half-life of 2 to 
3 weeks; therefore, its discontinuation results in slow elimination over several months. There 
is no available antidote for Bevacizumab. 
Subjects should be assessed clinically for toxicity prior to, during, and after each infusion. If 
unmanageable toxicity occurs because of Bevacizumab at any time during the study, 
treatment with Bevacizumab should be discontinued. 
 
Infusion Reaction: 
Infusion of Bevacizumab should be interrupted for subjects who develop dyspnea or 
clinically significant hypotension. Subjects who experience a NCI CTCAE v. 3.0 Grade 3 or 
4 allergic reaction / hypersensitivity, adult respiratory distress syndrome, or bronchospasm 
(regardless of grade) will be discontinued from Bevacizumab treatment. 
The infusion should be slowed to 50% or less or interrupted for subjects who experience any 
infusion-associated symptoms not specified above. When the subject’s symptoms have 
completely resolved, the infusion may be continued at no more than 50% of the rate prior to 
the reaction and increased in 50% increments every 30 minutes if well tolerated. Infusions 
may be restarted at the full rate during the next cycle. 
Adverse events requiring delays or permanent discontinuation of Bevacizumab are listed in 
the Table in section 12.3 
 
Toxicity: Toxicities associated with the intravenous administration of Bevacizumab include 
hypertension, hemorrhage, thromboembolic events, proteinuria, and diarrhea. These are 
described in detail under section 11.2. 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 Subject Inclusion Criteria 
• Histologically confirmed and radiographically measurable hepatocellular carcinoma 
(HCC) or intrahepatic cholangiocarcinoma (also variously reported as peripheral 
cholangiocarcinoma, cholangiolar carcinoma or cholangiocellular carcinoma) (ICC) 
with no clinical or radiographic evidence of extrahepatic disease. Confirmation of the 
diagnosis must be made at MSKCC. If the patient has a liver mass that is 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 21 of 59 
 
 
radiographically consistent with HCC and a serum alpha fetoprotein (AFP) > 400 
ng/dl, then biopsies will be performed at the time of pump placement. 
Radiographically measurable disease are lesions for which 2 dimensional 
measurements can be made on a cross sectional image. Minimum lesion size is 2 cm 
in greatest diameter as per RECIST criteria. 
• 
Patients with suspected ICC will undergo radiographic evaluation to exclude the 
possibility of metastatic liver disease. For patients who have undergone pre- or 
postoperative biopsies that definitively diagnose ICC, the diagnostic studies may be 
modified at the discretion of the Principal Investigator. 
 
• Mixed HCC/ICC is an uncommon variant of primary liver cancer with histologic 
features of both HCC and ICC. With respect to patient demographics and clinical 
behavior, mixed tumors are very similar to ICC. Patients suspected of having mixed 
tumors will be eligible and will be exempt from the extensive radiographic 
evaluation; they will have biopsies performed at the time of pump placement. 
• Patients with hepatocellular carcinoma who are not eligible for first-line MSKCC 
protocols for hepatocellular carcinoma will be eligible for this protocol if they have 
no clinical or radiographic evidence of extrahepatic disease. 
• Patients with HCC or ICC undergoing exploration for a possible curative resection 
but found to have unresectable disease confined to the liver will be eligible. 
• <70% liver involvement by cancer. 
• Disease must be considered unresectable at the time of preoperative evaluation. 
• Patients who have failed ablative therapy will be eligible. 
• Patients who have failed prior systemic chemotherapy will be eligible. 
• KPS > 60% and be considered candidates for general anesthesia and hepatic artery 
pump placement. 
• Patients with chronic hepatitis and/or cirrhosis are eligible but must be Child-Pugh 
class A. 
• Preoperative laboratory values, within 14 days of registration: 
➢ Serum albumin >2.5 g/dl 
➢ Total serum bilirubin <1.8 mg/dl 
➢ WBC >3500 cells/mm3 
➢ Platelet count >100,000/mm3 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 22 of 59 
 
 
➢ International normalized ratio (INR) < 1.5 (in patients not on coumadin 
therapy) 
• Patients discovered to have > 2+ proteinuria at baseline will undergo a 24-hour urine 
collection, which must be an adequate collection and must demonstrate < 1g of protein/24 
hours. 
• Age > 18 years. 
• Patients must be able to understand and sign informed consent. 
 
6.2 
Subject Exclusion Criteria 
• Prior treatment with FUDR. 
• Prior external beam radiation therapy to the liver. 
• Diagnosis of sclerosing cholangitis. 
• Diagnosis of Gilbert's disease. 
• Clinical ascites. 
• Hepatic encephalopathy. 
• Current, recent (with 4 weeks of the first infusion of this study), or planned 
participation in an experimental drug study other than a Genentech-sponsored 
Bevacizumab cancer study. 
• Life expectancy of less than 12 weeks. 
• Inability to comply with study and/or followup procedures 
• Inadequately controlled hypertension (defined as systolic blood pressure >150 
and/or diastolic blood pressure > 100 mmHg on antihypertensive medications). 
 
• Any prior history of hypertensive crisis or hypertensive encephalopathy. 
• New York Heart Association (NYHA) Grade II or greater congestive heart 
failure. 
 
• Patients with known CNS disease. 
 
• Significant vascular disease (e.g. aortic aneurysm, aortic dissection), or 
symptomatic peripheral vascular disease. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 23 of 59 
 
 
 
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 6 months prior to study enrollment. 
 
• History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Bevacizumab. 
 
• Serious or non-healing active wound, ulcer, or bone fracture. 
 
• Major surgical procedure, open biopsy or significant traumatic injury within 28 
days prior to first treatment with Bevacizumab, or anticipation of need for major 
surgical procedure during the course of the study (surgery performed to place 
pump will not exclude patient from protocol; first treatment with Bevacizumab 
will take place no sooner than 28 days after surgery). 
 
• Core biopsy, or other minor surgical procedure (excluding placement of a 
vascular access device) within 7 days prior to treatment start. 
 
• Current or recent use of a thrombolytic agent. 
• Patients must have adequate blood coagulation parameters: PT such that 
international normalized ratio (INR) is < 1.5 (or an in-range INR, usually between 
2 and 3, if a patient is on a stable dose of therapeutic warfarin), and a PTT < 1.5 
times the institution upper limit of normal. Patients not meeting this criteria will 
be ineligible for study. 
 
• Chronic daily treatment with aspirin (> 325 mg/d) or nonsteroidal anti- 
inflammatory medications known to inhibit the platelet function. 
 
• Presence of bleeding diathesis or coagulopathy. 
• Proteinuria at screening as demonstrated by either 
➢ Urine protein: creatinine (UPC) ratio > 1.0 at screening OR 
➢ Urine dipstick for proteinuria > 2+ (patients discovered to have >2+ 
proteinuria on dipstick analysis at baseline should undergo a 24 hour urine 
collection and must demonstrate <1g of protein in 24 hours to be eligible). 
 
• Patients with history of stroke, transient ischemic attack, unstable angina, or 
myocardial infarction MI) within 6 months. 
 
• Presence of central nervous system metastases. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 24 of 59 
 
 
 
• Patients who have radiographic evidence of esophageal varices or history of 
variceal hemorrhage. 
 
• Patients with occlusion of the main portal vein or of the right and left portal 
branches. 
 
• Patients that have concurrent malignancies (except localized basal cell or 
squamous cell skin cancers). 
 
• Patients with active infection. 
• Female patients who are pregnant or lactating. 
 
 
7.0 
RECRUITMENT PLAN 
All patients meeting the eligibility requirements will be considered for enrollment 
regardless of sex, race, or religion. Patients will be accrued from the 
Hepatopancreatobiliary, Gastrointestinal, and Gastric/Mixed Tumor services, and from 
both the Department of Surgery and Department of Medicine. Eligibility criteria may not 
be waived by the investigator. Discussions regarding protocol enrollment and patient 
eligibility will begin with any of the investigators named on the protocol. Patients will be 
made aware of the protocol, its specific aims and objectives, and the potential risks and 
benefits the patients may incur. Patients will be required to read, agree to, and sign an 
IRB-approved informed consent form prior to registration on this trial. Patients will be 
consented prior to surgery. Registration will consist of two steps: Step 1 will allow the 
procurement of preoperative blood samples and tissue at surgery and will take place 
preoperatively; Step 2 will register patient fully in order to receive chemotherapy 
treatment. Only patients registered to both Step 1 and 2 will be treated per protocol. 
There will be no financial compensation for patients enrolling on this protocol. 
 
 
8.0 PRETREATMENT EVALUATION 
Prior to treatment start, patients will undergo the following procedures, in order: 
 
1. 
CT angiogram (direct, MRI or CT angiography)to determine arterial structures; 
this may be done at any time prior to surgery 
2. 
Surgery to undergo cholecystectomy, place hepatic arterial infusion pump, and to 
obtain tissue biopsy 
3. 
Perfusion flow study (Tc-99 MAA) 
4. 
Baseline MRI scan of the chest, abdomen and pelvis 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 25 of 59 
 
 
 
The following tests are required of ALL patients: 
• CT or MRI of the chest/abdomen within 6 weeks of registration. 
• Hepatitis serology within 52 weeks of registration (if never previously tested or if 
previously negative for hepatitis B or C). 
 
The following tests are required of all patients with a presumptive diagnosis of ICC: 
• Colonoscopy within 2 years of registration (exemption may be made for patients who 
have biopsy-proven ICC). 
• Bilateral mammography (females only) within 24 weeks of registration. 
 
 
In addition, the following evaluations will be required at the indicated times: 
Within 14 days of 
Registration 
Within 14 days of 
surgery 
Post surgery, 
within 21 days of 
Cycle 1 
Post surgery, 
within 48 hours of 
Cycle 1 
EKG 
X 
X1 
HX, PE, BP 
X 
X 
Pregnancy test 
(females of child- 
bearing potential) 
X 
DCE-MRI 
Abdomen2 
X 
Tumor Size 
measurements2 
X 
KPS3 
X 
X 
Ht / Wt4 
X 
X 
PT 
X 
CBC with diff/plts 
X 
X 
Albumin 
X 
X 
Total bilirubin 
X 
X 
BUN, creatinine 
X 
X 
Alk Phos, SGOT, 
LDH 
X 
X 
CEA, AFP, CA 
19-95 
X 
X 
Urinalysis 
X 
X 
Serum electrolytes 
X 
CT angiogram or 
Celiac axis & 
SMA angiogram6 
X 5 
Tc-99m MAA 
hepatic artery 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 26 of 59 
 
 
 
catheter injection 
X 
1 
Required within 7 days of operation 
2 
Baseline MRI kinetic study/scan will be obtained on all patients prior to starting therapy 
and will be used for tumor measurement(s) and to assess disease response or progression 
during and after therapy. Exception will be made for any patient who cannot undergo 
MRI; in that case, CT scanning will be accepted. 
3 
KPS will be determined prior to surgery and prior to initiating chemotherapy. KPS will 
also be evaluated on day 1 of each cycle while undergoing therapy. 
4 
Height will only be assessed at initial visit; weight will be assessed at every MD visit. 
5 
Tumor markers will be measured as part of the patient’s standard bloodwork prior to 
initiating chemotherapy, and will be monitored at the attending MD’s discretion during 
treatment. 
6 
Either direct angiography, MR angiography, or CT angiography are acceptable, and can 
be performed at any time prior to surgery. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Administration: 
Chemotherapy will be administered on a 4-week cycle basis. Pump therapy with 
FUDR and Dex plus heparinized saline to make 30cc will be administered on Day 
1 of each cycle. The pump will be emptied and re-filled with heparin and normal 
saline on Day 15. Bevacizumab (5mg/kg) will be administered on Days 1 and 15 
of each cycle, however initial treatment with Bevacizumab will not take place 
until Day 15 of Cycle 1. Treatment recycles on Day 29. 
On Day 15 of cycle 1, patients will receive their initial treatment with 
Bevacizumab, administered by IV, administered per MSKCC guidelines. 
 
9.2 
Dose Calculation: 
For the first cycle, doses of FUDR and Dex will be calculated based on the 
predetermined flow rate provided by the pump manufacturer. Thereafter, doses 
will be adjusted (lowered, if necessary, but never increased) based on actual 
observed flow rate. The pump will be filled with FUDR, Dexamethasone, heparin 
and saline. 
 
FUDR Calculation: 
FUDR: 0.16 mg/kg X pump volume 
pump flow rate 
Dexamethasone: 1 mg/day X pump volume 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 27 of 59 
 
 
pump flow rate 
Overweight patients: 
If a patient is 25% above ideal weight, dose of FUDR and systemic chemotherapy 
will be calculated as follows: 
Ideal Body weight (kg): 
Males: 50kg + (2.3 x height in inches above 5 ft) 
(ie: for a patient who is 5’10”, use 10) 
Females: 45.5 kg + (2.3 x height in inches above 5 ft) 
Example: Male who is 100 kg and 5’10” 
Ideal Body Weight is: 50 + (2.3 x 10) = 73 kg 
Therefore, 100 + 73 = 173 ÷ 2 = 86.5 would be the Ideal Average Weight to use. 
Heparin: 
30,000 units total dose 
Normal saline: quantity sufficient to make total reservoir volume of 30 ml. 
If no dose modification due to toxicity is required, the dosages given above 
(adjusted for changes in weight and pump flow rate) will be repeated on Day 1 of 
Cycle 2 and all subsequent cycles. 
 
9.3 
Pump Empty 
On Day 15 of each cycle, the pump will be emptied and then filled with 30,000 
units of heparin in normal saline (q.s. 30cc) for 14 days. 
 
9.4 
Hematologic Criteria 
Patients must meet all hematologic and blood chemistry criteria outlined in 
Section 6.0 before beginning the first cycle of therapy. For subsequent cycles, 
patients must meet the following criteria: 
WBC 
> 2500 µL 
ANC 
> 1500 µL 
Platelet count 
>  75,000 µL 
Creatinine 
< 1.8 mg/dL 
Bilirubin 
< 1.5 mg/dL 
If counts are outside these levels on date of scheduled treatment, therapy will be 
delayed one week. 
Parameters for treatment with FUDR via intrahepatic pump are outlined in 
Section 12. 
 
9.5 
Treatment Duration: 
9.5.1 Patients will receive treatment until such time as progression is noted, or the 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 28 of 59 
 
 
patient develops unacceptable toxicity, or there is a change in diagnosis (see 
section 14.0, “Criteria for Removal from Study”). 
9.5.2 If FUDR is discontinued due to patient progression, then patient will be 
discontinued on study drug (Bevacizumab) as well 
9.5.3 If FUDR is held for reasons other than progression, patient will continue on 
Bevacizumab at the attending physician’s discretion. 
9.5.4 If Bevacizumab is discontinued due to toxicity (sections 11.0, 12.3), the 
patient will continue to receive FUDR as long as patient continues to respond, and 
at the discretion of the attending physician. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 29 of 59 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
 
At time of 
surgery 
Day 1* each 
Cycle 
q2 weeks 
q8 weeks 
q 12 weeks 
HX,PE, BP 
X 
X 
Tox assessment 
X 
X 
Weight 
X 
KPS 
X 
CBC, Plts 
X 
X 
BUN, Creat 
X 
X 
Bili, SGOT 
X 
X 
Alk phos, LDH 
X 
X 
Electrolytes 
X 
Tumor markers1 
X 
Urinalysis 
X 
EKG4 
X 
Chest x-ray/CT 
chest5 
X 
Dynamic MRI 
abdomen2 
X 
Tc-99m MAA 
hepatic artery 
catheter injection 
Plasma 
levels3/VEGF ** 
X 
X 
Tumor tissue 
levels / VEGF** 
X 
* Or within 48 hours prior to Day 1 
** Tissue and blood samples will be stored preparatory to analysis. 
1Tumor markers (CEA, AFP, CA19-9) will be drawn if elevated before treatment, or at the 
discretion of the attending physician. 
 
2All patients will undergo DCE MRI after initial treatment with FUDR, and again after 
initial treatment with Bevacizumab. DCE MRI will take place every 2 cycles thereafter, 
allowing for scheduling conflicts; a variance in the timing will not be considered a 
protocol deviation. The timing of the DCE MRI may be advanced at the discretion of the 
attending physician, in the interest of patient safety. 
 
3Patients will have one lavender-top tube (7 or 10cc) and 1 8cc BD CPT tube of whole blood 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 30 of 59 
 
 
drawn on Day 1 of each cycle. 
4EKG will be done every 12 weeks, allowing for scheduling conflicts; a variance in the timing 
will not be considered a protocol deviation. Other EKGs performed as deemed clinically 
necessary, at the discretion of the attending MD. 
5 CT of the pelvis may be added at the discretion of the attending MD. 
While being treated with protocol therapy, patients will be seen on or prior (within 48 hours) to 
the first day of each cycle by their medical oncologist. 
 
Specific Monitoring: 
Hypertension will be monitored through routine evaluation of blood pressure prior to each 
Bevacizumab treatment. Optimal control of blood pressure according to standard public health 
guidelines is recommended for patients on treatment with or without Bevacizumab. 
 
Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or dipstick at least every 
4 weeks, not to exceed 6 weeks. 
 
If patients on treatment with Bevacizumab require elective major surgery, it is recommended 
that Bevacizumab be held for 4-8 weeks prior to the surgical procedure. Patients undergoing a 
major surgical procedure should not begin/restart Bevacizumab until 4 weeks after that 
procedure (in the case of high risk procedures such as liver resection, thoracotomy, or 
neurosurgery, it is recommended that chemotherapy be restarted no earlier than 6 weeks and 
Bevacizumab no earlier than 8 weeks after surgery). 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
All toxicities will be rated as per the NCI Common Toxicity Criteria except neurosensory 
and hepatic enzyme toxicities related to intrahepatic pump therapy (see section 12.5 
FUDR Dose Modifications and Table I). 
 
11.1 Toxicity Related to Regional Chemotherapy: 
11.1.1 FUDR: gastritis, gastroduodenal ulcers, chemical hepatitis, biliary sclerosis 
with jaundice, pruritus, diarrhea. 
 
11.1.2 Dex: anxiety, mood alteration/lability, hyperglycemia, insomnia, peripheral 
edema, myopathy (with chronic use), acne, hirsutism, sodium retention, fluid 
retention, hypertension, development of cushingoid state, secondary 
adrenocortical and pituitary hypo-responsiveness, decreased carbohydrate 
tolerance, manifestations of latent diabetes. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 31 of 59 
 
 
 
 
 
11.2 Toxicity Related to Bevacizumab: 
In addition to fever, generalized aches, headache, rash, fatigue, shortness of breath, reversible 
liver function elevation and allergic reaction, the following toxicities may be seen: 
Hypertension: Hypertension has been commonly seen in Bevacizumab clinical trials to date 
and oral medications have been used to manage the hypertension when indicated. Grade 4 
and 5 hypertensive events are rare. Clinical sequelae of hypertension are rare but have 
included hypertensive crisis, hypertensive encephalopathy, and reversible posterior 
leukoencephalopathy syndrome (RPLS). RPLS may include signs and symptoms of 
headache, altered mental function, seizures, and visual disturbances/cortical blindness and 
requires treatment, which should include control of hypertension, management of specific 
symptoms, and discontinuation of Bevacizumab. 
Bleeding: In a lung cancer trial, there were six life-threatening bleeding events among 66 
subjects. There were no life-threatening hemorrhagic events in completed Phase III trials in 
breast and colorectal cancers. Minor mucocutaneous bleeding (epistaxis) has also been seen 
in all Bevacizumab clinical trials at a rate of approximately 20-40%. 
Thromboembolic events: Both venous and arterial thromboembolic (TE) events, ranging in 
severity from catheter-associated phlebitis to fatal, have been reported in patients treated with 
Bevacizumab in the colorectal cancer trials and, to a lesser extent, in patients treated with 
Bevacizumab in NSCLC and breast cancer trials. In the phase II pivotal trial in metastatic 
CRC, there was a slightly higher rate of venous TE events that was not statistically 
significant in patients treated with Bevacizumab plus chemotherapy compared with 
chemotherapy alone. There was also a higher rate of arterial TE events (3% vs. 1%) such as 
myocardial infarction, transient ischemia attack, cerebrovascular accident/stroke and 
angina/unstable angina. A pooled analysis of the rate of arterial TE events from 5 
randomized studies (1745 patients) showed that treatment with chemotherapy plus 
Bevacizumab increased the risk of having an arterial TE event compared with chemotherapy 
alone. Furthermore, subjects with certain baseline characteristics (age > 65 years and/or a 
history of a prior arterial TE event) may be a higher risk of experiencing such an event. 
Proteinuria: Proteinuria has been commonly seen in Bevacizumab clinical trials to date. The 
severity of proteinuria has ranged from asymptomatic and transient events detected on 
routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria events have 
been grade 1 or 2. Rare events of nephrotic syndrome have occurred, and Bevacizumab 
should be discontinued in patients with nephrotic syndrome. 
Gastrointestinal Perforation: Bevacizumab should be permanently discontinued in patients 
who develop gastrointestinal perforation. A causal association of intra-abdominal 
inflammatory process and gastrointestinal perforation to Bevacizumab has not been 
established. Nevertheless, caution should be exercised when treating patients with intra- 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 32 of 59 
 
 
abdominal inflammatory processes with Bevacizumab. Gastrointestinal perforation has been 
reported in other trials in non-colorectal cancer populations (e.g. ovarian, renal cell, pancreas, 
and breast) and may be higher in incidence in some tumor types. 
CHF: CHF has been reported in Bevacizumab clinical trials and may be increased in 
incidence in patients with prior exposure to anthracyclines or prior irradiation to the chest 
wall. Patients receiving anthracyclines or with prior exposure to anthracyclines should have a 
baseline MUGA or ECHO with a normal ejection fraction. 
Wound Healing: Wound healing complications such as wound dehiscence have been 
reported in patients receiving Bevacizumab. In an analysis of pooled data from two trials in 
metastatic colorectal cancer, patients undergoing surgery 28-60 days before study treatment 
with 5FU/LV plus Bevacizumab did not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone. Surgery in patients 
currently receiving Bevacizumab is not recommended. No definitive data are available to 
define a safe interval after Bevacizumab exposure with respect to wound healing risk in 
patients receiving elective surgery; however, the estimated half-life of Bevacizumab is 20 
days. Bevacizumab should be discontinued in patients with severe wound healing 
complications. 
 
11.3 
Toxicity Related to the Pump and Catheters 
11.3.1 Infection, hepatic artery thrombosis, pump malfunction, catheter occlusion, intra- 
abdominal bleed. 
 
 
12.0 DOSE MODIFICATIONS 
 
12.1 
FUDR Dose Modifications : 
Elevations in SGOT, alkaline phosphatase, and serum bilirubin are common 
during treatment with intrahepatic FUDR and have been managed adequately by 
modifying the dose or delaying treatment, as reported in previous studies. 
Elevations in these laboratory values will be managed as outlined in the table 
below. 
Percentages listed under “FUDR Dose” refer to percentage of last dose of FUDR 
administered; however, changes in flow rate and weight must be considered. 
Therefore, the modified dose will be calculated using the indicated percentage of 
the desired dose multiplied by patient’s weight and pump volume, then divided by 
current pump flow rate. For example, if a 75 kg patient required a 50% dose 
reduction, and the pump had an actual flow rate of 1.6 ml/day, then the FUDR 
dose would be calculated as follows: 
.16mg/kg/day X dose attenuation [.50] X 75kg X 30ml = 131.3 mg FUDR 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 33 of 59 
 
 
pump flow rate [1.6 ml/day] 
 
 
 
FUDR DOSE MODIFICATION TABLE: 
 
Reference Value* 
% FUDR dose 
SGOT (at pump emptying or 
day of planned retreatment, 
whichever is higher) 
0 to < 2 x reference value 
100% 
2 to < 3 x reference value 
80% 
3 to < 4 x reference value 
50% 
> 4 x reference value 
Hold 
ALK PHOS (at pump 
emptying or day of planned 
retreatment, whichever is 
higher) 
0 to < 1.2 x reference value 
100% 
1.2 to < 1.5 x reference value 
50% 
> 1.5 x reference value 
Hold 
TOT BILI (at pump emptying 
or day of planned retreatment, 
whichever is higher) 
0 to < 1.2 x reference value 
100% 
1.2 to < 1.5 x reference value 
50% 
> 1.5 x reference value 
Hold 
If SGOT > 4X reference value, alkaline phosphatase > 1.5X reference value, total bilirubin > 
1.5X reference value, then treatment will be held and will not be reinstituted until values come 
down to more normal levels, as indicated in section “Resuming Treatment After Temporary 
Discontinuation”. 
 
"Reference value" is the value obtained on the day the patient received last FUDR 
dose. To determine if an FUDR dose modification is necessary, compare reference 
value to either the value obtained on the day the pump was emptied or on day of 
planned pump filling, whichever is higher. 
If a patient's Alkaline Phosphatase or T bili shows a continual rise from Day 1 of treatment, then 
the Day 1 value will be used as the reference value for that patient when determining whether to 
hold treatment, and time of re-treatment after hold. 
 
12.2 
Resuming Treatment After Temporary Discontinuation: 
 
REASON FOR 
TREATMENT DELAY 
Chemotherapy resumed 
when value has returned to: 
% FUDR dose 
SGOT elevation 
3 X reference value 
25% of last dose 
Alkaline Phosphatase 
elevation 
1.2 X reference value 
25% of last dose 
Total bilirubin elevation 
1.2 X reference value 
25% of last dose 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 34 of 59 
 
 
 
 
12.2.1 Biliary Toxicity: If patient develops a total bilirubin > 3.0 mg/dl, the pump 
should be emptied and Dex 25 mg plus heparin 30,000 u and saline 30 cc placed in 
the pump q 14 days. Once there is no longer evidence of toxicity, Dex dose should be 
tapered in increments of 5 mg every 14 days. Tapering will continue unless enzymes 
increase. FUDR should be permanently discontinued unless there is evidence of 
disease progression (increasing CEA, worsening CT scan, worsening clinical status) 
AND bilirubin has returned to < 1.5 mg/dl. In this case, FUDR can be restarted as 
follows: Use 25% of the last FUDR dose given with Dex, heparin and saline in the 
pump for 7 days. Pump should be emptied after 7 days, and patients given a 3-week 
rest period. This treatment and treatment schedule should continue as long as 
bilirubin remains < 1.5 mg/dl and liver enzyme values do not increase. 
 
12.2.2 Epigastric pain unresponsive to oral H2 blocker use is suggestive of 
gastroduodenal irritation or ulcer. Severe pain should prompt workup with an upper 
gastrointestinal endoscopy. Serum amylase should be checked along with the routine 
blood (screening profile, creatinine, and CBC) in patients with abdominal pain. If an 
ulcer or gastroduodenitis is documented, therapy should be held for one month to 
allow healing. If abdominal pain is severe, the pump should be emptied of FUDR 
until results of workup are available. 
12.2.3 Severe diarrhea (Grade 3 or 4) may result from extrahepatic perfusion of 
FUDR. If a patient develops diarrhea at the level of dose limiting toxicity, the 
pump will be emptied of FUDR and a repeat flow scan will be obtained to 
exclude the possibility of extrahepatic perfusion. If the flow scan suggests 
extrahepatic perfusion, then an arteriogram will be obtained through the side port 
of the pump and all mis-perfusing arteries will be embolized. Treatment will 
resume only after this is done and the diarrhea resolves. If the flow scan is 
normal, then the possibility of infectious diarrhea will be investigated. If such 
investigations are negative, then the diarrhea will be considered a dose-limiting 
toxicity (DLT). Treatment may resume with FUDR at 0.14mg/kg/day. 
12.3 
Bevacizumab Treatment Modifications 
Drug treatment will be modified in the event of certain adverse events (as shown in the 
following table). Regardless of the reason for holding the drug treatment, the maximum 
allowable length of treatment interruption is 2 months (2 cycles). 
Bevacizumab Dose Modification Table: 
 
Event 
Action to be Taken 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 35 of 59 
 
 
 
Hypertension 
Grade 3 
Grade 4 (including RPLS 
[confirmed by MRI] or 
hypotensive encephalopathy) 
If not controlled to 150/100 mmHg with medication, discontinue 
Bevacizumab 
Discontinue Bevacizumab 
Hemorrhage 
Grade > 2 pulmonary or CNS 
hemorrhage 
Grade 3 nonpulmonary and non- 
CNS hemorrhage 
Grade 4 
Discontinue Bevacizumab 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving Bevacizumab 
All other subjects will have study treatment held until all of the 
following criteria are met: 
• 
The bleeding has resolved and hemoglobin is stable 
• 
There is no bleeding diathesis that would increase the risk of 
therapy 
• 
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence 
Patients who experience a repeat Grade 3 hemorrhagic event will 
be discontinued from receiving Bevacizumab 
Discontinue Bevacizumab 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 36 of 59 
 
 
 
Venous Thrombosis 
Grade 3/asymptomatic Grade 4 
Symptomatic Grade 4 
Arterial Thromboembolic Event 
(Angina, MI, TIA, CVA, and any 
other arterial thromboembolic 
event 
Any Grade 
Hold study drug treatment. If the planned duration of full-dose 
anticoagulation is < 2 weeks, study drug should be held until the 
full-dose anticoagulation period is over. If the planned duration of 
full-dose anticoagulation is > 2 weeks, drug may be resumed during 
the period of full-dose anticoagulation if all of the following criteria 
are met: 
• 
The patient must have an in-range INR (usually between 2 
and 3) on a stable dose of warfarin (or other anticoagulant) 
prior to restarting study drug treatment 
• 
The patient must not have had a Grade 3 or 4 hemorrhagic 
event while on anticoagulation 
• 
The patient must not have had evidence of tumor involving 
major blood vessels on any prior CT scan 
Discontinue Bevacizumab 
Discontinue Bevacizumab 
Arterial Thromboembolic Event 
(angina, myocardial infarction, 
transient ischemic attack, 
cerebrovascular accident, and any 
other arterial thromboembolic 
event) 
Any Grade 
Discontinue Bevacizumab 
Congestive Heart Failure 
(Left ventricular systolic 
dysfunction) 
Grade 3 
Grade 4 
Hold Bevacizumab until resolution to Grade < 1 
Discontinue Bevacizumab 
Proteinuria 
Grade 3 (UPC > 3.5, urine 
collection > 3.5 g/24 hr, or dipstick 
4+) 
Grade 4 (nephrotic syndrome) 
Hold Bevacizumab treatment until < Grade 2, as determined by 
either UPC ration < 3.5, or 24 hr collection < 3.5 g 
Discontinue the patient from the study 
GI Perforation 
Discontinue Bevacizumab 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 37 of 59 
 
 
 
Bowel Obstruction 
Grade 1 
Grade 2 
Grade 3/4 
Continue patient on study for partial obstruction NOT requiring 
medical intervention 
Hold Bevacizumab for partial obstruction requiring medical 
intervention. Patient may restart upon complete resolution. 
Hold Bevacizumab for complete obstruction. If surgery is 
necessary, patient may restart Bevacizumab after full recovery from 
surgery, and at investigator’s discretion 
Wound dehiscence (requiring 
medical or surgical therapy) 
Discontinue Bevacizumab 
Other Unspecified Bevacizumab- 
Related Adverse Events 
Grade 3 
Grade 4 
Hold Bevacizumab until recovery to < Grade 1 
Discontinue Bevacizumab 
Patients who have an ongoing bevacizumab-related Grade 4 or serious adverse event at the time 
of discontinuation from study treatment will continue to be followed until resolution of the event 
or until the event is considered irreversible 
12.4 
General 
If any patient on this protocol has a sudden change in condition, liver function tests will 
be checked immediately. The pump will be emptied of chemotherapy if there is any 
suspicion of drug-induced toxicity. 
 
All reasonable efforts will be made to adhere to treatment and evaluation schedules, 
however variations to accommodate holidays, transportation issues, or patient's personal 
schedule will be permitted if these do not, in the opinion of the investigator, constitute a 
major safety or compliance issue. Additionally, evaluations (e.g. EKGs, scans) may be 
performed off-schedule if, in the estimation of the attending physician, patient condition 
so warrants. Such variations, assuming they do not occur with unreasonable frequency or 
regularity, will not be considered protocol violations. 
 
 
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
The primary objective of this Phase II study will be to assess anti-tumor efficacy. 
 
13.1 
Complete Response (CR): The disappearance of all target and non-target lesions. 
If necessary, persistent target or non-target lesions that appear to be residual scar 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 38 of 59 
 
 
tissue may undergo biopsy and the best overall response may be classified as CR 
if no evidence of active cancer is found. 
 
13.2 
Partial Response (PR): A 30% decrease in the sum of the longest diameter of 
target lesions, taking as reference the baseline sum longest diameter. 
13.3 
Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response 
nor sufficient increase to qualify for progressive disease, taking as reference the 
smallest sum longest diameter since the treatment start, or the persistence of one 
or more non-target lesions. 
13.4 
Progressive Disease (PD): At least a 20% increase in the sum of the longest 
diameter of target lesions, taking as reference the smallest sum longest diameter 
recorded since the treatment start, or the appearance of one or more new lesions 
and/or unequivocal progression of non-target lesions. 
 
 
14.0 
CRITERIA FOR REMOVAL FROM STUDY 
• If at any time the patient develops progressive disease he/she will be taken off 
study and referred for alternative therapy. 
• If at any time the patient develops unacceptable toxicity he/she will be removed 
from study. 
• If at any time the patient is found to be ineligible for the protocol as designated in 
the section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), 
the patient will be removed from the study. 
• Patient elects to discontinue treatment. 
 
• Changes in a patient’s condition which render the patient unacceptable for further 
treatment in the judgment of the investigator. 
 
• Grade 4 hypertension or reversible posterior leukoencephalopathy syndrome 
(RPLS) 
• Nephrotic syndrome 
• Grade > 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
• Symptomatic Grade 4 venous thromboembolic event 
• Any grade arterial thromboembolic event 
• Grade 4 congestive heart failure 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 39 of 59 
 
 
• Gastrointestinal perforation 
• Wound dehiscence requiring medical or surgical intervention 
• Inability of subject to comply with study requirements 
• Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
• All Grade 4 events thought to be related to bevacizumab by the investigator 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 40 of 59 
 
 
15.0 
CORRELATIVE STUDIES 
 
15.1 
DYNAMIC CONTRAST-ENHANCED MRI 
MRI will be the primary imaging modality used to assess disease response. Standard 
sequences will be used for unidimensional tumor measurement, which is a primary 
outcome determinant. In addition, as part of each scan, dynamic contrast-enhanced 
images will be obtained to measure parameters related to tumor perfusion (initial slope of 
the contrast uptake curve), and permeability (Akep, see below). 
 
Data Acquisition 
DCE-MRI studies will be performed on a 1.5T GE (Milwaukee, WI) Signa LX scanner. 
Gadolinium (Gd-DTPA) will be administered at a concentration of 0.1 mmol/kg, 
resulting in a standard dose of 1mL gadopentetate dimeglumine per 10 kg of patient 
weight. A saline flush will be administered at the same flow rate with a volume of 20 cc 
following gadopentetate dimeglumine administration, to ensure complete mixing of the 
bolus upon delivery. A power injector delivery system (Medrad, Inc. Indianola, PA) will 
be used to provide accurate flow rates. Patients with a central venous silastic catheter will 
require a slower flow rate of 0.8-1.0 cc/s to prevent damage to the catheter. All other 
patients will receive contrast at a rate of 2 cc/s. All patients will receive contrast while at 
scan position in the magnet. 
Dynamic contrast-enhanced images will be acquired using a fast multi-phase spoiled 
gradient echo sequence. Single slice images, passing through the center of the tumor and 
possibly covering aorta (whenever feasible) will be acquired with 9 ms repetition time 
(TR), a 2 ms echo time (TW), 30○ flip angle, 15.63 kHz receive bandwidth, 20-24 cm 
(depending on patient size) field of view (FOV), and a 256 x 128 matrix, yielding a 
temporal resolution of ~1.0 seconds/image. This time resolution is sufficient to observe 
the initial uptake of Gd-DTPA into the region. The first 5 images obtained during the 
study will be pre-Gd-DTPA injection, to assure accurate baseline signal intensity. These 
data will also be used (in combination with the proton density image) to measure T10. 
Dynamic imaging data will be obtained under shallow breathing for a total of 5 minutes 
to acquire 225 time points to characterize the time intensity curves (TIC). 
 
Data Analysis 
Following on-line reconstruction, data will be exported to a Sun Ultra 20 workstation for 
analysis. Software was been written to display and analyze the data using IDL 6.0 
(Research Systems, Inc., Boulder CO). Time intensity curves will be analyzed for each 
voxel in the image. The initial uptake slope will use a 5-point sliding linear regression 
applied to the first 2 minutes of the time intensity curve. A baseline signal intensity (SI) 
value, SIpre, will be calculated as the mean intensity of 3 points prior to injection. The 
percent increase/minute for each voxel is then calculated according to equation 1 (fig. 1): 
 
Fig. 1 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 41 of 59 
 
 
 
 
In addition, the data will be analyzed using a two-compartment model proposed by 
Hoffman, based on that of Brix , which incorporates rate constants of Gd-DTPA between 
the lesion to plasma compartments (kep) and elimination by the plasma (kel). The plasma 
concentration is not directly measured since the clearance rate (kel) can be estimated from 
the measured tissue curve. After a bolus injection (τ = bolus duration), if one assumes 
kepτ < < 1 and kel τ < < 1, Hoffman’s initial equation reduces to equation 2 (fig. 2) which 
has three fitted parameters: A (normalized amplitude), kep (min -1), and kel (min -1): 
 
Fig 2: 
 
 
. 
 
At short times after injection (small values of t), the right side of equation 2 reduces to 
1+Akept, thus the initial slope is proportional to Akep. This product will be determined for 
each voxel in the ROI and placed in a histogram. 
 
DCE-MRI scans will be obtained after hepatic artery pump placement but prior to 
treatment start (baseline). The first post-treatment scan will be obtained in the middle of 
cycle 1, immediately after completing the initial 14-day infusion of FUDR, but before 
initial treatment with Bevacizumab; the second post-treatment scan will be obtained at 
the end of cycle 1, after initial treatment with Bevacizumab only. DCE-MRI scans will be 
obtained at two month intervals thereafter. Comparisons will be made between the pre- 
and post-treatment slope of the contrast uptake curve (perfusion) and Akep (permeability). 
The initial and post-treatment changes in these parameters will also be correlated to 
disease response, as assessed on unidimensional tumor measurements, and 
immunohistochemical markers of tumor hypoxia (see below). 
 
15.2 VEGF and VEGFR Assays 
This clinical trial is based on the hypothesis that the growth and progression of primary 
liver cancer is dependent on the factors that support angiogenesis and lymphangiogenesis. 
As signaling molecules regulating these two processes are driven by three different 
tyrosine kinase receptors, namely VEGFR1 (hemangiogenesis), VEGFR2 (angiogenesis), 
and VEGFR3 (lymphangiogenesis), information regarding the expression pattern of these 
receptors and their cognate ligands (VEGF-A, -B, -C, -D, and P1GF) is essential in order 
to rationally interpret the results. Since bevacizumab selectively blocks the activity of 
VEGF-A, but not the other ligands, these studies will help clarify if inhibition of the 
VEGF-A/VEGFR2 signaling pathway is sufficient to block angiogenesis and 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 42 of 59 
 
 
lymphangiogenesis in primary hepatic malignancy. It is anticipated that tumors primarily 
over-expressing VEGF-A/VEGFR2 will be more responsive to bevacizumab (anti- 
VEGF-A) therapy. On the other hand, tumors that over-express both VEGF-A/VEGFR2 
and VEGF-C, -D/VEGFR3 signaling pathways may be less sensitive to bevacizumab, as 
angiogenesis may be promoted through these alternative mediators. Therefore, evaluating 
the spectrum of VEGF ligand and receptor expression will help clarify the mechanism or 
mechanisms through which primary hepatic malignancy maintains angiogenesis despite 
VEGF-A inhibition. As new agents emerge that target other members of the VEGF and 
VEGFR families, the results of these studies will help identify other potential sites of 
therapeutic intervention in primary liver cancer. 
In parallel to these studies, VEGF-A, -B, -C, -D and PlGF levels in plasma and VEGFR- 
1, -2, and -3 expression on peripheral blood mononuclear cells will be measured. In 
addition, the number of circulating CD133+VEGFR2+ EPCs and CD34+VEGFR1+ pro- 
angiogenic HPC’s will be quantified. These assays will be performed at baseline and on 
day 1 of each cycle during treatment. The proposed studies will determine if these 
surrogate markers have utility in assessing response to treatment with bevacizumab. 
Since no bio-marker reliably describes the angiogenic propensity of primary liver cancer 
or its response to anti-angiogenesis therapy, these data will provide insights regarding 
treatment-induced changes that are measurable in the peripheral blood. 
Planned Experiments 
The correlative studies in this section will be performed on biopsy samples of tumor and 
non-tumor bearing liver taken at operation (pre-treatment) and on peripheral blood taken 
before treatment and on day 1 of each cycle during treatment, as described above. The 
methods used in these experiments have been previously described and are currently in 
routine use. 
 
1. Tissue. Biopsy samples of tumor and non-tumorous liver will be obtained at the time 
of operation, some of which will be frozen and some embedded in paraffin. Frozen cut 
sections of the tumor biopsy sample will be analyzed for the expression of VEGF-A, -B, - 
C, -D, PlGF, and VEGFR-1, -2, -3 using standard immunohistochemical techniques and 
commercially available antibodies (Santa Cruz Biotechnology), as previously described. 
Non-tumor involved liver from each patient will be simultaneously stained. Human 
umbilical vein endothelial cells (HUVEC) will be used as positive controls for VEGF 
receptors and leukemia cell lines (KG1a, KG1 and HL60) will be used as positive 
controls for VEGF ligands. Slides will be reviewed by a reference pathologist and scored 
for proportion of positively stained cells.43 
 
2. Peripheral Blood. Samples of peripheral blood (~10 ml) will be collected and 
processed to separate plasma and circulating mononuclear cells. Plasma levels of VEGF- 
A, -B, -C, -D and PlGF will be measured in triplicate by ELISA using commercially 
available assay kits (R&D Systems), taking precautions to eliminate contribution by 
activated platelets. Both pro-VEGF-C and active VEGF-C will be quantified.44 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 43 of 59 
 
 
 
A portion of the peripheral blood monocytes will be set aside for protein extraction and 
subsequent analysis of VEGF-A, -B, -C, -D, PlGF, and VEGFR-1, -2, -3 using Western 
blot and commercially available antibodies (see below). The remaining cells will be used 
for dual-color flow cytometry, according to well-established methods,45-47 to determine 
the proportion of circulating CD133+VEGFR2+ EPCs and CD34+VEGFR1+ HPCs. The 
mononuclear cell fraction is separated with Ficoll-Hypaque centrifugation and CD34 
purification is performed with a Clinimacs CD34-separation kit (Miltenyi Biotech) and 
the purity assessed by flow cytometry. CD34+ cells are then further analyzed for co- 
expression of CD133 and VEGFR2 by dual color flow cytometry using a PE-conjugated 
monoclonal anti-body to CD133 and FITC-conjugated monoclonal antibody to VEGFR2; 
separate analyses will be performed to identify CD34+VEGFR1+ cells. Assays will be 
performed in triplicate and expressed as proportions, which have been shown to be on the 
order of 10 -20%.32, 50 In separate studies, freshly isolated CD34+ cells will be analyzed 
for their capacity to form late outgrowth vascular colonies, a feature that is characteristic 
of progenitor cells.48-50 Approximately 105 CD34+ cells are cultured in endothelial 
culture medium containing VEGF. Endothelial cell colonies are then quantified by co- 
staining with DiI-acetylated-LDL (DiI-Ac-LDL, PerImmune) and von Willebrand factor 
(vWf). DiI-Ac-LDL+vWf+ endothelial cell colonies formed after 14 days are scored as 
late outgrowth colonies. Analyses will be performed in triplicate and expressed as the 
percent of late outgrowth colonies/105 peripheral blood monocytes. Late outgrowth 
vascular colonies will also be harvested for protein extraction and analysis of VEGF and 
VEGFR expression by Western blot, as described below. 
 
In separate studies, a small portion of plasma will also be assessed with an in vitro 
functional angiogenic assay using human umbilical vein endothelial cells (HUVEC-based 
angiogenic scale), modified from previously described methods.51 Early passaged 
HUVECs will be maintained in enriched endothelial cell culture medium until 
approximately 70% confluent, and then changed to serum-free medium. Patient plasma 
will be added to the cells to final concentration of 2.5% (in triplicate). After 24 hours, 
angiogenic morphology will be examined under light microscopy and scored by 2 
independent observers according to an angiogenic scale (Figure 2): 0 – well separated 
individual cells; 1 – cells begin to migrate and align; 2 – visible capillary tubes, no 
sprouting; 3 – sprouting of new capillary tubes; 4 – polygonal structures begin to form; 5 
– presence of complex mesh-like structures. The HUVEC-based system provides a 
global assessment of the plasma angiogenic activity before and during treatment, and its 
simplicity makes it potentially ideal for use as a bio-marker for assessing treatment 
efficacy. To evaluate this further, changes in the HUVEC-score during treatment will be 
correlated with changes in the other circulating pro-angiogenic variables measured. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 44 of 59 
 
 
 
 
Figure 2. Summary of HUVEC-based functional angiogenic scale. 
 
Protein extraction and Western blotting 
Western blotting will be used to detect and validate the expression of VEGFs and VEGFRs 
on the peripheral blood mononuclear cells and late outgrowth colonies (CFU-EC) from 
CD133+VEGFR2+ EPCs and CD34+VEGFR1+ HPCs isolated from the peripheral blood 
cells. Endothelial colonies (CFU-EC) will be generated by incubating the peripheral blood 
mononuclear cells with VEGF; late outgrowth endothelial colonies and other hematopoietic 
mononuclear cells will be lysed in cold RIPA buffer in the presence of protease inhibitors. 
As controls, protein will also be extracted from HUVEC and leukemia cells. HUVECs will 
be used as positive controls for the expression of VEGFR-1, -2 and -3. Leukemia cell lines 
(KG1a, KG1 and HL60) will be used as positive controls for the expression of VEGF-A, -B, 
-C, -D and PlGF. After centrifugation to remove cell debris, supernatants (a total protein 
minimum of 500 ng) will be immunoprecipitated overnight at 4◦ C with protein G-agarose 
beads and an anti-phosphotyrosine antibody (Santa Cruz Biotechnology) to precipitate 
phosphorylated proteins or with a mouse antihuman VEGFs or VEGF receptors. Precipitated 
proteins/antibody/beads are then washed, re-suspended in loading buffer, and then subjected 
to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (7.5% gels) under reducing 
conditions. Proteins are subsequently blotted onto a nitrocellulose membrane following 
conventional protocols. Finally, blots will be blocked in 1% bovine serum 
albumin/phosphate-buffered salin-0.1%. Tween 20 for 1 hour at room temperature followed 
by incubation with primary and secondary antibodies. Antibodies used will include 
commercially available mouse antihuman VEGFs or VEGFRs, and a secondary peroxidase- 
labeled goat antimouse antibody. The ECL chemiluminescence detection system and ECL 
film will be used to visualize the presence of proteins on the nitrocellulose blots. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 45 of 59 
 
 
 
15.3 Analysis of Tumor Hypoxia 
Paraffin-embedded biopsy specimens, obtained during operation and processed as above, 
will be used for these studies. Immunohistochemical staining will be overseen by Dr. Jinru 
Shia of the Department of Pathology, MSKCC, and will be performed through the 
Immunohistochemical Core Facility. Tumor and tumor-free liver specimens will be stained 
for HIF-1α, CA IX, Glut-1, Glut-3, and Ki-67 using well-characterized monoclonal 
antibodies and appropriate positive and negative controls. The slides will be evaluated and 
graded for both intensity and percentage of stained cells. Ki-67 will be scored as a 
continuous variable. For all other antibodies, <10% staining will be considered negative, 
while >10% staining will be considered positive. Correlations will be made between the 
immunohistochemical markers of hypoxia and pre- and post-treatment DCE-MRI 
measurements of tumor perfusion and permeability. 
 
 
16.0 
BIOSTATISTICS 
The primary objective of this study is to assess the efficacy of continuous hepatic arterial 
infusion (HAI) of FUDR plus systemic bevacizumab in patients with unresectable HCC and ICC. 
The primary endpoint is median time to progression (TTP), as measured from time of pump 
placement to date of first documented progression. As explained in section 3.0, the median TTP 
was approximately 7 months in the investigator’s Phase II study of HAI FUDR. We hypothesize 
that addition of systemic bevacizumab will result in a 50% improvement. A total of 48 events 
will give us 90% power to detect the hypothesized improvement, therefore we will enroll 55 
patients, allowing for 15% censoring. This calculation assumes a Type I error of 5%, a one-sided 
test, and a median follow-up time of 2 years. It also assumes that survival times are exponentially 
distributed. This last assumption is for planning purposes only, and actual analysis will employ 
non-parametric methods for estimating the survival distribution. 
 
The secondary objective is to assess dynamic MRI for measuring changes in tumor perfusion 
parameters during treatment. The measurements that will be obtained from this MRI scan are 
explained in detail above. Initial and post-treatment changes related to tumor perfusion (slope) 
and permeability (Akep) will be compared and correlated with tumor response (as determined on 
unidimensional measurements) using two-sample tests and logistic regression. 
 
The tertiary objectives include evaluating the expression patterns of VEGFR-1, -2, and –3 
and their cognate ligands (VEGF-A, -B, -C, -D, and P1GF). These findings will be correlated to 
disease progression and survival using proportional hazards regression and Kaplan-Meier 
methods. Correlations will also be made between initial and post-treatment changes in tumor 
perfusion kinetics (as measured by DCE-MRI) and the tumor expression patterns of VEGF 
ligands and VEGF receptors. In addition, robust regression methods will be used to assess the 
relationship between baseline tissue and plasma levels of VEGF ligands and changes in the pre- 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 46 of 59 
 
 
and post-treatment levels of VEGF ligands, VEGFR+ peripheral blood mononuclear cells, the 
proportion of circulating CD133+VEGFR2+ EPCs and CD34+VEGFR1+ HPCs, and HUVEC- 
based functional angiogenic scale. Correlation between treatment-related changes in the 
HUVEC scale and changes in other variables measured on peripheral blood and plasma samples 
will be assessed. Markers of tumor hypoxia (hypoxia inducible factor [HIF-1, carbonic 
anhydrase IX [CA IX], and the glucose transporters Glut-1 and Glut-3, and microvessel density 
[CD31]) will be assessed on pre-treatment biopsies on a dichotomous scale. These data will be 
correlated with treatment efficacy and initial and post-treatment changes in tumor perfusion 
kinetics using logistic regression (for binary data such as treatment response) or linear regression 
(for continuous data such as tumor perfusion kinetics) analyses. 
 
 
17.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
17.1 Subject Registration 
The following person(s) can obtain informed consent: 
William Jarnagin, MD 
Nancy Kemeny, MD 
Yuman Fong, MD 
Peter Allen, MD 
Ghassan Abou-Alfa, MD 
Ki-Young Chung, MD 
David D’Adamo, MD 
David Ilson, MD 
 
David Kelsen, MD 
Mary Keohan, MD 
Robert Maki, MD 
Diane Reidy, MD 
Eileen O’Reilly, MD 
Leonard B. Saltz, MD 
Gary Schwartz, MD 
Neil Segal, MD 
Manish Shah, MD 
Archie Tse, MD 
Leslie Blumgart, MD 
Michael D’Angelica, MD 
Ronald DeMatteo, MD 
 
Confirm in the electronic medical record that the patient has received the Notice of 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 47 of 59 
 
 
Privacy Practice. This must be obtained before the eligibility confirmation and obtaining 
of the research informed consent. 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
eligibility. 
Obtain written informed consent, by following procedures defined in section entitled 
Informed Consent Procedures. 
Patients must be registered to Step One, pending registration to Step Two before 
undergoing surgery in order to obtain liver tissue biopsy and research bloodwork. After 
pump placement, before treatment start, the Research Study Assistant will proceed with 
Step 2 of the registration process, thus allowing the patient to commence protocol 
therapy. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at (646) 735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the informed consent form, the completed signature page of the 
Research Authorization and a completed Eligibility Checklist must be faxed to PPR. 
 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 
Research Authorization 
[Date] 
MSKCC IRB Protocol # 
Attending of Record (if applicable) [Last, First Name] 
Consenting Professional 
[Last, First Name] 
Informed Consent Date 
Participant’s Full Name 
[Last, First Name] 
Participant’s MRN 
 
17.2 Randomization 
This is a non-randomized study. 
 
18.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 48 of 59 
 
 
18.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extext and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
18.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can be 
found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will 
be addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
 
19.0 
PROTECTION OF HUMAN SUBJECTS 
19.1 
Risks 
Treatment-related risks, including those related to pump placement and chemotherapy, 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 49 of 59 
 
 
were discussed in Sections 5.0 Hepatic Artery Infusion Pump Background, 12.0 
Toxicities/Side Effects and 13.0 Dose Modification. 
19.2 
Potential Benefits 
Liver-directed chemotherapy for primary hepatic malignancy may increase the likelihood 
of tumor response and may extend life. 
19.3 
Possible Toxicities/Side-Effects 
Treatment-related toxicity was discussed in Sections 5.0 and 11.0. Toxicity related to 
hepatic artery pump placement was discussed in Section 11.0. 
19.4 
Costs 
Patients will be charged for physician visits, and routine laboratory and radiologic studies 
required for monitoring their condition. Patients will not be charged for protocol-related 
correlative study charges, which include the MRI imaging processing quantification, and 
analysis charge and image processing for the nuclear flow scans, and tissue and blood 
processing charges for laboratory correlative studies. 
19.5 
Alternatives 
Patients eligible for this protocol are not candidates for resection. By virtue of their 
disease extent and relatively well-preserved hepatic function, these patients would not be 
considered for hepatic transplantation according to the current guidelines. These patients 
will have been treated with and failed at least one systemic regimen. The alternatives to 
the current protocol include systemic chemotherapy of a different type, either with 
standard or investigational agents, or ablative therapy. None of these options has been 
shown to improve survival. In addition, many patients will not be eligible for or will 
have failed ablative treatments. All of these issues will be discussed with the patients. 
19.6 
Patient Safety 
All patients will be monitored in the outpatient clinic and chemotherapy unit, both of 
which are staffed by physicians and nurses familiar with clinical trials. In case of an 
adverse reaction, trained staff is available to provide immediate medical care. In the 
evenings and on weekends, medical attention is available through the Urgent Care 
Center, which is staffed at all times. Also, the principal investigators or their designees 
are available at all times. 
19.7 
Risk/Benefit Ratio 
The treatment proposed in this study is aimed at patients with very limited, or no, 
effective alternatives. The investigators hope that the proposed treatment will be 
beneficial but this cannot be guaranteed. However, the investigators believe that the 
proposed treatment is based on sound scientific principles and draws on extensive 
experience from prior human studies. Every precaution has been and will be taken to 
ensure patient safety. 
 
19.8 Inclusion of Children in Research 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 50 of 59 
 
 
This protocol/project does not include children because the number of children is limited 
and because the majority are already accessed by a nationwide pediatric cancer research 
network. This statement is based on exclusion 4b of the NIH Policy and Guidelines on 
the Inclusion of Children as Participants in Research Involving Human Subjects. 
19.9 Privacy 
It is the responsibility of the Research Staff to ensure that protocol patients have received 
the Center’s Notice of Privacy Practices. If the subject has not already done so, MSK 
personnel must try to obtain acknowledgment before the patient participates in this study. 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board. 
19.10 Serious Adverse Event (SAE) Reporting 
All SAEs must be entered into the CRDB SAE form page. 
Any SAE must be reported to the IRB as soon as possible but no later than 5 calendar 
days. The IRB required a Clinical Research Database (CRDB) AE report to be delivered 
to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) containing the following 
information: 
 
Fields populated from the CRDB: 
 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o An explanation of how the AE was handled 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 51 of 59 
 
 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
 
19.11 Reporting of SAEs to Genentech, Inc. 
All SAE reports must also be forwarded as soon as possible to: 
Genentech Drug Safety 
Fax: (650) 225-4682 or (650) 225-4683 
 
For questions related to safety reporting, contact: 
 
Genentech Drug Safety 
Tel: 1-888-835-2555 
 
Genentech may contact the reporter for additional information, clarification, or current status of 
the subject for whom an adverse event was reported. 
 
Genentech Adverse Event Reporting Definitions 
A serious treatment emergent adverse event (STEAE) is any sign, symptom or medical condition 
that emerges during Bevacizumab treatment or during a post-treatment follow-up period that (1) 
was not present at the start of Bevacizumab treatment and is not a chronic condition that is part 
of the patient’s medical history, or (2) was present at the start of Bevacizumab treatment or as 
part of the patient’s medical history but worsened in severity and/or frequency during therapy, 
AND that meets any of the following regulatory serious criteria: 
 
• Results in death 
• Is life-threatening 
• Requires or prolongs inpatient hospitalization 
• Is disabling 
• Is a congenital anomaly/birth defect 
• Is medically significant or requires medical or surgical intervention to prevent one of 
the outcomes listed above 
 
Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that Bevacizumab 
caused or contributed to an adverse event. The following general guidance may be used. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 52 of 59 
 
 
Yes: if the temporal relationship of the clinical event to Bevacizumab administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying conditions 
do not provide a sufficient explanation for the observed event. 
 
No: if the temporal relationship of the clinical event to Bevacizumab administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the observed event. 
 
 
20.0 
INFORMED CONSENT PROCEDURES 
Consenting professionals are listed in section 17.0. Physicians qualified to conduct the 
informed consent process must be certified in the protection of human subjects for research. 
Before protocol-specified procedures are carried out, investigators or their staff will explain 
full details of the protocol and study procedures as well as the risks involved to the patients 
prior to their inclusion in the trial. Patients will also be informed that they are free to 
withdraw from the study at any time. All patients must sign an IRB-approved consent form 
indicating their consent to participate. This consent form will meet the requirements of the 
code of Federal regulations, the Institutional Review Board of this Center. The consent form 
will include the following: 
 
• The nature of the objectives, potential toxicities and benefits of the intended study. 
• The length of therapy and the likely follow-up required 
• Alternatives to the proposed therapy. This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care. 
• The name of the investigator(s) responsible for the protocol. 
• The right of the patient to accept or refuse treatment and to withdraw from 
participation in this study. 
 
The original signed consent forms will become a part of the patient’s research file, stored 
in the electronic medical record. Each patient will receive a copy of the signed consent 
form. 
 
 
20.1 
Research Authorization 
Procedures for obtaining Research Authorization: Before any protocol-specific 
procedures are carried out, investigators and/or designated staff will fully explain the 
details of the protocol, study procedures, and the aspects of patient privacy concerning 
research specific information. In addition to signing the IRB Informed Consent, all 
patients must sign the Research Authorization component of the informed consent form. 
The Research Authorization requires a separate set of signatures from the patient. The 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 53 of 59 
 
 
original signed documents will become part of the patient’s medical record, and each 
patient will receive a copy of the signed documents. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 54 of 59 
 
 
21.0 
REFERENCES 
1. Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, Wong J. Hepatectomy for 
hepatocellular carcinoma: toward zero hospital deaths. Annals of Surgery 1999; 229:322- 
330. 
2. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular 
carcinoma at a Western center. Annals of Surgery 1999; 229:790-799. 
3. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. Ca: a Cancer 
Journal for Clinicians 2000; 50:7-33. 
4. El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United 
States. New England Journal of Medicine 1999; 340:745-750. 
5. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in 
the United States. Hepatology 2001; 33:1353-1357. 
6. Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH. Intrahepatic 
cholangiocarcinoma: resectability, recurrence pattern, and outcomes. Journal of the 
American College of Surgeons 2001; 193:384-391. 
7. Leung TW, Johnson PJ. Systemic therapy for hepatocellular carcinoma. Seminars in 
Oncology 2001; 28:514-520. 
8. Llovet JM, Ruff P, Tassopoulos N, Castells L, Bruix J, El Hariry I, Peachey M. A phase II 
trial of oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma. 
European Journal of Cancer 2001; 37:1352-1358. 
9. Gebbia V, Maiello E, Serravezza G, Giotta F, Testa A, Borsellino N, Pezzella G, Colucci 
G. 5-Fluorouracil plus high dose levofolinic acid and oral hydroxyurea for the treatment of 
primary hepatocellular carcinomas: results of a phase II multicenter study of the Southern 
Italy Oncology Group (G.O.I.M.). Anticancer Research 1999; 19:1407-1410. 
10. Chen JS, Lin YC, Jan YY, Liau CT. Mitomycin C with weekly 24-h infusion of high-dose 
5-fluorouracil and leucovorin in patients with biliary tract and periampullar carcinomas. 
Anti-Cancer Drugs 2001; 12:339-343. 
11. Poplin E, Roberts J, Tombs M, Grant S, Rubin E. Leucovorin, 5-fluorouracil, and 
gemcitabine: a phase I study. Investigational New Drugs 1999; 17:57-62. 
12. Yang TS, Lin YC, Chen JS, Wang HM, Wang CH. Phase II study of gemcitabine in 
patients with advanced hepatocellular carcinoma. Cancer 2000; 89:750-756. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 55 of 59 
 
 
13. Kubicka S, Rudolph KL, Tietze MK, Lorenz M, Manns M. Phase II study of systemic 
gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepato- 
Gastroenterology 2001; 48:783-789. 
14. Patt YZ, Hoque A, Lozano R, Pozdur R, Chase J, Carrasco H, Chuang V, Delpassand ES, 
Ellis L, Curley S, Roh M, Jones DV. Phase II trial of hepatic arterial infusion of 
fluorouracil and recombinant human interferon alfa-2b for liver metastases of colorectal 
cancer refractory to systemic fluorouracil and leucovorin. J Clin Oncol 1997; 15:1432- 
1438. 
15. Verderame F, Mandina P, Abruzzo F, Scarpulla M, Di Leo R. Biliary tract cancer: our 
experience with gemcitabine treatment. Anti-Cancer Drugs 2000; 11:707-708. 
16. Sanz-Altamira PM, O'Reilly E, Stuart KE, Raeburn L, Steger C, Kemeny NE, Saltz LB. A 
phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma. Annals of 
Oncology 2001; 12:501-504. 
17. O'Reilly EM, Stuart KE, Sanz-Altamira PM, Schwartz GK, Steger CM, Raeburn L, 
Kemeny NE, Kelsen DP, Saltz LB. A phase II study of irinotecan in patients with advanced 
hepatocellular carcinoma. Cancer 2001; 91:101-105. 
18. Murren JR, Peccerillo K, DiStasio SA, Li X, Leffert JJ, Pizzorno G, Burtness BA, McKeon 
A, Cheng Y. Dose escalation and pharmacokinetic study of irinotecan in combination with 
paclitaxel in patients with advanced cancer. Cancer Chemotherapy & Pharmacology 2000; 
46:43-50. 
19. Adjei AA, Klein CE, Kastrissios H, Goldberg RM, Alberts SR, Pitot HC, Sloan JA, Reid 
JM, Hanson LJ, Atherton P, Rubin J, Erlichman C. Phase I and pharmacokinetic study of 
irinotecan and docetaxel in patients with advanced solid tumors: preliminary evidence of 
clinical activity. J Clin Oncol 2000; 18:1116-1123. 
20. Bilchik AJ, Wood TF, Allegra DP. Radiofrequency ablation of unresectable hepatic 
malignancies: lessons learned. Oncologist 2001; 6:24-33. 
21. Wood TF, Rose DM, Chung M, Allegra DP, Foshag LJ, Bilchik AJ. Radiofrequency 
ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. 
Annals of Surgical Oncology 2000; 7:593-600. 
22. A comparison of lipiodol chemoembolization and conservative treatment for unresectable 
hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. 
New England Journal of Medicine 1995; 332:1256-1261. 
23. Atiq OT, Kemeny N, Niedzwieki D, Botet J. Treatment of unresectable primary liver 
cancer with intrahepatic fluorodeoxyuridine and mitomycin c through an implantable 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 56 of 59 
 
 
pump. Cancer 1992; 69:920-924. 
24. Meric F, Patt YZ, Curley SA, Chase J, Roh MS, Vauthey JN, Ellis LM. Surgery after 
downstaging of unresectable hepatic tumors with intra-arterial chemotherapy. Annals of 
Surgical Oncology 2000; 7:490-495. 
25. Robertson JM, Lawrence TS, Dworzanin LM, Andrews JC, Walker S, Kessler ML, 
DuRoss DJ, Ensminger WD. Treatment of primary hepatobiliary cancers with conformal 
radiation therapy and regional chemotherapy. J Clin Oncol 1993; 11:1286-1293. 
26. Smith GW, Bukowski RM, Hewlett JS, Groppe CW. Hepatic artery infusion of 5- 
fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma. Cancer 
1984; 54:1513-1516. 
27. Seeger J, Woodcock TM, Blumenreich MS, Richardson JD. Hepatic perfusion with FUdR 
utilizing an implantable system in patients with liver primary cancer or metastatic cancer 
confined to the liver. Cancer Investigation 1989; 7:1-6. 
28. Clavien PA, Selzner N, Morse M, Selzner M, Paulson E. Downstaging of hepatocellular 
carcinoma and liver metastases from colorectal cancer by selective intra-arterial 
chemotherapy. Surgery 2002; 131:433-442. 
29. Bierman HR, Byron RL, Kelly KH. Treatment of inoperable visceral and regional 
metastases by intra-arterial catheterization. Cancer Res 11, 236-236. 1951. 
Ref Type: Abstract 
30. Breedis C, Young C. The blood supply of neoplasms in the liver. Am J Pathol 1954; 
30:969. 
31. Ensminger WD, Rosowsky A, Raso V. A clinical pharmacological evaluation of hepatic 
arterial infusions of 5-fluoro-2-deoxyuridine and 5-fluorouracil. Cancer Res 1978; 
38:3784-3792. 
32. Chang AE, Schneider PD, Sugarbaker PH, Simpson C, Culnane M, Steinberg SM. A 
prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine 
chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987; 206:685-693. 
33. Hohn DC, Stagg RJ, Friedman MA, Hannigan JF, Jr., Rayner A, Ignoffo RJ, Accord P, 
Lewis BJ. A randomized trial of continuous intravenous versus hepatic intraarterial 
floxuridine in patients with colorectal cancer metastatic to the liver: The Northern 
California oncology group trial. J Clin Oncol 1989; 7:1646-1654. 
34. Kemeny N, Daly J, Reichman B, Geller N, Botet J, Oderman P. Intrahepatic or systemic 
infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma - 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 57 of 59 
 
 
A randomized trial. Ann Intern Med 1987; 107:459-465. 
35. Kemeny N, Cohen A, Seiter K, Conti JA, Sigurdson ER, Tao Y, Niedzwiecki D, Botet J, 
Budd A. Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine 
versus floxuridine alone in previously treated patients with liver metastases from colorectal 
cancer. J Clin Oncol 1993; 11:330-335. 
36. Martin JK, O'Connell MJ, Wieand HS, Fitzgibbons RJ, Mailliard JA, Rubin J, Nagourney 
DM, Tschetter LK, Krook JE. Intra-arterial floxuridine vs systemic fluorouracil for hepatic 
metastases from colorectal cancer. Arch Surg 1990; 125:1022-1027. 
37. Rougier P, Laplanche A, Huguier M, Hay JM, Ollivier JM, Escat J, Salmon R, Julien M, 
Audy JR, Gallot D, Gouzi JL, Pailler JL, Elisa D, Lacaine F, Roos S, Ratman N, Luboinski 
M, Lasser P. Hepatic arterial infusion of floxuridine in patients with liver metastases from 
colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 
1992; 10:1112-1118. 
38. Kemeny N, Seiter K, Conti J, et al. Randomized trial of hepatic arterial FUDR, mitomycin 
and BCNU versus FUDR alone: Effective salvage therapy for liver metastases of colorectal 
cancer. J Clin Oncol 1993. 
39. Kemeny N, Conti J, Cohen A, Campana P, Huang Y, Ji Shi W, Botet J, Pulliam S, Bertino 
J. A phase II study of hepatic arterial FUDR, leucovorin, and dexamethasone for 
unresectable liver metastases from colorectal carcinoma. J Clin Oncol 1994; 12:2288-2295. 
40. Stagg RJ, Lewis BJ, Friedman MA, Ignoffo RJ, Hohn DC. Hepatic arterial chemotherapy 
for colorectal cancer metastatic to the liver. Annals of Internal Medicine 1984; 100:736- 
743. 
41. Venook AP, Warren RS. Regional chemotherapy approaches for primary and metastatic 
liver tumors. Surgical Oncology Clinics of North America 1996; 5:411-427. 
42. Verstraete KL, De Deene Y, Roels H, Dierick A, Uyttendaele D, Kunnen M. 
Benign and malignant musculoskeletal lesions: dynamic contrast-enhanced 
MR imaging--parametric "first-pass" images depict tissue vascularization and 
perfusion. Radiology 1994; 192:835-843. 
43. Salven P, Mustjoki S, Alitalo R, Alitalo K, Rafii S. VEGFR-3 and CD133 
(AC133) identify a population of CD34+lymphatic/vascular endothelial 
precursor cell. Blood 101:168-172, 2003. 
44. Rafii S, Skobe M. Splitting vessels: keeping lymph apart from blood. Nature 
Medicine 9:166-8, 2003. 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 58 of 59 
 
 
45. 
Rafii S. Vaccination against tumor neovascularization: promise and reality. Cancer Cell 
2:429-31, 2002. 
46. 
Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ,Zhu Z, Bohlen P, 
Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S. 
Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1 (+) stem cells 
from bone-marrow microenvironment. Nature Medicine 8:841-849, 2002. 
47. 
Heissig B, Hattori K, Dias S, Lyden D, Ferris D, Friedrich M, Hackett NR, Crystal RG, 
Moore MAS, Werb Z, Rafii S. Recruitment of stem and progenitor cells from the bone 
marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 109, 625-637, 2002. 
48. 
Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C 
signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and 
resistance to chemotherapy. Blood, 99:179-84, 2002. 
49. 
Dias S, Shmelkov SV, Lam G, Rafii S. VEGF(165) promotes survival of leukemic cells 
by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood 
99:2532-40, 2002. 
50. 
Lyden D, Hattori K, Dias S, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin 
D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii 
S. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor 
cells blocks tumor angiogenesis and growth. Nature Medicine 7:1194-1201, 2001. 
51. 
Dias S, Hattori K, Heissig B, Lane Z, Zhu Z, Witt L, Bohlen P, Moore MAS, Rafii S. 
Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is 
essential to induce long-term remission of zenotransplanted human leukemias. 
Proceedings, National Academy of Sciences, 98, 108057-10862, 2001. 
52. 
Salven P, Hattori K, Heissig B, Rafii S. Interleukin-1 alpha promotes angiogenesis in 
vivo via VEGFR-2 pathway by inducing inflammatory cell VEGF synthesis and 
secretion. Faseb Journal 16:1471-3, 2002. 
53. 
Morgan B, Thomas AL, Drevs J, Henning J, Buchert M, Jivan A, Horsfield MA, Mross 
K, Ball HA, Lee L, Mietlowski W, Fuxuis S, Unger C, O’Byrne K, Henry A, Cherryman 
GR, Laurent D, Dugan M, Marme D, Steward WP. Dynamic contrast-enhanced magnetic 
resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 
222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, 
in patients with advanced colorectal cancer and liver metastases: results from two phase I 
studies. J Clin Oncol. 2003 Nov 1;21(21):3955-64. 
54. 
Dyke J, Panicek D, Healey J, Meyers P, Huvos A, Schwartz LH, Thaler H, Tofts P, 
Gorlick R, Koutcher J, Ballon D. Osteogenic and Ewing sarcomas: estimation of necrotic 
fraction during induction chemotherapy with dynamic contrast-enhanced MR imaging. 
Radiology 2003;228:271-278. 
55. 
Glover KY, Thomas MB, Brown TD, Hoff PM, Iwasaki M, Abbruzzese JL. A phase II 
study of oxaliplatin and capecitabine (XELOX) in patients with unresectable 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-114A(6) 
Amended: 12/21/12 
Page 59 of 59 
 
 
cholangiocarcinoma, including carcinoma of the gallbladder and biliary tract. 
Proceedings, Am Soc Clin Onc (abst. 4123), 2005. 
56. 
Danso M, Jarnagin WR, Muruganandham M, Schwartz LH, Gönen M, Haviland D, 
Blumgart L, D’Angelica M, DeMatteo R, Kemeny N. Hepatic arterial infusion (HAI) 
therapy in patients with unresectable primary liver cancer: use of dynamic contrast 
enhanced MRI to evaluate response. Proceedings, Am Soc Clin Onc (abst. 4129), 2005. 
57. 
Park JO, Kang WK, Kim T-Y, Lee MA, Ahn M-J, Kim H-K, Lee NS, Lim HY, Park BJ, 
Kim JS. A phase II trial of gemcitabine plus cisplatin (GP) in patients with inoperable 
biliary tract cancer (BTC). Proceedings, Am Soc Clin Onc (abst. 4133), 2005. 
58. 
Funakoshi A, Okusaka T, Ishii H, Yamao K, Ohkawa S, Saito H, Saito S, Tsuyuguchi T. 
A multicenter phase II study of gemcitabine (GEM) in patients with unresectable biliary 
tract cancer. Proceedings, Am Soc Clin Onc (abst. 4145), 2005. 
59. 
Shibata S, Yen Y, Doroshow J, Leong L, ,Wagman L, Marx H, Clarke K, Frankel P, 
Lenz H, Gandara D. Phase II study of oxaliplatin in patients with unresectable, metastatic 
or recurrent hepatocellular cancer. Proceedings, Am Soc Clin Onc (abst. 4161), 2005. 
60. 
Chang HM, Ryu M-H, Lee J-L, Kim TW, Lee JS, Kim WK, Kang Y-K. Phase II trial of 
gemcitabine plus capecitabine in patients with advanced biliary tract cancer. Proceedings, 
Am Soc Clin Onc (abst. 4173), 2005. 
61. 
Shin D, Lee SI, Park J, Park SH, Bang S-M, Cho EK, Lee JH. Systemic chemotherapy 
with capecitabine, doxorubicin and cisplatin for metastatic hepatocellular carcinoma. 
Proceedings, Am Soc Clin Onc (abst. 4177), 2005.