Conditions: Liver Cancer
Keywords: Advanced Liver Cancer primary neoplasm of the liver Erlotinib Bevacizumab Hepatocellular Carcinoma HCC Avastin Anti-VEGF monoclonal antibody rhuMAb-VEGF OSI-774 Tarceva
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 45
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if the combination of AvastinTM (bevacizumab) and Tarceva (erlotinib hydrochloride) can help to control advanced liver cancer. The safety of this drug combination will also be studied.

Detailed description:
The Study Drugs:

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary for tumor growth. This may prevent or slow down the growth of cancer cells.

Erlotinib hydrochloride is designed to block the activity of a protein found on the surface of many tumor cells that may control tumor growth and survival. This may stop tumors from growing. There is a commercially available form of the drug (called Tarceva) that is expected to be very similar to the erlotinib being used for this study, but it is possible that there may be some differences between the 2 formulations.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive the study drugs during 28-day "study cycles."

You will receive bevacizumab by vein on Days 1 and 15 of each cycle. The first dose of bevacizumab will be given over about 90 minutes. If you do not have a reaction to the drug, such as fever and/or chills, the next dose will be given over about 60 minutes. If you still have no reaction after the second dose, each dose after that will be given over about 30 minutes. If you experience a reaction to the bevacizumab, you may be given Tylenol® (acetaminophen) by mouth and/or an antihistamine by vein over 30 minutes before each dose to help minimize the risk of further reactions.

You will take 1 erlotinib hydrochloride tablet by mouth every day. You should take erlotinib hydrochloride in the morning with a full glass of water (6-8oz) at least 1 hour before or 2 hours after any food, grapefruit juice, vitamins, iron supplements, or other non-prescription drugs.

Study Visits:

On Day 1 of Cycle 2 and beyond:

* Blood (about 3 tablespoons) will be drawn for routine blood tests and to check how well the blood clots.
* Urine will be collected for routine testing. A 24-hour urine sample may be collected if needed. If a 24-hour urine sample is needed, you will be provided with a special container to collect the sample.
* You will be asked questions about any side effects you may have had and about any drugs you may be currently taking or have taken since you last saw the study doctor.
* You will have a complete physical exam, including measurements of weight and vital signs.
* Your performance status will be recorded.

On Day 15 of Cycle 2 and beyond, your vital signs will be recorded.

At the end of Cycle 2, 4, and every 2 cycles after that (Cycles 6, 8, 10, and so on):

°You will have CT/MRI scans of the abdomen and pelvis and chest scan (if the doctor thinks they are needed) to check the status of the disease.

Additional tests may be done during the study if the study doctor thinks it is necessary.

Length of Treatment:

You will receive bevacizumab and erlotinib hydrochloride for as long as you are benefitting. There is no maximum number of cycles that you can receive. If you experience severe side effects, the treatment on this study may be delayed, stopped, or the study doctor may give you smaller doses of the study drugs. You will be taken off study if the disease gets worse, the side effects are too severe, or your doctor thinks that it is in your best interest to stop receiving treatment.

End-of-Treatment Visit:

After you stop receiving all of the study drugs, you will return for an end-of-treatment visit. At this visit, the following tests and procedures will be performed:

* Blood (about 3 tablespoons) and urine will be collected for routine tests and to learn how well the blood clots.
* You will be asked questions about any side effects you may have had and about any drugs you may be currently taking or have taken since you last saw the study doctor.
* You will have a complete physical exam, including measurements of weight and vital signs.
* Your performance status will be recorded.
* CT and/or MRI scans of the abdomen and pelvis will be performed to check the status of the disease.

Follow-Up:

After the end-of-treatment visit, the study doctor will continue to review your medical records every 3 months until the study analysis is complete. You will also be called every 3 months for as long as the study doctor thinks is needed. During these phone calls, you will be asked about how you are doing and if you are experiencing any health problems. The phone call should take about 15 minutes. During the follow-up period, if the study doctor thinks it is necessary, you may be asked to come in for a clinic visit.

This is an investigational study. Bevacizumab is FDA approved and commercially available for the treatment of metastatic colon and rectal cancer. Erlotinib hydrochloride is FDA approved and commercially available for the treatment of lung cancer. The use of this drug combination in patients with advanced liver cancer is investigational.

Up to 44 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Erlotinib 150 mg by mouth once a day. Bevacizumab 10 mg/kg by vein once every 2 weeks on days 1 and 15 of each cycle. The first dose of bevacizumab will be given over about 90 minutes.

Interventions: intervention 1: Bevacizumab intervention 2: Erlotinib
Intervention descriptions: intervention 1: 10 mg/kg by vein once every 2 weeks on days 1 and 15 of each cycle. The first dose of bevacizumab will be given over about 90 minutes intervention 2: 150 mg by mouth once a day.

Protocol document:
Prot_SAP_000.pdf: 
2009-0260 
 December 27, 2013 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
Department of GI Medical Oncology 
 
A Phase II Trial of Erlotinib plus Bevacizumab in Advanced Hepatocellular 
Carcinoma as a Second-line Therapy in Patients Who Have Received First-
line Sorafenib Therapy 
 
Study Drugs 
Bevacizumab (Avastin®)  
 Erlotinib (Tarceva) 
 
Support Provided By 
Genentech, Inc. 
OSI 
 
Principal Investigator 
Ahmed O Kaseb, MD* 
akaseb@mdanderson.org 
 
Sub-Investigators 
Christopher Garrett, MD* 
Milind Javle, MD* 
Gauri Varadhachary, MD* 
Linus Ho, MD* 
Kanwal P. Raghav* 
 
*U. T. M. D. Anderson Cancer Center,  
Department of GI Medical Oncology, Unit 426 
1515 Holcombe Blvd, Houston, TX 77030 
 
Study Statistician 
Jeffrey Morris, PhD 
U. T. M. D. Anderson Cancer Center, Department of Biostatistics 
 
 
 
 
 
Genentech Study Number:  AVF4572 
 
Protocol Version Date:   11/1/13   


2009-0260 
 December 27, 2013 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
                           
Page # 
 
1.0 BACKGROUND ........................................................................................... 1 
1.1 
Disease Background ...................................................................... 1 
1.2 
Bevacizumab Clinical Experience................................................... 4 
1.3 
Erlotinib Background ...................................................................... 12 
1.4 
Study Rationale .............................................................................. 19 
2.0 OBJECTIVES .............................................................................................. 21 
2.1  
Primary ........................................................................................... 21 
2.2  
Secondary ...................................................................................... 21 
3.0 STUDY DESIGN .......................................................................................... 21 
3.1 
Description of the Study .................................................................... 21 
3.2 
Rationale for Study Design................................................................ 22 
3.3 
Outcome Measures ........................................................................... 23 
4.0 SAFETY PLAN ............................................................................................ 23 
4.1 
General Plan to Manage Safety ........................................................ 23  
 
 
5.0 STUDY SUBJECTS ..................................................................................... 25 
5.1 
Subject Selection ............................................................................ 25 
5.2 
Inclusion Criteria ............................................................................. 25 
5.3 
Exclusion Criteria............................................................................ 27 
6.0 STUDY DESIGN .......................................................................................... 28 
6.1 
Treatment Plan ............................................................................... 28 
7.0 STUDY MEDICATION ................................................................................. 29 
7.1 
Bevacizumab Dosage and Formulation  ........................................... 29 
7.2 
Erlotinib Dosage and Formulation ..................................................... 30 
7.3 
Dose Modifications ............................................................................ 31 
7.4 
Concomitant and Excluded Medications …..      …… ........................ 36 
8.0 CLINICAL AND LABORATORY EVALUATIONS ......................................... 38 
8.1   Post-Treatment Evaluations .............................................................. 39 
9.0  SUBJECT DISCONTINUATION .................................................................. 40 
10.0 STUDY DISCONTINUATION ...................................................................... 41 
11.0 STATISTICAL METHODS ........................................................................... 41 
11.1  Study Design .................................................................................... 41 
11.2 Planned Efficacy Evaluations ............................................................ 42 


2009-0260 
 December 27, 2013 
12.0 SAFETY MONITORING PLAN………………………………………………….43 
13.0 DATA CONFIDENTIALITY………………………………………………………43 
14.0 REPORTING REQUIREMENTS .................................................................. 44 
14.1 Serious Adverse Event Reporting (SAE) for M. D. Anderson-
Sponsored IND Protocols .................................................................. 44 
14.2 Investigator Communication Supporting Companies ........................ 45 
14.3 Adverse Events Reporting (AE) ........................................................ 45 
 
REFERENCES 
 
 
APPENDICES 
 
 
 
Appendix A: New York Heart Association Guidelines 
Appendix B:  Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale 
Appendix C: Procedure for Obtaining a Urine Protein / Creatinine Ratio 
Appendix D:  Childs-Pugh Classification  
Appendix E:  Response Evaluation Criteria In Solid Tumors (RECIST) Criteria 
Appendix F:  List of Cytochrome P450 3A4 (CYP3A4) Inhibitors 
Appendix G: Genentech Safety Reporting FAX Cover Sheet


2009-0260 
 December 27,  2013 
Page 1 
 
1.0 
BACKGROUND 
Hepatocellular cancer (HCC) is the most common primary neoplasm of 
the liver, accounting for almost half a million deaths annually worldwide. 
Although the incidence of HCC is particularly high in parts of Asia and 
Africa, recent studies have documented a clear rise in the number of 
cases in Japan, Western Europe, and the United States, largely because 
of the increase in hepatitis C–related liver disease.[1] Unfortunately, most 
patients with HCC are not candidates for any curative treatments because 
of advanced disease at presentation and/or a background of chronic liver 
disease. Furthermore, the growth of HCC depends on stimulatory effects 
of various growth factors, which bind to tyrosine kinase receptors and 
hence activate various intracellular signaling pathways which 
subsequently lead to tumor cell proliferation, survival, migration and 
metastasis. Therefore, both the extracellular growth factors and the 
intracellular signaling pathways represent potential molecular targets for 
therapy of HCC. However, the anti-angiogenic pathway looks more 
promising in HCC. 
1.1 
DISEASE BACKGROUND 
HCC is potentially curable by surgical resection and liver transplantation. 
However, the majority of patients present with advanced stage disease, 
which is most commonly accompanied by severe background liver 
disease. Hence, surgery is feasible for only a small fraction of patients 
with localized disease, and liver transplantation is severely limited by the 
availability of liver donors. Systemic cytotoxic therapies have 
demonstrated a very limited impact on the natural history of advanced 
HCC.  
Molecular characterization of HCC has led to the recognition of defined 
aberrant signaling pathways which helped in subsequent development of 
targeted agents as potential choices for the treatment of this 
chemoresistant disease. In HCC, several crucial intracellular signaling 
pathways such as the Ras/Raf/Mek/Erk (Methyl ethyl ketone/Extracellular 
Signal-regulated kinase) pathway and PI3k/Akt/mTOR (mammalian target 
of rapamycin) pathway, in addition to several growth and angiogenic 
factors/receptors such as EGFR (Epidermal Growth Factor Receptor), 
PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth 
factor receptor), and VEGFR (Vascular Endothelial Growth Factor 
Receptor) have been recognized as outlined in a recent review. [2] 
Subsequently, targeted agents have entered clinical trials in HCC patients. 
This is of particular significance for HCC in light of the lack of existing 
effective systemic therapy for this cancer.  


2009-0260 
 December 27,  2013 
Page 2 
1.1.1   Targeting Growth Factors in Hepatocellular Carcinoma 
EGFR is frequently expressed in human hepatoma cells, and EGF 
may be one of the mitogens needed for the growth of hepatoma 
cells.[3, 4] Several strategies have been tested in HCC, including 
using a neutralizing monoclonal antibody such as cetuximab, and 
using small molecule tyrosine kinase inhibitor such as gefitinib and 
erlotinib, as demonstrated in HCC cell cultures.[5, 6] Erlotinib is an 
orally active and selective inhibitor of the EGFR/HER1 (Human 
Epidermal Receptor)-related tyrosine kinase enzyme. In two phase 
II studies of erlotinib in HCC, [7, 8] the response rates were 0% and 
9% but the disease control rates were 43% and 50%, and median 
survival times were 10.75 and 13 months, respectively. 
EGFR/HER1 expression was detected in 71% and 88% of 
evaluable patients, respectively, but there was no significant 
difference in terms of overall survival between the high-EGFR and 
low-EGFR groups. However, this assay detects the presence of 
EGFR receptors and does not determine the functional status of the 
receptor (eg, phosphorylated EGFR), as the latter can be performed 
on fresh tissue only.  
1.1.2   Rationale for Antiangiogenic Therapy of Hepatocellular Carcinoma  
The cancer cell has been the only target of anticancer therapy for more 
than 50 years. However, the cancer cell is genetically unstable, and 
mutations accumulate. On the other hand, antiangiogenic therapy targets 
endothelial cells which are genetically stable. The genetic stability of 
endothelial cells may make them less susceptible to acquired drug 
resistance. As a result, angiogenesis inhibitors are emerging as a new 
class of therapeutic agents. 
Angiogenesis’ role in the initial progression from a pre-malignant tumor to 
a cancer prompted investigators to study the role of VEGF in the natural 
history of HCC.[9] In 1999, a group of researchers suggested that the 
degree of tissue VEGF expression increased according to the stepwise 
development of HCC.[10]  In addition, studies have shown that VEGF was 
frequently expressed in HCC.  In a quantitative analysis study, VEGF 
expression was demonstrated in 63.9% of encapsulated HCC and 78.3% 
of non-encapsulated HCC.[11]  Another study reported VEGF tissue 
expression in HCC of 88.8%.[12] Notably, studies have suggested a 
correlation between the degree of tissue VEGF expression and the 
intensity of both the magnetic resonance signal and the computed 
tomographic enhancement of the hepatic artery, which represent 
radiological vascular signals.[13-15]  Hence, the hypervascular nature of 
HCC has led to increasing interest in exploring the potential of anti-
angiogenic therapy in this disease.  


2009-0260 
 December 27,  2013 
Page 3 
 
1.1.3   Clinical Trials of Anti-angiogenic Agents in Hepatocellular carcinoma 
 
Several vascular targeted agents, including thalidomide, sunitinib, 
sorafenib, and bevacizumab, have been tested in advanced HCC. 
Thalidomide’s mechanism was not clearly known but was thought to be 
partly based on its antiangiogenic effects.[16-18]  Nevertheless, several 
clinical trials of thalidomide alone or in combination with epirubicin or 
interferon showed rare responses ranging from 0-6.3%.[19-25]  A recent 
report in abstract form of 19 patients treated with oral thalidomide 200 
mg/day continuously showed a 6-month progression free survival of 
41%.[26]Sunitinib, an oral multikinase inhibitor, exerts an antiangiogenic 
effect by targeting VEGFR and platelet derived growth factor receptor 
(PDGFR) tyrosine kinases.  A phase II study of sunitinib alone in 19 
patients with unresectable or metastatic HCC reported a partial response 
(PR) in one patient.[27]  
Sorafenib, an oral multikinase inhibitor, exerts an antiangiogenic effect by 
targeting VEGFR and PDGFR tyrosine kinases.  It exerts its effect through 
targeting Raf/MEK/ERK signaling at the level of Raf kinase, and exerts an 
antiangiogenic effect by targeting VEGFR-2/-3. A phase II study of 
Sorafenib alone in advanced HCC showed 2.2% partial and 5.8% minor 
response.[28]  Recently, a randomized, placebo-controlled phase III trial of 
Sorafenib in advanced HCC reported a 2.8 month improvement in median 
overall survival (HR 0.69, 95% CI: 0.55-0.87; p=0.0006) along with 
increased time to progression and disease control rate.[29]  
Bevacizumab is a recombinant, humanized monoclonal antibody that 
targets VEGF and may augment chemotherapy administration by making 
tumor vasculature less permeable and decreasing the elevated tumor 
interstitial pressure.[30, 31]  Recent phase II trials of bevacizumab alone, 
and in combination with cytotoxic therapy, in advanced HCC suggested an 
improved disease control rate with one trial reporting a response rate of 
12.5% (all PR) with disease control rate [PR+ stable disease (SD)] of 
67%.[24, 32]  Bevacizumab was also combined with gemcitabine and 
oxaliplatin in a phase II trial of advanced HCC with an overall response 
rate of 20%. [33]  A phase II trial of bevacizumab + capecitabine as a first-
line treatment for advanced HCC recently reported response rate 
Complete Response (CR+PR) of 16% [95% confidence interval (CI) 4.5-
36.1%] and disease control rate (CR+PR+SD) of 60% (95% CI 38.7-
78.9%) with a median overall survival of 10.7 months (95% CI, 5.3-14.7) 
and median Progression-free survival (PFS) of 4.1 months.[34]  In 
addition, a phase II study of advanced or unresectable metastatic HCC 
treating 30 patients with bevacizumab, oxaliplatin and capecitabine 
reported an 11% response rate with mean PFS of 5.4 months.[35] Another 
study of 46 patients who received bevacizumab 5 mg/kg (n = 12) or 10 


2009-0260 
 December 27,  2013 
Page 4 
mg/kg (n = 34) every 2 weeks was recently reported.[36] Six patients had 
objective responses (13%; 95% CI, 3% to 23%), and 65% were 
progression free at 6 months. Median PFS time was 6.9 months (95% CI, 
6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 
years, and 23% at 3 years. In addition, our group at M. D.  Anderson 
Cancer Center has reported a phase II, single-arm, open-label trial of 
bevacizumab and erlotinib.[37] Ten patients achieved a PR, for a 
confirmed overall response rate of 25%. The PFS at 16 weeks of 
treatment was 62.5%. The median PFS was 39 weeks (95% CI: 24-45 
weeks) (9.75 months), and median overall survival of 68 weeks (17 
months) (95% CI: 48-78 weeks).  Moreover, there are a number of 
ongoing clinical trials of different vascular targeted agents in HCC.  
Preclinical studies of agents which target other foci that interact with 
VEGF, such as Hypoxia-Inducible Factor 1 (HIF-1) alpha and APRIL(a 
proliferation inducing ligand), have shown promising results with reduced 
VEGF expression in hepatocellular carcinoma cell cultures.[38, 39] 
Furthermore, the assessment of systemic treatment response to targeted 
agents, particularly anti-angiogenesis ones, has changed over the years. It 
is now well recognized that the conventional markers of radiographic 
response (World Health Organization [WHO] or RECIST criteria) are 
poorly related to tumor cell kill in liver tumors and that end points other 
than radiographic tumor shrinkage, such as time to tumor progression, 
progression-free survival, and certainly overall survival, are more 
meaningful measures of therapeutic benefit.  
1.2 
BEVACIZUMAB CLINICAL EXPERIENCE     
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical 
trials in more than 5000 patients and in multiple tumor types. In addition, 
data are available from 3,863 patients enrolled in two post marketing 
studies in metastatic colorectal cancer (CRC).  Approximately 130,000 
patients have been exposed to bevacizumab as a marketed product or in 
clinical trials.  The following discussion summarizes bevacizumab’s safety 
profile and presents some of the efficacy results pertinent to this particular 
trial. Please refer to the bevacizumab Investigator Brochure for 
descriptions of all completed Phase I, II, and III trials reported to date. 
In a large phase III study (AVF2107g) in patients with metastatic colorectal 
cancer, the addition of bevacizumab, a monoclonal antibody directed 
against vascular endothelial growth factor (VEGF), to irinotecan/5-
fluorouracil/leucovorin (IFL) chemotherapy resulted in a clinically and 
statistically significant increase in duration of survival, with a hazard ratio 
of death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).  
Similar increases were seen in progression-free survival (6.2 vs. 10.6 
months; p < 0.001), overall response rate (35% vs. 45%; p < 0.01) and 
duration of response (7.1 vs. 10.4 months; p < 0.01) for the combination 


2009-0260 
 December 27,  2013 
Page 5 
arm versus the chemotherapy only arm (bevacizumab Investigator 
Brochure, October 2005). 
Based on the survival advantage demonstrated in Study AVF2107g, 
bevacizumab was designated for priority review and was approved on 26 
February 2004 in the United States for first-line treatment in combination 
with IV 5-FUbased chemotherapy for subjects with metastatic colorectal 
cancer.  
Additional data from Phase III trials in metastatic CRC (E3200), nonsmall 
cell lung cancer (NSCLC; E4599), and metastatic breast cancer (E2100) 
have also demonstrated clinical benefit from bevacizumab when added to 
chemotherapy.  In Study E3200, the addition of bevacizumab to Folinic 
acid (leucovorin), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) (FOLFOX) 
chemotherapy resulted in improved overall survival compared with 
FOLFOX alone (13.0 vs. 10.8 months, respectively, HR   0.75; p  0.01) 
in a population of previously treated CRC patients.   
There was also improved overall survival in first-line NSCLC patients 
(E4599) treated with carboplatin/paclitaxel  bevacizumab compared with 
chemotherapy alone (12.3 vs. 10.3 months, respectively; HR   0.80; 
p = 0.003).  The results from this trial were the basis for FDA approval of 
bevacizumab for use in combination with carboplatin  paclitaxel as first-
line treatment of patients with unresectable, locally advanced, recurrent or 
metastatic, non-squamous NSCLC in October 2006.  Finally, patients with 
untreated metastatic breast cancer (E2100) who received bevacizumab in 
combination with weekly paclitaxel had a marked improvement in PFS 
compared with chemotherapy alone (13.3 vs. 6.7 months, respectively; 
HR   0.48; p  0.0001) (see the Bevacizumab Investigator Brochure for 
additional details). 
Two recent phase II trials of bevacizumab,  alone and in combination with 
cytotoxic therapy, in advanced HCC suggested an improved disease control 
rate with one trial reporting a response rate of 12.5% (all PR) with disease 
control rate (PR+SD) of 67%.[24, 32]  Bevacizumab was also combined with 
gemcitabine and oxaliplatin in a phase II trial of advanced HCC with overall 
response rate of 20%. [33]  A phase II trial of bevacizumab + capecitabine as 
a first-line treatment for advanced HCC recently reported response rate 
(CR+PR) of 16% (95% CI 4.5-36.1%) and disease control rate (CR+PR+SD) 
of 60% (95% CI 38.7-78.9%) with a median overall survival of 10.7 months 
(95% CI, 5.3-14.7) and median PFS of 4.1 months.[34]  In addition, a phase II 
study of advanced or unresectable metastatic HCC treating 30 patients with 
bevacizumab, oxaliplatin and capecitabine reported an 11% response rate 
with mean PFS of 5.4 months.[35] More recently, a study of bevacizumab in 
advanced HCC at 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks 
reported six patients had objective responses (13%; 95% CI, 3% to 23%), and 


2009-0260 
 December 27,  2013 
Page 6 
65% were progression free at 6 months. Median PFS time was 6.9 months 
(95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 
years, and 23% at 3 years. Grade 3 to 4 adverse events included 
hypertension (15%) and thrombosis (6%, including 4% with arterial 
thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, 
including one fatal variceal bleed. Bevacizumab was associated with 
significant reductions in tumor enhancement by dynamic contrast-enhanced 
magnetic resonance imaging and reductions in circulating VEGF-A and 
stromal-derived factor-1 levels.[36] 
Most recently, our group at M D Anderson Cancer Center has published a 
phase II, single-arm, open-label trial of bevacizumab and erlotinib.[37] Ten 
patients achieved a PR, for a confirmed overall response rate of 25%. The 
PFS at 16 weeks of treatment was 62.5%. The median PFS was 39 weeks 
(95% CI: 24-45 weeks) (9.75 months), and median overall survival of 68 
weeks (17 months) (95% CI: 48-78 weeks). Grade 3-4 drug-related toxicity 
included fatigue (8 pts, 20%), hypertension (6 pts, 15%), diarrhea (4 pts, 
10%) elevated transaminases (4 pts, 10%), gastrointestinal hemorrhage (2 
pts, 5%), thrombocytopenia (2 pts, 5%), proteinuria, hyperbilirubinemia, back 
pain, hyperkalemia, and wound infection (1 pt each).  
a. Bevacizumab Safety Profile 
In the initial Phase I and II clinical trials, four potential bevacizumab-
associated safety signals were identified: hypertension, proteinuria, 
thromboembolic events, and hemorrhage.  Additional completed Phase II 
and Phase 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) primarily in metastatic breast cancer, gastrointestinal 
perforations, wound healing complications, and arterial thromboembolic 
events (ATE). These and other safety signals are described in further 
detail as follows and in the bevacizumab Investigator Brochure. 
Hypertension: An increased incidence of hypertension has been 
observed in patients treated with bevacizumab.  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) (Ozcan et al., 
2006; Glusker et al., 2006).  
There is no information on the effect of bevacizumab in patients with 
uncontrolled hypertension at the time of initiating bevacizumab therapy.  
Therefore, caution should be exercised before initiating bevacizumab 
therapy in these patients.  Monitoring of blood pressure is recommended 
during bevacizumab therapy.  Optimal control of blood pressure according 
to standard public health guidelines is recommended for patients on 
treatment with or without bevacizumab.   


2009-0260 
 December 27,  2013 
Page 7 
Temporary interruption of bevacizumab therapy is recommended in 
patients with hypertension requiring medical therapy until adequate control 
is achieved.  If hypertension cannot be controlled with medical therapy, 
bevacizumab therapy should be permanently discontinued.  Bevacizumab 
should be permanently discontinued in patients who develop hypertensive 
crisis or hypertensive encephalopathy. 
Proteinuria:  An increased incidence of proteinuria has been observed in 
patients treated with bevacizumab compared with control arm patients.  In 
the bevacizumab-containing treatment arms of clinical trials (across all 
indications), the incidence of proteinuria (reported as an adverse event) 
was up to 38% (metastatic CRC Study AVF2192g). 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. NCI-CTC Grade 3 proteinuria was 
reported in up to 3% of bevacizumab-treated patients, and Grade 4 in up 
to 1.4% of bevacizumab-treated patients.  The proteinuria seen in 
bevacizumab clinical trials was not associated with renal impairment and 
rarely required permanent discontinuation of bevacizumab therapy.  
Bevacizumab should be discontinued in patients who develop Grade 4 
proteinuria (nephrotic syndrome) 
Patients with a history of hypertension may be at increased risk for the 
development of proteinuria when treated with bevacizumab.  There is 
evidence from the dose-finding, Phase II trials (AVF0780g, AVF0809s, 
and AVF0757g) suggesting that Grade 1 proteinuria may be related to 
bevacizumab dose. 
Proteinuria will be monitored by urine protein:creatinine (UPC) ratio at 
least every 4 weeks.  If the UPC ratio is not available, a dipstick urinalysis 
may be used to allow treatment to proceed. 
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.  
Venous thromboembolism (including deep venous thrombosis, 
pulmonary embolism, and thrombophlebitis:  In the phase III pivotal 
trial in metastatic CRC, there was a slightly higher rate of venous TE 
events in patients treated with bevacizumab plus chemotherapy compared 
with chemotherapy alone (19% vs. 16%).  
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE 
events, including deep venous thrombosis, pulmonary embolism, and 
thrombophlebitis, occurred in 15.2% of patients receiving chemotherapy 
alone and 16.6% of patients receiving chemotherapy  bevacizumab.  


2009-0260 
 December 27,  2013 
Page 8 
The incidence of NCI-CTC Grade t 3 venous VTE events in one NSCLC 
trial (E4599) was higher in the bevacizumab-containing arm compared to 
the chemotherapy control arm (5.6% vs. 3.2%).  One event (0.2%) was 
fatal in the bevacizumab-containing arm; not fatal events were reported in 
the carboplatin/paclitaxel arm (see Bevacizumab Investigator Brochure).  
In metastatic CRC clinical trials, the incidence of VTE events was similar 
in patients receiving chemotherapy  bevacizumab and those receiving 
the control chemotherapy alone.  
In clinical trials across all indications the overall incidence of VTE events 
was 2.8%17.3% in the bevacizumab-containing arms compared with 
3.2%15.6% in the chemotherapy control arms.  The use of bevacizumab 
with chemotherapy does not substantially increase the risk of VTE event 
compared with chemotherapy alone.  However, patients with metastatic 
CRC who receive bevacizumab and experienced a VTE event may be at 
higher risk for recurrence of VTE event. 
Arterial Thromboembotic Events:  An increased incidence of ATE 
events was observed in patients treated with bevacizumab compared with 
those receiving control treatment.  ATE events include cerebrovascular 
accidents, myocardial infarction, transient ischemic attacks (TIAs), and 
other ATE events.  In a pooled analysis of data from five randomized 
Phase II and III trials (mCRC [AVF2107g, AVF2192g, AVF0780g]; locally 
advanced or metastatic NSCLC [AVF0757g]; metastatic breast cancer 
[AVF2119g]), the incidence rate of ATE events was 3.8% (37 of 963) in 
patients who received chemotherapy  bevacizumab compared with 1.7% 
(13 of 782) in patients treated with chemotherapy alone.  ATE events led 
to a fatal outcome in 0.8% (8 of 963) of patients treated with 
chemotherapy  bevacizumab and 0.5% (4 of 782) of patients treated with 
chemotherapy alone.  Cerebrovascular accidents (including TIAs) 
occurred in 2.3% of patients treated with chemotherapy  bevacizumab 
and 0.5% of patients treated with chemotherapy alone.  Myocardial 
infarction occurred in 1.4% of patients treated with 
chemotherapy  bevacizumab compared with 0.7% of patients treated with 
chemotherapy alone (see the Bevacizumab Investigator Brochure for 
additional details). 
Aspirin is a standard therapy for primary and secondary prophylaxis of 
arterial thromboembolic events in patients at high risk of such events, and 
the use of aspirin  325 mg daily was allowed in the five randomized 
studies discussed above. Use of aspirin was assessed routinely as a 
baseline or concomitant medication in these trials, though safety analyses 
specifically regarding aspirin use were not preplanned. Due to the 
relatively small numbers of aspirin users and arterial thromboembolic 
events, retrospective analyses of the ability of aspirin to affect the risk of 
such events were inconclusive. However, similarly retrospective analyses 
suggested that the use of up to 325 mg of aspirin daily does not increase 
the risk of grade 1-2 or grade 3-4 bleeding events, and similar data with 


2009-0260 
 December 27,  2013 
Page 9 
respect to metastatic colorectal cancer patients were presented at ASCO 
2005 (Hambleton et al., 2005). Further analyses of the effects of 
concomitant use of bevacizumab and aspirin in colorectal and other tumor 
types are ongoing. 
Gastrointestinal perforation Patients with metastatic carcinoma may be 
at increased risk for the development of gastrointestinal perforation and 
fistula when treated with bevacizumab and chemotherapy. Bevacizumab 
should be permanently discontinued in patients who develop 
gastrointestinal perforation. A causal association of intra-abdominal 
inflammatory processes and gastrointestinal perforation to bevacizumab 
treatment has not been established. Nevertheless, caution should be 
exercised when treating patients with intra-abdominal inflammatory 
processes with bevacizumab. Gastrointestinal perforation has been 
reported in other trials in non-colorectal cancer populations (e.g., ovarian, 
renal cell, pancreas, breast, and NSCLC) and may be higher in incidence 
in some tumor types. 
Fistula:  Bevacizumab use has been associated with serious cases of 
fistulae including events resulting in death.  Fistulae in the GI tract are 
common (1%–10% incidence) in patients with metastatic CRC, but 
uncommon (0.1%1%) or rare (0.01%–0.1%) in other indications.  In 
addition, fistulae that involve areas of the body other than the GI tract 
(e.g., tracheoesophageal, bronchopleural, urogenital, biliary) have been 
reported uncommonly (0.1%–1%) in patients receiving bevacizumab in 
clinical studies and post marketing reports.  Events were reported at 
various time points during treatment, ranging from 1 week to ! 1 year 
following initiation of bevacizumab, with most events occurring within the 
first 6 months of therapy. 
Permanently discontinue bevacizumab in patients with tracheoesophageal 
fistulae or any Grade 4 fistula.  Limited information is available on the 
continued use of bevacizumab in patients with other fistulae.  In cases of 
internal fistula not arising in the GI tract, discontinuation of bevacizumab 
should be considered. 
Wound healing complications: 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 5-FU/LV plus bevacizumab did not appear to have an increased risk 
of wound healing complications compared to those treated with 
chemotherapy alone (Scappaticci et al., 2005). 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 21 days. Bevacizumab 
should be discontinued in patients with severe wound healing 
complications. 


2009-0260 
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Page 10 
If patients receiving 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 or 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). 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 
4.0% of 1132 patients treated with bevacizumab in a pooled database 
from eight phase I, II, and III clinical trials in multiple tumor types 
(bevacizumab Investigator Brochure, October 2005). The hemorrhagic 
events that have been observed in bevacizumab clinical studies were 
predominantly tumor-associated hemorrhage (see below) and minor 
mucocutaneous hemorrhage.  
Tumor-Associated Hemorrhage:  Major or massive pulmonary 
hemorrhage or hemoptysis has been observed primarily in patients with 
NSCLC.  Life-threatening and fatal hemoptysis was identified as a 
bevacizumab-related adverse event in NSCLC trials.  These events 
occurred suddenly and presented as major or massive hemoptysis.  
Among the possible risk factors evaluated (including squamous cell 
histology, treatment with anti-rheumatic/anti-inflammatory drugs, treatment 
with anticoagulants, prior radiotherapy, bevacizumab therapy, previous 
medical history of atherosclerosis, central tumor location, and cavitation of 
tumors during therapy), the only variables that showed statistically 
significant correlations with bleeding were bevacizumab therapy and 
squamous cell histology. 
GI hemorrhages, including rectal bleeding and melena have been reported 
in patients with CRC, and have been assessed as tumor-associated 
hemorrhages. 
Tumor-associated hemorrhages were also seen rarely in other tumor 
types and locations, including a case of CNS bleeding in a patient with 
hepatoma with occult CNS metastases and a patient who developed 
continuous oozing of blood from a thigh sarcoma with necrosis. 
Mucocutaneous Hemorrhage:  Across all bevacizumab clinical trials, 
mucocutaneous hemorrhage has been seen in 20%-40% of patients 
treated with bevacizumab. These were most commonly NCI-CTC Grade 1 
epistaxis that lasted less than 5 minutes, resolved without medical 
intervention and did not require any changes in bevacizumab treatment 
regimen.  
There have also been less common events of minor mucocutaneous 
hemorrhage in other locations, such as gingival bleeding and vaginal 
bleeding.  


2009-0260 
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Reversible Posterior Leukoencephalopathy Syndrome:  There have 
been rare reports of bevacizumab-treated patients developing signs and 
symptoms that are consistent with RPLS, a rare neurologic disorder that 
can present with the following signs and symptoms (among others):  
seizures, headache, altered mental status, visual disturbance, or cortical 
blindness, with or without associated hypertension.  Brain imaging is 
mandatory to confirm the diagnosis of RPLS.  In patients who develop 
RPLS, treatment of specific symptoms, including control of hypertension, 
is recommended along with discontinuation of bevacizumab.  The safety 
of reinitiating bevacizumab therapy in patients previously experiencing 
RPLS is not known (Glusker et al. 2006; Ozcan et al. 2006).   
Congestive heart failure:  In clinical trials CHF was observed in all 
cancer indications studied to date, but predominantly in patients with 
metastatic breast cancer.  In the Phase III clinical trial of metastatic breast 
cancer (AVF2119g), 7 (3%) bevacizumab-treated patients experienced 
CHF, compared with two (1%) control arm patients.  These events varied 
in severity from asymptomatic declines in left ventricular ejection fraction 
(LVEF) to symptomatic CHF requiring hospitalization and treatment.  All 
the patients treated with bevacizumab were previously treated with 
anthracyclines (doxorubicin cumulative dose of 240360 mg/m2).  Many of 
these patients also had prior radiotherapy to the left chest wall.  Most of 
these patients showed improved symptoms and/or left ventricular function 
following appropriate medical therapy (Miller et al. 2005). 
In a randomized, Phase III trial of patients with previously untreated 
metastatic breast cancer (E2100), the incidence of LVEF decrease 
(defined as NCI-CTC Grade 3 or 4) in the paclitaxel  bevacizumab arm 
was 0.3% versus 0% for the paclitaxel alone arm  
No information is available on patients with preexisting CHF of New York 
Heart Association (NYHA) Class IIIV at the time of initiating bevacizumab 
therapy, as these patients were excluded from clinical trials. 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall 
may be possible risk factors for the development of CHF.  Caution should 
be exercised before initiating bevacizumab therapy in patients with these 
risk factors. 
A Phase II trial in patients with refractory acute myelogenous leukemia 
reported 5 cases of cardiac dysfunction (CHF or LVEF decrease to  40%) 
among 48 patients treated with sequential cytarabine, mitoxantrone, and 
bevacizumab.  All but 1 of these patients had significant prior exposure to 
anthracyclines as well (Karp et al. 2004).  
Other studies in patients with various tumor types and either a history of 
anthracycline exposure or concomitant use with bevacizumab are 
ongoing.  


2009-0260 
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Patients with prior exposure to systemic anthracyclines will have, as a 
standard of care procedure, a baseline Multi Gated Acquisition (MUGA) 
scans or echocardiograms (ECHOs). 
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, 
or infection with severe neutropenia (including some fatalities) have been 
observed in patients treated with some myelotoxic chemotherapy 
regimens plus bevacizumab in comparison to chemotherapy alone 
(Sandler et al. 2006). 
Additional Adverse Events:  See the bevacizumab Investigator Brochure 
for additional details regarding the safety experience with bevacizumab. 
 
1.3 
ERLOTINIB (TARCEVA) BACKGROUND   
The control of cell growth is mediated by a complex network of signaling 
pathways responsive to external influences, such as growth factors, as 
well as to internal controls and checks.  Epidermal growth factor (EGF) 
was one of the first growth factors to be described.  It was shown to be 
mitogenic, an effect mediated by the binding of EGF (or other ligands) to 
the cell surface EGF receptor (EGFR), stimulating autophosphorylation of 
the intracellular tyrosine kinase domain of the receptor.  Subsequent 
investigations revealed EGFR to be one of a family of closely related 
receptors that includes EGFR (HER1), HER2, HER3, and HER4.   
EGFR and other HER family members are considered to be important in 
the development, progression, and aggressive behavior of human 
epithelial malignancies and to be relevant therapeutic targets.  A number 
of human malignancies are associated with aberrant or over-expression of 
EGFR (Salomon et al. 1995).  Stimulation of tumor cells via the EGFR is 
important for both tumor growth and tumor survival in vivo.  Over-
expression of EGFR in certain human tumors, including non–small cell 
lung carcinoma (NSCLC), has been correlated with both chemo-resistance 
and poor prognosis (Rusch et al. 1996, 1997; Davies and Chamberlin 
1996; Veale et al. 1987, 1993; Sekine et al. 1998; Pfeiffer et al. 1996; 
Cerny et al. 1986; IMPATH Inc 1998–1999; Reissmann et al. 1999; Fujino 
1996; Fontanini et al. 1995; Lei et al. 1999). Inhibitors of EGFR tyrosine 
kinase activity have been in development for a number of years, and 
although earlier compounds lacked specificity and potency, newer 
compounds have proven active in nonclinical and clinical studies. 
Erlotinib (previously known as OSI-774) is an orally active, potent, 
selective inhibitor of the EGFR tyrosine kinase.  Early clinical data with 
Erlotinib indicate that the compound is generally safe and well tolerated at 
doses that provide the targeted effective concentration based on 
nonclinical experiments.  A recently completed, randomized, double-blind, 
placebo-controlled trial has shown that Erlotinib as a single agent 


2009-0260 
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Page 13 
significantly improves the survival of patients with incurable Stage IIIb/IV 
NSCLC who have failed standard therapy for advanced or metastatic 
disease (Shepherd et al; Proceedings of American Society of Clinical 
Oncology (ASCO)  2004; Abst 7022). 
The epidermal growth factor receptor (EGFR) is frequently expressed in 
human hepatoma cells, and EGF may be one of the mitogens needed for 
the growth of hepatoma cells.[3, 4] Several strategies have been tested in 
HCC, one is through using neutralizing monoclonal antibody such as 
cetuximab, and another is through using small molecule tyrosine kinase 
inhibitor such as gefitinib and erlotinib, as demonstrated in HCC cell 
cultures.[5, 6] Erlotinib is an orally active and selective inhibitor of the 
EGFR/HER1-related tyrosine kinase enzyme. In two phase II studies of 
erlotinib in HCC, [7, 8] the response rates were 0% and 9% but the 
disease control rate was 43 % and 50%, and median survival times were 
10.75 and 13 months, respectively. EGFR/HER1 expression was detected 
in 71% and 88% of evaluable patients, respectively, but there was no 
significant difference in terms of overall survival between the high-EGFR 
and low-EGFR groups. However, this assay detects the presence of 
EGFR receptors and does not determine the functional status of the 
receptor (eg, phosphorylated EGFR), as the latter can be performed on 
fresh tissue only. 
1.3.1   Nonclinical Experience Data 
a. Pharmacology 
Erlotinib, a quinazoline, directly and reversibly inhibits the human EGFR 
tyrosine kinase with an Inhibition Concentration (IC)50  of 2 nM 
(0.79 ng/mL) in an in vitro enzyme assay and reduces EGFR 
autophosphorylation in intact tumor cells with an IC50 of 20 nM 
(7.9 ng/mL).  This potent inhibition is selective for the EGFR tyrosine 
kinase both in assays assessing the effects of erlotinib on a variety of 
other isolated tyrosine kinases and in cellular bioassays designed to 
isolate this functional pathway.  Erlotinib is designed to inhibit 
EGF-dependent proliferation of cells at submicromolar concentrations and 
blocks cell cycle progression in the G1 phase.  
Data on drug exposure and anti-tumor responses in human tumor 
xenograft models (HN5 and A431) were analyzed in order to estimate the 
plasma concentration of erlotinib associated with anti-tumor activity.  
Based on these efficacy models, the minimum steady-state plasma 
concentration targeted for clinical activity in humans is projected to be 500 
ng/mL. 


2009-0260 
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Page 14 
b. Toxicology 
Toxicology studies have been performed in mice, rats (up to 6 months), 
dogs (up to 1 year), and monkeys (1 week).  Treatment-related effects 
observed in at least one species or study included effects on the cornea 
(atrophy, ulceration), skin (follicular degeneration and inflammation, 
redness, and alopecia), ovary (atrophy), liver (necrosis), kidney (papillary 
necrosis and tubular dilatation), lacrimal glands (atrophy), salivary glands 
(atrophy), mandibular lymph nodes (inflammation), spleen 
(hematopoiesis), gastrointestinal tract (delayed gastric emptying and 
diarrhea), and embryo-fetal toxicity.  Red blood cell parameters were 
decreased, and white blood cells (primarily neutrophils) were increased.  
There were treatment-related increases in asparte aminotransferase 
(AST) and alanine aminotransferase (ALT), triglyceride and bilirubin and 
decreases in albumin; increases in bilirubin were likely caused by a 
treatment-related impairment of bilirubin metabolism.  
1.3.2 Clinical Experience Data 
a. Dose Selection for Single-Agent Trials of Erlotinib 
Phase I trials of Erlotinib explored both schedule and dose to evaluate the 
safety, tolerability, and pharmacokinetic profile of the compound given as 
a single agent.  A number of pharmacokinetic trials in healthy subjects 
have been conducted, along with three classic Phase I trials in patients 
with advanced cancer.  The single-agent maximum tolerated dose (MTD) 
was estimated to be 150 mg administered once daily.   
The primary toxicities of single-agent Erlotinib consisted of rash 
(dermatosis), diarrhea, nausea, fatigue, stomatitis, vomiting, and 
headache.  When given daily, dose-limiting toxicity (diarrhea) was 
observed at 200 mg/day.  At 150 mg/day, diarrhea was manageable with 
the addition of loperamide therapy; this dose was considered the maximal 
tolerated dose.  
Rash (variously referred to as dermatitis, acneiform rash, or 
maculopapular rash) has been variable in onset, duration, and severity, 
but typically appears on the face, neck, scalp, chest, and back starting 
after ~1 week of treatment.  The mechanistic basis of the rash remains 
uncertain; histopathologic examination of biopsies of the rash 
demonstrated inflammatory cell infiltrate and mild epidermal 
hyperproliferation.  In some cases, the rash gradually improved despite 
continued dosing and, in general, resolved without sequelae following 
Erlotinib discontinuation.  The rash did not result in study discontinuation 
in patients with cancer in the Phase I trials.  Laboratory abnormalities 


2009-0260 
 December 27,  2013 
Page 15 
observed infrequently with single-agent Erlotinib involved primarily liver 
function tests, including elevation of ALT, AST, and/or bilirubin. 
Selection of the 150 mg/day dose of Erlotinib for subsequent single-agent 
studies was based on pharmacokinetic parameters, as well as the safety 
and tolerability profile of this dose in Phase I trials in heavily pretreated 
patients with advanced cancer.  Drug levels seen in patients with cancer 
receiving the 150 mg/day dose were consistently above the average 
plasma concentration of 500 ng/mL targeted for clinical efficacy.  
b. Pharmacokinetics 
Oral Erlotinib is well absorbed and has an extended absorption phase, 
with mean peak plasma levels occurring at 3 hours after oral dosing of 150 
mg/dL at steady state.  A study in healthy subjects provided an estimate of 
bioavailability of 59% (95% CI:  55%, 63%).  The time to reach steady-
state plasma concentration was ~5 days.  The accumulation ratio with 
daily dosing of Erlotinib was estimated to be 2.0.  From a population 
pharmacokinetic analysis of 708 patients, the median trough concentration 
(Cmin) 24 hours following the previous dose was 1041 (r697) ng/mL.  
Median AUC achieved during the dosing interval at steady state was 
19,801 ng x hr/mL.  Exposure after an oral dose is increased by food.   
There is extensive binding of Erlotinib and metabolites to both serum 
albumin and AAG (alpha-1-acid glycoprotein), with total plasma protein 
binding for Erlotinib and OSI-420 of ~95% and 91%, respectively.  Erlotinib 
is extensively metabolized in the liver by the hepatic cytochromes in 
humans–primarily by CYP3A4 and to a lesser extent by CYP1A2.  The 
primary metabolite of Erlotinib, OSI-420, has potency comparable to that 
of erlotinib, but is present at levels that are  10% of erlotinib levels.  
Erlotinib is excreted predominantly via the feces (! 90%).  The elimination 
half-life after a 150-mg oral dose is ~30 hours.  In population-based data 
analyses, no relationships were identified between predicted steady-state 
trough concentration and patient age, body weight, sex, ethnicity, or 
creatinine clearance. 
d. Phase II and III Trials in Patients with Advanced Cancer  
Multiple Phase II trials evaluating the safety, tolerability, and antitumor 
activity of Erlotinib have been conducted in patients with advanced, 
refractory malignancies including cancer of the head and neck, lung, 
aerodigestive tract, ovary, breast, central nervous system (glioma), and 
others. Erlotinib has been evaluated both as a single agent and 
administered concurrently with conventional chemotherapy agents using 
various doses and schedules.     


2009-0260 
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Page 16 
Evidence of activity has been observed in squamous cell carcinoma of the 
head and neck, ovarian, breast and pancreatic carcinoma, non–small cell 
lung cancer (NSCLC), and glioblastoma multiforme (GBM).  Patients 
received 150 mg/day of Erlotinib in all of these studies except the GBM 
study where dose escalation was allowed until limited by rash and where a 
higher starting dose was tested in subjects receiving concomitant enzyme 
inducing anti-epileptic drugs.  Dose reduction was allowed in all studies in 
the case of intolerance.  Diarrhea was treated with loperamide therapy 
and/or dose reduction.  Rash was treated with a variety of agents, 
including oral and topical antibiotics, corticosteroids, and other agents.   
Patients receiving Erlotinib in combination with various chemotherapy 
agents have generally experienced the same type of adverse events 
(AEs) as with either agent alone.   
The first randomized placebo controlled trial to demonstrate a survival 
advantage for an EGFR inhibitor was the Phase III study, BR21.  This 
international trial, conducted by the National Cancer Institute of Canada 
Clinical Trial Group (NCIC CTG), included 731 patients with incurable 
Stage IIIb/IV NSCLC who have failed standard therapy for advanced or 
metastatic disease.  Patients randomized in a 2:1 ratio to single-agent 
Erlotinib 150 mg/day obtained a 42.5% improvement in median survival 
over placebo, from 4.7 to 6.7 months.  The one-year survival increased 
significantly (from 22% to 31%) as did the median and 6 month PFS, 
response rate, and the time to deterioration of tumor related symptoms of 
pain, cough, and dyspnea.  (Shepherd 2004). 
In BR-21, of the 727 patients evaluable for safety (485 Erlotinib, 242 
placebo), the most common AEs in the Erlotinib arm were rash (75% 
Erlotinib, 17% placebo), diarrhea (54% Erlotinib, 18% placebo) and 
stomatitis (17% Erlotinib, 18% placebo) events.  The majority of these 
events were mild to moderate in severity.  The incidence of interstitial lung 
disease (ILD) reported was the same in the placebo and Erlotinib groups 
at 0.8% in each arm. 
Two large, Phase III, randomized studies in first-line NSCLC patients 
evaluated Erlotinib in combination with platinum-based two-drug 
combination chemotherapy.  A total of 1079 previously untreated patients 
received carboplatin/paclitaxel with either Erlotinib or placebo in the 
TRIBUTE trial (OSI2298g) conducted in the United States.  An additional 
1172 patients received cisplatin/gemcitabine plus either Erlotinib or 
placebo in the TALENT trial (BO16411) conducted in 27 countries in 
Europe and other ex-U.S. locations.  Neither study met its primary 
endpoint of improved overall survival or a secondary endpoint of improved 
time to disease progression or overall response rate.  Overall, the number 
of adverse events and serious adverse events were well balanced 


2009-0260 
 December 27,  2013 
Page 17 
between the two arms of each study, with two exceptions.  As expected, 
rash and diarrhea occurred more frequently in the Erlotinib arms.  In the 
TRIBUTE study, more serious adverse events resulting in death were 
seen in the Erlotinib arm compared with the placebo arm (53 vs. 27).  
Most of the apparent imbalance was due to events reported as pneumonia 
or progression of underlying cancer. (Gatzemeier U. et al.- Talent trial  - 
ASCO 2004 - Abstract 7010 and Herbst R. et al. – Tribute trial - ASCO 
2004 - Abstract 7011). 
e. Patients with Hepatic or Renal impairment 
The influence of hepatic metastases and/or hepatic dysfunction on the 
pharmacokinetics of Erlotinib is not yet known.  However, Erlotinib is 
cleared predominately by the liver, and caution should be used when 
administering Erlotinib to patients with hepatic dysfunction. Erlotinib is also 
a strong inhibitor of the Uridine 5'-diphospho-(UDP)-
glucuronosyltransferase UGT1A1 enzyme responsible for the 
glucuronidation of bilirubin.  Hyperbilirubinemia appears most often to be a 
side effect related to genetic polymorphisms of UGT1A1.  Rare cases of 
hepatic failure (including fatalities) have been reported during the post 
marketing use of Erlotinib.  Confounding factors for severe hepatic 
dysfunction have included pre-existing liver disease such as cirrhosis, viral 
hepatitis, hepatocellular carcinoma, hepatic metastases, or concomitant 
treatment with potentially hepatotoxic drugs. 
Rare cases of myocardial infarction (including fatalities) have been 
reported during the post marketing use of Erlotinib. 
No clinical studies have been conducted in patients with compromised 
renal function since Erlotinib and its metabolites are not significantly 
excreted by the kidneys.   
f. Adverse Events Associated with ERLOTINIB  
Common adverse events associated with erlotinib administration include 
rash and diarrhea.  Other common adverse events include 
nausea/vomiting, mucositis/stomatitis, headache, and fatigue.  
A rash occurred in 75% of Erlotinib-treated NSCLC patients enrolled in 
BR.21.  Similar incidences of rash have occurred when erlotinib was 
administered concurrently with chemotherapy including gemcitabine, 
paclitaxel/carboplatin, and gemcitabine/cisplatin.  A papular, pustular rash 
manifesting most often on the face and upper trunk was common across 
all studies, but rash was rarely the cause of study drug discontinuation. 
Other dermatologic manifestations reported in clinical studies or post 
marketing use of Erlotinib include nail changes, paronychia, painful 
fissures or cracking of the skin on the hands and feet, and hair growth 


2009-0260 
 December 27,  2013 
Page 18 
abnormalities (alopecia, thinning hair, eyelash/eyebrow changes, 
hirsutism). 
Wearing of contact lenses while receiving Erlotinib therapy is not 
recommended.  The incidence of diarrhea in BR.21 was 54% of Erlotinib-
treated NSCLC patients.  The median time to onset of skin rash was 8 
days and median time to occurrence of first diarrheal symptom was 9 
days.  
There have been infrequent reports of serious (including fatal) interstitial 
lung disease (ILD) in patients receiving Erlotinib for treatment of NSCLC 
or other advanced solid tumors.  In Study BR.21, the incidence of ILD 
(0.8%) was the same in the placebo and Erlotinib groups.  The overall 
incidence in Erlotinib-treated patients from all studies (including 
uncontrolled studies and studies with concurrent chemotherapy) is 
approximately 0.6%.  Included in this rate of ILD are reported diagnoses of 
pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, 
interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, 
pulmonary fibrosis, acute respiratory distress syndrome, alveolitis, and 
lung infiltration, irrespective of investigator assessed causality.  Most of 
the cases were associated with confounding or contributing factors such 
as concomitant/prior chemotherapy, prior radiotherapy, preexisting 
parenchymal lung disease, metastatic lung disease, or pulmonary 
infections. 
Rare cases of acute renal failure or renal insufficiency have been reported 
(including fatalities).  Many of these cases have been associated with 
dehydration associated with nausea, vomiting, diarrhea, and/or anorexia.  
There have been rare reports of renal failure in patients receiving Erlotinib 
in combination with platinum-containing chemotherapy regimens. Febrile 
neutropenia has been reported in patients receiving concomitant 
chemotherapy.   
Erlotinib is both protein bound (92%–95%) and metabolized by hepatic 
cytochromes CYP3A4 and CYP3A5 and pulmonary cytochrome CYP1A1.  
Therefore, a potential for drug–drug interaction exists when Erlotinib is 
co-administered with drugs that are highly protein bound or that are 
CYP3A4 inhibitors/inducers.   
Co-administration of Erlotinib with omeprazole, a proton pump inhibitor, 
decreased the exposure of Erlotinib (AUC) by 46% and the maximum 
concentration (Cmax) by 61%. There was no change to Tmax or half-life.  
Therefore, drugs that alter the pH of the GI tract may alter the solubility of 
Erlotinib and hence its bioavailability. 
The exposure to Erlotinib (AUC) increased to a moderate extent, by 39%, 
and the maximum concentration (Cmax) by 17%, when Erlotinib was co-
administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2. 


2009-0260 
 December 27,  2013 
Page 19 
Co-administration of Erlotinib with an inhibitor of CYP3A4 metabolism 
(ketoconazole, 200 mg po BID for 5 days) resulted in increased exposure 
to Erlotinib as measured by an 86% increase in median Erlotinib AUC and 
a 69% increase Cmax, compared with administration of Erlotinib alone. 
Induction of CYP3A4 metabolism by a known enzyme inducer (rifampin, 
600 mg po QD for 7 days) resulted in a 69% decrease in the median 
Erlotinib AUC, compared with administration of Erlotinib alone.  However, 
the effect of rifampin on Cmax was negligible.  In another study, rifampicin 
pretreatment followed by co-administration of rifampicin with a single 450 
mg dose of Erlotinib resulted in a mean Erlotinib exposure (AUC) that was 
57.6% of that observed following a single 150 mg Erlotinib dose in the 
absence of rifampicin treatment.  Therefore, a potential for drug-drug 
interaction exists when Erlotinib is co-administered with drugs that are 
highly protein bound or that are potent CYP3A4 inhibitors or inducers. 
International normalized ratio (INR) elevations and/or bleeding events 
have been reported in some cancer patients while on Erlotinib alone and 
in combination with other chemotherapeutic agents, and concomitant Non-
steroidal anti-inflammatory drugs (NSAIDS) or anticoagulants, including 
warfarin. 
 
1.4 
STUDY RATIONALE 
 
In HCC, several crucial intracellular signaling pathways such as the 
Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway, in addition to 
several growth and angiogenic factors/receptors such as EGFR 
(Epidermal Growth Factor Receptor), PDGFR (platelet-derived growth 
factor receptor), FGFR (fibroblast growth factor receptor), and VEGFR 
(Vascular Endothelial Growth Factor Receptor) have been recognized. 
Subsequently, targeted agents have entered clinical trials for HCC 
patients and, most recently, sorafenib was approved by FDA for treatment 
of advanced HCC. Sorafenib exerts its effect through targeting 
Raf/MEK/ERK signaling at the level of Raf kinase, and exerts an 
antiangiogenic effect by targeting VEGFR-2/-3. It is currently considered 
the standard of care for HCC, based on a phase III study conducted in 
Europe that demonstrated survival benefit, although modest activity was 
observed. This is of particular significance for HCC in light of the lack of 
existing effective systemic therapy for this cancer.  Evolution of sorafenib 
resistance is going to be a major challenge and dealing with this clinical 
dilemma is obviously an unmet need. Furthermore, sorafenib effects are 
suggested to be related to inhibition of angiogenesis (VEGFR and 
PDGFR), and direct effects on tumor cell proliferation/survival (Raf kinase 
signaling-dependent and signaling-independent mechanisms). Thus, 
sorafenib resistance may be attributed to failure of one of these two 
mechanisms, which further indicates the importance of studying more 
effective mechanisms of targeting one of those two most important 


2009-0260 
 December 27,  2013 
Page 20 
pathways in HCC. 
The hypervascular nature of HCC has led to increasing interest in 
exploring the potential of anti-angiogenic therapy in this disease. While 
the cancer cell has been the only target of anticancer therapy for more 
than 50 years, it is genetically unstable, and mutations accumulate. On 
the other hand, antiangiogenic therapy targets endothelial cells which are 
genetically stable. Thus, the genetic stability of endothelial cells may 
make them less susceptible to acquired drug resistance. As a result, 
angiogenesis inhibitors are emerging as a new class of therapeutic 
agents. Antiangiogenic strategy has been shown to be very promising in 
HCC, as indicated by recent phase II trials of bevacizumab, alone and in 
combination with cytotoxic agents in advanced HCC that suggested an 
improved disease control.[33, 36, 40-42] In addition, two Phase II studies 
of erlotinib in HCC have been conducted.  The first study was conducted 
by our group at M. D. Anderson Cancer Center, Thomas MB et al,[43] and 
the other study was conducted by Philip P et al.[7] Both of these studies 
suggested that a dose of 150 mg/day was effective and well tolerated.  
Bevacizumab and Erlotinib in HCC: 
Journal of Clinical Oncology (JCO) has published the results from our  front-
line phase II study with erlotinib and bevacizumab combination for advanced 
HCC, with very promising data that was previously reported at ASCO 2007 as 
well.[37] Ten patients achieved PR for a confirmed overall response rate of 
25%. The PFS at 16 weeks of treatment was 62.5%. The median PFS was 39 
weeks (95% CI 24-45 weeks) (9.75 months), and median overall survival of 
68 weeks (17 months) (95% CI: 48-78 weeks). Grade 3-4 drug-related toxicity 
included fatigue (8 pts, 20%), hypertension (6 pts, 15%), diarrhea (4 pts, 
10%) elevated transaminases (4 pts, 10%), gastrointestinal hemorrhage (2 
pts, 5%), thrombocytopenia (2 pts, 5%), proteinuria, hyperbilirubinemia, back 
pain, hyperkalemia, and wound infection (1 pt each).  
As a major referral center, we have noted a recent change in referral 
patterns by local oncologists treating patients with advanced HCC. 
Patients are being started on sorafenib, the standard of care for HCC 
since its FDA approval in November 2007, based on a phase III study that 
showed a modest increase in overall survival of 2.8 months.[44] 
Therefore, patients who have progressed on sorafenib were allowed to 
participate in the study, after it was extended for a second cohort of 20. 
Analysis of this cohort is still ongoing with similar promising preliminary 
results in this important setting. We have seen a signal of activity of 
bevacizumab and erlotinib in this setting. Therefore, we propose to use 
this combination as a second-line systemic therapy for patients with 
advanced HCC who have progressed on sorafenib. 


2009-0260 
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Page 21 
 
2.0 
OBJECTIVES 
 
2.1 
Primary 
 
 
This is a Phase II, single-arm open-label study of erlotinib plus 
bevacizumab in advanced hepatocellular carcinoma as a second-
line therapy in patients who have progressed on first-line Sorafenib 
therapy.  
 
x The primary objective will be to assess progression-free survival 
(PFS) measured at 16 weeks following initiation of therapy with the 
combination of bevacizumab and erlotinib in patients who 
progressed on sorafenib treatment.  Progression-free survival is 
defined as the time from initiation of therapy until documented 
disease progression or death.  
 
 
 
2.2 
Secondary  
 
x The secondary objective will be to assess time to progression 
(TTP): this endpoint will reflect the time between treatment 
assignment and radiological progression as defined by the 
amendments of the Response Evaluation Criteria in Solid Tumors 
(RECIST). Due to the fact that death often occurs as a result of liver 
failure in patients with liver cancer, deaths during follow-up without 
evidence of radiological progression will be censored. This concept 
has been proposed by a group of experts most recently.[45] 
 
x Other secondary objectives include: response rate, median and 
overall survival, safety, toxicity and tolerability, stable disease at 16, 
24, and 36 weeks, and duration of response.   
 
 
3.0 
STUDY DESIGN  
3.1 
Description of the Study 
This will be a single-arm study. Bevacizumab will be administered 
intravenously at 10 mg/kg once every 2 weeks, and erlotinib at 150 mg will 
be taken orally once a day.  Patients will be evaluated every 28 days (a 
cycle is defined as 28 days), and will undergo restaging evaluation every 2 
cycles. Treatment will be administered on an outpatient basis at M. D. 
Anderson Cancer Center.  Patients will continue on therapy until disease 
progression as defined in modified RECIST, until development of 


2009-0260 
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Page 22 
intolerable toxicity, or withdrawal of patient consent. Evaluable patients 
include any patient who receives at least one 28-day cycle. Patients who 
do not complete 1 cycle of therapy will be replaced.  
3.2 
Rationale for Study Design 
Because erlotinib and bevacizumab act on two different pathways critical 
to tumor growth and dissemination, our group designed and completed a 
phase II study that demonstrated clinical benefits to HCC patients with 
advanced disease.  We propose that the combination of bevacizumab plus 
erlotinib may prove to be a viable second-line therapy for advanced HCC 
patients who have failed sorafenib therapy.    
We will follow the same design of our phase II study at MDACC, in 
unresectable HCC given its tolerability record in this patient population. An 
initial cohort of 40 patients with advanced HCC was completed and 
published at JCO.[37] An additional cohort of 20 additional patients is 
currently finishing accruing patients. The study objective was to determine 
the proportion of patients with HCC treated with the combination of 
bevacizumab and erlotinib, who were alive and progression-free at 16 
weeks (PFS16) of continuous therapy. Secondary objectives included 
response rate, median PFS, survival, and toxicity. Patients received 
bevacizumab at 10 mg/kg every 14 days, and erlotinib at 150 mg orally 
daily, continuously, for 28 day cycles. Tumor response was evaluated 
every 2 cycles using modified RECIST criteria. 
The median age was 64, 31 males (77%), 27 (67.5%) patients had 
pathologic or radiographic evidence of cirrhosis, 25 patients (62%) were 
Caucasian, 35 patients (87.5%) had Childs-Pugh A liver function, 8 
patients (20%) had prior systemic therapy; 19 patients (47.5%) had 
”Cancer for the Liver Italian Program” (CLIP) score 0-2, with 21 patients 
(52.5%) with a CLIP score of 3-4.  
Ten patients achieved a partial response (PR) for a confirmed overall 
response rate (ORR) of 25%. The PFS at 16 weeks of treatment was 
62.5%. The median time to progression was 39 weeks (95% CI 24-45 
weeks), and median overall survival (MS) was 68 weeks (95% CI:48-78 
weeks), all of which are substantially higher than any other regimen tested 
in HCC and higher than the results in both the Phase II and Phase III 
sorafenib trials.  
Overall the frequency of grade 3-4 events in this study such as 
neutropenic fever, myelosuppression, nausea, vomiting and fatigue, was 
low relative to studies of cytotoxic agents in HCC. Several grade 1-2 drug-
related adverse events were commonly experienced by a majority of 
patients and represented chronic side effects that affected patients’ quality 
of life. These included dry skin, acne, anorexia, diarrhea, dry 
mouth/mucositis, and fatigue. These occurred most frequently during the 


2009-0260 
 December 27,  2013 
Page 23 
first 1-4 months of therapy, and generally resolved and/or responded to 
supportive care measures including oral and topical antibiotics for acne, 
low-dose steroids for appetite stimulation and fatigue, and anti-diarrhea 
medications. Nine patients required one dose reduction of erlotinib (150 
mg to 100 mg daily) and 2 patients required 2 dose reductions (to 50 mg 
daily) of erlotinib. Seven patients were removed from the study for toxicity 
including: fatigue (1 patient), proteinuria (2 patients), delayed wound 
healing (1 patient), gastrointestinal hemorrhage, (3 patients). Two patients 
with known portal hypertension developed life-threatening gastrointestinal 
hemorrhage while on study. One patient recovered and the other patient 
succumbed within 30 days due to complications of the bleeding event. 
One patient had grade 1 esophageal varices but was receiving concurrent 
warfarin.  At the time of the bleeding event the prothrombin time (PT) was 
significantly prolonged. Two patients had known portal hypertension but 
had poor tolerance to beta blockade therapy and thus remained at risk for 
variceal bleeding. Following implementation of PillCam™ screening, which 
was utilized due to its low cost and low morbidity, there were no further 
episodes of variceal hemorrhage. 
3.3  
Outcome Measures  
 
3.3.1 Primary Outcome Measures 
x Progression-free survival: measured at 16 weeks 
3.3.2 Secondary Outcome Measures 
x Time to Progression: the time between assignment and radiological 
progression as defined by the amendments of the Response 
Evaluation Criteria in Solid Tumors (RECIST). 
x Response rate (CR and PR) by RECIST amendments 
x Median and Overall survival 
x Stable Disease at 16, 24, and 36 weeks 
x Duration of response 
 
4.0 
SAFETY PLAN 
4.1 
GENERAL PLAN TO MANAGE SAFETY  
A number of measures will be taken to ensure the safety of patients 
participating in this trial.  These measures will be addressed through 
exclusion criteria (see Section 5.3) and routine monitoring as follows. 


2009-0260 
 December 27,  2013 
Page 24 
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in 
this study.  Safety evaluations will consist of medical interviews, recording 
of adverse events, physical examinations, blood pressure, and laboratory 
measurements.  Patients will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit for the duration of their 
participation in the study.  Patients discontinued from the treatment phase 
of the study for any reason will be evaluated ~30 days (28–42 days) after 
the decision to discontinue treatment (see Section 12.0).   
a. Bevacizumab-Specific 
 Specific monitoring procedures are as follows: 
x 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. 
x Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or 
dipstick every 4 weeks. A 24-hour urine specimen will be collected if  
proteinuria is  Grade 3. 
x 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). 
b. Erlotinib-Specific 
x Skin toxicities will be monitored by routine physical examination and 
managed symptomatically.    The following agents may be used to 
treat rash:  diphenhydramine, topical or oral corticosteroids, and topical 
(clindamycin) or oral antibiotics (tetracycline, minocycline, 
doxycycline).  Topical drying agents are not recommended.   
x Diarrhea will be monitored and managed symptomatically.  Guidelines 
for management include administration of loperamide and Erlotinib 
dose reduction/interruption as described in Section 7.3.2  and Table 3. 
x Although quite rare, ILD can be life threatening.  Therefore, patients 
should be monitored closely for symptoms consistent with ILD, such as 
new onset dyspnea without an obvious cause.  In the event that ILD is 
suspected, Erlotinib treatment should be discontinued and the patient 
should receive appropriate medical management.  Although there is no 


2009-0260 
 December 27,  2013 
Page 25 
proven therapy, systemic corticosteroids are often provided.  Erlotinib 
should not be restarted in those patients suspected of having drug-
related ILD.  See Section 7.3.2 and Table 3 for management 
guidelines, including Erlotinib dose interruption. 
x Liver function abnormalities, including elevated serum ALT, AST, 
and/or bilirubin, have been observed infrequently with single-agent 
Erlotinib and occasionally with Erlotinib in combination with 
concomitant chemotherapy.  Periodic monitoring of liver function is 
recommended.  Erlotinib dosing should be interrupted if changes in 
liver function are severe. 
x Women of childbearing potential should have a negative pregnancy 
test prior to starting therapy with Erlotinib and should use adequate 
contraceptive methods during and after Erlotinib therapy. 
x It is not known whether Erlotinib is excreted in human milk.  Because 
many drugs are excreted in human milk and because the effects of 
Erlotinib on infants have not been studied, women should be advised 
against breast-feeding while receiving Erlotinib therapy. 
 
5.0 
STUDY SUBJECTS 
5.1 
Subject Selection 
Potential study patients will be screened according to the Eligibility 
Criteria. Study-specific evaluations may be performed only after written 
informed consent has been obtained. 
5.2 
Inclusion Criteria 
1. Patients with histological or cytologically documented HCC not  
amenable to curative resection (documentation of original biopsy for 
diagnosis is acceptable if tumor tissue is unavailable) or clinical 
diagnosis by American Association for the Study of Liver Diseases 
(AASLD) criteria (see Appendix Q) in cirrhotic subjects is required. For 
subjects without cirrhosis, histological or cytological confirmation is 
mandatory. 
2. Patients must have measurable disease as per the modified RECIST 
criteria (Appendix E).  Measurable target lesions are defined at baseline 
as lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) 20 mm using conventional 
techniques (CT or MRI) or 10 mm using  spiral CT scan. Lesion must 
not be chosen from a previously irradiated field, unless there has been 
documented disease progression in that field after irradiation.   


2009-0260 
 December 27,  2013 
Page 26 
3. Patients who have progressed on, or were intolerant to, one prior 
systemic therapy with sorafenib, completed 14 days prior to treatment 
day 1. Previous treatments also allowed that do not count as systemic 
therapy include: surgical resection, transarterial 
embolization/chemoembolization (TAE/TACE), radiofrequency ablation 
(RFA), percutaneous ethanol injection (PEI), provided that the lesion(s) 
to be evaluated in this study are separate from the previously treated 
lesions(s).  
4. Eastern Cooperative Oncology Group (ECOG) performance status of </= 
2 (Appendix B) 
5. Childs-Pugh liver function status (Appendix D) of A or B (only 7 
points allowed).  
6. Organ function: Absolute peripheral granulocyte count of >/= 1500 mm3, 
platelet count of >/= 40,000 mm3, hemoglobin >/= 10 gm/dL. Total 
bilirubin </= 2.0 gm/dL; serum albumin >/= 2.5 gm/dL; asparte 
aminotransferase (AST) and alanine aminotransferase (ALT) up to 5 X 
the upper limit of institutional normal (AST – 46 and ALT – 56); and 
prothrombin time prolonged not more than 3 seconds greater than 
institutional normal, once attempts to correct a prolonged PT have been 
made. Patients who require full dose anticoagulation, who are otherwise 
eligible for this trial, are allowed to have an appropriately prolonged 
International Normalized Ratio (INR). 
7. Negative serum pregnancy test in women with childbearing potential 
WKRVHZKRDUHQRWVXUJLFDOO\VWHULOL]HGRUZKRDUHQRWDPHQRUUKHLFIRU
12 months), within one week prior to initiation of treatment. 
8. Men and women of childbearing potential must agree to use effective 
means of contraception prior to study entry and for at least 180 days 
after the last dose of study treatment.  They must agree to use two forms 
of birth control, for example, barrier methods (such as a diaphragm, 
cervical cap, contraceptive sponge, female condom, or male condom), 
and an intrauterine device (IUD). 
9. $JH\HDUV7KHDJHQWVbevacizumab and erlotinib have not been 
studied in pediatric patients, thus the doses to be used in this study 
cannot be assumed to be safe in children.  
10. Radiographic evidence of disease progression during or following prior 
treatment with sorafenib.  
11.  Patients must have proteinuria < 2+ or a urine protein:creatinine (UPC) 
ratio < 1.0 (Appendix C). Patients who have proteinuria  2+ and UPC 
ratio t 1.0 must undergo a 24 hour urine collection and must 
GHPRQVWUDWHJRI protein in 24 hours to be eligible. 
 


2009-0260 
 December 27,  2013 
Page 27 
5.3  
Exclusion Criteria 
a. Disease-Specific Exclusions 
1. Patients who have had prior systemic therapy other than sorafenib. 
Patients may not have received any systemic chemotherapy </=14 days of 
Treatment Day 1.     
2. Active malignancy other than superficial basal cell and superficial 
squamous (skin) cell, or carcinoma in situ of the cervix within last five 
years.    
3. Current, recent (within 4 weeks of Treatment Day 1) or planned 
participation in an experimental drug study, other than this study.   
4. Gastrointestinal disease resulting in an inability to take oral medication or 
a requirement for intravenous hyperalimentation.  
5. History of rupture of existing HCC lesion, or HCC lesion with large necrotic 
areas seen on conventional imaging studies, as determined by the 
Principal Investigator, if there is no measurable solid tumor area > 1.5 cm. 
6. Inadequately controlled hypertension (defined as systolic blood pressure 
>140 and/or diastolic blood pressure > 90). 
7. Prior history of hypertensive crisis or hypertensive encephalopathy. 
8. New York Heart Association  (Appendix A) Class II or greater congestive 
heart failure  
9. Cardiac arrhythmia not controlled by medication.  
10. History of myocardial infarction or unstable angina within 6 months of 
Treatment Day 1. 
11. History of stroke or transient ischemic attack within 6 months prior to Day 
1 of treatment.   
12. Significant vascular disease (e.g., aortic aneurysm requiring surgical 
repair or recent peripheral arterial thrombosis) within 6 months prior to 
Day 1. 
13. Evidence of clinically significant (CTC Grade 3 or 4) venous or arterial 
thrombotic disease within previous 6 months. 
14. Radiographic evidence of major tumor thrombus in the vena cava. 
15. History of hemoptysis (t 1/2 teaspoon of bright red blood per episode) 
within 1 month prior to Day 1. 
16. Evidence of bleeding diathesis or significant coagulopathy (in the absence 
of therapeutic anticoagulation). 
17. History of significant gastrointestinal bleeding requiring procedural 
intervention (eg variceal banding, Transjugular Intrahepatic Portosystemic 


2009-0260 
 December 27,  2013 
Page 28 
Shunt (TIPS) procedure, arterial embolization) within three months prior to 
treatment day 1.  Patients at risk for varices (based on the following: 
known history of esophageal or gastric varices; evidence of hepatic 
cirrhosis and/or portal hypertension including biopsy-proven cirrhosis, 
radiographic evidence of cirrhosis, hypersplenism, or radiographic findings 
of varices) will be screened for esophageal varices.  If varices are 
identified that require intervention (banding) that patient will not be eligible 
for the trial until the varices have been adequately treated. 
18. Known CNS disease, except for treated brain metastases.   Treated brain 
metastases are defined as having no evidence of progression or 
hemorrhage after treatment and no ongoing requirement for 
dexamethasone, as ascertained by clinical examination and brain imaging 
(MRI or CT) during the screening period.  Anticonvulsants (stable dose) 
are allowed. Treatment for brain metastases may include whole brain 
radiotherapy (WBRT), radiosurgery [RS; Gamma Knife, Linear Accelerator 
(LINAC), or equivalent] or a combination as deemed appropriate by the 
treating physician.  Patients with CNS metastases treated by 
neurosurgical resection or brain biopsy performed within 3 months prior to 
Day 1 will be excluded. 
19. Major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to Day 1, or anticipation of need for major surgical 
procedure during the course of the study. 
20. Core biopsy, fine needle aspiration, or other minor surgical procedure, 
excluding placement of a vascular access device, within 7 days prior to 
Day 1. 
21. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 6 months prior to Day 1. 
22. Serious, non-healing wound, active ulcer, or untreated bone fracture. 
23. Ongoing or active infection requiring parenteral therapy. 
24. Known HIV disease. 
25. Uncontrolled psychiatric illness.  
26. Known hypersensitivity to any component of bevacizumab and erlotinib. 
27. Pregnancy (positive pregnancy test) or lactation.   
28. Inability to comply with study and/or follow-up procedures. 
 
 
6.0 
STUDY DESIGN 
 
6.1 
Treatment Plan 
 
 


2009-0260 
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Page 29 
This is an open-label single arm single institution phase II study designed to 
evaluate the efficacy and safety of bevacizumab and erlotinib in patients with 
HCC who progressed on first-line sorafenib therapy.   Bevacizumab 10 mg/kg will 
be administered intravenously once every 2 weeks and erlotinib 150 mg will be 
taken orally daily. Treatment may continue until occurrence of disease 
progression, unacceptable toxicity, or patient withdrawal from the study. Patients 
will be evaluated every 28 days (a cycle is defined as 28 days), and will undergo 
restaging evaluation every 2 cycles. Treatment will be administered on an 
outpatient basis at M. D. Anderson Cancer Center.  
The estimated number of patients to be enrolled is 44, the estimated rate of 
accrual is 1-2 patients per month, with an estimated date of study completion of 3 
years from initiation of enrollment, including follow-up. 
 
Doses and Schedule 
Bevacizumab 
 
10 mg/kg IV 
Once every 2 weeks 
Erlotinib 
150 mg Oral  
Once Daily 
 
For patients who experience treatment-related toxicity, criteria for study drug(s) 
reduction and/or dose withholding are provided in section 7.   
 
7.0 
STUDY MEDICATION  
 
7.1  
BEVACIZUMAB DOSAGE AND FORMULATION 
Bevacizumab will be administered intravenously at 10 mg/kg once every 2 
weeks. 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 20-cc (400-mg) glass vials containing 16 mL bevacizumab 
(25 mg/mL).  Vials contain bevacizumab with phosphate, trehalose, polysorbate 
20, and Sterile Water for Injection (SWFI), United States Pharmacopeia (USP).  
Vials contain no preservative and are suitable for single use only. 
For further details and molecule characterization, see the bevacizumab 
Investigator Brochure. 
7.1.1 Bevacizumab Administration 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium Chloride 
Injection, USP.  Administration will be as a continuous IV infusion.  Anaphylaxis 
precautions should be observed during study drug administration.   It is not 
necessary to correct dosing based on ideal weight. 
The initial dose will be delivered over 90r15 minutes.  If the first infusion is 
tolerated without infusion-associated adverse events (fever and/or chills), the 
second infusion may be delivered over 60r10 minutes.  If the 60-minute infusion 
is well tolerated, all subsequent infusions may be delivered over 30r10 minutes.   


2009-0260 
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Page 30 
If a subject experiences an infusion–associated adverse event, he or she may be 
premedicated for the next study drug infusion; however, the infusion time may 
not be decreased for the subsequent infusion.  If the next infusion is well 
tolerated with premedication, the subsequent infusion time may then be 
decreased by 30r10 minutes as long as the subject continues to be 
premedicated.  If a subject experiences an infusion-associated adverse event 
with the 60-minute infusion, all subsequent doses should be given over 
90r15 minutes.  Similarly, if a subject experiences an infusion-associated 
adverse event with the 30-minute infusion, all subsequent doses should be given 
over 60r10 minutes. 
7.1.2 Bevacizumab Storage 
Upon receipt of the study drug, vials are to be refrigerated at 2qC–8qC  
(36qF–46qF) 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.. 
Any unused or expired study drug will be destroyed per institutional policy. 
 
7.2 
ERLOTINIB DOSAGE AND FORMULATION 
7.2.1 Formulation 
Erlotinib oral tablets are conventional, immediate-release tablets 
containing erlotinib as the hydrochloride salt. In addition to the active 
ingredient, Erlotinib contains lactose (hydrous), microcrystalline cellulose, 
sodium starch glycolate, sodium lauryl sulfate, and magnesium stearate.   
Tablets containing 25 mg, 100 mg, and 150 mg of Erlotinib are available. 
Each bottle will contain 30 tablets, a quantity sufficient for 4 consecutive 
weeks of dosing, with overage.   
For further details, see the Erlotinib Investigator’s Brochure. 
 
7.2.2 Dosage, Administration, and Storage 
Erlotinib will be administered at 150 mg, one tablet orally once a day. 
Erlotinib will be self-administered in an open-label, unblinded manner to all 
patients enrolled in the study. Tablets should be taken at the same time 
each day with 200 mL of water at least 1 hour before or 2 hours after a 
meal.  On Day 1 of treatment, since the dispensing time may vary, 
patients should take the dose as soon as it is dispensed. 


2009-0260 
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Erlotinib tablets will be supplied for this clinical trial in white, high-density 
polyethylene (HDPE) bottles with child-resistant closures and should be 
stored at temperatures between 15°C and 30°C (59°F and 86°F). 
For each cycle, patients will be instructed to return any leftover erlotinib.  
Patients will also be given a diary to document erlotinib dosing.  The diary 
plus returned drug will be used to assess compliance with the treatment.  
 
Any unused or expired study drug returned by the patient will be destroyed 
per institutional policy. 
 
7.3 
Dose Modifications 
7.3.1 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. Discontinuation of 
bevacizumab will have no immediate therapeutic effect. Bevacizumab has a 
terminal half-life of 21 days; 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 Table 1  
Regardless of the reason for holding study drug treatment, the maximum 
allowable length of treatment interruption is 2 months.  


2009-0260 
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Table1:  
Bevacizumab Dose Management Due to Adverse Events 
 
Event 
Action to be Taken 
Hypertension 
No dose modifications for grade 1/2 events 
Grade 3 
If not controlled to 150/100 mmHg with medication, discontinue bevacizumab. 
Grade 4 (including 
hypertensive encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1/2 non-pulmonary and non-CNS events 
  Grade 3   
  Non-pulmonary and 
    non-CNS hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be discontinued from 
receiving bevacizumab.   
All other subjects will have bevacizumab held until all of the following criteria  are 
met: 
x 
The bleeding has resolved and hemoglobin is stable. 
x 
There is no bleeding diathesis that would increase the risk of therapy. 
x 
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence. 
Subjects who experience a repeat Grade 3 hemorrhagic event will be discontinued 
from receiving bevacizumab. 
  Grade 4  
     non-pulmonary or  
    non-CNS hemorrhage 
Discontinue bevacizumab. 
   Grade 1pulmonary or CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be discontinued from 
receiving bevacizumab.   
All other subjects will have bevacizumab held until all of the following criteria  are 
met: 
x 
The bleeding has resolved and hemoglobin is stable. 
x 
There is no bleeding diathesis that would increase the risk of therapy. 
x 
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence. 
 
Grade 2, 3, or 4 pulmonary or 
CNS hemorrhage 
Discontinue bevacizumab 
Venous Thrombosis 
No dose modifications for grade 1/2 events 
 


2009-0260 
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Page 33 
Bevacizumab Dose Management due to Adverse Events (continued) 
 
Grade 3 or 4 
Hold study drug treatment.  If the planned duration of full-dose anticoagulation is 
<2 weeks, bevacizumab should be held until the full-dose anticoagulation period is 
over.  If the planned duration of full-dose anticoagulation is >2 weeks, bevacizumab 
may be resumed during the period of full-dose anticoagulation if all of the following 
criteria  are met: 
x 
The subject must have an in-range INR (usually between 2 and 3) if on 
warfarin; LMWH, warfarin, or other anticoagulant dosing must be stable 
prior to restarting bevacizumab treatment. 
x 
The subject must not have had a Grade 3 or 4 hemorrhagic event while 
on anticoagulation. 
Arterial Thromboembolic event 
(New onset, worsening, or unstable 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)  
No dose modifications for grade 1/2 events 
Grade 3 
Hold bevacizumab until resolution to Grade  1. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria 
No dose modifications for grade 1/2 events 
Grade 3 
(UPC> 3.5, urine collection 
> 3.5 g/24 hr)   
 
Hold bevacizumab treatment until d Grade 2, as determined by either UPC ratio  3.5 
or 24 hr collection  3.5 g 
 
Grade 4 (nephritic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
 
Discontinue bevacizumab. 
Fistula  
 
Any grade (TE fistula) 
Discontinue bevacizumab. 
Grade 4 fistula 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring medical intervention. 
 


2009-0260 
 December 27,  2013 
Page 34 
Bevacizumab Dose Management due to Adverse Events (continued) 
 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention.  Patient may 
restart upon complete resolution. 
Grade 3/4 
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 Any 
grade (requiring medical or 
surgical therapy) 
Discontinue bevacizumab. 
Reversible Posterior Leukoencephalopathy   
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
+ROGEHYDFL]XPDEXQWLOUHFRYHU\WR*UDGH 
Discontinue bevacizumab. 
 
7.3.2 Erlotinib Dose Modification and Toxicity Management 
 
 
Dose Modification  
Dose reduction or interruption of erlotinib for toxicity may take place at any 
time during the study.  Toxicity grading is based on NCI-CTCAE, v 3.0.  
Dose level reductions are presented in Table 2.  If patients do not tolerate 
the second dose reduction, erlotinib is to be discontinued.  
 
 
Table 2  
Erlotinib Dose Level Reductions 
Starting Dose  
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
Dose modification guidelines are summarized in Table 3.  
Management of a tolerable Grade 2 or 3 rash should include continuation 
of erlotinib at the current dose and symptomatic management.  If skin rash 
is intolerable, dose reduction according to Table 3 should be considered.  
When skin toxicity improves by at least one grade level, the dose may be 
re-escalated as tolerated.  In Phase II trials, this approach enabled dose 
re-escalation for the majority of patients requiring dose reduction for skin 
toxicity.  Patients experiencing Grade 4 skin toxicity should be 
discontinued from study treatment.     


2009-0260 
 December 27,  2013 
Page 35 
For Grade 1 or 2 diarrhea, early intervention should include continuation of 
erlotinib at the current dose and initiation of loperamide therapy as 
described in Table 3.  Grade 2 diarrhea that persists over 48–72 hours, 
despite optimal medical management, should be managed by dose 
reduction according to Table 3.  Patients experiencing Grade 3 diarrhea 
should interrupt erlotinib until resolution to Grade d1 and re-start at a 
reduced dose according to Table 3.  Patients should be maintained at the 
reduced dose without attempt at dose re-escalation.  Patients 
experiencing Grade 4 diarrhea should be discontinued from study 
treatment. 
Erlotinib should not be restarted in those suspected of having drug-related 
ILD.  


2009-0260 
 December 27,  2013 
Page 36 
Table 3 
Dosage Modification Criteria and Guidelines for Management  
of Erlotinib-Related Toxicities 
NCI-CTCAE (v 3.0) 
Grade 
Erlotinib Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at 
first onset, followed by 2 mg q 
2–4 hours until free of diarrhea 
for 12 hours) 
Grade 2 
None 
(Dose reduction of Erlotinib is 
necessary if diarrhea persists 
over 48–72 hours despite 
optimal medical management) 
Loperamide (4 mg at first 
onset, followed by 2 mg q 2–4 
hours until diarrhea free for 12 
hours) 
Grade  3 
Interrupt then dose reduce 
Erlotinib.  Erlotinib should not 
be re-escalated. 
Interrupt Erlotinib until 
resolution to Grade d1, and 
restart at next reduced dose 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events if possibly ILD 
All Grades 
Temporarily interrupt Erlotinib 
pending the diagnostic 
evaluation.  If the pulmonary 
adverse event is assessed as 
related to Erlotinib, discontinue 
the patient from study 
treatment. 
Unexplained dyspnea, either 
new or progressive, should be 
aggressively evaluated.   
Rash 
Grade 1 and 2 
Tolerable rash 
None 
Any of the following: oral 
antibiotics (tetracycline, 
minocycline, doxycycline) 
topical clindamycin, 
diphenhydramine, topical or 
oral corticosteroids at 
discretion of investigator 
Grade 3 
Intolerable rash 
Consider interruption and or 
dose reduction if unresponsive 
to symptomatic management.  
Re-escalation is allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
Manage as described above 
 
 
 
7.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, 
including chemotherapy, radiation therapy, immunotherapy, and hormonal 


2009-0260 
 December 27,  2013 
Page 37 
anticancer therapy, is not permitted while participating in this study. Use of 
concurrent investigational agents is not permitted. 
Low-dose aspirin ( 325 mg/d) may be continued in subjects at higher risk 
for arterial thromboembolic disease. Subjects developing signs of arterial 
ischemia or bleeding on study should be evaluated for possible 
bevacizumab discontinuation per Table 1, Bevacizumab Dose 
Management Due To Adverse Events. 
There are potential interactions between Erlotinib and CYP3A4 inhibitors 
and CYP3A4 promoters.  Although caution and careful monitoring are 
recommended when use of these compounds is necessary, use of these 
compounds does not exclude patients from participating in this trial (see 
Appendix F for a list of CYP3A4 inhibitors and inducers). 
Grapefruit juice is a CYP3A4 inhibitor, therefore, consumption of grapefruit 
or grapefruit juice should be avoided during Erlotinib treatment. 
The solubility of Erlotinib is pH dependent.  Erlotinib solubility decreases 
as pH increases. Co-administration of Erlotinib with omeprazole, a proton 
pump inhibitor, decreased the exposure of Erlotinib (AUC) by 46% and the 
maximum concentration (Cmax) by 61%.  There was no change to Tmax or 
half-life.  Therefore, drugs that alter the pH of the GI tract may alter the 
solubility of Erlotinib and hence its bioavailability. 
The exposure to Erlotinib (AUC) increased to a moderate extent, by 39%, 
and the maximum concentration (Cmax) by 17%, when Erlotinib was co-
administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2. 
Erlotinib clearance can be induced by smoking via CYP1A2 induction. 
Potential drug-drug interaction is expected when erlotinib is taken with 
CYP1A2 inducers or inhibitors.  In a single-dose study in healthy 
volunteers, the AUC was reduced by 64% in smokers when compared 
with nonsmokers.  In BR.21, current smokers achieved Erlotinib trough 
plasma concentrations that were approximately 2-fold lower than never 
smokers.  Smokers should be advised to stop smoking while taking 
Erlotinib as plasma concentrations of erlotinib are reduced due to the 
effect of cigarette smoking. 
Pretreatment or co-administration of erlotinib did not alter the clearance of 
a prototypical CYP3A4 substrate, midazolam.  Therefore, significant 
metabolic interactions with other CYP3A4 substrates are unlikely.  
However, the oral bioavailability of midazolam decreased by up to 24% 
following Erlotinib treatment, which was not attributed to a metabolic 
interaction. 
Patients taking warfarin or other warfarin-derivative anticoagulants should 
be monitored regularly for changes in prothrombin time or INR. 
 


2009-0260 
 December 27,  2013 
Page 38 
8.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
Pre- 
Study@ 
Cycle 
1, 
Day 1 
Cycle 
1,  
Day 15 
Cycle 2  & 
Sub-
sequent 
Cycles, 
Day 1g# 
Cycle 2 & 
Sub-
sequent 
Cycles, 
Day 15  
End of  
Cycle 2, 4,  
& every 2 
subsequent 
cycles 
End of 
Treat-
ment 
Post 
Treat-
ment 
Follow-
up 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
X 
 
 
X 
 
Concurrent Medications* 
X 
 
 
X 
 
 
X 
 
Physical Exam 
X 
 
 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
X 
 
Vital Signs (Includes SBP/DBP) 
X 
X 
X 
X 
X 
 
X 
 
Urinalysis w/urine protein 
determination 
Xm 
 
 
Xk 
 
 
X 
 
Performance status 
X 
 
 
X 
 
 
X 
 
HBV and HCV serology  
X 
 
 
 
 
 
 
 
PT/PTT/INRa 
X 
 
 
X 
 
 
X 
 
CBC with differential, platelets 
X 
 
 
X 
 
 
X 
 
Serum chemistry 
b 
X 
 
 
X 
 
 
X 
 
Liver function tests 
c 
X 
 
 
X 
 
 
X 
 
ECGl 
X 
 
 
 
 
 
 
 
Serum ß-HCG (women of child-
bearing potential) 
X 
 
 
 
 
 
 
 
AFP
d 
X 
 
 
X 
 
 
X 
 
CT/MRI chest/abdomen/pelvis 
tumor Assessment 
e 
X 
 
 
 
 
X 
X 
 
Esophageal-gastric (EGD) 
endoscopyi 
X 
 
 
 
 
 
 
 
Bevacizumab  
 
X 
Xf 
Xf 
Xf 
 
 
 
Erlotinib  
 
Once daily continuously until treatment discontinuation 
 
Adverse events 
Continuous monitoring during study participation 
Xj 
Survival 
 
 
 
 
 
 
 
Xh 
@ Prestudy evaluations except for imaging studies, HBV, & HCV must be obtained within 7 days 
prior to first day of treatment. Baseline imaging studies may be obtained up to 28 days prior to 
first day of treatment. HBV & HCV must be obtained within 3 months prior to first day of treatment 
 
# Evaluations may be obtained within 72 hours prior to starting a new cycle, except for imaging 
studies which may be obtained within 7 days prior to starting a new cycle.   
*All medications, including prescription and over-the-counter, vitamins, supplements and "herbal" 
preparations must be disclosed by the patient and recorded.  Patients will be instructed to check 
with study staff before taking any new prescription or over-the-counter medication(s), vitamins, 
supplements and/or “herbal" preparations 
a Weekly monitoring of INR for patients on warfarin, however, these patients will be switched to 
enoxaparin if possible. 
b Includes BUN, creatinine, sodium, potassium, carbon dioxide, chloride, phosphorus, 
magnesium. calcium, protein, glucose. 


2009-0260 
 December 27,  2013 
Page 39 
c Includes AST (SGOT), ALT (SGPT); total, direct and indirect bilirubin; LDH, alkaline 
phosphatase, albumin; (GGT will be run for alkaline phosphatase that is >/= 150 IU/L.  GGT will 
be run with the first elevation of alkaline phosphatase and will not be repeated for future alkaline 
phosphatase elevations) 
d Alpha-feto protein. 
e CT will be the radiographic study of choice for baseline and re-staging evaluations; MRI may be 
substituted at any time in the course of the study as clinically warranted (eg iodine dye 
intolerance, elevated creatinine). At baseline, CT/MRI scans of chest/abdomen/pelvis will be 
performed. At restaging, CT/MRI scans of abdomen/pelvis will be performed and chest scan as 
needed. 
f  Treatment may be given within a 72-hour window (Cycle 1, Day 15 and subsequent treatment 
days of each cycle).  
g Treatment may continue after Course 2, including the same study assessment schedule, until 
one of the criteria for treatment discontinuation applies.   
h Every 3 months after discontinuation of study treatment until death. 
i If not done within 6 months prior to study enrollment, esophageal-gastric (EGD) endoscopy 
will be performed in patients at risk for varices based on the following:  known history of 
esophageal or gastric varices, evidence of hepatic cirrhosis and/or portal hypertension 
including biopsy-proven cirrhosis, radiographic evidence of cirrhosis, hypersplenism, or 
radiographic findings of varices.  
j 3DWLHQWVZKRKDYHDQRQJRLQJ*UDGHRUVHULRXVDGYHrse event that is at least possibly 
related to treatment will be contacted by the investigator or designee every week until the event 
is resolved or determined to be irreversible.  
k Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or dipstick every 4 weeks. A 
24-hour urine specimen will be collected if proteinuria is  Grade 3. 
l. Patients with prior exposure to systemic anthracyclines will have a baseline Multi Gated 
Acquisition (MUGA) scans or echocardiograms (ECHOs). 
m. Patients who have proteinuria  2+ and UPC ratio t 1.0 will undergo a 24 hour urine collection  
 
8.1 
POST-TREATMENT EVALUATIONS  
The visit at which a response assessment shows disease progression or 
the decision was made to discontinue treatment for other reasons, such as 
toxicity, will be considered the End of Treatment visit.  
 
After the treatment completion visit, patients will continue to be followed 
for adverse events by phone call or clinic visit as needed until at least 30 
days after the last dose of study drug.  
 
Patients who have an ongoing Grade  or serious adverse event that is 
at least possibly related to treatment will be contacted by the investigator 
or designee every week until the event is resolved or determined to be 
irreversible.  
 
Patients will be followed for survival by clinic visit, review of medical 
record, and/or telephone call every 3 months from treatment 
discontinuation date, until death. Information to be obtained will include 
post-study discontinuation HCC therapy, as available. 
 


2009-0260 
 December 27,  2013 
Page 40 
 
9.0 
SUBJECT DISCONTINUATION  
Subjects who meet the following criteria should be discontinued from 
study treatment:  
x Grade 4 hypertension or Grade 3 hypertension not controlled with 
medication 
x Nephrotic syndrome 
x Grade  2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
x Symptomatic Grade 4 venous thromboembolic event (for lung 
protocols: any venous thromboembolic event requiring full dose 
warfarin or equivalent (i.e., unfractionated or low molecular weight 
heparin)  
x Any grade arterial thromboembolic event 
x Grade 4 congestive heart failure 
x Gastrointestinal perforation  
x Tracheoesophageal fistula (any grade) or Grade 4 fistula 
x Grade  2 bowel obstruction that has not fully recovered despite 
medical or surgical intervention 
x Wound dehiscence requiring medical or surgical intervention 
x ILD 
x Grade 4 skin toxicity 
x Grade 4 diarrhea 
x Unwillingness or inability of subject to comply with study requirements 
x Determination by the investigator that it is no longer safe for the 
subject to continue therapy 
x All Grade 4 events thought to be related to study drug(s) by the 
investigator 
Patients who have an ongoing study drug -related Grade  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. 
 
 


2009-0260 
 December 27,  2013 
Page 41 
10.0 STUDY DISCONTINUATION  
If, after 14 patients are enrolled and are evaluable for PFS, the criteria for 
proceeding to the second stage of accrual are not met, the study will be 
discontinued.  Otherwise, the study will continue to the planned maximum 
accrual.   
 
11.0 STATISTICAL METHODS 
This is a single-arm phase II trial assessing the efficacy of erlotinib and 
bevacizumab in 44 patients with unresectable HCC who have progressed 
on sorafenib treatment.  
 
11.1 STUDY DESIGN 
 
44 patients evaluable for response will be included in the study. The primary 
endpoint is the binary variable progression free survival (PFS) at 16 weeks of 
treatment with the combination of bevacizumab and erlotinib.  A patient is said to 
be failure free at 16 weeks if they are alive, and their disease has not 
progressed. Success is considered stable disease or objective response by 16 
weeks of continuous treatment.  
 
This trial will follow a Simon’s two-stage design. The optimal two-stage 
design to test the null hypothesis that P<=0.350 versus the alternative that 
P>=0.550 with 80% power at one-sided alpha level of 0.05 will be used. 
After testing the drug on 14 patients in the first stage, the trial will be terminated if 
5 or fewer are alive and progression free at 16 weeks. If the trial goes on to the 
second stage, a total of 44 patients will be studied. If the total number responding 
is less than or equal to 20, the drug is rejected.  This design has an expected 
sample size of 24.78 and a probability of early termination of 0.641. If the drug is 
actually not effective, there is a 0.046 probability of concluding that it is (the 
target for this value was 0.050). If the drug is actually effective, there is a 0.200 
probability of concluding that it is not (the target for this value was 0.200).  
 
A competing risks approach will be used to analyze the secondary endpoint; 
TTP; where deaths from other causes and discontinuation due to adverse event 
will be considered competing risks. 
Other secondary endpoints of interest will include overall survival, defined as the 
time from initiation of therapy until documented disease progression or death, or 
time from initiation of therapy to death, respectively.  We will also include 
response rate, median and overall survival, toxicity and tolerability, and time to 
radiologic progression defined as time from initiation of therapy until documeted 
radiologic disease progression. These will be summarized by their corresponding 
Kaplan-Meier curves. 
 
 


2009-0260 
 December 27,  2013 
Page 42 
11.2 PLANNED EFFICACY EVALUATIONS 
11.2.1  
Primary Efficacy Variables 
The primary endpoint, PFS at 16 weeks, will be summarized by the estimated 
proportion and 95% confidence interval.  For this analysis, patients will be 
considered success if they are alive and progression free at 16 weeks; otherwise 
they will be considered failures. 
 
 
11.2.2  
Secondary Efficacy Variables 
The secondary endpoint is TTP. Time to progression is defined as the time from 
initiation of therapy until documented radiologic disease progression. 44 patients 
evaluable for response will be included in the study. A competing risks approach 
will be used to analyze TTP where deaths from other causes and discontinuation 
due to adverse event will be considered competing risks. Specifically, patients 
will be  
(a) censored if they have had neither death nor disease progression by study end 
(b) treated as a progression if they have disease progression prior to death or 
study end, or if death is due to disease 
(c) treated as a death from other cause if they have died due to a cause 
unrelated to disease 
(d) treated as an AE discontinuation if they are removed from the study due to an 
study-related AE 
Statistical methods for estimation and comparison of competing risks are well-
described.[46]  
Other secondary objectives are: response rate, median and overall survival, 
toxicity and tolerability. Overall survival will be analyzed using Kaplan-Meier 
methods. Proportions and their exact 95% confidence intervals will be estimated 
for binary outcomes (i.e., response, toxicity and tolerability). Responders will 
include complete and partial responders as defined by modified RECIST criteria.* 
 
*The original RECIST publication did not address measures of antitumor activity 
other than tumor shrinkage.[47] In 2000, however, a panel of experts convened 
by European Association for the Study of the Liver (EASL) recommended that 
the response criteria be amended to take into account tumor necrosis induced by 
treatment.[48] That panel considered estimation of the reduction in viable tumor 
area using contrast-enhanced radiological imaging to be the optimal method to 
assess treatment response. Viable tumor was defined as uptake of contrast 
agent in the arterial phase of dynamic CT or MRI. 
 
 
 
 


2009-0260 
 December 27,  2013 
Page 43 
12.0   Safety Monitoring Plan 
A number of measures will be taken to ensure the safety of patients participating 
in this trial.  These measures will be addressed through exclusion criteria and 
routine monitoring as follows. 
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals defined in the protocol during their 
participation in this study.  Safety evaluations will consist of medical interviews, 
recording of adverse events, physical examinations, blood pressure, and 
laboratory measurements.  Patients will be evaluated for adverse events (all 
grades), serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit for the duration of their 
participation in the study.  Patients discontinued from the treatment phase of the 
study for any reason will be evaluated ~30 days (28–42 days) after the decision 
to discontinue treatment. 
The P.I. will meet with the Research Nurse as necessary to discuss patients’ 
status. Any serious adverse events (SAEs) occurring in study patients will be 
reviewed by the GI Medical Oncology Department Head and clinical research 
faculty, including sub-investigators, as part of a weekly departmental Clinical 
Research Review meeting.  The PI also will present updated reports on the study 
status, including accrual, efficacy, and any safety issues, every 4-5 weeks at this 
same meeting when hepatobiliary clinical studies are reviewed.   
In the event of any significant safety concerns, the P.I. will take all action 
necessary to protect study participants, such as modifying the protocol, holding 
accrual until safety concerns are addressed, and/or discontinuing participants 
from study drugs if warranted.  
13.0 Data Confidentiality 
The Principal Investigator will take steps to guard against any loss of 
confidentiality.  The Principal Investigator and authorized research staff have 
completed training in Health Insurance Portability and Accountability Act of 1996 
(HIPAA) requirements for protection of Private Health Information (PHI).   Only 
the Principal Investigator and the authorized research staff will have access to 
the participant’s identifiable information from this study.  Data will be kept on the 
institutional password - protected computer system known as Protocol Data 
Management System (PDMS).  Employees must have clearance through the M. 
D. Anderson Cancer Center Information Services Security Department to be 
authorized as a PDMS user.  
 
Clinical trial data and results obtained during the conduct of the study will be 
made available exclusively to M. D. Anderson Cancer Center, Genentech, OSI, 
and the FDA, as appropriate and unless additional disclosure is required by law 
or court order. Data provided to Genentech and OSI will be encrypted with all 
potential personal identifiers stripped from the file.      


2009-0260 
 December 27,  2013 
Page 44 
Additionally, all clinical data and results will be collected, used, and disclosed 
consistent with all applicable federal statutes and regulations for the protection of 
human subjects including, the Standards for Privacy of Individual Health 
Information set forth in 45 C.F.R. Part 164. 
 
14.0 Reporting Requirements 
 
14.1   Serious Adverse Event Reporting (SAE) for M. D. Anderson-
Sponsored IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 

xDeath 
xA life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death. 
xInpatient hospitalization or prolongation of existing hospitalization 
xA persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
xA congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
xImportant medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
Office. 
 
xAll events occurring during the conduct of a protocol and meeting the definition 
of a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 


2009-0260 
 December 27,  2013 
Page 45 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
xAll life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.  
 
xUnless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB.  
 
xSerious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event.  
 
xAdditionally, any serious adverse events that occur after the 30 day 
time period that are related to the study treatment must be reported to 
the IND Office. This may include the development of a secondary 
malignancy. 
 
Reporting to FDA: 
 
xSerious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure 
serious adverse events are reported according to the Code of 
Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
 
14.2  Investigator Communication with Supporting Companies: 
 
All serious adverse events will be faxed (using the safety reporting fax cover 
sheet) to 
 
Genentech Drug Safety  
Fax: (650) 225-4682 or (650) 225-5288 
 
 
 


2009-0260 
 December 27,  2013 
Page 46 
 
14.3 Adverse Events Reporting (AE) 
 
Adverse events for this protocol will be recorded using the Recommended 
Adverse Event Recording Guidelines for phase II protocols. 
 
The Investigator is responsible for verifying and providing source documentation 
for all adverse events and assigning attribution for each event for all subjects 
enrolled on the trial. 
 
Adverse events will be documented in the medical record (event name, grade, 
start/stop date, and attribution) and entered into the electronic case report form 
(PDMS). 
 
 
Recommended Adverse Event Recording Guidelines  
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
Phase II 
Phase II 
Phase II 
Unlikely 
 
 
Phase II 
Phase II 
Phase II 
Possible 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Probable 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Definitive 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2009-0260 
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Page 47 
 
 
 
 
 
 
 
 
 
 
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Pang, R.W., et al., Biology of hepatocellular carcinoma. Ann Surg Oncol, 2008. 
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Fausto, N., Growth factors in liver development, regeneration and 
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Hisaka, T., et al., Expressions of epidermal growth factor family and its receptor 
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Hopfner, M., et al., Targeting the epidermal growth factor receptor by gefitinib 
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Kanematsu, M., et al., Expression of vascular endothelial growth factor in 
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Kanematsu, M., et al., Magnetic resonance imaging and expression of vascular 
endothelial growth factor in hepatocellular nodules in cirrhosis and hepatocellular 
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Wang, B., Z.Q. Gao, and X. Yan, Correlative study of angiogenesis and 
dynamic contrast-enhanced magnetic resonance imaging features of 
hepatocellular carcinoma. Acta Radiol, 2005. 46(4): p. 353-8. 
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D'Amato, R.J., et al., Thalidomide is an inhibitor of angiogenesis. Proc Natl 
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APPENDIX A:  NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES 
 
Class I 
People whose physical activity is not limited. Ordinary physical 
activity does not cause undue fatigue, heart palpitations, 
trouble breathing, or chest pain. 
Class II 
People who have some limitation on physical activity. They are 
comfortable at rest, but ordinary physical activity causes 
fatigue, heart palpitations, trouble breathing, or chest pain. 
Class III 
People who have a marked limitation on physical activity. They 
are comfortable at rest, but less-than-ordinary physical activity 
causes fatigue, heart palpitations, trouble breathing, or chest 
pain. 
Class IV 
People who are unable to carry on any physical activity without 
discomfort.  Symptoms may be present even at rest. If any 
physical activity is undertaken, discomfort is increased. 
 


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Appendix B:   
 
 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG)  
PERFORMANCE STATUS CRITERIA 
 
Grade 
Scale 
 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction (Karnofsky 90-100) 
 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, i.e., light housework, office 
work (Karnofsky 70-80) 
 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours (Karnofsky 50-
60) 
 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours (Karnofsky 30-40) 
 
 
4 
Completely disabled.  Cannot carry out any self-care.  Totally confined to 
bed or chair (Karnofsky 10-20) 
 
 
5 
Dead 
 


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APPENDIX C:  PROCEDURE FOR OBTAINING A URINE PROTEIN: 
CREATININE RATIO 
 
1)  Obtain at least 4 ml of a random urine sample (does not have to be a 24 
hour urine)  
2)  Determine protein concentration (mg/dL)  
3)  Determine creatinine concentration (mg/dL)  
4)  Divide #2 by #3 above:      urine protein / creatinine ratio = protein 
concentration (mg /dL) / creatinine concentration (mg /dL) 
 
The UPC directly correlates with the amount of protein excreted in the urine per 
24 hrs (i.e. a UPC of 1 should be equivalent to 1g protein in a 24hr urine 
collection) 
                                            
Protein and creatinine concentrations should be available on standard reports 
of urinalyses, not dipsticks. If protein and creatinine concentrations are not 
routinely reported at an Institution, their measurements and reports may need 
to be requested. 
 


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APPENDIX D  - Childs-Pugh Scale 
 
 
 
Chemical and Biochemical  
Parameters 
 
Scores (Points) for Increasing Abnormality 
 
 
1 
2 
3 
Encephalopathy 
 None 
1-2 
3-4 
Ascites 
None 
Slight 
Moderate 
Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time prolonged (sec) 
1-4 
4-6 
>6 
Bilirubin (mg/dL) 
For primary biliary cirrhosis 
 
1-2 
1-4 
2-3 
4-10 
>3 
>10 
 
 
Class A = 5-6 points; Class B = 7-9 points; Class C = 10-15 points 
 


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Appendix E:   Guide to Using Modified RECIST For Assessment of Disease 
Response 
 
The RECIST Criteria were developed and published by Therasse et al (2000) and will be 
employed in this study with modifications based on current practices of the medical 
community. 
 
Eligibility 
 
To be eligible, subjects must have at least 1 uni-dimensionally measurable lesion 
measuring  20 mm using conventional techniques (CT scan or MRI) or 10 mm using 
spiral CT scan. 
 
Measurable Lesions 
 
Measurable target lesions are defined at baseline as lesions that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 20 mm using 
conventional techniques (CT or MRI) or 10 mm using  spiral CT scan. All sites of 
disease must be evaluated. 
 
Target lesions must not be chosen from a previously irradiated field, unless there has 
been documented disease progression in that field after irradiation and prior to 
enrollment. 
 
The distribution of the target lesions should be representative of the subject’s overall 
disease. 
 
Non-Measurable Lesions 
 
All other lesions (longest diameter < 20 mm), including small lesions and other truly non-
measurable lesions are considered non-measurable and characterized as non-target 
lesions. 
 
This will include any measurable lesions beyond the maximum number of 10 that were 
not chosen as target lesions. 
 
Other examples of non-measurable lesions include bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, lymphangitis cutis/pulmonis, cystic lesions 
and groups of lesions that are small and numerous. 
 
Lesions clinically measured by the investigator, and not imaged by radiographic methods 
(ie, skin nodules and palpable lymph nodes) will automatically be considered non-target 
lesions. 
 
Method 
 
CT or MR scans will be performed at screening and during the study to evaluate tumor 
response. The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at screening and during the study. All 
measurements should be taken and recorded in metric notation (mm), using a ruler or 


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calipers. 
 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions and qualitatively assess non-target lesions selected for response assessment. 
Conventional CT (non-spiral or non-helical) and conventional MRI (MRI performed 
without fast scanning techniques) should produce images contiguously reconstructed at 
10 mm or less. Spiral (helical or multidetector CT) should product images contiguously 
reconstructed between 5 and 8 mm. 
 
Lesions on chest X-ray should be imaged by CT or MRI scan. 
 
A switch from CT to MRI (or visa versa) of the liver is considered the only acceptable 
change in modality and should not preclude response assessment if, in the judgment of 
the site radiologist, there is no significant difference in the assessment by changing 
modalities. This may occur if a subject has developed a medical contraindication to IV 
contrast for CT scan while on study. 
 
Ultrasound should not be used for assessment of visceral index lesions for the pre-study 
documentation of progressive disease in order to meet the eligibility criteria, or the on-
study assessment of response. Ultrasound can be used during the study to assess 
superficial lesions such as skin lesions, lymph nodes or masses. However, ultrasound is 
a possible alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions and thyroid nodules, or to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
 
Positron Emission Tomography (PET) with fluoro-2-deoxy-D-glucose (FDG) [FDG-PET] 
is occasionally used to assess subjects with colon cancer. However, for this study, a 
response of CR, PR, or SD will be determined by cross sectional imaging techniques 
(CR or MRI). PET will not be used or contribute to the assessment of response (CR, 
PR, or SD). 
 
If a combined FDG-PET/CT scan is performed at the discretion of the investigator, the 
CT portion of that exam should not necessarily be substituted for the dedicated CT 
exams required by this protocol. RECIST still applies. 
 
Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a subject to be considered in complete 
clinical response (ie, CR) when all lesions have disappeared. 
 
Baseline Documentation of “Target” and “Non-Target” Lesions 
 
Screening (baseline) images will be used to prospectively identify all sites of disease 
present at the start of treatment. Sites of disease will be characterized as either target 
or non-target lesions. 
 
Up to 10 target lesions (a maximum of 5 per organ) will be chosen to measure over the 
course of therapy. The distribution of these target lesions should be representative of 
the subject’s overall disease status. 
 
Target lesions should be selected on the basis of their size (20 mm in the longest 
dimension using CT or MRI) and suitability for accurate repeated measurements by 


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imaging techniques. 
 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
All other lesions (or sites of disease), including any measurable lesions that were not 
chosen as target lesions, should be identified as non-target lesions and should also be 
recorded and assessed qualitatively over the course of therapy. 
 
Evaluation of Overall Response: 
 
The subject response will be assessed based on the response of the target lesions, the 
response of the non-target lesions and the presence or absence of new lesions. The 
convention will be used that if a lesion being measured decreases in size to 5 mm in 
the LD, a value of 5 mm will be assigned. If the lesion subsequently increases in size to 
5 mm in one dimension, its true size will be recorded. 
 
The following criteria as outlined in Table 1 and 2 will be used to assess tumor response 
in the target and non-target lesions, respectively 
 
 
 
 
Table 1. Evaluation of Target Lesions at Each Assessment Point 
 
 
 
 
 
 
 
 
 


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Table 2. Evaluation of Non-target Lesions at Each Assessment Point 
 
 
 
 
The following criteria as outlined in Table 3 will be used to assess the subject’s overall 
disease status based on target and non-target lesions and the presentation of a new 
lesion(s) since the last assessment.