Clinical trial NCT00780494
Conditions: Stomach Cancer Gastric (Stomach) Cancer Neoplasm of Cardioesophageal Junction Gastrointestinal Stromal Tumor (GIST)
Sponsor: Stanford University
Start date: 2009-02-01; Completion date: 2017-12-31
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To investigate bevacizumab in combination with carboplatin and capecitabine for patients with unresectable or metastatic GEJ or gastric cancers. We hope that by adding bevacizumab to standard chemotherapy for this patient population we will improve Progression Free Survival by 90% over historical controls.

Detailed description:
Primary Objectives:

To investigate if the addition of Bevacizumab to standard chemotherapy for metastatic or unresectable GEJ and gastric adenocarcinoma will improve PFS by 90% over historical controls.

Secondary Objectives:

* Assess toxicities using CTCAE v3.0
* Evaluate overall survival (OS) using Kaplan-Meier analysis
* Evaluate objective response rate (RR) by RECIST criteria
* Explore biomarkers of tumor response: CEA, CA 19.9, and serum VEGF
* Bank serum and tissue for future correlative studies
* Evaluate CT Perfusion to predict early therapeutic response to combination chemotherapy and anti-angiogenic therapy (OPTIONAL).

Arms: arm 1: Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Interventions: intervention 1: bevacizumab intervention 2: carboplatin intervention 3: capecitabine
Intervention descriptions: intervention 1: Intravenous 15 mg/kg intervention 2: AUC 6, Intravenously Day 1 every 21 days intervention 3: 850mg/m2, Orally twice daily days 1-14 every 21 days.

Protocol documents:
Prot_SAP_000.pdf: 
Kunz/Fisher: Phase II Cap-Carbo-Bev for Metastatic or Unresectable GEJ and Gastric Adenocarcinomas 
 
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A Phase II Study of Capecitabine, Carboplatin, and Bevacizumab for 
Metastatic or Unresectable Gastroesophageal Junction and Gastric 
Adenocarcinoma 
 
Principal Investigator: 
 
Pamela L. Kunz, MD 
 
 
 
 
 
Stanford Cancer Center  
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA 94305 
 
 
 
 
 
pkunz@stanford.edu 
 
 
Co-Investigators: 
 
 
George A. Fisher, MD, PhD 
 
 
 
 
 
Stanford Cancer Center  
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA 94305 
 
 
 
 
 
650-725-9057 
 
 
 
 
 
georgeaf@stanford.edu 
 
James M. Ford, MD 
 
 
Stanford University Medical Center 
 
 
269 Campus Drive West, CCSR-South, Rm 1245C 
 
 
 
Stanford, CA 94305-5152 
 
 
 
jmf@stanford.edu 
 
Aya Kamaya, MD 
Stanford University School of Medicine 
Department of Radiology 
300, Pasteur Drive, Rm H1307 
Stanford, CA 94305-5105 
                                                      kamaya@stanford.edu 
 
 
 
NCT00780494 
DATE: 7Mar2013 
 
 
 
 
Statistician: 
 
Alex McMillan, PhD 
 
 
Stanford University 
Biostatistics, Health Research and Policy 
259 Campus Drive, HRP Redwood Building 
Stanford, CA 94305-5405 
alexmcm@stanford.edu 


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Research Coordinators: 
 
Prachi Nandoskar 
 
 
Stanford Cancer Center 
 
 
800 Welch Road 
 
 
Palo Alto, CA 94304 
 
 
650-725-0438 
 
 
prachin@stanford.edu 
 
 
 
Flordeliza Mendoza 
 
 
Stanford Cancer Center 
 
 
800 Welch Road 
 
 
Palo Alto, CA 94304 
 
 
650-721-3114 
 
 
flormend@stanford.edu 
 
                                                       Vilay Khandelwal 
                                                       Stanford Cancer Center 
                                                       800 Welch Road 
                                                       Palo Alto, CA 94304 
                                                       650- 724-9057 
                                                       vilayk@stanford.edu 
  
 
 
 
 
Protocol Version Date: 
 
Version 1.11 03/07/2013 
Support Provided by Genentech, Inc. 


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PROTOCOL SYNOPSIS 
A Phase II Study of Capecitabine, Carboplatin, and Bevacizumab for Metastatic or 
Unresectable Gastroesophageal Junction and Gastric Adenocarcinomas 
 
Principal Investigator: 
 
Pamela Kunz, M.D. 
 
Assistant Professor of Medicine (Oncology) 
 
Stanford University School of Medicine 
 
875 Blake Wilbur Drive 
 
Stanford, CA 94305-5820 
 
Phone (650) 725-1755 
 
Fax (650) 736-8092 
 
pkunz@stanford.edu 
Sub Investigator:  
George Fisher, M.D., PhD 
 
Associate Professor of Medicine (Oncology) 
 
Stanford University School of Medicine 
 
875 Blake Wilbur Drive 
 
Stanford, CA 94305-5151 
 
Phone (650) 725-6427 
 
Fax (650) 736-1454 
 
georgeaf@stanford.edu 
 
 
 
Study Center: Stanford University Medical Center 
 
 
Number of subjects planned: 35 
 
Planned accrual:  
 2 patients per month with enrollment complete in 18 months. 
 Median time on study estimated at 6 months. 
 Median follow-up at time of study completion estimated at 12 months. 
 
Objectives 
Primary Objectives 
 To investigate if the addition of Bevacizumab to standard chemotherapy for 
metastatic or unresectable GEJ and gastric adenocarcinoma will improve PFS by 
90% over historical controls.   
 
Secondary Objectives 
 To assess toxicities using CTCAE v3.0 
 To evaluate overall survival (OS) using Kaplan-Meier analysis 
 To evaluate objective response rate (RR) by RECIST criteria 


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 To explore biomarkers of tumor response: CEA, CA 19.9, and serum VEGF 
 To bank serum and tissue for future correlative studies 
 To evaluate CT Perfusion to predict early therapeutic response to combination 
chemotherapy and anti-angiogenic therapy (OPTIONAL). 
 
 
Study Design 
We propose a single-institution, phase II, single-arm, non-randomized study 
investigating bevacizumab in combination with carboplatin and capecitabine for patients 
with unresectable or metastatic GEJ or gastric cancers as first-line metastatic therapy.  
Treatment will be given every 21 days as per the schema outlined below.  Patients will 
receive CT scans at baseline and after every 3 cycles (approximately 9 weeks) and be 
evaluated by RECIST criteria.  We estimate that most patients will complete between 3-
6 cycles of treatment.  If, after 3 cycles, patients develop significant toxicities attributed 
to either carboplatin (cytopenias, >2 dose reductions) and/or capecitabine (diarrhea, 
hand-foot syndrome) patients may discontinue either carboplatin and/or capecitabine 
and continue receiving .  Upon documentation of first disease progression by RECIST 
criteria, the patient will either restart the original schedule of capecitabine, carboplatin, 
and  or be discontinued from the study, at the investigator’s discretion.  We will continue 
treatment indefinitely until one of the following occurs: patient withdraws consent and 
decides to discontinue study treatment, development of unacceptable toxicities, or 
evidence for second disease progression (after restarting original schedule as above).  
The patient may withdraw from the study at any time. 
 
 
Target Subject Population: 
Patients with histologically confirmed adenocarcinomas of the gastroesophageal 
junction (GEJ) or stomach which are deemed unresectable or metastatic will be eligible 
for enrollment in this study.  Patients receiving prior treatment for metastatic disease 
and/or prior anti-VEGF therapy will be excluded from the study. 
 
Investigational Products, Dosage and Mode of Administration: 
Capecitabine:  850 mg/m2 PO BID days 1-14 (21-day cycle)  
Carboplatin: AUC 6 IV day 1 (21-day cycle) 
Bevacizumab: 15 mg/kg IV day 1 (21-day cycle) 
 
Duration of Treatment: 
Screening 
Evaluation 
R 
E 
G 
I 
S 
T 
E 
R 
Bevacizumab 15 mg/kg IV day 1 
Carboplatin AUC 6 IV day 1 
Capecitabine 850 mg/m2 PO days 1-14 
Cycle = 21 days 
Continue Treatment until  
Progression 


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Each cycle lasts 21 days.  Patients will continue on treatment until one of the following 
occurs: 
 Patient chooses to withdraw from study 
 Unacceptable toxicity occurs 
 Evidence of progressive disease by RECIST criteria  
 
Safety: 
Safety assessments will consist of routine and frequent monitoring and recording of all 
adverse events and serious adverse events, regular monitoring of hematology and 
serum chemistry, coagulation tests, urinalysis, regular measurement of vital signs, 
weight, WHO Performance Status and the performance of physical examination.  The 
toxicities experienced by each patient on the study, and the study’s overall progress, will 
be reviewed weekly by the Stanford University Developmental Therapeutics Meeting, 
chaired by Drs. Branimir Sikic and George Fisher. 
 
Statistical Methods: 
Data from Kang, et al1 show that in patients with advanced gastric cancer treated with 
cisplatin and capecitabine the 6-month progression-free survival (PFS) rate is 50% and 
the 12-month rate is 24% which we will use as our historical control.  We propose a trial 
of 35 patients with PFS as the primary endpoint and a therapeutic target of increasing 
the 12-month PFS by 90% to a rate of 46%.  If the target is met, there is 80% probability 
(power) that the 95% lower confidence for PFS at 12-month will lie above the historical 
rate of 24%.  
 
PFS curves will be generated using Kaplan-Meier method and compared to historical 
controls using a z-test with Greenwood formula.  OS will also be generated using 
Kaplan-Meier method.  RR will be estimated with a binomial confidence interval.  CEA 
will be summarized (mean, standard deviation, median, range) at each time point and 
then compared with PFS using a log rank test. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................................................. 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................................... 10 
1.0 
BACKGROUND ............................................................................................................................................ 12 
1.1 
DISEASE BACKGROUND ................................................................................................................................. 12 
1.2 
BEVACIZUMAB CLINICAL EXPERIENCE ........................................................................................................... 12 
1.3 
CAPECITABINE AND CARBOPLATIN CLINICAL EXPERIENCE ............................................................................ 16 
1.4 
STUDY RATIONALE ......................................................................................................................................... 17 
1.5 
CORRELATIVE STUDIES BACKGROUND .......................................................................................................... 18 
2.0 
OBJECTIVES ................................................................................................................................................. 19 
2.1 
PRIMARY ........................................................................................................................................................ 19 
2.2 
SECONDARY ................................................................................................................................................... 19 
3.0 
STUDY DESIGN ............................................................................................................................................ 19 
3.1 
DESCRIPTION OF STUDY ................................................................................................................................ 19 
3.2 
RATIONALE FOR STUDY DESIGN .................................................................................................................... 20 
3.3  
OUTCOME MEASURES .............................................................................................................................. 21 
3.3.1 
Primary Outcome Measures ................................................................................................................ 21 
3.3.2 
Secondary Outcome Measures ............................................................................................................ 21 
3.3.3 
Safety Outcome Measures................................................................................................................... 21 
3.3.4 
Correlative Outcome Measures ........................................................................................................... 21 
4.0 
SAFETY PLAN .............................................................................................................................................. 22 
4.1 
GENERAL PLAN TO MANAGE SAFETY ............................................................................................................ 22 
4.1.1 Bevacizumab-Specific ................................................................................................................................ 22 
4.1.2  
Capecitabine-Specific ........................................................................................................................... 22 
4.1.3  
Carboplatin-Specific ............................................................................................................................. 22 
4.2 
DEFINITION OF A DOSE LIMITING TOXICITY (DLT) ......................................................................................... 23 
5.0 
STUDY SUBJECTS ......................................................................................................................................... 24 
5.1 
SUBJECT SELECTION ....................................................................................................................................... 24 
5.2 
INCLUSION CRITERIA ..................................................................................................................................... 24 
5.3  
EXCLUSION CRITERIA ................................................................................................................................ 26 
6.0 
STUDY MEDICATION ................................................................................................................................... 28 
6.1 
BEVACIZUMAB ............................................................................................................................................... 28 
6.1.1 
Bevacizumab Dosage and Formulation ................................................................................................ 28 
6.1.2 
Bevacizumab Administration ............................................................................................................... 28 
6.1.3 
Bevacizumab Storage ........................................................................................................................... 29 
6.1.4 
Bevacizumab Dose Modification and Toxicity Management ............................................................... 29 


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6.2 
CAPECITABINE ............................................................................................................................................... 32 
6.2.1 
Capecitabine Administration ............................................................................................................... 32 
6.2.2 
Capecitabine Storage ........................................................................................................................... 33 
6.2.3 
Capecitabine Drug Interactions ........................................................................................................... 33 
6.2.4 
Capecitabine Dose Modification and Toxicity Management ............................................................... 33 
6.3 
CARBOPLATIN ................................................................................................................................................ 36 
6.3.1 
Carboplatin Administration ................................................................................................................. 36 
6.3.2  
Carboplatin Dose Modification and Toxicity Management ................................................................. 36 
6.4      GENERAL DOSE MODIFICATIONS .................................................................................................................. 37 
6.5 
CONCOMITANT MEDICATIONS ...................................................................................................................... 37 
7.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................................................... 38 
7.1 
STUDY SCHEDULE .......................................................................................................................................... 38 
7.2 
PRE-TREATMENT EVALUATIONS ................................................................................................................... 38 
7.3 
EVALUATIONS DURING TREATMENT ............................................................................................................. 39 
7.4 
POST-TREATMENT EVALUATIONS ................................................................................................................. 39 
8.0 
CORRELATIVE/SPECIAL STUDIES ................................................................................................................. 40 
8.1 
SERUM VEGF ................................................................................................................................................. 40 
8.2 
CT PERFUSION (OPTIONAL) ........................................................................................................................... 40 
9.0 
STUDY TREATMENT DISCONTINUATION ..................................................................................................... 41 
10.0 
STUDY FOLLOW UP ................................................................................................................................ 41 
11.0 
STATISTICAL METHODS .......................................................................................................................... 42 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................................... 42 
11.2 
PLANNED EFFICACY EVALUATIONS ........................................................................................................... 42 
11.2.1 
Primary Efficacy Variables ............................................................................................................... 42 
11.2.2 
Secondary Efficacy Variables ........................................................................................................... 42 
11.2.3 
Methods of Analysis ........................................................................................................................ 42 
Definitions of Other Efficacy Markers ..................................................................................................................... 45 
12.0 
SAFETY REPORTING OF ADVERSE EVENTS .............................................................................................. 46 
12.1 
GENERAL ................................................................................................................................................... 46 
12.2 
BEVACIZUMAB-SPECIFIC ........................................................................................................................... 46 
12.2.1 
Adverse Event Reporting and Definitions ....................................................................................... 46 
12.2.2 
Reporting of Serious Treatment Emergent Adverse Events ........................................................... 47 
13.0 
RETENTION OF RECORDS ........................................................................................................................ 48 
14.0 
REFERENCES/BIBLIOGRAPHY .................................................................................................................. 49 
15.0 
APPENDICES ........................................................................................................................................... 51 
APPENDIX A:  STUDY FLOW CHART/SCHEMA ......................................................................................................... 51 


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APPENDIX B: INFORMED CONSENT......................................................................................................................... 51 
APPENDIX C:  CURRENT NCI COMMON TOXICITY CRITERIA Version 3.0 ................................................................. 51 
APPENDIX D: FDA MEDWATCH 3500a FORM ......................................................................................................... 51 
APPENDIX E: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES ...................................................................... 51 
APPENDIX F Procedure for obtaining a urine protein : creatinine ratio .................................................................. 52 
APPENDIX G Formulas for Carboplatin dose calculation ........................................................................................ 53 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
ADL 
Activities of daily living 
AE 
Adverse event 
ALT/SGPT 
Alanine transaminase/Serum glutamate pyruvate transaminase 
ANC 
Absolute neutrophil count 
AST/SGOT 
Aspartate transaminase/Serum glutamic oxaloacetic transaminase 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete Blood Count 
CI 
Confidence interval 
Cmax 
Maximum concentration of drug 
CNS 
Central Nervous System 
CRC 
Colorectal cancer 
CRF 
Case Report/Record Form 
CR 
Complete response  
CrCl 
Creatinine Clearance 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EGFR 
Epidermal growth factor receptor 
5-FU 
5-Fluorouracil 
G-CSF 
Granulocyte colony-stimulating factor (filgrastim) 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field 
HTN 
Hypertension 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
LLN 
Lower limit of normal 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival  
PLT 
Platelet 
PO 
Per os/by mouth/orally 
PD 
Progressive disease  


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PFS 
Progression free survival  
PR 
Partial response  
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
Once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate  
SAE 
Serious adverse event 
SD 
Stable disease  
TTP 
Time to progression  
ULN 
Upper Limit of Normal 
UNK 
Unknown 
VEGF 
Vascular Endothelial Growth Factor 
VEGF-R 
Vascular Endothelial Growth Factor Receptor 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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1.0 
BACKGROUND 
1.1 
DISEASE BACKGROUND 
Gastroesophageal junction (GEJ) and gastric adenocarcinomas constitute a 
major health problem worldwide.  Gastric cancer is the fourth most prevalent 
malignancy and the second leading cause of cancer death worldwide2.  In the 
United States, an estimated 22,280 cases of gastric cancer were diagnosed and 
11,260 patients died from this disease in 20063.  Esophageal cancer is overall 
less common, but the incidence of adenocarcinoma of the esophagus, GEJ and 
gastric cardia has risen faster than any other malignancy in the last 25 years in 
the United States and other Western countries4.   
 
Although treatment for patients with unresectable or metastatic disease remains 
palliative, chemotherapy improves survival and quality of life when compared to 
best supportive care5.  With standard treatment options, the median time to 
progression for unresectable or metastatic disease is 4 to 6 months and median 
overall survival is 7 to 10 months.   
 
We propose a single-institution, phase II, single-arm, non-randomized study 
investigating bevacizumab in combination with carboplatin and capecitabine for 
patients with unresectable or metastatic GEJ or gastric cancers. We hope that by 
adding bevacizumab to standard chemotherapy for this patient population we will 
improve PFS by 90% over historical controls.   
 
 
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. 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 arm versus the chemotherapy only arm (Bevacizumab Investigator 
Brochure, October 2005). 


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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.  
 
a. 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), gastrointestinal perforations, 
gallbladder 
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: Hypertension has been commonly seen in bevacizumab clinical 
trials to date and oral medications have been used to manage the hypertension 
when indicated. Grade 4 and 5 hypertensive events are rare. Clinical sequelae of 
hypertension are rare but have included hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leukoencephalopathy syndrome 
(RPLS) (Ozcan et al., 2006; Glusker et al., 2006). RPLS may include signs and 
symptoms of headache, altered mental function, seizures, and visual 
disturbances / cortical blindness and requires treatment, which should include 
control of hypertension, management of specific symptoms, and discontinuation 
of bevacizumab. 
Proteinuria: Proteinuria has been commonly seen in bevacizumab clinical trials 
to date. The severity of proteinuria has ranged from asymptomatic and transient 
events detected on routine dipstick urinalysis to nephrotic syndrome; the majority 
of proteinuria events have been grade 1 or 2. In study AVF2107g, none of the 
118 patients receiving bolus-IFL plus placebo, three of 158 patients (2%) 
receiving bolus-IFL plus bevacizumab, and two of 50 (4%) patients receiving 5-
FU/LV plus bevacizumab who had a 24-hour collection experienced grade 3 
proteinuria (> 3.5 g protein/24 hr). Rare events of nephrotic syndrome have 
occurred, and bevacizumab should be discontinued in patients with nephrotic 
syndrome.  
Thromboembolic Events: Both venous and arterial thromboembolic (TE) 
events, ranging in severity from catheter-associated phlebitis to fatal, have been 
reported in patients treated with bevacizumab in the colorectal cancer trials and, 
to a lesser extent, in patients treated with bevacizumab in NSCLC and breast 
cancer trials. In the phase III pivotal trial in metastatic CRC, there was a slightly 
higher rate of venous TE events that was not statistically significant in patients 
treated with bevacizumab plus chemotherapy compared with chemotherapy 
alone (19% vs. 16%). There was also a higher rate of arterial TE events (3% vs. 
1%) such as myocardial infarction, transient ischemia attack, cerebrovascular 


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accident/stroke and angina/unstable angina. A pooled analysis of the rate of 
arterial TE events from 5 randomized studies (1745 patients) showed that 
treatment with chemotherapy plus bevacizumab increased the risk of having an 
arterial TE event compared with chemotherapy alone (3.8% vs. 1.7%, 
respectively) (Skillings et al., 2005). Furthermore, subjects with certain baseline 
characteristics (age ≥ 65 years and/or a history of a prior arterial TE event) may 
be at higher risk of experiencing such an event. . See the bevacizumab 
Investigator Brochure for additional information on risk factors. 
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 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 when treated 
with bevacizumab and chemotherapy. Bevacizumab should be permanently 
discontinued in patients who develop gastrointestinal perforation. A causal 
association of intra-abdominal inflammatory process and gastrointestinal 
perforation to bevacizumab has not been established. Nevertheless, caution 
should be exercised when treating patients with intra-abdominal inflammatory 
processes with bevacizumab. Gastrointestinal perforation has been reported in 
other trials in non-colorectal cancer populations (e.g., ovarian, renal cell, 
pancreas, and breast) and may be higher in incidence in some tumor types. 
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 20 days. Bevacizumab should be discontinued in 
patients with severe wound healing complications. 


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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 – was observed in phase I and phase II 
bevacizumab studies. Six serious events, of which 4 had fatal outcome, were 
observed in a phase II trial of patients with non-small cell lung cancer receiving 
bevacizumab. These events occurred suddenly and presented as major or 
massive hemoptysis in patients with either squamous cell histology and/or 
tumors located in the center of the chest in close proximity to major blood 
vessels. In five of these cases, these hemorrhages were preceded by cavitation 
and/or necrosis of the tumor. Tumor-associated hemorrhage was also seen 
rarely in other tumor types and locations, including central nervous system (CNS) 
bleeding in a patient with hepatoma with occult CNS metastases and continuous 
oozing of blood from a thigh sarcoma with necrosis.  
Across all bevacizumab clinical trials, mucocutaneous hemorrhage has been 
seen in 20%-40% of patients treated with bevacizumab. These were most 
commonly 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.  
Congestive heart failure: CHF has been reported in bevacizumab clinical trials 
and may be increased in incidence in patients with prior exposure to 
anthracyclines or prior irradiation to the chest wall. In a phase III trial (AVF2119g) 
of capecitabine with or without bevacizumab for metastatic breast cancer, 7 
subjects (3.1%) who received capecitabine plus bevacizumab developed 
clinically significant CHF compared with 2 subjects (0.9%) treated with 
capecitabine alone; of note, all subjects in this trial had had prior anthracycline 
treatment. In addition, 2 subjects had a left ventricular ejection fraction < 50% at 
baseline and 2 others had prior left chest wall irradiation. A recently published 
phase II study in subjects with refractory acute myelogenous leukemia reported 5 
cases of cardiac dysfunction (CHF or decreases to <40% in left ventricular 
ejection fraction) of 48 subjects treated with sequential cytarabine, mitoxantrone, 
and bevacizumab. All but one of these subjects had significant prior exposure to 
anthracyclines as well (Karp et al., 2004). Other studies are ongoing in this 
patient population. Patients receiving anthracyclines or with prior exposure to 
anthracyclines should have a baseline MUGA or ECHO with a normal ejection 
fraction. 
Fistulae: Patients may be at increased risk for the development of fistulae when 
treated with bevacizumab. A recent review revealed that most fistulae were 
involving the GI tract. Among fistulae forms not involving the GI tract, the only 
fistula event that was not consistent with what would be expected, either by 


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indication or reporting rate, is tracheoesophageal (TE) fistulae in the small cell 
lung cancer population.  The incidence of GI fistulae and abscess is a 
bevacizumab ADR of “common” incidence (<2%) in mCRC with the majority of 
events being of gastrointestinal or genitourinary in nature. It should be noted that 
most of the patients have significant risk factors that would increase the chance 
of fistula formation even if they were not receiving bevacizumab. Although 
fistulae formation is higher with bevacizumab in combination with chemotherapy 
than with chemotherapy alone, these patients often have multiple risk factors for 
developing fistulae. Surgery, radiotherapy, and carcinomatosis all predispose 
both bevacizumab-treated and non–bevacizumab-treated patients to fistula 
formation. Bevacizumab will be discontinued in patients with TE fistulae or any 
Grade 4 fistula. 
 
Ovarian Failure: The incidence of new cases of ovarian failure (defined as 
amenorrhoea lasting 3 or more months, FSH level≥30 mIU/mL and a negative 
serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 
women receiving mFOLFOX chemotherapy alone (n=84 or with bevacizumab 
(n=95). New cases of ovarian failure were identified in 34% (32/95) of women 
receiving bevacizumab in combination with chemotherapy compared with 2% 
(2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 
53)]. After discontinuation of bevacizumab treatment, recovery of ovarian function 
at all time points during the post-treatment period was demonstrated in 22% 
(7/32) of the bevacizumab-treated women. Recovery of ovarian function is 
defined as resumption of menses, a positive serum β-HCG pregnancy test, or a 
FSH level < 30 mIU/mL during the post-treatment period. Repeat dose safety 
studies in animals have shown that bevacizumab may have an adverse effect on 
female fertility. Long term effects of the treatment with bevacizumab on fertility 
are unknown. The risk of ovarian failure will be informed to female with 
reproductive potential and fertility preservation strategies will be discussed prior 
to starting treatment with bevacizumab. 
Additional Adverse Events: See the bevacizumab Investigator Brochure for 
additional details regarding the safety experience with bevacizumab. 
 
1.3 
CAPECITABINE AND CARBOPLATIN CLINICAL EXPERIENCE 
There is no formal consensus or evidence-based rationale regarding the best 
chemotherapy regimen for advanced GEJ and gastric cancer.  However, 5-FU 
has been the backbone of therapy.  Parenteral 5-FU has been used since the 
1980’s to treat advanced GEJ and gastric cancers.  In the 1990s, a Phase III trial 
by Kim, et al6 demonstrated that 5-FU in combination with cisplatin (FP) had 
improved response rates when compared with 5-FU monotherapy and 
combination therapy with 5-FU, doxorubicin and mitomycin (FAM), although 
overall survival did not differ.  Similarly, an EORTC study by Vanhoefer, et al7 
demonstrated a trend towards increased response rates with FP compared with 


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5-FU, doxorubicin and methotrexate (FAMTX) and etoposide, leucovorin, and 
bolus 5-FU (ELF). 
 
Capecitabine is an oral fluoropyrimidine that mimics continuous infusion 5-FU 
and has since replaced it in the treatment of many gastrointestinal malignancies.  
The conversion to 5-FU is dependent on the enzyme thymidine phosphorylase, 
which is more highly expressed in tumor tissue than healthy tissue resulting in 
the preferential generation of 5-FU at the tumor site8.   
 
Capecitabine is currently approved in the United States for treatment of 
advanced breast and colorectal cancers and in South Korea for treatment of 
advanced gastric cancers.  Some recent Phase II studies have evaluated the 
safety and efficacy of capecitabine with cisplatin as first-line treatment of 
advanced gastric cancer9-10 and recurrent gastric cancer after fluoropyrimidine-
based adjuvant therapy1.  These studies demonstrated that the combination of 
capecitabine and cisplatin was well tolerated and active, with TTP and OS 
equivalent to standard treatments.   
 
Carboplatin is a second generation platinum analogue and has been associated 
with greater convenience of administration and a more favorable toxicity profile 
compared to cisplatin.  Capecitabine has also been studied in combination with 
the newer platinum agents, carboplatin11 and oxaliplatin12, for the treatment of 
advanced gastric cancer; these regimen have also demonstrated equivalent 
safety and efficacy profiles compared to standard treatments. 
 
The combination of carboplatin and capecitabine for metastatic upper GI cancer 
has been used at our institution and found to have acceptable toxicity and 
promising anti-tumor activity (retrospective data forthcoming).   
 
1.4 
STUDY RATIONALE 
Bevacizumab in combination therapies is approved for use in the metastatic 
setting for colorectal13, breast14, and lung cancers15-16.  Bevacizumab in 
combination with other standard chemotherapies for the treatment of upper 
gastrointestinal tract adenocarcinomas has shown some early promising data.  A 
Phase II study of irinotecan, cisplatin, and bevacizumab in patients with 
metastatic gastric or GEJ adenocarcinoma showed improvements in time to 
progression and overall survival compared to historical controls and was well 
tolerated17.   
 
Given the lack of other viable treatment options for metastatic and unresectable 
GEJ and gastric adenocarcinoma, contrasted with our positive anecdotal 
experience, we propose a single-institution phase II trial investigating the efficacy 
of capecitabine, carboplatin and bevacizumab for patients with metastatic GEJ 
and gastric adenocarcinoma. 


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1.5 
CORRELATIVE STUDIES BACKGROUND 
 Blood-based assays of angiogenic response. 
 CT Perfusion:  
Perfusion computed tomography (CT) imaging has been established for many 
years in stroke imaging. With the introduction of multi-detector row CT 
technology increasing substantially the spatial and temporal resolution as well 
as offering new detector array configurations, CT perfusion imaging has 
become feasible for assessment of tumor perfusion in applications outside the 
brain, including the abdomen. Recent studies indicate that perfusion CT can 
be performed successfully in patients with gastric cancer.18-19 Different 
parameters of tumor perfusion have been assessed in patients with gastric 
cancer and compared to normal gastric tissue including blood flow (BF), blood 
volume (BV), mean transit time (MTT), time to peak (TTP), permeability 
surface, and volume transfer constant (Ktrans). The implications of those 
parameters on grade of tumor vascularization, correlation with ex vivo 
parameters of angiogenesis including microvessel density (MVD), or 
expression profiles of molecular markers of tumor angiogenesis such as 
vascular endothelial growth factor receptor (VEGFR) or integrins in gastric 
cancer still need to be assessed. However, a recent study in patients with 
pancreatic endocrine tumors undergoing preoperative perfusion CT has 
shown high correlation between the tumor BV parameter as assessed by 
perfusion CT and ex vivo MVD analysis, as well as histoprognostic factors 
such as proliferation index and WHO classification obtained from tumor 
samples.20 Another recent study in patients with locally advanced pancreatic 
cancer has shown that the parameter Ktrans may be a valuable quantitative 
biomarker for predicting favorable treatment response to concurrent 
chemotherapy and radiotherapy.21 
 
Although the technique of CT perfusion is still evolving and the value of 
different perfusion parameters in different tumor types still warrants further 
evaluation, the use of perfusion CT as a non-invasive biomarker to determine 
treatment response following the application of the vascular disruptive agent 
ASA404 in gastric cancer patients is intriguing. CT imaging in general is a 
robust, widely available imaging technology that has been used for cancer 
imaging for several decades. It is the preferred imaging modality due to its 
reliability, comparability and robustness. Since the perfusion analysis part of 
the CT examination can be easily integrated into current CT imaging 
protocols, there is no need to schedule another exam for a dedicated 
perfusion exam at the standard baseline and follow-up CT scans in cancer 
patients. 
 
In this phase II protocol using capecitabine, carboplatin and bevacizumab for 
metastatic or unresectable gastroesophageal junction or gastric 
adenocarcinoma we propose to include CT perfusion imaging as an optional 
part of the regular CT imaging protocol in patients with gastric cancer. The CT 


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perfusion part can be included into the standard baseline and 9-week follow-
up CT scan.  This will not require any additional imaging or radiation 
exposure. 
 
 
 
 
 
         
2.0 
OBJECTIVES 
 
2.1 
PRIMARY 
 To investigate if the addition of bevacizumab to standard chemotherapy for 
unresectable and metastatic and GEJ and gastric adenocarcinoma will 
improve PFS by 90% over historical controls.   
 
2.2 
SECONDARY 
 To assess toxicities using CTCAE v3.0 
 To evaluate overall survival (OS) using Kaplan-Meier analysis 
 To evaluate objective response rate (RR) by RECIST criteria 
 To explore biomarkers of tumor response: CEA, CA 19.9, and serum VEGF 
 To bank serum and tissue for future correlative studies 
 To evaluate CT Perfusion as a tool to predict early therapeutic response to 
combination chemotherapy and anti-angiogenic therapy. (participation in this 
secondary objective is optional) 
 
3.0 
STUDY DESIGN  
3.1 
DESCRIPTION OF STUDY 
We propose a single-institution, phase II, single-arm, non-randomized study 
investigating bevacizumab in combination with carboplatin and capecitabine for 
patients with unresectable or metastatic GEJ or gastric cancers as first-line 
metastatic therapy.   
 
All enrolled patients will receive bevacizumab 15 mg/kg intravenously followed by 
carboplatin AUC 6 intravenously on day 1 of a 21 day cycle.  Patients will receive 
capecitabine 850 mg/m2 twice daily by mouth on days 1-14, followed by a one 
week break.   Patients will be assessed by clinical and laboratory exam at least 
once per cycle (more frequently as needed) and dose reductions will be allowed 


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for unacceptable toxicity.  Please note that patients may be seen within a 3 day 
window of the assigned study visit (within 3 days before or 3 days after).  
Patients will be assessed for response by CT imaging once every 3 cycles 
(approximately every 9 weeks), or until symptoms suggestive of progressive 
disease arise. 
 
Standard anti-emetics will be administered to include a 5HT3 antagonist with 
each dose of chemotherapy.  In the event of an infusion reaction with 
bevacizumab, subsequent doses may be premedicated with diphenhydramine 
and/or steroid medications.   
 
We estimate that most patients will complete between 3-6 cycles of treatment.  If, 
after 3 cycles, patients develop significant toxicities attributed to either 
carboplatin (cytopenias, >2 dose reductions) and/or capecitabine (diarrhea, 
hand-foot syndrome) patients may discontinue either carboplatin and/or 
capecitabine and continue receiving bevacizumab.  Upon documentation of first 
disease progression by RECIST criteria, the patient will either restart the original 
schedule of capecitabine, carboplatin, and bevacizumab or be discontinued from 
the study, at the investigator’s discretion.  We will continue treatment indefinitely 
until one of the following occurs: patient withdraws consent and decides to 
discontinue study treatment, development of unacceptable toxicities, or evidence 
for second disease progression (after restarting original schedule as above).  The 
patient may withdraw from the study at any time. 
If patients with unresectable primary disease have an objective response, they 
will be referred to surgery for possible resection. 
 
The schema is shown below: 
 
 
With a planned accrual of 2 patients per month we plan to complete enrollment in 
18 months.  Median time on study will be estimated to be 6 months, and median 
follow-up at the time of study completion is estimated to be 12 months. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
Screening 
Evaluation 
R 
E 
G 
I 
S 
T 
E 
R 
Bevacizumab 15 mg/kg IV day 1 
Carboplatin AUC 6 IV day 1 
Capecitabine 850 mg/m2 PO days 1-14 
Cycle = 21 days 
Continue Treatment until  
Progression 


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Our planned doses, Carboplatin AUC 6 given IV every 21 days and Capecitabine 
850 mg/m2 PO BID days 1-14 repeated every 21 days, are standard dosing 
regimen in GI and other malignancies. 
 
The study by Shah, et al17 in metastatic gastric and gastroesophageal junction 
adenocarcinoma, and other studies in lung15-16 and metastatic colorectal22 have 
all used a bevacizumab dose of 5 mg/kg/week IV dose.  The study in non-small 
call lung cancer by Johnson, et al did not find a significant difference in toxicity 
profiles between a 7.5 mg/kg and 15 mg/kg dose and found a trend towards 
improved time to progression with the higher dose.  Overall, across studies, no 
dose related adverse events have occurred.  We will also use the 5 mg/kg/week 
dose in our protocol with a specific schedule of 15mg/kg every 21 days. 
 
 
3.3  
OUTCOME MEASURES 
3.3.1 Primary Outcome Measures 
 PFS 
3.3.2 Secondary Outcome Measures 
 OS 
 RR 
 Biomarkers (CEA, CA 19.9, VEGF), evaluated as dichotomous variables 
3.3.3 Safety Outcome Measures 
Toxicities will be assessed per CTCAE v3.0.  As bevacizumab administration has 
been associated with hemorrhage (particularly hemoptysis) and thromboembolic 
events, we will monitor for these events.  In addition, patients will be monitored 
for systemic, renal, gastrointestinal, hematologic, neurological and liver toxicities.  
Specifically, patients will have laboratory tests (including CBC with differential, 
basic metabolic panel, calcium, magnesium and liver function tests) performed 
every 3 weeks.  In addition, patients will be seen in the clinic for history and 
physical and assessed for side effects and toxicities every 3 weeks.   
3.3.4 Correlative Outcome Measures 
 Serum will be banked for future testing of angiogenesis factors (collected at 
baseline and with each cycle)   
 Tissue will be banked for future testing (collected at baseline and at time of 
progression by endoscopic biopsy if clinically indicated) 
 CT Perfusion (OPTIONAL) will be performed to assess tumor blood flow 
(performed at baseline and after 3 cycles) 
 


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4.0 
SAFETY PLAN 
4.1 GENERAL PLAN TO MANAGE SAFETY  
4.1.1 Bevacizumab-Specific 
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. 
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 
(see Section 7.0).  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 7.1.4).   
Specific monitoring procedures are as follows: 
 Hypertension will be monitored through routine evaluation of blood pressure prior 
to each bevacizumab treatment.  Optimal control of blood pressure according to 
standard public health guidelines is recommended for patients on treatment with 
or without bevacizumab. 
 Proteinuria will be monitored by urine protein: creatinine (UPC) ratio or dipstick at 
least every 6 weeks.  
 If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical 
procedure. Patients undergoing a major surgical procedure should not 
begin/restart bevacizumab until 4 weeks after that procedure (in the case of high 
risk procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that chemotherapy be restarted no earlier than 6 wk and 
bevacizumab no earlier than 8 wk after surgery). 
Other Study Drug(s)-Specific 
Please see Section 6.1 for detailed instructions for the management of study 
drug–related toxicities. 
4.1.2  Capecitabine-Specific 
Please see Section 6.2 for the management of capecitabine toxicity.  
4.1.3  Carboplatin-Specific 
Please see Section 6.3 for the management of carboplatin toxicity 


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4.2 
DEFINITION OF A DOSE LIMITING TOXICITY (DLT) 
The definition of DLT will be any adverse event occurring during the first cycle of 
treatment that can be causally related to the study treatments and that meets the 
criteria as described below in this section.  See Sections 6.1, 6.2, 6.3 for dose 
modifications when toxicities are encountered.  All toxicity in this study will be 
graded according to the NCI Common Toxicity Criteria Adverse Events (CTCAE) 
version 3.0.   
Hematologic toxicity: Hematologic DLT will be defined as CTCAE grade 4 
neutropenia (< 500/mm3) lasting > 5 days, CTCAE grade 4 neutropenia of any 
duration if associated with fever, CTCAE grade 4 anemia (< 6.5 g/dl) of any 
duration, or CTCAE grade 4 thrombocytopenia (< 25,000/mm3) of any duration. 
Hepatic toxicity:  An elevation to CTCAE ≥ grade 3 toxicity in one or more liver 
function tests (bilirubin, AST, or ALT) will be considered a DLT.  If liver 
metastases are present, and the enrollment liver function test in question is 
above the institutional normal, elevations will be considered a DLT as follows: 
 For serum bilirubin an elevation of ≥ 3 times the enrollment value will be 
considered a DLT (note that patients with liver metastases and serum 
bilirubin ≤ 3x ULN are eligible for the study).   
 For AST and ALT an elevation of ≥ 5 times the enrollment value will be 
considered a DLT (note that patients with liver metastases and serum AST 
or ALT of ≤ 5x ULN are eligible for the study).   
 If the elevation in liver function test is attributed to a cause other than 
study treatment (e.g. occlusion of biliary stent or reactivation of viral 
hepatitis), then study treatment may be held while the cause is addressed, 
but this will not be considered a DLT. 
Electrolytes: CTCAE ≥ grade 3 toxicity of electrolytes will be considered a DLT 
with the following notable exceptions: 
 If the toxicity is attributed to a cause other than study treatment, then 
study treatment may be held while the cause is addressed, but this will not 
be considered a DLT 
 CTCAE grade 3 hypokalemia (2.5-3.0 mmol/L) will not be considered a 
DLT unless it persists for one week despite appropriate medical 
management.  CTCAE grade 4 hypokalemia will be considered a DLT 
upon first occurrence. 
 Asymptomatic CTCAE grade 3 hyponatremia (120-130 mmol/L) will not be 
considered a DLT.  CTCAE grade 4 hyponatremia will be considered a 
DLT upon first occurrence. 
Nausea, vomiting and diarrhea: CTCAE grade 3 nausea, vomiting or diarrhea 
will be considered a DLT only if the adverse event occurs and persists > 24 hours 


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despite institution of appropriate and adequate supportive measures (e.g. 
antiemetics and antidiarrheal medications).  Any CTCAE grade 4 nausea, 
vomiting or diarrhea (characterized by life-threatening consequences) will be 
considered a DLT. 
Hypertension: Any elevation in blood pressure deemed by the treating physician 
to require immediate/urgent lowering of blood pressure, and lasting > 24 hours 
despite optimization of their antihypertensive medication regimen, will be 
considered a DLT and result in a treatment interruption.  Please refer to Section 
7.1.3 for bevacizumab dose modifications.  Management of hypertension during 
the interruption period and remainder of the study period will be at the discretion 
of the treating physician.   
Ataxia/dizziness 
and 
other 
neurologic 
toxicity: 
CTCAE 
grade 
3 
ataxia/dizziness or other grade 3 neurologic toxicity will be considered a DLT if 
persistent > 10 days with continued dosing of study agents.  If the toxicity begins 
during the first cycle of treatment, and the 10 day symptomatic period extends 
into cycle 2, the toxicity will still be considered a DLT associated with the first 
cycle of treatment.  CTCAE grade 4 ataxia/dizziness or other grade 4 neurologic 
toxicity will be considered a DLT regardless of duration. 
Gastrointestinal Perforation: Any gastrointestinal perforation ≥ CTCAE grade 2 
will be considered a DLT. 
Fistulae: Bevacizumab will be discontinued permanently for all grades of 
tracheoesophageal fistulae or any grade 4 non-TE fistulae.  
All other study treatment related toxicities: Any other adverse event, 
excluding fatigue, directly attributed to the study medications that are ≥ CTCAE 
grade 3 will be considered a DLT.  At the investigator’s discretion, administration 
of the study treatment may be delayed for any toxicity encountered (any CTCAE 
grade) in the best interests of the patient.  Any treatment-related toxicity resulting 
in a treatment delay of > 14 days will be considered a DLT.   
 
5.0 
STUDY SUBJECTS 
5.1 
SUBJECT SELECTION 
Patients with histologically confirmed adenocarcinoma of the GEJ or stomach 
which are deemed unresectable or metastatic will be eligible for enrollment in this 
study. This study is open to both men and women and to all racial/ethnic groups.  
According to most recent studies on gastrointestinal cancer, there is no evidence 
for outcome to be affected by either race or gender.  Thus, this study will not 
have separate accrual targets for these different subgroups. 
5.2 
INCLUSION CRITERIA 


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1. Patients with histologically or cytologically confirmed adenocarcinoma of the 
GEJ or stomach.   
2. Patients must be deemed unresectable due to involvement of critical 
vasculature or adjacent organ invasion.  If unresectable, patients must show 
evidence of disease progression prior to enrollment. 
3. Patients with prior surgical resection who develop radiological or clinical 
evidence of metastatic cancer do not require separate histological or 
cytological confirmation of metastatic disease unless an interval of > 5 years 
has elapsed between the primary surgery and the development of metastatic 
disease.  Clinicians should consider biopsy of lesions to establish diagnosis of 
metastatic disease if there is substantial clinical ambiguity regarding the 
nature or source of apparent metastases. 
4. Prior carboplatin as neoadjuvant or adjuvant therapy will be allowed if ≥ 6 
months from the time of study entry. 
5. If patients use aspirin (>325mg/day) or NSAIDS at the time of enrollment, 
they must have a 10 day washout period prior to beginning protocol 
treatment. 
6. Low molecular weight heparin (or its equivalent, excluding warfarin) will be 
allowed for treatment of venous thromboembolic events if patients have no 
evidence of bleeding on full-dose anticoagulation. 
7. Patients must have a primary or metastatic lesion measurable in at least one 
dimension by Modified RECIST criteria (see Section 11.2.3) within 4 weeks 
prior to entry of study 
8. Patients must have ECOG performance status of 0-1 
9. Patients must be ≥ 18 years of age 
10. Laboratory values ≤ 2 weeks prior to randomization: 
 Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (≥ 1500/mm3)  
 Platelets (PLT) ≥ 100 x 109/L (≥ 100,000/mm3) 
 Hemoglobin (Hgb) ≥ 9 g/dL  
 Serum creatinine ≤ 1.5 x ULN  
 Serum bilirubin ≤ 1.5 x ULN  (≤ 3.0 x ULN  if liver metastases present) 
 Aspartate aminotransferase (AST/SGOT), alanine aminotransferase 
(ALT/SGPT) ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present).  Note:  
ERCP or percutaneous stenting may be used to normalize the liver 
function tests. 
11. Life expectancy ≥ 12 weeks 
12. Ability to give written informed consent according to local guidelines 
 
 


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5.3  
EXCLUSION CRITERIA 
a. Disease-Specific Exclusions 
1. Prior chemotherapy for metastatic disease 
2. Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 
weeks prior to enrollment.  Patients must have recovered from all therapy-
related toxicities.  The site of previous radiotherapy should have evidence 
of progressive disease if this is the only site of disease. 
3. Prior biologic or immunotherapy ≤ 2 weeks prior to registration. Patients 
must have recovered from all therapy-related toxicities  
4. Prior therapy with anti-VEGF agents 
5. If history of other primary cancer, subject eligible only if she or he has: 
 Curatively resected non-melanomatous skin cancer  
 Curatively treated cervical carcinoma in situ 
 Other primary solid tumor curatively treated with no known active 
disease present and no treatment administered for the last 3 years 
6. Concurrent use of other investigational agents and patients who have 
received investigational drugs ≤ 4 weeks prior to enrollment. 
7. Hypersensitivity to capecitabine, fluorouracil, or any component of the 
formulation and or a known deficiency of dihyropyrimidine dehydrogenase. 
b. General Medical Exclusions 
1. Subjects known to have chronic or active hepatitis B or C infection 
2. History of any medical or psychiatric condition or laboratory abnormality 
that in the opinion of the investigator may increase the risks associated 
with study participation or study drug administration or may interfere with 
the conduct of the study or interpretation of study results 
3. Male subject who is not willing to use adequate contraception upon 
enrollment into this study and for 6 months following the last dose of 
second-line treatment 
4. Female subject (of childbearing potential, post-menopausal for less than 6 
months, not surgically sterilized, or not abstinent) who is not willing to use 
an oral, patch or implanted contraceptive, double-barrier birth control, or 
an IUD during the course of the study and for 6 months following the last 
dose of second-line treatment 
5. Female subject who is breast-feeding or who has positive serum 
pregnancy test 72 hours prior to randomization 
6. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE 
grade 2 dyspnea) 


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7. Any of the following concurrent severe and/or uncontrolled medical 
conditions within 24 weeks of enrollment which could compromise 
participation in the study: 
 Unstable angina pectoris 
 Symptomatic congestive heart failure 
 Myocardial infarction ≤ 6 months prior to registration and/or 
randomization 
 Serious uncontrolled cardiac arrhythmia  
 Uncontrolled diabetes 
 Active or uncontrolled infection 
 Interstitial pneumonia or extensive and symptomatic interstitial fibrosis 
of the lung. 
 Chronic renal disease 
 Acute or chronic liver disease (e.g., hepatitis, cirrhosis) 
 
8. Patients unwilling to or unable to comply with the protocol 
 
9. Current, recent (within 4 weeks of the first infusion of this study), or 
planned participation in an experimental drug study other than a 
Genentech-sponsored bevacizumab cancer study 
c. Bevacizumab-Specific Exclusions 
1. Inadequately controlled hypertension (defined as systolic blood pressure 
150 and/or diastolic blood pressure > 100 mmHg on antihypertensive 
medications) 
2. Any prior history of hypertensive crisis or hypertensive encephalopathy 
3. New York Heart Association (NYHA) Grade II or greater congestive heart 
failure (see Appendix A) 
4. History of myocardial infarction or unstable angina within 6 months prior to 
study enrollment 
5. History of stroke or transient ischemic attack within 6 months prior to study 
enrollment  
6. Known CNS disease, brain metastases. 
7. Significant  vascular disease (e.g., aortic aneurysm, aortic dissection) 
8. Symptomatic peripheral vascular disease  
9. Evidence of bleeding diathesis or coagulopathy 


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10. Major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to study enrollment or anticipation of need for major 
surgical procedure during the course of the study 
11. Core biopsy or other minor surgical procedure, excluding placement of a 
vascular access device, within 7 days prior to study enrollment 
12. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 6 months prior to study enrollment 
13. Serious, non-healing wound, ulcer, or bone fracture 
14. Urine protein ≥ 2+ on urinalysis dipstick and ≥ 1.0 gram on 24-hour urine 
collection 
15. Known hypersensitivity to any component of bevacizumab  
16. History of GI bleeding (hemoptysis/melena/hematochezia,   1/2 teaspoon 
of bright red blood per episode) within 3 month prior to Day 1. 
17. Current, ongoing treatment with full-dose warfarin. 
 
6.0 
STUDY MEDICATION  
6.1 
BEVACIZUMAB 
6.1.1 Bevacizumab Dosage and Formulation 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile 
liquid concentrate for solution for intravenous (IV) infusion.  Bevacizumab may be 
supplied in 5-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL or 16 
mL of bevacizumab, respectively (all at 25 mg/mL).  Vials contain bevacizumab 
with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection (SWFI), 
USP.  Vials contain no preservative and are suitable for single use only. For 
further details and molecule characterization, see the bevacizumab Investigator 
Brochure. 
6.1.2 Bevacizumab Administration 
Bevacizumab will be administered at a dose of 15 mg/kg intravenously on day 1 
of a 21-day cycle.   
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.    
The initial dose will be delivered over 9015 minutes.  If the first infusion is 
tolerated without infusion-associated adverse events (fever and/or chills), the 
second infusion may be delivered over 6010 minutes.  If the 60-minute infusion 
is well tolerated, all subsequent infusions may be delivered over 3010 minutes.   


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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 3010 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 
9015 minutes.  Similarly, if a subject experiences an infusion-associated 
adverse event with the 30-minute infusion, all subsequent doses should be given 
over 6010 minutes. 
6.1.3 Bevacizumab Storage 
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C  
(36F–46F) 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. 
6.1.4 Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events occur that 
require holding bevacizumab, the dose will remain the same once treatment 
resumes. 
Any toxicities associated or possibly associated with bevacizumab treatment 
should be managed according to standard medical practice. Bevacizumab has a 
terminal half-life of 2 to 3 weeks; therefore, its discontinuation results in slow 
elimination over several months. There is no available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion. If unmanageable toxicity occurs because of bevacizumab at any time 
during the study, treatment with bevacizumab should be discontinued.  
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects 
who develop dyspnea or clinically significant hypotension. Subjects who 
experience a NCI CTCAE v. 3.0 Grade 3 or 4 allergic reaction / hypersensitivity, 
adult respiratory distress syndrome, or bronchospasm (regardless of grade) will 
be discontinued from bevacizumab treatment. 
The infusion should be slowed to 50% or less or interrupted for subjects who 
experience any infusion-associated symptoms not specified above. When the 
subject’s symptoms have completely resolved, the infusion may be continued at 
no more than 50% of the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. Infusions may be restarted at the 
full rate during the next cycle.  


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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. 
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 
RPLS (confirmed by 
MRI) or hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1/2 nonpulmonary and non-CNS events 
Grade ≥ 2 pulmonary 
or CNS hemorrhage 
Discontinue bevacizumab. 
Grade 3  
nonpulmonary and 
non-CNS hemorrhage 
Subjects who are also receiving full-dose anticoagulation will 
be discontinued from receiving bevacizumab.   
All other subjects will have study treatment held until all of the 
following criteria  are met: 
 The bleeding has resolved and hemoglobin is stable. 
 There is no bleeding diathesis that would increase 
the risk of therapy. 
 There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
Subjects who experience a repeat Grade 3 hemorrhagic event 
will be discontinued from receiving bevacizumab. 
Grade 4 
Discontinue bevacizumab. 


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Table 1: Bevacizumab Dose Management due to Adverse Events cont’d 
 
Table 1: Bevacizumab Dose Management due to Adverse Events cont’d 
 
Venous Thrombosis 
No dose modifications for grade 1/2 events 
Grade 3/ 
Asymptomatic Grade 
4 
Hold study drug treatment.  If the planned duration of full-dose 
anticoagulation is <2 weeks, study drug should be held until the 
full-dose anticoagulation period is over.  If the planned duration 
of full-dose anticoagulation is >2 weeks, study drug may be 
resumed during the period of full-dose anticoagulation if all of 
the following criteria  are met: 
 The subject must not have had a Grade 3 or 4 
hemorrhagic event while on anticoagulation. 
 The subject must not have had evidence of tumor 
involving major blood vessels on any prior CT scan. 
 As per exclusion criteria, warfarin is not allowed 
Symptomatic Grade 4 
Discontinue bevacizumab. 
Arterial Thromboembolic event 
(Angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, and 
any other arterial thromboembolic event) 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1/2 events 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria 
Grade 1 
Grade 2  
 
 
 
 
Grade 3 
No bevacizumab dose modifications 
Hold bevacizumab for ≥ 2 grams/24 hours, and resume when 
proteinuria is < 2 grams/24 hours  
For 2+ dipstick: May administer bevacizumab; obtain 24 hour 
urine prior to next bevacizumab dose. 
For 3+ dipstick: Obtain 24 hour urine prior to bevacizumab 
administration 
Hold bevacizumab. Resume when proteinuria is < 2 grams/24 
hours  
Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
Discontinue bevacizumab. 


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Table 1: Bevacizumab Dose Management due to Adverse Events cont’d 
 
Bowel Obstruction 
Grade 1 
Continue patient on study for partial obstruction NOT requiring 
medical intervention. 
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 
requiring medical or 
surgical therapy 
Discontinue bevacizumab. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab. 
 
6.2 
CAPECITABINE 
6.2.1 Capecitabine Administration 
Capecitabine is a fluoropyrimidine carbamate that is an orally active prodrug of 5-
fluorouracil.   Normal cells, as well as tumor cells metabolize 5- fluorouracil into 
5-fluoro-2’deoxyuridinemonophosphate 
(FdUMP) 
and 
5-fluorouridine 
triphosphate (FUTP). Both are metabolites that cause cell injury by two different 
mechanisms.  FdUMP and the folate factor, N5-10-methylenetetrahydrofolate, 
bind to thymidylate synthase (TS) to inhibit the formation of thymidylate. This 
deficiency of thymidylate causes cell cycle division to halt. This is because 
thymidylate is necessary for thymidine triphosphate production, which is essential 
for DNA synthesis.  FUTP works by incorporating itself into transcription in place 
of uridine triphosphate therefore interfering with RNA transcription and protein 
synthesis. 
Capecitabine is supplied as biconvex, oblong film-coated tablets, available as 
150 mg tablets (light peach) and 500 mg tablets (peach).  Capecitabine tablets 
should be swallowed with water within 30 minutes after a meal.  The calculated 
dose by body surface area (BSA) will be rounded down to allow equivalent 
morning and evening doses using a combination of 150 mg and 500 mg tablets.   
Capecitabine will be administered at an initial dose of 850 mg/m2 by mouth twice 
daily, on days 1-14 of a 21-day cycle.    


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6.2.2 Capecitabine Storage  
Capecitabine is stored at 25 oC, with excursions permitted to 15 to 30 oC.   
6.2.3 Capecitabine Drug Interactions 
Capecitabine Cmax and AUC have been shown to increase by approximately 20-
35% when given concurrently with antacids.  Therefore administration of 
capecitabine should be separated by two hours from any antacids. 
Capecitabine increases the serum level of warfarin with concomitant 
administration.  Therefore, a patient who takes both requires more frequent 
testing of INR and PT so the appropriate dose adjustment can be made. 
Capecitabine also increases the serum level of phenytoin. The patient may need 
more frequent monitoring of phenytoin levels so dosing adjustments can be 
made appropriately. 
Capecitabine has not been shown to interact with CYP450 isoenzymes although 
extra care should be expressed when administering CYP2C9 substrates. 
6.2.4 Capecitabine Dose Modification and Toxicity Management 
Potential toxicities of capecitabine are as follows: 
Hematologic: anemia, neutropenia 
Constitutional: fatigue, pyrexia, edema, pain, chest pain 
Dermatologic: hand-foot syndrome, dermatitis, skin discoloration, alopecia 
Gastrointestinal:  diarrhea, nausea, vomiting, stomatitis, abdominal pain, 
gastrointestinal motility disorder, constipation, oral discomfort, upper GI 
inflammatory disorders, gastrointestinal hemorrhage, ileus 
Hepatic:  hyperbilirubinemia 
Infections:  bacterial or viral 
Metabolic: appetite decreased, dehydration 
Musculoskeletal:  back pain, arthralgia 
Neurologic:  peripheral sensory neuropathy, headache, dizziness, insomnia, taste 
disturbance 
Ocular:  eye irritation, vision abnormal 
Psychiatric:  mood alteration, depression 
Pulmonary:  dyspnea, cough, pharyngeal disorder, epistaxis, sore throat 
Vascular:  venous thrombosis 
A dose reduction will be instituted upon any grade 3 or 4 toxicity that is 
attributable to capecitabine.  If there is uncertainty as to which agent in the 


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treatment regimen is responsible for a particular toxicity, then the particular agent 
reduced will be at the investigator’s discretion.   
For all grade 3 or 4 toxicities related to capecitabine, the study treatment will be 
withheld for up to 3 weeks until the toxicity has resolved to CTCAE grade 1 or 
better, and then treatment may be restarted.  Dose reduction/re-challenge for 
each toxicity criterion will be managed as discussed in the sections that follow.  
Patients will be withdrawn from the study if toxicity does not resolve to  CTCAE 
grade 1 within 3 weeks.   
Myelosuppression 
On Day 1 of each cycle, if the neutrophil count is < 1500/mm3, or the platelet 
count is < 100,000/mm3, then treatment with carboplatin, capecitabine, and 
bevacizumab will be held until the neutrophil count is ≥ 1500/mm3, and platelet 
count is ≥ 100,000/mm3.  If treatment is required to be held for ≥ 3 weeks, then 
study treatment will be discontinued.  Refer to section 6.3.2 for carboplatin dose 
adjustments to carboplatin for myelosuppression. 
The investigator(s) may allow a patient to continue on bevacizumab if initiation of 
the next carboplatin treatment is delayed due to the presence of 
myelosuppression. 
GI Toxicity 
Nausea, vomiting, or both may be controlled with antiemetic therapy.  Diarrhea 
should be treated with standard medications to avoid dose modification or 
interruption, if possible.  Electrolyte supplementation with regular laboratory 
monitoring should be used, when appropriate, to maintain electrolytes within 
normal limits.  Patients who are clinically unstable because of diarrhea or other 
intercurrent medical illness must be admitted and evaluated using telemetry, until 
clinically stable.   
Dose modifications for diarrhea will be as follows: 
If  ≥ grade 3 diarrhea refractory to oral anti-diarrheal medication occurs, all 
treatment will be held until the toxicity is < grade 2, then the capecitabine dosage 
will be reduced according to Table 2 shown below: 
 


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Table 2.  Capecitabine dose modification 
Starting 
Capecitabine 
Dose 
1st Reduction 
Incremental 
Percent 
Reduction 
2nd Reduction 
Incremental 
Percent 
Reduction 
1000 mg BID 
1000 mg AM 
650 mg PM 
18% 
650 mg AM 
650 mg PM 
21% 
1500 mg AM 
1000 mg PM 
1000 mg BID 
20% 
1000 mg AM 
650 mg PM 
18% 
1500 mg BID 
1500 mg AM 
1000 mg PM 
17% 
1000 mg BID 
20% 
2000 mg AM 
1500 mg PM 
1500 mg AM 
1300 mg PM 
20% 
1150 mg AM 
1150 mg PM 
18% 
2000 mg BID 
1650 mg AM 
1500 mg PM 
21% 
1500 mg AM 
1000 mg PM 
20% 
If ≥ grade 3 diarrhea occurs after the first capecitabine dose reduction, then 
treatment will be held until the toxicity is < grade 2 and then a second 
capecitabine dose reduction according to Table 2 will be instituted.  If ≥ grade 3 
diarrhea occurs following 2 capecitabine dose reductions, then treatment will 
again be held until the toxicity is < grade 2, then treatment will resume at the 
same doses except that the carboplatin dosage will be reduced by 20%. If ≥ 
grade 3 diarrhea persists, patients will be withdrawn from the study. 
If treatment must be withheld for more than 3 weeks for resolution of diarrhea, 
the patient will not restart treatment with study medication and the patient will be 
withdrawn from the study.   
Mucositis or Hand/Foot Syndrome (HFS) 
If ≥ grade 3 mucositis or HFS occurs, capecitabine will be interrupted for a 
minimum of 1 week. If the toxicity has not improved to < grade 2, the treatments 
will be held for up to 2 additional weeks. Once restarted, the dose of capecitabine 
will be reduced according to Table 2.  Beyond two dose reductions, if further 
toxicity is encountered, the patient will be discontinued from study treatment. 
Other toxicities 
If ≥ grade 3 toxicities directly attributable to capecitabine other than those 
discussed above occur (except fatigue, alopecia, or nausea/emesis in the 
absence of anti-emetics), therapy will be discontinued until the toxicity is < grade 
2. If there is no evidence of tumor progression, therapy may resume with a dose 
reduction according to Table 2. 
 


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6.3 
CARBOPLATIN 
Carboplatin is a second generation platinum analogue and has been associated 
with greater convenience of administration and a more favorable toxicity profile 
compared to cisplatin.  Carboplatin is commercially available agents and further 
details regarding storage, administration, dose modification and toxicity 
management can be obtained in the package inserts. 
 
6.3.1 Carboplatin Administration 
The carboplatin dose will be based on the Calvert formula (Appendix E) and 
given at a target area under the curve (AUC) of 6 mg/mL x min and glomerular 
filtration rate (GFR) estimated for males as GFR = (140-age) x weight/72 x 
(serum creatinine). For females, a correction factor of 0.85 will be used 
(Appendix E).  The initial dose weight will be used. Carboplatin will be 
administered over 30-60 minutes on day 1 every 21 days. 
6.3.2  Carboplatin Dose Modification and Toxicity Management 
Table 3: Carboplatin dose modifications 
Toxicity 
Carboplatin 
ANC≥1500 
Platelets≥100,000 
Full dose 
ANC≥1000 but <1500 
Platelets≥10,000 but <100,000 
Delay chemotherapy by one 
week and reduce subsequent 
dose by 20%*† 
ANC<1000 
Platelets<10,000 
Delay chemotherapy by one or 
more weeks and reduce 
subsequent dose by 20%*†, 
growth factors may be given as 
clinically indicated. 
*If patient requires >2 reductions for neutropenia and thrombocytopenia within first 
3 cycles, the patient will be taken off study.   If this occurs after 3 cycles patients 
may discontinue carboplatin and continue receiving bevacizumab with or without 
capecitabine (as per study design).  Upon documentation of first disease 
progression by RECIST criteria, the patient will either restart the original schedule 
of capecitabine, carboplatin, and bevacizumab or be discontinued from the study, 
at the investigator’s discretion.  If the patient has persistent neutropenia and/or 
thrombocytopenia for more than 3 weeks he/she will be taken off study. 
†Carboplatin dose reductions will be a percentage reduction of prior AUC (ie. If 
patient started at AUC 6, a 20% dose reduction would be an AUC of 4.8) or prior 
total dose in milligrams whichever is lower. 
Note: growth factors may be used at investigator’s discretion. 


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6.4      GENERAL DOSE MODIFICATIONS 
Dose will be modified for all three drugs if there is 10% change in patient’s weight 
while on study. 
Any of the three drugs can be discontinued at the investigator’s discretion for any 
adverse event with severity of grade 3 or more 
If patient is in confirmed Complete Remission (CR) for a period of 18 weeks or 
more, investigator may give chemotherapy break; surveillance CT scan every 9 
weeks will be continued. Upon documentation of first disease progression by 
RECIST criteria, the patient will restart chemotherapy, at the investigator’s 
discretion. 
If patient is on maintenance Bevacizumab, upon documentation of first disease   
progression by RECIST criteria, the patient will restart the original schedule of 
Capecitabine, Carboplatin, and Bevacizumab, at the investigator’s discretion. 
6.5 
CONCOMITANT MEDICATIONS 
In general, concomitant medications and therapies deemed necessary for the 
supportive care and safety of the patient are allowed, provided their use is 
documented in the patient records and on the appropriate case report form.  All 
supportive care measures consistent with optimal patient care will be given 
throughout the study.  Patients should be maintained on the same medications 
throughout the study period, if medically appropriate. All medications taken within 
30 days of the screening visit should be recorded on the data collection forms. All 
cancer medications/therapies given to the patient within 28 days after the last 
dose of study drug must also be recorded on the data collection forms.  
 Other chemotherapy, investigational agents, radiation or biologic therapy 
may not be used while the patient is in this study. 
 Hematologic growth factors are not part of this study. However, growth 
factor support for anemia and/or neutropenia will be at the discretion of the 
treating physician and should be documented. 
 Megace can be used for appetite support and needs to be reported on the 
case report forms. 
 No data exists regarding the interaction of the study medications with 
commonly used herbal or non-traditional medications. Patients should be 
instructed not to use such medications while receiving study treatment. 


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 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. 
 
7.0 
CLINICAL AND LABORATORY EVALUATIONS 
7.1 
STUDY SCHEDULE 
Cycle 
Screen 
1 
2 
3 
Withdrawal 
of Study 
treatment 
Week 
0 
1 
4 
7 
 
Dayd 
0 
1 
1 
1 
 
Informed consent 
X 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Hematology/chemistry  
X 
X 
X 
X 
X 
Biomarkersc 
X 
X 
X 
X 
X 
Urinalysisb 
X 
X 
 
X 
X 
Pregnancy test 
X 
 
 
 
 
Performance Status 
X 
X 
X 
X 
X 
RECIST 
Xa 
 
 
Xa 
Xa 
Tolerability/AE reporting 
 
X 
X 
X 
X 
Concurrent medication 
X 
X 
X 
X 
X 
a- 
Measurement of tumor will be done at baseline, every 3 cycles (end of cycle 3, 6, 9, etc.) and at withdrawal of study 
treatment 
b- 
Urinalysis obtained at screening and every other cycle thereafter (cycles 3, 5, 7 etc).  If urine dipstick reveals protein ≥ 2+, 
then 24-hour urine collection will be obtained to quantify proteinuria.   
c- 
Sampling of serum for CEA, CA 19.9, and circulating VEGF levels will be done on the first day of each cycle 
d- 
Patients may be seen within a 3 day window of the assigned study visit. 
 
7.2 
PRE-TREATMENT EVALUATIONS 
 Medical history, physical exam, and assessment of performance status 
 Vital signs, including blood pressure 
 Blood: Complete blood count with differential, comprehensive metabolic 
panel, CEA, CA 19.9, VEGF level, and serum banked for future studies. 
 Urine: Urinalysis, Pregnancy test if female 
 Tissue: Banked for future studies, HER2 status will be also evaluated  


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 Imaging:  
 Radiographic imaging, CT or MRI preferred, of measurable disease for 
assessment by RECIST criteria (standard clinical care) 
 CT Perfusion as a correlative study (Optional) 
 
7.3 
EVALUATIONS DURING TREATMENT 
On the first day of each cycle (concurrent with each bevacizumab treatment): 
 Medical history and physical exam 
 Vital signs, including blood pressure 
 Blood: Complete blood count with differential, comprehensive metabolic 
panel, CEA, CA 19.9, VEGF level, and serum banked for future studies. 
 CEA, CA 19.9, VEGF level and serum banking need not be repeated if it is 
done within last 3 weeks in case of delayed cycle or chemotherapy break. 
 Urine for urineanalysis:  If dipstick reveals protein ≥ 2+, then 24-hour urine will 
be obtained to quantify proteinuria.  Patient may continue on study if there is 
< 1.0 gram protein in a 24-hour collection of urine. 
 Imaging:  
o CT or MRI scans with measurement of target lesions by RECIST criteria 
will be done at the conclusion of every 3 cycles (approximately every 9 
weeks). 
o CT Perfusion will be performed after 3 cycles as a correlative study. 
(Optional) 
 
7.4 
POST-TREATMENT EVALUATIONS 
Upon patient withdrawal from study, every effort will be undertaken to obtain the 
following: 
 Medical history and physical exam 
 Vital signs, including blood pressure 
 Blood: Complete blood count with differential, comprehensive metabolic 
panel, CEA, CA 19.9, VEGF level, and serum banked for future studies. 
 Imaging:  
 CT or MRI scans with measurement of target lesions by RECIST criteria 
and CT Perfusion (OPTIONAL) as a correlative study will be performed if 
not done within 4 weeks prior to withdrawal from study. 
 


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8.0 
CORRELATIVE/SPECIAL STUDIES 
8.1 
SERUM VEGF 
 Collection of Specimen:  
o Plasma (NO HEPARIN) 
o 5 aliquots of 50 microliters each 
 Handling of Specimen23  
 Site Performing Correlative Study:  
o Hanlee Ji, MD PhD 
Assistant Professor of Medicine (Oncology) 
Stanford University Medical School 
CCSR 1115, mailstop 5151  
269 Campus Drive   
Stanford, California 94305  
phones (650) 721-1503, (650) 721-1731  
fax (650) 725-1420  
genomics_ji@stanford.edu 
 
8.2 
CT PERFUSION (OPTIONAL) 
 
Routine screening procedures for contrast-enhanced CT at all Stanford imaging 
centers will be followed, with no additional laboratory values obtained for the 
purposes of this study. Screening for patients undergoing contrast-enhanced CT 
at Stanford includes but is not limited to questions about prior reactions to 
intravenous iodinated contrast, possibility of pregnancy, history of diabetes or 
renal disease, and if greater than 70 years of age, a recent serum creatinine.  If 
any absolute contraindications to contrast-enhanced CT are detected during 
screening, the patient will be excluded from the study.  If needed, the referring 
clinician will then be contacted.   
 
The duration of each CT scan is approximately 30 minutes.  Analysis of each 
scan for a given participant is estimated to take 30-60 minutes. The participants 
will also be followed per clinical routine with periodic CT scans until disease 
progression is detected, which may occur greater than one year following 
treatment.  Thus, while this study is based on data obtained from the first year 
following treatment, we will also be looking at data from the participant’s 
subsequent CT scans in an exploratory longitudinal study to detect possible 
relationships between disease progression and changing perfusion 
characteristics.  
 


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On a technical note, previous studies of perfusion CT have been limited by the 
relatively short scan ranges permitted by available CT scanner models. A new 
dual-source CT scanner was installed at Stanford in July 2009 that is capable of 
performing perfusion imaging. Two new dual-source scanners will be installed at 
Stanford in the Spring 2010 with unprecedented scanning speed and temporal 
resolution. This speed will allow for perfusion imaging over larger scan ranges, 
thus making CT perfusion of whole pancreatic tumors possible. 
 
9.0 
STUDY TREATMENT DISCONTINUATION 
 
Subjects who meet the following criteria should be discontinued from study 
treatment:  
 Disease progression by clinical presentation or by RECIST criteria while on 
study treatment, at the investigator’s discretion. 
 Grade 4 hypertension or reversible posterior leukoencephalopathy syndrome 
(RPLS) 
 Nephrotic syndrome 
 Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
 Symptomatic Grade 4 venous thromboembolic event (for lung protocols: any 
venous thromboembolic event requiring full dose warfarin or equivalent (i.e., 
unfractionated or low molecular weight heparin)  
 Any grade arterial thromboembolic event 
 Grade 4 congestive heart failure 
 Gastrointestinal perforation  
 Wound dehiscence requiring medical or surgical intervention 
 Inability of subject to comply with study requirements 
 Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 All Grade 4 events thought to be related to bevacizumab by the investigator 
Patients who have an ongoing bevacizumab-related Grade 4 or serious adverse 
event at the time of discontinuation from study treatment will continue to be 
followed until resolution of the event or until the event is considered irreversible 
(see Section 6.1.3). 
10.0 STUDY FOLLOW UP  
After study treatment discontinued patients will be followed every 6 months till 
death for disease progression and survival.   Discontinuation of the study will be 
considered after review of the data by the DSMB for any of the following events: 


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 Major toxicity (i.e. life-threatening hemorrhage) attributable to study treatment. 
 Determination by the DSMB that excessive toxicity attributed to the regimen 
has been identified that does not meet the safety reason 1 above. 
 
11.0 STATISTICAL METHODS 
11.1 DETERMINATION OF SAMPLE SIZE  
Data from Kang, et al1 show that in patients with advanced gastric cancer treated 
with cisplatin and capecitabine the 6-month progression-free survival (PFS) rate 
is 50% and the 12-month rate is 24% which we will use as our historical control.  
We propose a trial of 35 patients with PFS as the primary endpoint and a 
therapeutic target of increasing the 12-month PFS by 90% to a rate of 46%.  If 
the target is met, there is 80% probability that the 95% lower confidence for PFS 
at 12-month will lie above the historical rate of 24%.  The 95% confidence margin 
of error for proportions based on 35 patients is at most 18 percentage points. 
 
PFS curves will be generated using Kaplan-Meier method and compared to 
historical controls using a z-test with Greenwood formula.  OS will also be 
generated using Kaplan-Meier method.  RR will be estimated with a binomial 
confidence interval.  CEA will be summarized (mean, standard deviation, median, 
range) at each time point and then compared with PFS using a log rank test.  
The correlation of CT Perfusion parameters with PFS will be assessed using the 
Cox proportional hazards model. 
 
11.2 PLANNED EFFICACY EVALUATIONS 
11.2.1 Primary Efficacy Variables 
 PFS 
11.2.2 Secondary Efficacy Variables 
 OS 
 RR 
 Biomarkers (CEA, CA 19.9, VEGF) 
11.2.3 Methods of Analysis 
Efficacy Assessment using Response Evaluation Criteria in Solid Tumors 
Guideline (RECIST v 1.1)24  
 
Definitions: At baseline, tumor lesions/lymph nodes will be categorized 
measurable or non-measurable as follows: 
 
Measurable: 


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 Tumor lesions: Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a 
minimum size of: 
o 10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
o 10mm caliper measurement by clinical exam (lesions which cannot 
be accurately measured with calipers should be recorded as non-
measurable). 
o 20mm by chest X-ray. 
 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.  
 
Non-measurable: 
 All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with P10 to <15mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging 
 
Specifications by methods of measurements 
Measurement of lesions:  
 All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close 
as possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
 
Method of assessment 
 The same method of assessment and the same technique should be used 
to characterize each identified and reported lesion at baseline and during 
follow-up. Imaging based evaluation should always be done rather than 
clinical examination unless the lesion(s) being followed cannot be imaged 
but are assessable by clinical exam. 
 
 Clinical lesions: Clinical lesions will only be considered measurable when 
they are superficial and ≥10mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since 
it is more objective and may also be reviewed at the end of the study. 
 


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 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-
ray, particularly in identifying new lesions. However, lesions on chest X-
ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.  
 
 CT, MRI: CT is the best currently available and reproducible method to 
measure lesions selected for response assessment. This guideline has 
defined measurability of lesions on CT scan based on the assumption that 
CT slice thickness is 5mm or less.  
 
 Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
 Endoscopy, laparoscopy: The utilization of these techniques for objective 
tumor evaluation is not advised.  
 
 Tumor markers: Tumor markers alone cannot be used to assess objective 
tumor response. If markers are initially above the upper normal limit, 
however, they must normalize for a patient to be considered in complete 
response.  
 
 Cytology, histology: These techniques can be used to differentiate 
between PR and CR in rare cases if required by protocol. 
 
Tumor response evaluation 
 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
 When more than one measurable lesion is present at baseline all lesions 
up to a maximum of five lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. 
 
 Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  
 
 A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, 
then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
 Response criteria 


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 Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
 Partial Response (PR): At least a 30% decrease in the sum of diameters 
of target lesions, taking as reference the baseline sum diameters.  
 
 Progressive Disease (PD): At least a 20% increase in the sum of 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression). 
 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sumdiameters while on study.  
 
For other details and special circumstances of the RECIST guidelines refer directly to 
reference. 
 
Table 1 – Time point response: patients with target (+/– 
 
Definitions of Other Efficacy Markers 
Overall Survival (OS):  Time from the date of enrollment to the date of death due 
to any cause or the last date the patient was known to be alive (censored 
observation) at the date of data cutoff for the final analysis 


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Time to Progression (TTP):  Time from the date of enrollment to the date of the 
first observation of documented disease progression or death to due cancer 
Progression-Free Survival (PFS): Duration of time from start of treatment to time 
of documented progression or death.  
12.0 SAFETY REPORTING OF ADVERSE EVENTS 
12.1 GENERAL  
 Data and Safety Monitoring Board  
The status of each patient on the study, and the study’s overall progress, will 
be reviewed regularly.  This review will take place at the Stanford University 
Cancer Center Gastrointestinal Team Meetings, chaired by Dr. George 
Fisher.  In addition, the study will be monitored semi-annually by the Stanford 
University Data Safety Monitoring Committee.  
 
 Confidentiality 
The protection of the patient’s identity will be ensured. Patients will be 
identified by code number and initials only in any publication of data requiring 
specific patients results. As required by federal law, patient records may be 
made available to the Food and Drug Administration. 
 
12.2 BEVACIZUMAB-SPECIFIC 
12.2.1 Adverse Event Reporting and Definitions 
In the event of an adverse event the first concern will be for the safety of the 
subject.  Investigators are required to report to Genentech Drug Safety ANY 
serious treatment emergent adverse event (STEAE) as soon as possible.   
 
A STEAE is any sign, symptom or medical condition that emerges during 
Bevacizumab treatment or during a post-treatment follow-up period that (1) was 
not present at the start of Bevacizumab treatment and it is not a chronic condition 
that is part of the patient’s medical history, OR (2) was present at the start of 
Bevacizumab treatment or as part of the patient’s medical history but worsened 
in severity and/or frequency during therapy, AND that meets any of the following 
regulatory serious criteria: 
 Results in death  
 Is life-threatening  
 Requires or prolongs inpatient hospitalization  
 Is disabling  
 Is a congenital anomaly/birth defect  
 Is medically significant or requires medical or surgical intervention to prevent 
one of the outcomes listed above. 


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12.2.2 Reporting of Serious Treatment Emergent Adverse Events  
 
All STEAEs should be recorded on a MedWatch 3500a Form and faxed to: 
 
Genentech Drug Safety  
Fax: (650) 225-4682 or (650) 225-4683 
(Please use the safety reporting fax cover sheet attached to this document for 
your fax transmission) 
 
AND: 
 
Study Coordination Center/Principal Investigator 
Pamela L. Kunz, MD 
 
Stanford Cancer Center  
875 Blake Wilbur Drive 
 
Stanford, CA 94305 
           pkunz@stanford.edu 
 
AND: 
 
Stanford University IRB 
 
MedWatch 3500a Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect 
medication information, the report should include the following information within 
the Event Description (section 5) of the MedWatch 3500a form: 
 
 Treatment regimen (dosing frequency, combination therapy) 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up information:  Additional information may be added to a previously 
submitted report by any of the following methods: 
 
 Adding to the original MedWatch 3500a report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500a form  
 Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e. D.O.B. initial, subject number), protocol description and 
number, if assigned, suspect drug, brief adverse event description, and 
notation that additional or follow-up information is being submitted  (The 


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subject identifiers are important so that the new information is added to the 
correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the subject for whom and adverse event was 
reported.  
 
Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that 
bevacizumab caused or contributed to an adverse event.  The following general 
guidance may be used. 
Yes: if the temporal relationship of the clinical event to bevacizumab 
administration makes a causal relationship possible, and other drugs, therapeutic 
interventions or underlying conditions do not provide a sufficient explanation for 
the observed event. 
 
No: 
if the temporal relationship of the clinical event to bevacizumab 
administration makes a causal relationship unlikely, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
 
13.0 RETENTION OF RECORDS 
All documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence will be maintained for at least 3 years 
after the investigation is completed. 


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14.0 REFERENCES/BIBLIOGRAPHY 
 
 
[Bevacizumab specific references provided as separate document on 
Bevacizumab diskette] 
 
1. 
Kang HJ, Chang HM, Kim TW, et al. Phase II study of capecitabine and cisplatin 
as first-line combination therapy in patients with gastric cancer recurrent after 
fluoropyrimidine-based adjuvant chemotherapy. British journal of cancer 2005;92:246-
51. 
2. 
Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, 
and prevalence across five continents: defining priorities to reduce cancer disparities in 
different geographic regions of the world. J Clin Oncol 2006;24:2137-50. 
3. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA: a cancer journal 
for clinicians 2006;56:106-30. 
4. 
Parfitt JR, Miladinovic Z, Driman DK. Increasing incidence of adenocarcinoma of 
the gastroesophageal junction and distal stomach in Canada -- an epidemiological study 
from 1964-2002. Canadian journal of gastroenterology = Journal canadien de 
gastroenterologie 2006;20:271-6. 
5. 
Wagner A. Chemotherapy for advanced gastric cancer. Cochrane Database Syst 
Rev 2005:CD004064. 
6. 
Kim NK, Park YS, Heo DS, et al. A phase III randomized study of 5-fluorouracil 
and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil 
alone in the treatment of advanced gastric cancer. Cancer 1993;71:3813-8. 
7. 
Vanhoefer U, Rougier P, Wilke H, et al. Final results of a randomized phase III 
trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus 
etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in 
advanced gastric cancer: A trial of the European Organization for Research and 
Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 
2000;18:2648-57. 
8. 
Schuller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in 
tumor following oral administration to colorectal cancer patients. Cancer chemotherapy 
and pharmacology 2000;45:291-7. 
9. 
Kim TW, Kang YK, Ahn JH, et al. Phase II study of capecitabine plus cisplatin as 
first-line chemotherapy in advanced gastric cancer. Ann Oncol 2002;13:1893-8. 
10. 
Lee SS, Lee JL, Ryu MH, et al. Combination chemotherapy with capecitabine (x) 
and Cisplatin (p) as first line treatment in advanced gastric cancer: experience of 223 
patients with prognostic factor analysis. Jpn J Clin Oncol 2007;37:30-7. 
11. 
Tsai JY, Iannitti D, Berkenblit A, et al. Phase I study of docetaxel, capecitabine, 
and carboplatin in metastatic esophagogastric cancer. Am J Clin Oncol 2005;28:329-33. 
12. 
Park YH, Lee JL, Ryoo BY, et al. Capecitabine in combination with Oxaliplatin 
(XELOX) as a first-line therapy for advanced gastric cancer. Cancer chemotherapy and 
pharmacology 2007. 


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13. 
Hurwitz H, Fehrenbacher L, Novotny W, et al. Avastin plus irinotecan, 
fluorouracil, and leucovorin for metastatic colorectal cancer. The New England journal of 
medicine 2004;350:2335-42. 
14. 
Miller K. E2100: A randomized phase III trial of paclitaxel versus paclitaxel plus 
bevaciuzumab as first line therapy for locally recurrent or metastatic breast cancer. 
Breast Cancer Treatment Research 2005;35. 
15. 
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial 
comparing Avastin plus carboplatin and paclitaxel with carboplatin and paclitaxel alone 
in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin 
Oncol 2004;22:2184-91. 
16. 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with Avastin 
for non-small-cell lung cancer. The New England journal of medicine 2006;355:2542-50. 
17. 
Shah MA, Ramanathan RK, Ilson DH, et al. Multicenter phase II study of 
irinotecan, cisplatin, and Avastin in patients with metastatic gastric or gastroesophageal 
junction adenocarcinoma. J Clin Oncol 2006;24:5201-6. 
18. 
Yao J, Yang ZG, Chen TW, Li Y, Yang L. Perfusion changes in gastric 
adenocarcinoma: evaluation with 64-section MDCT. Abdominal imaging 2009. 
19. 
Zhang H, Pan Z, Du L, et al. Advanced gastric cancer and perfusion imaging 
using a multidetector row computed tomography: correlation with prognostic 
determinants. Korean J Radiol 2008;9:119-27. 
20. 
d'Assignies G, Couvelard A, Bahrami S, et al. Pancreatic endocrine tumors: 
tumor blood flow assessed with perfusion CT reflects angiogenesis and correlates with 
prognostic factors. Radiology 2009;250:407-16. 
21. 
Park MS, Klotz E, Kim MJ, et al. Perfusion CT: noninvasive surrogate marker for 
stratification of pancreatic cancer response to concurrent chemo- and radiation therapy. 
Radiology 2009;250:110-7. 
22. 
Giantonio BJ, Catalano PJ, Meropol NJ, et al. Avastin in combination with 
oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic 
colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. 
J Clin Oncol 2007;25:1539-44. 
23. 
Gullberg M, Gustafsdottir SM, Schallmeiner E, et al. Cytokine detection by 
antibody-based proximity ligation. Proceedings of the National Academy of Sciences of 
the United States of America 2004;101:8420-4. 
24. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
 
 
 
 
 
 


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15.0 APPENDICES 
APPENDIX A:  STUDY FLOW CHART/SCHEMA 
[protocol specific ] 
 
APPENDIX B: INFORMED CONSENT 
(Provided as separate document on Bevacizumab diskette- do not forward to 
Genentech for review) 
APPENDIX C:  CURRENT NCI COMMON TOXICITY CRITERIA Version 3.0 
[Provided as separate document on Bevacizumab diskette] 
 
APPENDIX D: FDA MEDWATCH 3500a FORM 
[Provided as separate document. on Bevacizumab diskette] 
 
APPENDIX E: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES 
[Provided as separate document on BevacizumabAvastin diskette] 
 
 
 
 
 


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APPENDIX F 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 G Formulas for Carboplatin dose calculation 
 
Cockcroft-Gault Formula for Calculation of Creatinine Clearance 
Males: (140 –age) x actual body weight (kg)  =   mL/min 
 
    72 X serum creatinine (mg/dL) 
 
Females:  Estimated creatinine clearance for males x 0.85  =  mL/min 
 
Calvert’s Formula for the calculation of Carboplatin dose 
 
Carboplatin Dose =  (Target AUC) x (GFR + 25)