Phase II Trial of CAPOX, Bevacizumab and Trastuzumab for Patients With HER2-Positive Metastatic Esophagogastric Cancer
Phase: PHASE2
Conditions: Esophageal Cancer, Gastric Cancer
Sponsor: Dana-Farber Cancer Institute

[cover page generated for ClinicalTrials.gov only. This page was not part of the IRB approved document  
which follows] 
 
Identifiers: NCT01191697 
Unique Protocol ID: 09-457  
Brief Title: CAPOX/BEV/TRASZ FOR HER2+ ESOPHAGOGASTRIC 
Full Title: Phase II trial of CAPOX+Bevacizumab+Trastuzumab for patients with HER2-  
positive metastatic esophagogastric cancer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date document downloaded from OncPro portal: 4.5.2023  
Document Date: Protocol Version: 03.18.2019 

 
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.
1
Local Protocol #:  09-457
TITLE:   Phase II trial of CAPOX+Bevacizumab+Trastuzumab for patients with HER2-   
positive metastatic esophagogastric cancer.
Protocol Version # / Version Date:          Version 16 / March 18, 2019
Coordinating Center:                                   Dana-Farber Cancer Institute
Principal Investigator (PI):                          Peter C. Enzinger, MD
Dana-Farber Cancer Institute
Peter_Enzinger@dfci.harvard.edu
T: 617-632-6855
F: 617-632-5370
Other Investigators:                                     Samuel Klempner, MD 
Massachusetts General Hospital
sklempner@partners.org
T: 617-643-3415
F: 617-724-3166
Ronan Kelly, MD
Johns Hopkins University 
Sidney Kimmel Comprehensive Cancer Center
rkelly25@jhmi.edu 
T: 443-287-0007
F: 410-614-0610
Supporting Investigator:                              Correlative Sciences
Alec Kimmelman, MD
Dana-Farber Cancer Institute
Alec_kimmelman@dfci.harvard.edu 
T: 617-732-6310
Responsible Research Nurse:                      Christopher Graham, RN
Dana-Farber Cancer Institute
Christopher_graham @dfci.harvard.edu 
and
Victoria Germon, RN
Dana-Farber Cancer Institute
VBROCK@partners.org
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Responsible Study Coordinator:                 Katie Metayer
Dana-Farber Cancer Institute
KatherineA_Metayer@DFCI.HARVARD.EDU 
T: 617-632-6316
F: 617-582-7988
Responsible Regulatory Coordinator:        Suzanne M. Lemoine
Dana-Farber Cancer Institute
SusanM_Lemoine@DFCI.HARVARD.EDU 
T: 617-632-8669
F: 617-582-7988
Agent(s):                                                        Trastuzumab (Herceptin®) - Genentech, Inc.
Bevacizumab (Avastin®) – Genentech, Inc.
Capecitabine
Oxaliplatin
Support Provided By:                                  Genentech, Inc.
 
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SCHEMA
A Phase II trial of CAPOX+Bevacizumab+Trastuzumab for patients with HER2- 
positive metastatic esophagogastric cancer.
Consent 
Screening 
(Part II: Pre-treatment biopsy)
Cycle 1
Day 1
Trastuzumab IV (loading dose)
(Part II: Mandatory biopsy day 7)
Cycle 2 (and subsequent cycles)
Day 1
Bevacizumab IV 
Trastuzumab IV
Oxaliplatin IV
Days 1-14
Capecitabine po
Cycle 1 is one week. After cycle 1, each cycle is 21 
days.
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SCHEMA ................................................................................................................3
1.  OBJECTIVES ....................................................................................................6
1.1  Study Design ....................................................................................................6
1.2  Primary Objectives ............................................................................................6
1.3  Secondary Objectives...........................................................................................6
2.  BACKGROUND.................................................................................................7
2.1  Investigational Agents......................................................................................7
2.2  Study disease..................................................................................................20
2.3  Rationale........................................................................................................20
3.  PARTICIPANT SELECTION ..........................................................................21
3.1  Eligibility Criteria.............................................................................................21
3.2  Exclusion Criteria ...........................................................................................22
4.  REGISTRATION PROCEDURES ...................................................................24
4.1  General Guidelines for DF/HCC and DF/PCC Institutions.......................................26
4.2  Registration for DF/HCC and DF/PCC Institutions.................................................26
4.3  General Guidelines for Other Participating Institutions...........................................27
4.4  Registration for Other Participating Institutions.....................................................28
5.  TREATMENT PLAN .......................................................................................26
5.1  Pre-treatment Criteria ......................................................................................27
5.2  Agent Administration.......................................................................................28
5.2.1  TRASTUZUMAB ........................................................................................31
5.2.2  Bevacizumab ...............................................................................................31
5.2.3  OXALIPLATIN ...........................................................................................32
5.3  Other Modality (ies) or Procedures: ...................................................................32
5.4  General Concomitant Medication and Supportive Care Guidelines...........................33
5.5  Duration of Therapy...........................................................................................34
5.6  Duration of Follow Up ....................................................................................34
5.7  Criteria for Removal from Study....................................................................34
6.  EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
..............................................................................................................................34
6.1  ANTICIPATED TOXICITIES.............................................................................35
6.1.1  Trastuzumab...................................................................................................35
6.1.2  Bevacizumab ...............................................................................................38
6.1.3   Oxaliplatin .................................................................................................42
6.1.4 Capecitabine....................................................................................................45
6.2   Toxicity Management...................................................................................48
6.2.1  Trastuzumab Toxicity Management............................................................48
6.2.2  Bevacizumab Toxicity Management ............................................................48
6.3  Dose Modifications/Delays...................................................................................53
7. DRUG FORMULATION...................................................................................55
7.1  Ordering: .........................................................................................................55
7.2  Bevacizumab ..................................................................................................56
7.3  Trastuzumab ..................................................................................................57
7.4  Oxaliplatin .....................................................................................................58
8.  CORRELATIVE/SPECIAL STUDIES .............................................................60
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8.1  General ..........................................................................................................60
8.2  Collection of tumor blocks/slides ...................................................................61
8.3  Evaluation of signaling pathways...................................................................61
8.4   Sample Management of tumor blocks and slides..............................................................62
8.5  Sample Management of tumor blocks and slides............................................63
8.6  Blood sample management .............................................................................64
9.  STUDY CALENDAR.........................................................................................67
10.  MEASUREMENT OF EFFECT..........................................................................68
10.1  Antitumor Effect– Solid Tumors..................................................................68
11.  ADVERSE EVENT REPORTING REQUIREMENTS..........................................74
11.1  General.........................................................................................................74
11.2  Definitions....................................................................................................74
11.3  Recording Adverse Events ...........................................................................74
11.4  Reporting Adverse Events............................................................................74
11.5  Hospital Risk Management Notification by Investigator .............................74
12.  DATA AND SAFETY MONITORING ..............................................................74
12.1  Data Reporting................................................................................................74
12.2  Safety Meetings ............................................................................................74
12.3  Monitoring ...................................................................................................74
13.  REGULATORY CONSIDERATIONS...............................................................74
13.1  Protocol Review and Amendments ...............................................................74
13.2  Informed Consent.........................................................................................74
13.3  Ethics ...........................................................................................................74
13.4  Study Documentation ...................................................................................74
13.5  Records Retention...........................................................................................74
14.  STATISTICAL CONSIDERATIONS .............................................................74
14.1  Statistical Design..........................................................................................74
14.2  Endpoints .....................................................................................................74
14.3  Sample Size/Accrual Rate ..................................................................................74
14.4  Analysis of Secondary Endpoints........................................................................74
14.5  Reporting and Exclusions ...............................................................................74
15.  PUBLICATION PLAN ...................................................................................74
16.  REFERENCES / BIBLIOGRAPHY ..................................................................74
17.  APPENDICES..................................................................................................74
Appendix A:  Patient Diary .......................................................................................74
Appendix B:  Performance Status Criteria...................................................................74
Appendix C:  Urine Protein/Creatinine Ratio (UPCR):........................................74
Appendix D: DF/HCC Multi-Center Data and Safety Monitoring Plan..............................108
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1. OBJECTIVES
1.1
Study Design
This is a Phase II study of CAPOX (capecitabine and oxaliplatin) plus bevacizumab plus 
trastuzumab for patients with HER2-positive esophagogastric adenocarcinoma that is metastatic 
or unresectable.  A total of 36 evaluable patients will be enrolled in this study.  
The study will have a three stage design.  Part I of this study will consist of two stages that will 
include the first 20 patients.  Initially 5 patients will be enrolled, treated, and evaluated through 
the first two cycles of therapy.  Following an interim safety analysis, an additional 15 patients 
will then be enrolled and will also be evaluated for efficacy, safety and tolerability.  We have 
enrolled 16patients to date.  The interim efficacy, safety and tolerability data have been 
reviewed. It is evident that this is a well tolerated regimen and the response rates are 
encouraging.  We therefore will be moving to Part II (third stage of the study) which will now 
consist of 20 patients.  All patients at DF/HCC sites will be required to have mandatory pre and 
post trastuzumab biopsy.  
1.2
Primary Objectives
The primary objective of this study is to determine the major response rate of CAPOX plus 
bevacizumab plus trastuzumab for patients with HER2-positive metastatic or unresectable 
esophagogastric adenocarcinoma
1.3
Secondary Objectives
Determine toxicity profile
Determine the duration of response
Rate of median, overall and progression free survival
1.4
Correlative Science Objectives (Part II only): Utilizing tumor biopsy specimens
Determine signal transduction pathways by immunohistochemistry (IHC) with the following 
antibodies; pAKT, pERK, pEGFR, pPDGFR, and HER2.
Correlate pre-treatment pathway action with one week post trastuzumab treatment.
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2. BACKGROUND
2.1 
Investigational Agents
2.1.1       HER2/neu and Trastuzumab Clinical Experience
The HER2/neu oncogene lies on chromosome 17q, and encodes a transmembrane 
glycoprotein (p185) with homology to the epidermal growth factor receptor.  HER2 
over expression and/or amplification has been observed in breast, colon, bladder, 
ovarian, endometrial, lung, cervical, head and neck, esophageal and gastric carcinomas.  
In breast cancer, HER2 positivity is noted in 20-25% and may correlate with clinical 
outcome and has been shown to be a predictive factor for prognosis.  
The overexpression/amplification of HER2/neu has been reported in 6-35% of 
esophagogastric cancers and is a significant negative prognostic factor.  Overexpression 
of HER2 protein in gastric cancer using immunohistochemistry (IHC) was first 
described in 1986 (Sakai K, Mori S et al).  In the 1990’s, it was reported that 9-38% of 
gastric tumors where HER2-positive tumors using polyclonal antibodies directed 
against different domains of HER2 protein and restricting the evaluation to the staining 
of the cell membrane (Yonemura Y; Ishida T; Tokunaga, A).  More recent studies 
which determine HER2 overexpression by IHC using monoclonal antibody 
(HercepTest™) and/or gene amplification by fluorescence in situ hybridization (FISH) 
have observed similar rates.  To date, most studies have noted a higher incidence of 
positivity in the gastroesophageal junction than in other areas of the stomach.
The recently reported ToGA trial centrally tested tumor samples using validated 
detection methods; IHC and FISH, and provided valuable information specific to 
gastroesophageal junction and stomach cancer.  This international, multicenter trial was 
the first large Phase III trial to provide prospective information on the incidence of 
HER2 positivity in advanced gastroesophageal junction- and gastric- cancer.  The 
investigators noted that of 2,168 tumors tested, 460 were positive (IHC 3+ and/or FISH 
+).  Of these, 20% of gastric cancer samples were positive and 34% of 
gastroesophageal junction samples were positive (Kang, et al, ASCO abstract 2008). 
Because of its selective expression on tumor cells, HER2 is a potential target for anti 
tumor therapies.  To facilitate the development of appropriate reagents for treating 
human cancer, a murine antibody against HER2 was “humanized”, that is, engineered 
so that the conserved units of the antibody molecule were transcribed from human 
DNA sequences, while the specific anti-HER2 domain remained of mouse DNA origin. 
As a result of these modifications, the antibody is not immunogenic in the vast majority 
of people.  The resulting antibody (Herceptin; Trastuzumab; Genentech) has been 
studied both as a single agent and in combination therapy.   
At least 3 clinical trials are exploring the addition of trastuzumab to chemotherapy in 
trials specifically for HER2-positive esophagogastric cancer.  Cortes-Funes, et al are 
conducting a Phase II trial to investigate the efficacy and tolerability of trastuzumab 
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plus cisplatin in chemo-naive patients.  The main inclusion criteria are: no prior 
chemotherapy, measurable and non resectable disease, ECOG < 2, LVEF ≥ 50%, and 
adequate organ function.  Prior adjuvant treatment is allowed.  Trastuzumab 8mg/kg 
(loading dose) and cisplatin 75mg/m2 on day one, followed by trastuzumab 6 mg/kg 
(maintenance dose) and cisplatin 75mg/m2 every 21 days.  Preliminary results show a 
35% response rate; no grade 4 toxicity has been documented.  
Nicholas et al are conducting a multicenter Phase II study of trastuzumab, cisplatin and 
docetaxel in patients with metastatic gastric and gastroesophageal junction cancer with 
FISH+ or IHC 3+ for HER2 overexpression.   They noted that 16% of tumors screened 
were HER2-positive.  The treatment regimen for this trial consists of cisplatin 
75mg/m2, docetaxel 75mg/m2, trastuzumab 8mg/kg (loading dose in cycle 1) and then 
6mg/kg in subsequent cycles (21 day cycles).  Grade 3 or 4 toxicities noted to date 
include peripheral neuropathy, abdominal cramping, neutropenia (one patient each).  
One patient died of an upper GI bleed.  Responses were recorded in five patients: one 
CR, three PR, and one SD.  
The study of trastuzumab added to standard chemotherapy in first-line human 
epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, known as 
the ToGA trial was presented at the ASCO Annual Meeting in 2009 (van Cutsem, et 
al).  Patients with HER2 positive tumors were randomized to receive trastuzumab and 
chemotherapy or chemotherapy alone every three weeks for 6 cycles.  After 6 cycles of 
chemotherapy, patients on the trastuzumab arm continued receiving trastuzumab alone 
until disease progression.  The primary objective of the study was to demonstrate 
superiority in overall survival of the trastuzumab arm, compared to standard 
chemotherapy alone. The chemotherapy regimen included capecitabine 1000mg/m2 po 
BID on days 1-14, or 5 F-U 800mg/m2/day as a continuous infusion on days 1-5 
(physicians choice) and cisplatin 80mg/m2 on day 1 of a three week cycle.   
Trastuzumab was administered as an 8mg/kg loading dose followed by 6 mg/kg every 
three weeks until disease progression.  
 
The ToGA trial demonstrated a 2.7 month improvement in overall survival (from 11.1 
months to 13.8 months; p=0.0046) for patients receiving trastuzumab.   Additionally, 
there was a 1.2 month improvement in progression-free survival and a 12.8% 
improvement in response rate for the patients receiving trastuzumab.  Trastuzumab 
increased the response rate from 34.5% to 47.3%.  Except for a slight increase in 
fatigue and diarrhea in the trastuzumab group, there was no significant increase in 
toxicity.   Cardiac toxicity included asymptomatic decline in LVEF (4.6% of patients) 
and was not thought to be clinically significant.  The investigators also noted that 
tumors exhibiting high (2+ or 3+) levels of HER2 expression experienced greater 
benefit; these patients had a median overall survival of 16 months.  The investigators 
concluded that trastuzumab is the first biologic agent to show a survival benefit in 
patients with advanced gastric cancer and suggested that the combination of 
trastuzumab plus chemotherapy be added as a treatment option for patients with HER2-
positive gastric cancer. 
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Trastuzumab is associated with the potential for left ventricular cardiac dysfunction and 
congestive heart failure (CHF).  In the pivotal trial of trastuzumab for metastatic breast 
cancer, the rate of cardiac dysfunction was highest when given concurrently with 
doxorubicin, with a rate of New York Heart Association (NYHA) class III/IV CHF of 
19%, versus 3% in the control group.  The rate of NYHA class III/IV CHF was much 
lower (4%) in patients receiving trastuzumab with paclitaxel (Slamon et al., 2001).  In 
an adjuvant study of carboplatin, docetaxel, and trastuzumab (BCIRG 006), the rate of 
grade 3 or 4 left ventricular cardiac dysfunction was 0.3% (4 events/1,056 patients) and 
no cardiac deaths were observed (Slamon et al., 2006).
Other reported adverse events include infusion reactions, characterized by fever, chills, 
nausea, vomiting, headache, dyspnea, hypotension, and rash.  Trastuzumab may also 
exacerbate chemotherapy-induced neutropenia. Trastuzumab treatment can very rarely 
result in serious pulmonary toxicity.  
               
2.1.2       Bevacizumab Clinical Experience
Bevacizumab has been evaluated in more than 5000 clinical subjects, having multiple 
different tumor types. In addition, data are available from 3,863 patients enrolled in two 
post-marketing studies in metastatic colorectal cancer (CRC).  Approximately 130,000 
patients have been exposed to bevacizumab as a marketed product or in clinical trials.  
The following discussion summarizes bevacizumab’s safety profile and presents some 
of the efficacy results pertinent to this particular trial. Please refer to the bevacizumab 
Investigator Brochure for descriptions of all completed Phase I, II, and III trials 
reported to date.
In a large Phase III study (AVF2107g) in patients with metastatic colorectal cancer, the 
addition of bevacizumab, a monoclonal antibody directed against vascular endothelial 
growth factor (VEGF), to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy 
resulted in a clinically and statistically significant increase in duration of survival, with 
a hazard ratio of death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).  
Similar increases were seen in progression-free survival (6.2 vs. 10.6 months; 
p < 0.001), overall response rate (35% vs. 45%; p < 0.01) and duration of response 
(7.1 vs. 10.4 months; p < 0.01) for the combination arm versus the chemotherapy only 
arm (bevacizumab Investigator Brochure, October 2005).
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was 
designated for priority review and was approved on February 26, 2004 in the United 
States for first-line treatment in combination with IV 5-FUbased chemotherapy for 
subjects with metastatic colorectal cancer. 
Additional data from Phase III trials in metastatic CRC (E3200), nonsmall cell lung 
cancer (NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated 
clinical benefit from bevacizumab when added to chemotherapy.  In Study E3200, the 
addition of bevacizumab to FOLFOX chemotherapy resulted in improved overall 
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survival compared with FOLFOX alone (13.0 vs. 10.8 months, respectively, HR  0.75; 
p  0.01) in a population of previously treated CRC patients.  
There was also improved overall survival in first-line NSCLC patients (E4599) treated 
with carboplatin/paclitaxel  bevacizumab compared with chemotherapy alone (12.3 
vs. 10.3 months, respectively; HR  0.80; p = 0.003).  The results from this trial were 
the basis for FDA approval of bevacizumab for use in combination with 
carboplatin  paclitaxel as first-line treatment of patients with unresectable, locally 
advanced, recurrent or metastatic, non-squamous NSCLC in October 2006.  
Among patients with metastatic breast cancer treated in the first-line setting (E2100), 
the combination of bevacizumab with paclitaxel was associated with significantly 
longer PFS compared with paclitaxel alone (median, 11.8 vs. 5.9 months, HR for 
progression 0.60; p<0.001).  The objective response rate was also significantly higher 
(36.9% vs. 21.2%, p<0.001) (Miller et al., 2007)
2.1.2.1
       Safety Profile
In the initial Phase I and II clinical trials, four potential bevacizumab-associated 
safety signals were identified: hypertension, proteinuria, thromboembolic events, 
and hemorrhage.  Additional completed Phase II and Phase III studies of 
bevacizumab as well as spontaneous reports have further defined the safety profile 
of this agent. Bevacizumab-associated adverse events identified in Phase III trials 
include congestive heart failure (CHF) (primarily in metastatic breast cancer), 
gastrointestinal 
perforations, 
wound 
healing 
complications, 
and 
arterial 
thromboembolic events (ATE). These and other safety signals are described in 
further detail as follows and in the bevacizumab Investigator Brochure.
Hypertension: An increased incidence of hypertension has been observed in 
patients treated with bevacizumab.  Grade 4 and 5 hypertensive events are rare. 
Clinical sequelae of hypertension are rare but have included hypertensive crisis, 
hypertensive encephalopathy, and reversible posterior leukoencephalopathy 
syndrome (RPLS) (Ozcan et al., 2006; Glusker et al., 2006). 
There is no information on the effect of bevacizumab in patients with uncontrolled 
hypertension at the time of initiating bevacizumab therapy.  Therefore, caution 
should be exercised before initiating bevacizumab therapy in these patients.  
Monitoring of blood pressure is recommended during bevacizumab therapy.  
Optimal control of blood pressure according to standard public health guidelines is 
recommended for patients on treatment with or without bevacizumab.  
Temporary interruption of bevacizumab therapy is recommended in patients with 
hypertension requiring medical therapy until adequate control is achieved.  
If hypertension cannot be controlled with medical therapy, bevacizumab therapy 
should be permanently discontinued.  Bevacizumab should be permanently 
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discontinued in patients who develop hypertensive crisis or hypertensive 
encephalopathy.
Proteinuria:  An increased incidence of proteinuria has been observed in patients 
treated with bevacizumab compared with control arm patients.  In the 
bevacizumab-containing treatment arms of clinical trials (across all indications), the 
incidence of proteinuria (reported as an adverse event) was up to 38% (metastatic 
CRC Study AVF2192g). The severity of proteinuria has ranged from asymptomatic 
and transient events detected on routine dipstick urinalysis to nephrotic syndrome; 
the majority of proteinuria events have been grade 1. NCI-CTC Grade 3 proteinuria 
was reported in up to 3% of bevacizumab-treated patients, and Grade 4 in up to 
1.4% of bevacizumab-treated patients.  The proteinuria seen in bevacizumab 
clinical trials was not associated with renal impairment and rarely required 
permanent discontinuation of bevacizumab therapy.  Bevacizumab should be 
discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome).
Patients with a history of hypertension may be at increased risk for the development 
of proteinuria when treated with bevacizumab.  There is evidence from the dose-
finding, Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that 
Grade 1 proteinuria may be related to bevacizumab dose.
Proteinuria will be monitored by urine protein: creatinine (UPC) ratio 
approximately every 6 weeks (2 cycles).  
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, 
ranging in severity from catheter-associated phlebitis to fatal, have been reported in 
patients treated with bevacizumab in the colorectal cancer trials and, to a lesser 
extent, in patients treated with bevacizumab in NSCLC and breast cancer trials. 
Venous thromboembolism (including deep venous thrombosis, pulmonary 
embolism, and thrombophlebitis:  In the Phase III pivotal trial in metastatic CRC, 
there was a slightly higher rate of venous TE events in patients treated with 
bevacizumab plus chemotherapy compared with chemotherapy alone (19% vs. 
16%). 
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, 
including deep venous thrombosis, pulmonary embolism, and thrombophlebitis, 
occurred in 15.2% of patients receiving chemotherapy alone and 16.6% of patients 
receiving chemotherapy  bevacizumab. 
The incidence of NCI-CTC Grade  3 venous VTE events in one NSCLC trial 
(E4599) was higher in the bevacizumab-containing arm compared to the 
chemotherapy control arm (5.6% vs. 3.2%).  One event (0.2%) was fatal in the 
bevacizumab-containing arm; not fatal events were reported in the 
carboplatin/paclitaxel arm (see bevacizumab Investigator Brochure).  In metastatic 
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CRC clinical trials, the incidence of VTE events was similar in patients receiving 
chemotherapy  bevacizumab and those receiving the control chemotherapy alone. 
In clinical trials across all indications the overall incidence of VTE events was 
2.8%17.3% in the bevacizumab-containing arms compared with 3.2%15.6% in 
the chemotherapy control arms.  The use of bevacizumab with chemotherapy does 
not substantially increase the risk of VTE event compared with chemotherapy 
alone.  However, patients with metastatic CRC who receive bevacizumab and 
experienced a VTE event may be at higher risk for recurrence of VTE event.
Arterial Thromboembolic Events:  An increased incidence of ATE events was 
observed in patients treated with bevacizumab compared with those receiving 
control treatment.  ATE events include cerebrovascular accidents, myocardial 
infarction, transient ischemic attacks (TIAs), and other ATE events.  In a pooled 
analysis of data from five randomized Phase II and III trials (mCRC [AVF2107g, 
AVF2192g, AVF0780g]; locally advanced or metastatic NSCLC [AVF0757g]; and 
metastatic breast cancer [AVF2119g]), the incidence rate of ATE events was 3.8% 
(37 of 963) in patients who received chemotherapy  bevacizumab compared with 
1.7% (13 of 782) in patients treated with chemotherapy alone.  ATE events led to a 
fatal 
outcome 
in 
0.8% 
(8 
of 
963) 
of 
patients 
treated 
with 
chemotherapy  bevacizumab and 0.5% (4 of 782) of patients treated with 
chemotherapy alone.  Cerebrovascular accidents (including TIAs) occurred in 2.3% 
of patients treated with chemotherapy  bevacizumab and 0.5% of patients treated 
with chemotherapy alone.  Myocardial infarction occurred in 1.4% of patients 
treated with chemotherapy  bevacizumab compared with 0.7% of patients treated 
with chemotherapy alone (see the bevacizumab Investigator Brochure for additional 
details).
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of aspirin 
≤ 325 mg daily was allowed in the five randomized studies discussed above. Use of 
aspirin was assessed routinely as a baseline or concomitant medication in these 
trials, though safety analyses specifically regarding aspirin use were not preplanned. 
Due to the relatively small numbers of aspirin users and arterial thromboembolic 
events, retrospective analyses of the ability of aspirin to affect the risk of such 
events were inconclusive. However, similarly retrospective analyses suggested that 
the use of up to 325 mg of aspirin daily does not increase the risk of grade 1-2 or 
grade 3-4 bleeding events, and similar data with respect to metastatic colorectal 
cancer patients were presented at ASCO 2005 (Hambleton et al., 2005). Further 
analyses of the effects of concomitant use of bevacizumab and aspirin in colorectal 
and other tumor types are ongoing.
Gastrointestinal perforation: Patients with metastatic carcinoma may be at 
increased risk for the development of gastrointestinal perforation and fistula when 
treated with bevacizumab and chemotherapy. Bevacizumab should be permanently 
discontinued in patients who develop gastrointestinal perforation. A causal 
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association of intra-abdominal inflammatory processes and gastrointestinal 
perforation to bevacizumab treatment has not been established. Nevertheless, 
caution should be exercised when treating patients with intra-abdominal 
inflammatory processes with bevacizumab. Gastrointestinal perforation has been 
reported in other trials in non-colorectal cancer populations (e.g., ovarian, renal cell, 
pancreas, breast, and NSCLC) and may be higher in incidence in some tumor types.
Fistula:  Bevacizumab use has been associated with serious cases of fistulae 
including events resulting in death.  Fistulae in the GI tract are common (1%–10% 
incidence) in patients with metastatic CRC, but uncommon (0.1%1%) or rare 
(0.01%–0.1%) in other indications.  In addition, fistulae that involve areas of the 
body other than the GI tract (e.g., tracheoesophageal, bronchopleural, urogenital, 
biliary) have been reported uncommonly (0.1%–1%) in patients receiving 
bevacizumab in clinical studies and postmarketing reports.  Events were reported at 
various timepoints during treatment, ranging from 1 week to  1 year following 
initiation of bevacizumab, with most events occurring within the first 6 months of 
therapy.
Bevacizumab 
should 
be 
permanently 
discontinued 
in 
patients 
with 
tracheoesophageal fistulae or any Grade 4 fistula.  Limited information is available 
on the continued use of bevacizumab in patients with other fistulae.  In cases of 
internal fistula not arising in the GI tract, discontinuation of bevacizumab should be 
considered.
Wound healing complications: Wound healing complications such as wound 
dehiscence have been reported in patients receiving bevacizumab. In an analysis of 
pooled data from two trials in metastatic colorectal cancer, patients undergoing 
surgery 28-60 days before study treatment with 5-FU/LV plus bevacizumab did not 
appear to have an increased risk of wound healing complications compared to those 
treated with chemotherapy alone (Scappaticci et al., 2005). Surgery in patients 
currently receiving bevacizumab is not recommended. No definitive data are 
available to define a safe interval after bevacizumab exposure with respect to 
wound healing risk in patients receiving elective surgery; however, the estimated 
half life of bevacizumab is 21 days. Bevacizumab should be discontinued in 
patients with severe wound healing complications.
If patients receiving treatment with bevacizumab require elective major surgery, it 
is recommended that bevacizumab be held for 4–8 weeks prior to the surgical 
procedure.  Patients undergoing a major surgical procedure should not begin or 
restart bevacizumab until 4 weeks after that procedure (in the case of high-risk 
procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that chemotherapy be restarted no earlier than 6 weeks and 
bevacizumab no earlier than 8 weeks after surgery).
Hemorrhage: Overall, Grade 3 and 4 bleeding events were observed in 4.0% of 
1132 patients treated with bevacizumab in a pooled database from eight Phase I, II, 
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and III clinical trials in multiple tumor types (bevacizumab Investigator Brochure, 
October 2005). The hemorrhagic events that have been observed in bevacizumab 
clinical studies were predominantly tumor-associated hemorrhage (see below) and 
minor mucocutaneous hemorrhage. 
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC.  Life-threatening 
and fatal hemoptysis was identified as a bevacizumab-related adverse event in 
NSCLC trials.  These events occurred suddenly and presented as major or massive 
hemoptysis.  Among the possible risk factors evaluated (include squamous cell 
histology, treatment with anti-rheumatic/anti-inflammatory drugs, treatment with 
anticoagulants, prior radiotherapy, bevacizumab therapy, previous medical history 
of atherosclerosis, central tumor location, and cavitation of tumors during therapy), 
the only variables that showed statistically significant correlations with bleeding 
were bevacizumab therapy and squamous cell histology.
Of patients experiencing pulmonary hemorrhages requiring medical intervention, 
many had cavitation and/or necrosis of the tumor, either preexisting or developing 
during bevacizumab therapy.  Patients developing lung cavitation on treatment 
should be assessed by the treating physician for risk-benefit.
In Study E4599, in which squamous cell carcinoma was excluded, the rate of any 
type of Grade  3 hemorrhage was 1.0% in the control arm (carboplatin and 
paclitaxel) versus 4.1% in the carboplatin and paclitaxel  bevacizumab arm 
(Sandler et al. 2006).  
GI hemorrhages, including rectal bleeding and melena have been reported in 
patients with CRC, and have been assessed as tumor-associated hemorrhages.
Tumor-associated hemorrhages were also seen rarely in other tumor types and 
locations, including a case of CNS bleeding in a patient with hepatoma with occult 
CNS metastases and a patient who developed continuous oozing of blood from a 
thigh sarcoma with necrosis.  A recent review examined the risk of CNS 
hemorrhage in association with anti-VEGF therapy.  Among 669 patients treated on 
Phase I and II studies of bevacizumab that excluded brain metastases, only 1 case 
(0.2%) of CNS bleeding was reported (Carden et al, 2008).  Bevacizumab has also 
been studied as treatment for refractory, high-grade gliomas.  
Mucocutaneus 
Hemorrhage: 
 
Across 
all 
bevacizumab 
clinical 
trials, 
mucocutaneous hemorrhage has been seen in 20%-40% of patients treated with 
bevacizumab. These were most commonly NCI-CTC Grade 1 epistaxis that lasted 
less than 5 minutes, resolved without medical intervention and did not require any 
changes in bevacizumab treatment regimen. 
There have also been less common events of minor mucocutaneous hemorrhage in 
other locations, such as gingival bleeding and vaginal bleeding. 
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Reversible Posterior Leukoencephalopathy Syndrome:  There have been rare 
reports of bevacizumab-treated patients developing signs and symptoms that are 
consistent with RPLS, a rare neurological disorder that can present with the 
following signs and symptoms (among others):  seizures, headache, altered mental 
status, visual disturbance, or cortical blindness, with or without associated 
hypertension.  Brain imaging is mandatory to confirm the diagnosis of RPLS.  In 
patients who develop RPLS, treatment of specific symptoms, including control of 
hypertension, is recommended along with discontinuation of bevacizumab.  The 
safety of reinitiating bevacizumab therapy in patients previously experiencing 
RPLS is not known (Glusker et al. 2006; Ozcan et al. 2006).  
Congestive heart failure:  In clinical trials, CHF was observed in all cancer 
indications studied to date, but predominantly in patients with metastatic breast 
cancer.  In the Phase III clinical trial of metastatic breast cancer (AVF2119g), 7 
(3%) bevacizumab-treated patients experienced CHF, compared with two (1%) 
control arm patients.  These events varied in severity from asymptomatic declines in 
left ventricular ejection fraction (LVEF) to symptomatic CHF requiring 
hospitalization and treatment.  All the patients treated with bevacizumab were 
previously treated with anthracyclines (doxorubicin cumulative dose of 
240360 mg/m2).  Many of these patients also had prior radiotherapy to the left 
chest wall.  Most of these patients showed improved symptoms and/or left 
ventricular function following appropriate medical therapy (Miller et al. 2005).
In a randomized, Phase III trial of patients with previously untreated metastatic 
breast cancer (E2100), the incidence of LVEF decrease (defined as NCI-CTC Grade 
3 or 4) in the paclitaxel  bevacizumab arm was 0.3% versus 0% for the paclitaxel 
alone arm. 
No information is available on patients with preexisting CHF of New York Heart 
Association (NYHA) Class IIIV at the time of initiating bevacizumab therapy, as 
these patients were excluded from clinical trials.
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall may be 
possible risk factors for the development of CHF.  Caution should be exercised 
before initiating bevacizumab therapy in patients with these risk factors.
A Phase II trial in patients with refractory acute myelogenous leukemia reported 
5 cases of cardiac dysfunction (CHF or LVEF decrease to  40%) among 
48 patients treated with sequential cytarabine, mitoxantrone, and bevacizumab.  All 
but 1 of these patients had significant prior exposure to anthracyclines as well (Karp 
et al. 2004). 
Two additional studies investigated concurrent administration of anthracyclines and 
bevacizumab.  In 21 patients with inflammatory breast cancer treated with 
neoadjuvant docetaxel, doxorubicin, and bevacizumab, no patients developed 
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clinically apparent CHF; however, patients had asymptomatic decreases in LVEF to 
 40% (Wedam et al. 2004).  In a small Phase II study in patients with soft tissue 
sarcoma, 2 of the 17 patients treated with bevacizumab and high-dose doxorubicin 
(75 mg/m2) developed CHF (one Grade 3 event after a cumulative doxorubicin dose 
of 591 mg/m2, one Grade 4 event after a cumulative doxorubicin dose of 
420 mg/m2); an additional 4 patients had asymptomatic decreases in LVEF 
(D’Adamo et al. 2004).
Other studies in patients with various tumor types and either a history of 
anthracycline exposure or concomitant use with bevacizumab are ongoing. 
Patients receiving concomitant anthracyclines or with prior exposure to 
anthracyclines should have a baseline MUGA scans or echocardiograms (Echo’s) 
with a normal LVEF.
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or 
infection with severe neutropenia (including some fatalities) have been observed in 
patients treated with some myelotoxic chemotherapy regimens plus bevacizumab in 
comparison to chemotherapy alone (Sandler et al. 2006).
Additional Adverse Events:  See the bevacizumab Investigator Brochure for 
additional details regarding the safety experience with bevacizumab.
2.1.3      Platinum and Fluorouracil Based Chemotherapy
In the United States, platinum and fluorouracil based regimens of chemotherapy are 
considered the standard of care for both locally advanced and metastatic esophagogastric 
cancers.  These regimens include: CF, ECF, ECX, EOX, EOF, FOLFOX, CAPOX and 
have response rates of 40-67%.  Among these, regimens that incorporate the combination 
of oxaliplatin and a fluropyrimidine have response rates of 38-56%, time to progression 
of 5.2-7.1 months, and overall survival of 7.1-11.4 months.  Grade 3 and 4 toxicity has 
included neutropenia (5-63%), febrile neutropenia (2-11%), thrombocytopenia (2-13%), 
diarrhea (4-17%), emesis (2-13%), stomatitis (0-9%), asthenia (0-17%), and neurological 
toxicity (0-13%).
Mauer and colleagues (Ann Oncol, 2005) evaluated the FOLFOX regimen in 30 patients 
with esophageal cancer and 5 patients with gastric cancer.  The majority of these patients 
had adenocarcinoma.  34 of these patients were evaluable for response; the overall 
response rate was 40% (95% confidence interval, 24-57%).  The median duration of 
response was 4.6 months, median overall survival was 7.1 months, and the 1-year 
survival was 31%.  Grade 3 and 4 toxicity was primarily neutropenia (63%), diarrhea 
(11%), fatigue (9%), and anorexia (6%).  The authors concluded that there was 
significant anti-tumor activity and a favorable toxicity profile with this regimen for 
patients with esophagogastric cancer.
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The REAL2 trial (Cunningham, NEJM 2008) was a large randomized trial that compared 
four different chemotherapy regimens in 1002 patients with advanced gastric cancer.  The 
regimens were ECF (epirubicin, cisplatin and infusional 5-FU), ECX (epirubicin, 
cisplatin and capecitabine), EOF (epirubicin, oxaliplatin and infusional 5-FU) and EOX 
(epirubicin, oxaliplatin and capecitabine).  The study demonstrated comparable outcomes 
with either infusional 5-FU or oral capecitabine and with either cisplatin or oxaliplatin.  
There was also a trend towards improved median overall survival for the EOX arm when 
compared to ECF arm: 11.2 months vs. 9.9 months, [HR 0.85, 95% CI (0.65-0.97)].  
More recent clinical trials by Kang (ASCO 2006, Ann Oncol 2009) and Al-Batran (JCO 
2008) also suggest that oxaliplatin and capecitabine are good substitutes for the more 
traditional cisplatin and infusional 5-FU.
In a Phase II trial by the NCCTG (North Central Cancer Treatment Group), Jatoi and 
colleagues studied CAPOX (capecitabine and oxaliplatin) in patients with metastatic 
adenocarcinoma of the esophagus, GE junction and gastric cardia (Jatoi, Ann Oncol, 
2006).   Oxaliplatin 130mg/m2/day 1 and capecitabine 1000mg/m2/bid po/days 1-14 
were initially given to chemo-naïve patients.  The investigators found it necessary to 
reduce the dose of capecitabine to 850mg/m2/bid/po on days 1-14 due to toxicity noted 
in the first 24 patients.  Of the 43 patients evaluable for response, there was an overall 
response rate of 35% [95% confidence interval (CI) 23% to 50%].   Due to the findings 
of the forementioned study, we initiated 09-457 study with the recommended dose of 
oxaliplatin 130 mg/m2 every 3 weeks and capecitabine 850 mg/m2 po bid on days 1-14 
of a 21-day cycle.  The PI has discovered that 4 of the first 5 patients treated on this 
trial have required dose attenuation of capecitabine after the 3rd cycle due to diarrhea.  
Diarrhea is an expected toxicity of capecitabine, and this trend is reflective of the 
known median time to first occurrence of diarrhea being approximately 34 days.  As a 
result of this, there will be a modification of the starting dose of capecitabine to 
600mg/m2 po bid on days 1-14 for all subsequent patients enrolled to this trial.  
Two recent studies have demonstrated that the addition of bevacizumab to 
chemotherapy regimens for metastatic esophagogastric cancer is well tolerated and can 
be administered safely.  In both studies there also appears to be an improvement in 
response rate when compared to standard chemotherapy regimens (Shah, JCO 2005; 
Enzinger, ASCO 2008).    Shah observed no significant increase in chemotherapy 
related toxicity.  Possible bevacizumab related toxicity included a 28% incidence of 
Grade 3 hypertension, gastric perforation (6%), and myocardial infarction (2%).  Grade 
3 or 4 thromboembolic events occurred in 25% of patients.  They concluded that 
bevacizumab could be added to chemotherapy safely and is active in the treatment of 
advanced gastric and GE junction adenocarcinoma.   A Phase II study at Dana-Farber 
Harvard Cancer Center (Enzinger, ASCO 2008) of Docetaxel, Cisplatin, Irinotecan and 
Bevacizumab in Metastatic Esophageal and Gastric Cancer (TPCA), is currently under 
investigation. The study is now closed to enrollment and the data are being compiled.  
The palliative effect of this regimen appears to be significant, with many patients 
noting improvement or resolution of their dysphagia after one cycle of therapy.  An 
EGD was performed on consenting patients after one cycle of therapy to perform visual 
tumor assessment and obtain biopsy sample of tumor for correlative science studies.  
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The procedure was well tolerated by all patients, with no toxicity or hemorrhagic events 
noted after the EGD was performed.   Preliminary data suggests that this regimen can 
be safely administered to patients with advanced esophagogastric cancer and there are 
promising results in the first 32 patients that are evaluable.  Partial responses are noted 
in 22 patients (69%).   Survival data is being analyzed.   Patients were required to take 
ASA 81 mg po daily (unless contraindicated due to allergy or other reasons).  To date, 
there have been significantly less thromboembolic events (9%, Grade 3 or 4 events) 
than reported by Shah, et al. (25%). Only one patient is reported to have had a Grade 3 
or 4 hemorrhagic event.
The combination of trastuzumab and bevacizumab has been studied in both Phase I and 
II clinical trials (Pegram, et al, 2004; Pegram, et al, 2006).  The Phase 1 study indicated 
a potentially enhanced antitumor response and the PK data set indicates that co-
administration of trastuzumab and bevacizumab does not alter the PK of either agent.  
The MTD was not reached on this study, as there were no Grade 3 or 4 adverse events 
noted.  Grade 1 or 2 adverse events possibly or probably related to the combination 
included diarrhea, fatigue, and nausea.  No cases of Grade 3 or 4 cardiac dysfunction 
were observed and the recommended Phase 2 dose was set as 10 mg/kg of bevacizumab 
every 14 days plus trastuzumab 4 mg/kg loading dose, then 2 mg/kg weekly.
Final results from the Phase 2 trial in first-line treatment of HER2- amplified advanced 
breast cancer was presented in a poster at the 32nd San Antonio Breast Cancer 
Symposium, on December 13th, 2009 (Hurvitz SA, Pegram, MD, et al: Poster 6094).  In 
this trial, 50 patients were enrolled between 12/2004-4/2007.   Based on results from 
phase 1 trial, the treatment consisted of Bevacizumab 10mg/kg every 2 weeks, and 
Trastuzumab 4mg/kg loading dose, followed by 2mg/kg weekly.   Major inclusion 
criteria: women, aged 18-75 years, confirmed unresectable or metastatic breast cancer, 
confirmed HER2- amplification by FISH, ECOG: 0-2, normal left ventricular function 
by MUGA scan or echocardiogram.  Major exclusion: more than 3 different organ sites 
of metastasis, prior chemotherapy, bevacizumab or trastuzumab in the metastatic 
setting, adjuvant trastuzumab was allowed if discontinued 1 year prior to study entry, 
uncontrolled hypertension, history of bleeding diathesis or coagulopathy, and 
proteinuria.   Patients were treated with median of 6.25 cycles.  Adverse events leading 
to withdrawal from the study were grade 3 proteinuria (n = 3), grade 2 recurrent 
proteinuria (n = 1), grade 2 decreased LVEF (n = 2), grade 4 LV dysfunction (n = 1), 
required surgery for T2 compression fracture (n = 1), grade 2 bevacizumab-related 
rectal vaginal fistula (n = 1), poor quality of life due to grade 2 epistaxis and grade 1 
fatigue (n = 1), and death due to sepsis after surgery for bevacizumab-related gastric 
perforation (n = 1).  The authors noted that hypertension was the most common adverse 
event with this combination, noted as a grade 3 event in 18 (36%) and as a grade 1 or 2 
event in 12 additional patients.  (**Of note, this is based on Version 2.0 of the CTCAE 
criteria, guidelines for documentation of hypertension have been changed in more 
recent versions.   Most events considered grade 3 in version 2.0 would be grade 2 with 
the more current versions).  One patient, who had previously received doxorubicin, 
experienced a grade 4 decrease in LVEF at the end of cycle 2.  Fifteen additional 
patients had grade 1/2 treatment-related asymptomatic decreases in LVEF.  No 
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significant correlation was found between prior anthracycline exposure and decrease in 
LVEF of any grade (Spearman correlation 0.11, P = .4) No significant correlation was 
found between hypertension events and decrease in LVEF (Spearman correlation 0.17, 
P = .22).  Grade 3/4 treatment-related adverse events occurring in ≥2 patients were 
dyspnea (1 grade 4, 1 grade 3), grade 3 hypertension (n = 18), proteinuria (n = 4), 
headache (n = 2), and infusion reaction (n = 2).  Treatment-related adverse events of 
any grade occurring in ≥10 patients were hypertension (n = 30), cardiac events (n = 19), 
headache (n = 17), epistaxis (n = 17), fatigue (n = 15), proteinuria (n = 12), elevated 
aspartate transaminases (AST) and/or alanine transaminase (ALT) levels (n = 12), 
fever/chills (n = 12), and diarrhea (n = 10).  The authors noted objective responses in 24 
patients (48%), including 2 CRs (WHO criteria).  The authors concluded that despite 
the absence of chemotherapy, trastuzumab plus bevacizumab is clinically feasible and 
active as first line therapy for patients with locally advanced and unresectable 
metastatic breast cancer.   Also presented at the 2009 San Antonio Breast Cancer 
symposium was an abstract (Falchook, G.S., Moulder, S, et al: Abstract 244) of a Phase 
1 trial combining trastuzumab, lapatinib, and bevacizumab in HER2- positive breast 
cancer and other malignancies.   Patients with advanced malignancy refractory to 
standard therapy were eligible.  The treatment consisted of 3 week cycles with 
trastuzumab 6mg/kg loading dose, and 4mg/kg maintenance dose, lapatinib 750mg and 
bevacizumab 7.5mg/kg.  Data on 24 treated patients was presented in this abstract.  The 
most common drug related toxicities were hypertension (21%), fatigue (21%) and 
diarrhea (17%).  No cardiomyopathy was observed in these patients.  The authors noted 
that the combination was well tolerated and demonstrated preliminary evidence of 
clinical activity in advanced HER-2 positive breast cancer refractory to prior 
trastuzumab and lapatinib, suggesting that this combination of agents may overcome 
resistance to previous HER-2 therapy.  
Additional studies combining bevacizumab, trastuzumab and chemotherapy agents 
have been presented at recent ASCO meetings.  A multicenter trial of weekly nab-
paclitaxel, carboplatin plus bevacizumab and trastuzumab in HER2- positive locally 
advanced breast cancer (Yardley, D.A., et al.  ASCO 2009: Abstract: 527) reports data 
on 29 patients evaluable for toxicity.  Treatment consisted of nab-paclitaxel 125mg/m2 
on days 1, 8, 15 and carboplatin AUC 6 on day 1 every 28 days. In addition, 
trastuzumab 4mg/kg loading dose, followed by 2mg/kg weekly maintenance dose plus 
bevacizumab 5mg/kg weekly for 6 cycles followed by surgery.  Post surgery 
trastuzumab and bevacizumab continued for 52 weeks.  The authors reported no 
unexpected toxicity and evidence of LVEF dysfunction in 1 patient.  Also presented at 
ASCO 2009 meeting (Smith, J. W., et al: ASCO2009, Abstract:580) was a trial of 
Epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab and 
bevacizumab as neoadjuvant therapy for HER2-positive breast cancer or as adjuvant 
therapy for HER2-positive stage III breast cancer.  The purpose of this trial was to 
determine the cardiac safety profile of the agents.  Preliminary data showed grade 2 
LVEF dysfunction in 5 patients and grade 3 LVEF dysfunction in 2 patients, one of 
whom had symptomatic CHF.  The authors concluded the regimen had an acceptable 
preliminary rate of cardiac toxicity.  
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There is one active, IRB approved Phase II study at DF/HCC that combines 
chemotherapy (carboplatin) with bevacizumab and trastuzumab for breast cancer 
patients with brain metastasis (09-224, Nancy Lin, MD).  This Phase II study has 
enrolled 4 patients to date with all four of these patients receiving both bevacizumab 
and trastuzumab as well as carboplatin. Of the 4 patients, one was taken off study for 
progressive disease at the time of the first restaging, and 3 patients have had first 
restaging and are continuing on treatment.  The patient that was taken off study had an 
incidental finding of a grade 3 IVC thrombus that was considered possibly related to 
the study medication.  No significant cardiac toxicity has been reported (conversation 
with study staff).
A trial to evaluate the combination of oxaliplatin and trastuzumab in patients with 
metastatic breast cancer (Yardley, 2008 Breast Cancer Symposium) demonstrated 
tolerability of this combination with no significant increase in Grade 3 or 4 toxicity.  
The combination of CAPOX plus trastuzumab has not been reported in any cancer.  
2.2     Study disease
In 2009, the American Cancer Society estimates that 37,600 Americans will be diagnosed with 
esophagogastric cancer and predicts there will be 25,100 deaths.   The prognosis is related to the 
stage of disease at diagnosis. The majority of patients, however, present with metastatic or 
advanced disease. Symptoms such as dysphagia, GI bleeding or weight loss often do not develop 
until the disease is locally advanced or metastatic.  Patients with locally advanced disease have a 
five-year survival of 20-30%.  Despite recent chemotherapeutic advances, median survival for 
patients with metastatic disease remains less than 10 months.  
The histopathology and natural history of esophageal and gastric adenocarcinoma appears to be 
quite similar and the two cancers respond similarly to chemotherapy. The goal of chemotherapy 
with esophagogastric cancer is most often to palliate symptoms and improve survival.  The 
addition of targeted therapies to chemotherapy is being studied in esophagogastric cancer with 
the goal of improving response rates and overall survival.
2.3     Rationale
Based on the above data, we propose to conduct this Phase II study to determine the rate of 
response for patients with HER2-positive esophagogastric adenocarcinoma receiving CAPOX 
plus bevacizumab plus trastuzumab.  Recent data presented at ASCO 2009 and the 2009 San 
Antonio Breast Cancer symposium have demonstrated safety and tolerability of the combination 
of bevacizumab and trastuzumab with chemotherapy. The ToGA study has made 
capecitabine/platinum + trastuzumab a recommended standard of care for HER2 positive 
esophagogastric cancers (van Cutsem, Proc ASCO 2009).  The recently completed AVAGAST 
study (Protocol ID NCT00548548) may similarly elevate capecitabine/platinum + bevacizumab 
to another standard of care in this disease at the ASCO 2010 meeting.  If the AVAGAST study is 
positive, medical oncologists will want to combine these two regimens in patients with HER2 
positive tumors.
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The REAL 2 study, the largest ever phase III study in advanced esophageal and gastric cancer, 
found that capecitabine may replace 5-FU and oxaliplatin may replace cisplatin in regimens used 
for the treatment of advanced esophageal and gastric cancer.  The CAPOX regimen is a well 
established regimen, with known toxicity profile and is used for the treatment of a variety GI 
malignancies. Oral capecitabine allows for ease of administration, independence and patient 
convenience.  The schedule of every-three-week oxaliplatin, bevacizumab and trastuzumab will 
allow us to recruit from a larger geographical area.  
3.  PARTICIPANT SELECTION
3.1 
Eligibility Criteria
Participants must meet the following criteria to be eligible to participate in the study:
3.1.1
Participants must have confirmed HER2-positive esophageal, GE junction or gastric 
adenocarcinoma (including undifferentiated and adenosquamous carcinoma) that is 
metastatic or unresectable.  HER-2 testing will be performed using IHC or FISH.  
Any one of the following criteria would apply for this study:
IHC: 3+
IHC: 2+, with confirmation by FISH required
FISH positive 
           
3.1.2       All patients must have available tumor sample (either paraffin block or 15 freshly cut, 
unstained slides) prior to study entry.  
Part II: All patients must have primary esophagogastric tumor in place or other tumor 
that is accessible for mandatory biopsy.
3.1.3       Participants must have measurable disease, defined in RECIST 1.1.  Refer to section 10.
3.1.4     Age: ≥18 years. 
3.1.5      Life expectancy of greater than 12 weeks.
3.1.6   ECOG performance status <2. 
3.1.7
  Organ and marrow function as defined below:

Absolute neutrophil count > 1,500/mcL

Platelets > 100,000/mcL

Hemoglobin ≥ 9

total bilirubin less than 1.5 X institutional upper limit of normal

AST (SGOT) and ALT (SGPT) < 3 X institutional upper limit of normal, or <5 X 
upper limit of normal if liver metastases are  present
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
Alkaline phosphatase <2.5X institutional upper limit of normal or <5X if liver 
metastases are present or <10X if bone metastases are present

Serum creatinine less than 2.0mg/dL.

eGFR greater than 50ml/min/1.73m2 (if patient is African-American, multiply results 
by 1.21)

Urine Protein/Creatinine ratio less than 1
3.1.8      Women of child-bearing potential and men must agree to use adequate     
contraception (hormonal or barrier method of birth control; abstinence) during study 
participation, and for 30 days from the date of the last study drug administration. 
3.1.9
  Ability to understand and the willingness to sign a written informed consent document. 
3.1.10
 Part II only: Participant agrees to undergo mandatory pre and post loading dose of  
trastuzumab biopsy for correlative science.
3.2       Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study.
                      
3.2.1 
Prior therapy with any of the following: capecitabine, oxaliplatin, bevacizumab or 
trastuzumab is not allowed.  May have received and completed adjuvant therapy at least 
6 months prior to study entry or one prior therapy for metastatic disease as long as it did 
not include any of the above agents.
3.2.2      Chemotherapy within 4 weeks prior to entering the study or radiotherapy to greater 
than 25% of bone marrow within 4 weeks prior to entering the study.    
3.2.3 
Palliative radiation therapy to isolated bone metastasis within 2 weeks of initiating 
therapy.
3.2.4 
Major surgery, open biopsy, significant traumatic injury within 4 weeks prior to study 
entry.    
3.2.5
Minor surgery, including placement of vascular access device within 7 days prior to 
first dose of bevacizumab.
3.2.6 
Residual toxicity from prior chemotherapy and/or radiation therapy of Grade 2 or 
greater.                 
3.2.7      Participants may not be receiving any concurrent investigational agents.
3.2.8      Active brain or other CNS metastasis by history or clinical examination.
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3.2.9 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to capecitabine, bevacizumab or trastuzumab.  No known 
allergy or hypersensitivity to Chinese hamster ovary, or any of the study agents.  
No known DPD deficiency.
3.2.10    Warfarin is prohibited; anticoagulation using low molecular weight heparin is 
allowed.
3.2.11    Uncontrolled, intercurrent illness including, but not limited to ongoing or active 
infection, history of congestive heart failure, or psychiatric illness/social situations 
that would limit compliance with study requirements.
3.2.12    Patients with history of other malignancy are not eligible except for the   following 
circumstances:
Individuals with a history of other malignancies are eligible if they have been disease-
free for at least 3 years and are deemed by the investigator to be at low risk for 
recurrence of that malignancy. 
Individuals with the following cancers are eligible if diagnosed and treated with 
curative intent within the past 5 years: cervical cancer in situ, basal cell or squamous 
cell carcinoma of the skin. 
3.2.13     Known HIV seropositivity, Hepatitis C, acute or chronic Hepatitis B or other serious 
active infection.
3.2.14     LVEF less than 50% as determined by MUGA scan or echocardiogram within 28 days 
prior to initiation of therapy.
3.2.15     Inadequately controlled hypertension, defined as BP greater than systolic 150 and/or 
diastolic of greater than 100 mmHg.   Initiation of antihypertensive medication is 
recommended, and adequate control must be documented prior to C1D1.
3.2.16     History of prior hypertensive crisis or hypertensive encephalopathy.
3.2.17     History of any arterial thrombosis, CVA, TIA, MI or unstable angina in past6 months.
3.2.18     Evidence of bleeding diathesis or coagulopathy (other than deep venous thrombosis, 
portal vein thrombosis, treated pulmonary embolism, atrial fibrillation).  Patients on 
therapeutic anticoagulation with low molecular weight heparin may be enrolled 
provided they have been clinically stable on anticoagulation for at least 2 weeks prior to 
initiation of bevacizumab therapy.
3.2.19     Serious, unhealed wounds, bone fractures or skin ulcers.
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3.2.20     Pregnant or breast feeding. (Women of child bearing potential must have negative 
urine or serum pregnancy test within 14 days prior to start of therapy)
3.2.21     >Grade 1 peripheral neuropathy at baseline.
3.2.22     Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome
4. REGISTRATION PROCEDURES
4.1. General Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registration must occur prior to the 
initiation of therapy. Any participant not registered to the protocol before treatment begins 
will be considered ineligible and registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will complete 
the QACT protocol-specific eligibility checklist.
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study may be canceled. Notify the QACT Registrar of registration cancellations as soon as 
possible.
4.2   Registration Process for DF/HCC and DF/PCC Institutions
The QACT registration staff is accessible on Monday through Friday; from 8:00 AM to 5:00 
PM Eastern Standard Time. In emergency situations when a participant must begin treatment 
during off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours.  
The registration procedures are as follows:
1.
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments.
2.
Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical and/or research record. To 
be eligible for registration to the protocol, the participant must meet all 
inclusion and exclusion criterion as described in the protocol and reflected 
on the eligibility checklist. 
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Reminder: Confirm eligibility for ancillary studies at the same time as eligibility 
for the treatment study. Registration to both treatment and ancillary studies 
will not be completed if eligibility requirements are not met for all studies. 
3.
Fax the eligibility checklist and all pages of the consent form to the QACT at 
617-632-2295. 
4.
The QACT Registrar will (a) review the eligibility checklist, (b) register the 
participant on the protocol, and (c) randomize the participant when applicable. 
5.
An email confirmation of the registration and/or randomization will be sent to 
the Overall PI, study coordinator(s) from the Lead Site, treating investigator 
and registering person immediately following the registration and/or 
randomization. 
4.3    General Guidelines for Other Participating Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Study Coordinator.  All sites should call the Study Coordinator [617-632-6316] to verify slot 
availabilities.  Following registration, participants should begin protocol treatment within 5 days. 
Issues that would cause treatment delays should be discussed with the Overall PI.  If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible.
4.4   Registration Process for Other Participating Institutions
To register a participant, the following documents should be completed by the research nurse or 
data manager and faxed [Fax # 617-582-7988] or e-mailed [Katharine_Straw@dfci.harvard. edu] 
to the DFCI Study Coordinator:
    Copy of pathology report confirming cancer diagnosis, laboratory results (CBC with 
differential and platelets, comprehensive chemistry panel, PT/PTT/INR, urinalysis 
and urine protein/creatinine ratio, pregnancy test, if applicable, baseline CT/MRI 
report, MUGA/Echocardiogram report, EKG)
    Signed participant consent form
    HIPAA authorization form
    Eligibility Checklist
The research nurse or data manager at the participating site will then call [617-632-6316] or e-
mail [katharine_straw@dfci.harvard.edu] the DFCI Study Coordinator to verify eligibility.  To 
complete the registration process, the Coordinator will:
   register the participant on the protocol with the QACT
   fax or e-mail the participant study number, and if applicable the dose treatment level 
to the participating site
   call the research nurse or data manager at the participating site and verbally confirm 
registration
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NOTE: Registration and randomization with the QACT can only be conducted during the 
business hours of 8:00 AM and 5:00 PM Eastern Standard Time Monday through Friday. 
Same day treatment registrations will only be accepted with prior notice and discussion with the 
DF/HCC Lead Institution. 
5. TREATMENT PLAN 
Treatment will be administered on an outpatient basis or if necessary, inpatient (for 
DF/HCC patients at BWH or MGH). Expected toxicities and potential risks as well as 
dose modifications for CAPOX+bevacizumab+trastuzumab are described in Section 6 
(Expected Toxicities and Dosing Delays/Dose Modifications). 
No other investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the participant's malignancy.
Premedication for trastuzumab and bevacizumab will not be required.  However, 
premedication is recommended if there has been an infusion reaction in a previous cycle. 
Table 1: Treatment plan
Agent
Dose
Route
Schedule
Cycle
Trastuzumab
4 mg/kg
Loading 
dose
IV
Day 1
Cycle 1
Only
(cycle 1 is 
one week)
Bevacizumab
7.5mg/kg
IV
Day 1
Trastuzumab
6mg/kg
IV
Day 1
Administer after 
bevacizumab
Oxaliplatin
130mg/m2
IV
Day 1
Administer after 
trastuzumab
Capecitabine*
1200*
mg/m2
PO *
Days 1-14
in divided dose
Administer after 
oxaliplatin
Cycle 2  
(and all 
subsequent 
cycles)
Each cycle 
is 21 days
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*calculate dose for 1200mg/m2, then round to nearest multiple of 500mg tablets, then give 
in divided dose daily.  If an odd number of pills, the patient should take the extra tablet in 
the evening. Examples:

1200mg/m2 x BSA of 2.0=2400mg    Round to 2500 mg in divided dose, take 2 
tablets in am and take 3 tablets in pm.

1200mg/m2 x BSA of 1.7=2040 mg   Round to 2000 mg in divided dose, take 2 
tablets in am and 2 tablets in pm
5.1
Pre-treatment Criteria
5.1.1
   Cycle 1, Day 1

Screening labs must meet eligibility criteria and must have been done within 14 
days of C1D1.  Do not have to be repeated on C1D1.

Screening labs will include: CBC with differential, Platelets, comprehensive 
chemistry panel, PT/PTT/INR, U/A and Urine protein/creatinine ratio (UPCR)

Pregnancy test is required within 14 day for women of child bearing potential 
(urine or serum)

EKG within 28 days 

MUGA scan or echocardiogram within 28 days

ECOG 0-1.  No significant change in ECOG performance status in past two 
weeks.

CT scan of chest, abdomen and pelvis within 28 days. 

No evidence of active bleeding from tumor in past 2 weeks

No clinically significant concurrent illness or infection (determined by treating 
investigator). 

Pre treatment mandatory biopsy within 2 weeks of loading dose of 
trastuzumab.
5.1.2
    Cycle 1 Day 7 

Mandatory biopsy of tumor for correlative science.  
This must be done on day 7. Cycle 1 loading dose of trastuzumab must be 
given on a Tuesday, Wednesday, Thursday or Friday as biopsy procedures 
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are performed Monday – Friday (please refer to Section 9., Study 
Calendar).  
 5.1.3      Cycle 2, Day 1 and all Subsequent Cycles (refer to study calendar for required 
study tests).

ANC ≥1000 /mcL

Platelet count ≥75,000 /mcL

Recovery of clinically significant study drug related non-hematological toxicity 
to grade 1 or less.  Exceptions as noted in table 4 (page 50) and table 7 (page 56) 
are allowed.

Part I:  Cycle 2 will begin 1 week after loading dose of trastuzumab

Part II only: Tumor biopsy must have been completed C1D7. (Cycle 2 will 
begin 9-11 days after loading dose of trastuzumab. This will allow a minimum of 
2 days rest post biopsy).   Approval by PI: Dr Peter Enzinger will be required to 
continue patient on study if this biopsy was not performed.

ECOG: ≤ 2
5.2   Agent Administration 
Please refer to table 2 (pg 32) 
 Calculation of BSA will be per institutional policy. Weight will be documented on day 1 of 
each cycle and BSA will be recalculated.  

Vital signs: temperature, pulse, BP, respiratory rate

At each visit, pre dose

C1D1: one hour after trastuzumab has infused

Bevacizumab will be administered first, followed by trastuzumab.  Oxaliplatin will be 
administered after trastuzumab.  

Pre Hydration is not required for any of the study agents below. 

Pre medication for hypersensitivity or possible allergic reaction is not required prior to the 
first dose of any of the study agents.  

Pre medication with anti-emetics are recommended prior to oxaliplatin infusion.  

Oxaliplatin has vesicant and irritant properties and may cause pain if given peripherally.  
Central venous access is recommended but not required. 
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
Capecitabine tablets may be crushed if necessary. We recommended that only the patient do 
this due to risk of exposure to the chemotherapy when crushing tablets.
  Table 2: Agent administration             
Agent
Route
Schedule
Cycle 1
Trastuzumab
Loading dose
Do not 
administer I.V. 
push or by rapid 
bolus. 
Do not 
administer with 
D5W
* give patient 
prescription  
for capecitabine 
to fill at local 
pharmacy
IV
Cycle 1 Day 1
Administer over 
approximately 90 minutes
Observe for one hour 
post infusion 
For infusion related 
adverse reaction refer to 
section 5.2.1
Vital signs prior to 
infusion and  after  one 
hour of observation post 
infusion
(Part II: Cycle 1 
Day 7 EGD/biopsy)
(note: cycle 1 is 7 
days)
Agent
Route
Schedule
Cycle 2 and 
subsequent cycles
Bevacizumab
Dilute prescribed 
dose of 
bevacizumab in 
NS. Do not mix 
with dextrose-
containing 
solutions
IV
Day 1
Administer at 
approximately 
0.5mg/kg/minute 
For infusion related 
adverse reaction refer to 
section 5.2.2
Trastuzumab
Do not 
administer I.V. 
push or by rapid 
bolus. 
Do not 
administer with 
D5W. 
IV
Day 1
If loading dose was 
tolerated, administer over 
approximately 30 
minutes.
Administer after 
bevacizumab.
If infusion reaction, refer 
to section 5.2.1 for 
guidelines for subsequent 
administration.
Part I:  Cycle 2 
begins 1 week post 
loading dose of 
trastuzumab
Part II: Cycle 2 will 
begin 9-11 days post 
loading dose of 
trastuzumab.
Each cycle is 21 days
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Oxaliplatin
Mix in D5W
IV 
Day 1
Administer over 
approximately 2 hours
Lengthen infusion time 
to 6 hours if ACUTE 
laryngopharyngeal 
dysesthesia  or 
hypersensitivity noted in 
any cycle
For infusion related 
adverse reaction refer to 
section 5.2.3
Administer after 
bevacizumab and 
trastuzumab
Oxaliplatin has vesicant 
and irritant properties.  
Capecitabine
Round to the 
nearest multiple 
of whole 500 mg 
tablets and 
divide as equally 
as possible.  If 
there is odd 
number of 
tablets, the 
patient should 
take the extra 
tablet with the 
evening dose.
Instruct patient 
to take each dose 
with 8 oz.  of 
H2O.
Patient diary is 
in appendix
PO
BID 
Days 1-14
Administer 30 minutes 
after a meal, with H2O 
approximately 12 hours 
apart.
Day 1: if start time is 
delayed to afternoon, one 
dose will be taken for that 
day and the final dose for 
cycle will be taken on day 
15 in the am.
Missed or vomited doses 
are not to be made up
Cycle 2  (and all 
subsequent cycles)
Part I:  Cycle 2 
begins 1 week post 
loading dose of 
trastuzumab
Part II: Cycle 2 will 
begin 9-11 days post 
loading dose of 
trastuzumab.
Each cycle is 21 days
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5.2.1      Trastuzumab Administration
            
Trastuzumab will be administered as a loading dose on Cycle 1 Day 1.  The initial 
loading dose infusion of trastuzumab will be administered over approximately 90 
minutes.  There will be a 60-minute observation period after the infusion is complete.   
Vital signs will be checked after 60 minutes of observation.
During the first infusion with trastuzumab, a symptom complex consisting of chills 
and/or fever is observed commonly in patients.  Other signs and/or symptoms may 
include nausea, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia.  
These symptoms are usually mild to moderate in severity, and occur infrequently with 
subsequent trastuzumab infusion.  If the initial infusion is well tolerated (no fever, chills, 
or rigors with or post infusion), all subsequent infusions may be given over 30 minutes.  
If adverse reaction is noted with any infusion, subsequent infusions will be administered 
over 90 minutes. 
Administer medications including but not limited to acetaminophen, meperidine 
(Demerol), diphenhydramine, steroids, and ranitidine or equivalent H2 blocker except 
for cimetidine due to possible interaction with capecitabine.    If the 90 minute infusion 
is well tolerated, may reduce infusion time to 30-minutes for subsequent infusions.  Pre 
medication with acetaminophen may be given in subsequent cycles if necessary.  
Trastuzumab will be administered after bevacizumab and before oxaliplatin in cycle 2 
and all subsequent cycles.
5.2.2      Bevacizumab Administration 
The first dose of bevacizumab will be administered on cycle 2 day 1.  Cycle 2 should 
start one week after the loading dose of trastuzumab.  Premedication will not be required 
prior to first dose.
Bevacizumab will be infused at a rate of approximately 0.5 mg/kg/minute.  For infusion 
related adverse reaction, the infusion will be interrupted until recovery and necessary 
support has been administered (i.e., diphenhydramine, steroids, or ranitidine).  For any 
Grade 3 or 4 (CTCAE version 4.0) allergic reaction or anaphylaxis, or any grade of 
bronchospasm, bevacizumab will be permanently discontinued (may remain on 
study and receive other agents at the discretion of the treating investigator).  
Upon recovery of adverse reaction, the infusion will be resumed at the slower rate, and 
administered over 30+/-10 minutes.  If this is well tolerated, the next infusion will be 
administered following pre-medication (i.e., diphenhydramine, steroids, ranitidine) over 
30+/-10 minutes.   At the discretion of the treating investigator, and if no further 
evidence of adverse reaction with premedication, all subsequent infusions may be 
administered at the starting rate of approximately 0.5mg/kg/minute.
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5.2.3      Oxaliplatin Administration
Acute laryngopharyngeal dysesthesia (LPD), is the subjective loss of sensation of 
breathing without any objective evidence of respiratory distress (i.e., laryngospasm, 
bronchospasm or hypoxia) and been observed in patients during oxaliplatin 
administration.  It may be cold induced or related to rate of infusion and may occur with 
any infusion. LPD should be distinguished from an acute hypersensitivity or allergic 
reaction.  It is managed initially by suspending the infusion, while supportive measures 
are carried out.  Vital signs including pulse oximetry should be monitored.  If pulse 
oximetry is normal, the use of a benzodiazepine or other anti anxiety medication or 
measures are prescribed as necessary.  Upon recovery, the infusion may be resumed at a 
reduced rate for the remainder of the infusion and should be administered over 6 hours.  
All subsequent infusions will be administered over 6 hours.  Patients will be instructed 
to avoid cold liquids or exposure to cold for 24-48 hours post infusion.
Oxaliplatin hypersensitivity reaction is most commonly seen after multiple doses of 
treatment.  For any (CTCAE version 4.0) Grade 3 or 4 hypersensitivity or anaphylaxis, 
oxaliplatin will be permanently discontinued.  For Grade 1 or 2 hypersensitivity 
reactions, the infusion will be suspended and supportive measures will be applied.  
Treatment may resume at reduced delivery rate, following complete resolution of 
symptoms (bronchospasm, hypotension, etc). Infuse over 6 hours for all subsequent 
infusions. Premedication with corticosteroids, diphenhydramine, and ranitidine is 
recommended 30-60 minutes prior to all subsequent infusions.  The doses of which may 
be determined by the treating investigator. Oxaliplatin should be permanently 
discontinued if premedication, or prolonged administration measures fail to prevent 
oxaliplatin related hypersensitivity.  
5.3   Other Modality(ies) or Procedures:
 Mandatory biopsies of tumor (Part II only):
In Part II of the study, there will be two mandatory biopsies of tumor for patients enrolled at 
DF/HCC, the cost of which will be covered by the study.  The first will be performed within 2 
weeks of loading dose of trastuzumab.  The second will be performed on Cycle 1 Day 7.  The 
treating investigator will determine the most appropriate site to biopsy.  These biopsies will be 
performed for correlative science studies; therefore, we do not intend to send these samples for 
processing in the clinical pathology laboratory, unless there is a concern about any findings 
during the biopsy procedure as determined by the MD performing the biopsy. If a patient is 
unwilling or unable (i.e. biopsy is too difficult to obtain) to undergo the required biopsy, the 
treating investigator may request a biopsy waiver, which will be granted at the discretion of the 
Principal Investigator.
Esophagogastric duodenoscopy (EGD) is the preferred modality to obtain the biopsy if the 
primary tumor is in place.  EGD is usually performed on an outpatient basis and performed 
under conscious sedation.   Visualization of the tumor and surrounding area should be noted 
in the final report. Specific pre and post endoscopy instructions will be given to the patient by 
the endoscopy lab performing the procedure.  The procedure is generally well tolerated; 
however, the risks associated include possible esophageal or gastric perforation, bleeding or 
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trauma at tumor or biopsy site, adverse reaction to the local anesthetic or medication which can 
lead to bradycardia, apnea, or laryngospasm.  
Other possible sites for biopsy include liver or lymph node.  
The biopsies will be performed at either Brigham and Women’s Hospital or Massachusetts 
General Hospital.
5.4   General Concomitant Medication and Supportive Care Guidelines

Diarrhea should be managed aggressively with the use of loperamide and other anti 
diarrheal regimens as determined by the treating investigator.  IV hydration and other 
supportive measures should be used as needed.  Patients with neutropenia and diarrhea 
should be considered for use of prophylactic antibiotics, such as oral quinolones.

Anti nausea medications including 5-HT3 antagonists (i.e., ondansetron) with 
corticosteroids (i.e. dexamethasone) are highly recommended prior to oxaliplatin 
administration.   The dose and regimen are to be determined by the treating investigator.  
Prochlorperazine may also be used as needed.  If necessary, supportive measures such as 
IV hydration may be used.

Cold induced acute laryngopharyngeal dysesthesia (LPD) or peripheral 
parestheias/dysesthesias are associated with oxaliplatin administration. Patients should be 
instructed to avoid ice and cold liquids during infusion of oxaliplatin and for 24-48 hours 
post infusion.  LPD should be distinguished from an acute hypersensitivity or allergic 
reaction.  Refer to section 5.2.3 for management of LPD and hypersensitivity.

Erythropoietin growth factors will be allowed as needed.

The use of leukocyte growth factors is not allowed to avoid dose delay or reduction.  If 
clinically indicated for febrile neutropenia, ASCO guidelines should be followed.

Sunscreens and daily use of skin moisturizers are highly recommended while taking 
capecitabine.  The use of fragrance free, hypoallergenic and non irritating products is 
recommended.

As a result of the potential for interaction with other concomitantly administered drugs 
through the cytochrome P450 system, the case report form must capture the concurrent 
use of all other drugs or over-the-counter medications. 

Capecitabine has known interaction with phenytoin and warfarin.  The use of warfarin is not 
allowed on this protocol.  The use of phenytoin should be used with caution; levels should 
be monitored closely and dose may need to be reduced.  No formal drug-drug interaction 
studies between capecitabine and other CYP2C9 substrates have been conducted; therefore 
care should be exercised when co administration is medically necessary.  
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
Oxaliplatin has vesicant and irritant properties.  There have been reported cases of 
extravasation induced necrosis to skin and surrounding tissues. Cool compress may be used 
for immediate management of extravasation, with consideration of potential for peripheral 
neuropathy exacerbated by cold. Warm compresses may avoid peripheral neuropathic 
discomfort, however, while possibly increasing drug removal through local vasodilation 
may increase cellular uptake and injury.
5.5   Duration of Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s)

Participant decides to withdraw from the study

General or specific changes in the participant's condition render the 
participant unacceptable for further treatment in the opinion of the 
treating investigator.
5.6 Duration of Follow Up 
Participants will be followed until resolution of any treatment related Grade 3-4 toxicity after 
removal from study or until death, whichever occurs first. Participants removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
5.7 Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 5.5 applies. The 
reason for study removal and the date the participant was removed must be documented in the 
study-specific case report form (CRF). Alternative care options will be discussed with the 
participant.
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Dr. Peter C. Enzinger, via phone 617.632.6855 
or email at peter_enzinger@dfci.harvard.edu.
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
There will be no dose modifications for bevacizumab or trastuzumab.
NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0) will be used for all 
toxicity assessment.  
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All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
6.1   Anticipated Toxicities 
6.1.1      Trastuzumab 
 

Cardiomyopathy: [U.S. Boxed Warning]: Trastuzumab is associated with 
symptomatic and asymptomatic reductions in left ventricular ejection fraction 
(LVEF) and severe heart failure (HF) and may result in mural thrombus formation 
and stroke, and even cardiac death; discontinue for cardiomyopathy. Evaluate LVEF 
in all patients prior to and during treatments. Extreme caution should be used in 
patients with pre-existing cardiac disease or dysfunction. Concomitant 
administration of anthracyclines and prior exposure to anthracyclines or radiation 
therapy significantly increases the risk of cardiomyopathy; other potential risk 
factors include advanced age, high or low body mass index, smoking, diabetes, and 
hyper/hypothyroidism. Discontinuation should be strongly considered in patients 
who develop a clinically significant reduction in LVEF during therapy; treatment 
with HF medications (e.g., ACE inhibitors, beta-blockers) should be initiated. 
Cardiomyopathy due to trastuzumab is generally reversible over a period of 1-3 
months after discontinuation. (When LVEF returns to baseline, reinitiation may be 
considered if indicated.) Trastuzumab is also associated with arrhythmias and 
hypertension.

Infusion reactions: [U.S. Boxed Warning]: Infusion reactions (including fatalities) 
have been associated with use; discontinue for anaphylaxis or angioedema. Most 
reactions occur during or within 24 hours of the first infusion; interrupt infusion for 
dyspnea or significant hypotension. Retreatment of patients who experienced severe 
hypersensitivity reactions has been attempted (with premedication). Some patients 
tolerated retreatment, while others experienced a second severe reaction. 

Pulmonary toxicity: [U.S. Boxed Warning]: May cause serious pulmonary toxicity 
(dyspnea, hypoxia, interstitial pneumonitis, pulmonary infiltrates, pleural effusion, 
noncardiogenic pulmonary edema, pulmonary insufficiency, acute respiratory 
distress syndrome [ARDS], and/or pulmonary fibrosis); discontinue for ARDS or 
interstitial pneumonitis. Use caution in patients with pre-existing pulmonary disease 
or patients with extensive pulmonary tumor involvement; these patient populations 
may have more severe toxicity. Pulmonary events may occur during or within 24 
hours of administration; delayed reactions have occurred. 
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              Concurrent drug therapy issues:
• Chemotherapy: When used in combination with myelosuppressive chemotherapy, 
trastuzumab may increase the incidence of neutropenia (moderate-to-severe) and 
febrile neutropenia.
Table 3   Expected Toxicities Associated with Trastuzumab by Body System
Body System
>10%
1-10%
<1%
Cardiovascular
•
LVEF Decreased (4%-
22%)
• Peripheral edema       
(5%-10%)
• Edema (8%)
• CHF (2% -7%; severe: 
<1%) 
• Tachycardia (5%)
• Hypertension (4%)
• Arrhythmia (3%)
• Palpitation (3%)
• Cardiac arrest
• Cardiomyopathy
• Hypotension
• Ventricular 
dysfunction
• Pericardial effusion
Central 
Nervous 
System
•
Pain (47%)
•
Fever (6%-36%)
•
Chills (5%-32%)
•
Headache (10%-26%)
•
Insomnia (14%)
•
Dizziness (4%-13%)
• Depression (6%)
• Seizure
• Stroke
• Syncope
• Hydrocephalus
• Amblyopia
• Confusion
• Deafness
• Mania
Dermatologic
•
Rash (4%-22%)
• Acne (2%)
• Nail disorder (2%)
• Pruritus (2%)
• Skin ulcers
• Angioedema
• Cellulitis
Gastrointestinal/ 
Hepatic
•
Nausea (6%-33%)
•
Diarrhea (7%-25%)
•
Vomiting (4%-23%)
•
Abdominal pain (2%-
22%)
•
Anorexia (14%)
• Constipation (2%)
• Dyspepsia (2%)
• Colitis
• Hepatic failure
• Hepatitis
• Pancreatitis
• Esophageal ulcer
• Gastroenteritis
• Ileus
• Intestinal obstruction
• Ascites
• Stomatitis
Genitourinary/
Renal
• Urinary tract infection 
(3%-5%)
• Oligohydramnios
Renal
• Hydronephrosis
• Renal failure
• Pyelonephritis
• Nephrotic syndrome
• Glomerulonephritis 
(membranous, focal and 
fibrillary)
• Glomerulopathy
• Glomerulosclerosis
• Hemorrhagic cystitis
Neuromuscular 
& Skeletal
•
Weakness (4%-42%) 
•
Back pain (5%-22%)
• Paresthesia (2%-9%) 
• Bone pain (3%-7%)
• Bone necrosis
• Myopathy
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• Arthralgia (6%-8%)
• Myalgia (4%)
• Muscle spasm (3%)
• Peripheral neuritis 
(2%)
• Neuropathy (1%)
• Pathological fracture
Respiratory
•
Cough (5%-26%) 
•
Dyspnea (3%-22%)
•
Rhinitis (2%-14%)
•
Pharyngitis (12%)
• Sinusitis (2%-9%)
• Nasopharyngitis (8%)
• Upper respiratory 
infection (3%)
• Epistaxis (2%)
• Pharyngolaryngeal 
pain (2%)
• Acute respiratory 
distress syndrome 
(ARDS)
• Apnea
• Asthma
• Ataxia
• Bronchospasm
• Respiratory failure
• Hematemesis
• Hypoxia
• Pleural effusion
• Pneumonitis
• Pneumothorax
• Pulmonary edema 
(noncardiogenic)
• Pulmonary fibrosis
• Pulmonary 
hypertension
• Pulmonary infiltrate
• Respiratory distress
• Interstitial 
pneumonitis
• Paroxysmal nocturnal 
dyspnea
• Laryngitis
Hematologic
• Anemia (4%)
• Leukopenia (3%)
• Coagulopathy
• Pancytopenia
• Leukemia (acute)
• Neutropenia
Miscellaneous/
Other
•
Infusion reaction 
(21%-40% chills and 
fever most common; 
severe: 1%)
•
Infection (20%)
• Flu-like syndrome (2%-
10%)
• Accidental injury (6%)
• Influenza (4%)
• Allergic reaction (3%)
• Herpes simplex (2%)
• Anaphylaxis
• Anaphylactoid 
reaction
• Hemorrhage
• Hypersensitivity
• Herpes zoster
• Radiation injury
• Hypercalcemia
• Hypothyroidism
• Lymphangitis
• Mural thrombosis
• Sepsis
• Shock
• Thyroiditis 
(autoimmune)
• Vascular thrombosis
• Volume overload
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6.1.2      Bevacizumab:
Boxed warnings:
•
Gastrointestinal perforation: See “Concerns related to adverse effects” below.
•
Hemorrhage: See “Concerns related to adverse effects” below. 
•
Wound dehiscence: See “Concerns related to adverse effects” below.
             Concerns related to adverse effects:
•
Fistula formation (nongastrointestinal): Nongastrointestinal fistula formation 
(including tracheoesophageal, bronchopleural, biliary, vaginal, and bladder fistulas) 
has been observed, most commonly within the first 6 months of treatment. 
Permanently discontinue in patients who develop internal organ fistulas. 
•
Gastrointestinal perforation: [U.S. Boxed Warning]: Gastrointestinal perforation, 
fistula (including gastrointestinal, enterocutaneous, esophageal, duodenal, and 
rectal fistulas), and intra-abdominal abscess have been reported in patients 
receiving bevacizumab for colorectal cancer and other cancers (not related to 
treatment duration). Most cases occur within 50 days of treatment initiation; may 
be fatal in some cases; monitor patients for signs/symptoms (e.g., fever, abdominal 
pain with constipation and/or nausea/vomiting). Permanently discontinue in patients 
who develop these complications. 
•
Hemorrhage: [U.S. Boxed Warning]: Severe or fatal hemorrhage, including 
hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, 
epistaxis, and vaginal bleeding have been observed. Avoid use in patients with 
serious hemorrhage or recent hemoptysis (≥2.5 mL blood). Serious pulmonary 
hemorrhage has been reported in patients receiving bevacizumab (primarily in 
patients with nonsmall cell lung cancer with squamous cell histology [not an FDA-
approved indication]). Intracranial hemorrhage, including cases of Grade 3 or 4 
hemorrhage has occurred in patients with previously treated glioblastoma. Treatment 
discontinuation is recommended in all patients with intracranial bleeding or other 
serious hemorrhage. Use with caution in patients at risk for thrombocytopenia. 
•
Hypertension: May cause and/or worsen hypertension significantly; use caution in 
patients with pre-existing hypertension and monitor BP closely in all patients. 
Permanent discontinuation is recommended in patients who experience a 
hypertensive crisis or encephalopathy. Temporarily discontinue in patients who 
develop uncontrolled hypertension.
•
Infusion reactions: Infusion reactions (e.g., hypertension, hypertensive crisis, 
wheezing, oxygen desaturation, hypersensitivity, chest pain, rigors, headache, and 
diaphoresis) may occur with the first infusion (uncommon). Interrupt therapy in 
patients experiencing severe infusion reactions; there are no data to address 
reinstitution of therapy in patients who experience severe infusion reactions. 
•
Nephrotic syndrome/proteinuria: Proteinuria and/or nephrotic syndrome have been 
associated with use; risks may be increased in patients with history of hypertension. 
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Thrombotic microangiopathy has been associated with bevacizumab-induced 
proteinuria. Withhold treatment for ≥2 g proteinuria/24 hours and resume when 
proteinuria is <2 g/24 hours; discontinue in patients with nephrotic syndrome. 
•
Reversible posterior leukoencephalopathy syndrome (RPLS): Cases of reversible 
posterior leukoencephalopathy syndrome (RPLS) have been reported. Symptoms 
(which include headache, seizure, confusion, lethargy, blindness and/or other vision, 
or neurologic disturbances) may occur from 16 hours to 1 year after treatment 
initiation. Resolution of symptoms usually occurs within days after discontinuation; 
however, neurologic sequelae may remain. RPLS may be associated with 
hypertension; discontinue therapy and begin management of hypertension, if present. 
•
Thromboembolism: Bevacizumab is associated with an increased risk for arterial 
thromboembolic events (ATE), including stroke, MI, TIA, and angina, when used in 
combination with chemotherapy. History of ATE or ≥65 years of age may present an 
even greater risk; permanently discontinue with serious ATE; the safety of treatment 
reinitiation after ATE has not been studied. Although patients with cancer are at risk 
for venous thromboembolism (VTE), a meta-analysis of 15 controlled trials has 
demonstrated an increased risk for VTE in patients who received bevacizumab 
(Nalluri, 2008).
•
Wound dehiscence: [U.S. Boxed Warning]: Wound dehiscence/wound healing 
complications have been reported in patients (not related to treatment 
duration); monitor patients for signs/symptoms of improper wound healing. 
Permanently discontinue in patients who develop these complications. The 
appropriate intervals between administration of bevacizumab and surgical 
procedures to avoid impairment in wound healing has not been established. Therapy 
should not be initiated within 28 days of major surgery and only following complete 
healing of the incision. Bevacizumab should be discontinued at least 28 days prior to 
elective surgery.
•
The incidental finding of pneumatosis intestinalis has been found in two patients in 
the first stage of this trial on routine restaging CT scans.  This resolved without 
intervention in both patients and is thought to be probably associated with 
bevacizumab.  
             Disease-related concerns:
•
Cardiovascular disease: The risk for heart failure (HF), including left ventricular 
dysfunction, is higher in patients receiving bevacizumab plus chemotherapy when 
compared to chemotherapy alone. Use with caution in patients with cardiovascular 
disease; patients with significant recent cardiovascular disease were excluded from 
clinical trials. The safety of therapy resumption or continuation in patients with 
cardiac dysfunction has not been studied.
Percentages reported as monotherapy and as part of combination chemotherapy regimens. 
Some studies only reported hematologic toxicities Grades ≥4 and nonhematologic 
toxicities Grades ≥3.
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Table 4: Frequency of Toxicities Associated with Bevacizumab Monotherapy by Body System
Body System
>10%
1%-10%
<1%
Cardiovascular
• Hypertension (23%-
67%; Grades 3/4: 
5%-18%)
• Thromboembolic 
event (≤21%; 
Grades 3/4: 15%; 
venous thrombus/ 
embolus: 8%; 
Grades 3/4: 5%-7%; 
arterial thrombosis 
6%; Grades 3/4: 
3%), hypotension 
(7%-15%)
• DVT (6%-9%; 
Grades 3/4: 9%)
• Syncope (Grades 3/4: 
3%)
• Intra-abdominal 
venous thrombosis 
(Grades 3/4: 3%), 
cardio-
/cerebrovascular 
arterial thrombotic 
event (2%-4%)
• CHF (with prior 
anthracycline therapy: 
4%; Grades 3/4: 2%)
• Left ventricular 
dysfunction (Grades 
3/4: 1%)
• Angina
• Hypertensive crises
• Myocardial 
infarction
Central 
Nervous 
System
•Pain (31%-62%)
•Headache (26%-
37%; Grades 3/4: 
2%-4%)
•Dizziness (19%-
26%)
•Fatigue (≤45%; 
Grades 3/4: 4%-
19%)
•Sensory neuropathy 
(Grades 3/4: 1%-
17%; in combination 
with paclitaxel: 
24%)
• Confusion (1%-6%)
• Abnormal gait (1%-
5%)
• CNS hemorrhage 
(1%-5%; Grades 3/4: 
1%)
• Reversible posterior 
leukoencephalopathy 
syndrome ([RPLS] 
≤1%)
• Cerebral infarction
• Transient ischemic 
attack
• Subarachnoid 
hemorrhage
• Hemorrhagic stroke
• Hypertensive 
encephalopathy
Dermatologic
• Alopecia (6%-32%)
• Dry skin (7%-20%)
• Exfoliative 
dermatitis (3%-
19%)
• Skin discoloration 
(2%-16%)
• Nail disorder (2%-
8%)
• Skin ulcer (≤6%)
• Rash desquamation 
(Grades 3/4: 3%)
• Wound dehiscence 
(1%-6%)
• Wound healing 
complications
• Polyserositis
• Nasal septum 
perforation
• Enterocutaneous 
fistula
Endocrine & 
Metabolic
• Hypokalemia 
(12%-16%)
• Dehydration (Grades 
3/4: 3%-10%)
• Hyponatremia 
(Grades 3/4: 4%)
Gastrointestinal
• Abdominal pain 
(50%-61%; Grades 
3/4: 8%)
• Vomiting (47%-
52%; Grades 3/4: 
6%-11%)
• Anorexia (35%-
• Xerostomia (4%-7%)
• Colitis (1%-6%), 
ileus (Grades 3/4: 
4%-5%)
• Gingival bleeding 
(2%)
• Fistula (1%)
• Intestinal necrosis
• Intestinal obstruction
• Fistula (biliary, 
duodenal, 
esophageal, 
gastrointestinal, 
rectal)
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43%)
• Constipation (29%-
40%)
• Diarrhea (Grades 
3/4: 1%-34%)
• Stomatitis (25%-
32%)
• Gastrointestinal 
hemorrhage (19%-
24%)
• Dyspepsia (17%-
24%)
• Taste disorder 
(14%-21%)
• Flatulence (11%-
19%)
• Weight loss (9%-
16%)
• Nausea (Grades 3/4: 
4%-12%)
• Gastrointestinal 
perforation (≤4%)
• Intra-abdominal 
abscess (1%)
Hematologic
• Hemorrhage 
(≤40%; Grades 3/4: 
1%-5%)
• Leukopenia 
(Grades 3/4: 37%)
• Neutropenia (Grade 
4: 6%-27%)
• Neutropenic 
fever/infection (5%; 
Grades 3 and/or 4: 
4% -5%)
• Thrombocytopenia 
(5%)
• Microangiopathic 
hemolytic anemia 
(when used in 
combination with 
sunitinib)
• Pancytopenia
Hepatic
• Bilirubinemia (1%- 
6%)
Neuromuscular 
& skeletal
• Weakness (57%-
74%)
• Myalgia (8%-15%)
• Bone pain (Grades 
3/4: 4%)
• Neuropathy (other 
than sensory: Grades 
3/4: 1%-5%)
Ocular
• Tearing increased 
(6%-18%)
• Eye inflammation
• Vision blurred
• Toxic anterior 
segment syndrome 
(TASS)
• Endophthalmitis 
fistula
Renal
• Proteinuria (4% to 
36%; Grade 3: 
≤21%; Grades 3/4: 
1%-3%)
• Renal failure
• Renal thrombotic 
microangiopathy
• Nephrotic syndrome
• Ureteral stricture
• Bladder fistula
Genitourinary
• Polyuria/urgency 
(3%-6%)
• Vaginal hemorrhage 
(4%)
• Vaginal fistula
Respiratory
• Upper respiratory 
infection (40%-
•Voice alteration (6%-
9%)
• Pulmonary 
hypertension
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47%)
• Epistaxis (16%-
35%)
• Dyspnea (25%-
26%)
•Pneumonitis/pulmona
ry infiltrates (Grades 
3/4: 5%)
•Hemoptysis 
(nonsquamous 
histology 2%)
• Pulmonary embolism
• Pulmonary 
hemorrhage
• Bronchopleural 
fistula
Miscellaneous
• Infection (≤55%; 
serious: 9% to 14%; 
pneumonia, 
catheter, or wound 
infections)
• Infusion reactions 
(<3%)
• Anaphylaxis
• Sepsis
• Hypersensitivity
• Mesenteric venous 
occlusion
• Anastomotic 
ulceration
• Tracheoesophageal 
fistula
6.1.3       Oxaliplatin
•
Anaphylaxis: [U.S. Boxed Warning]: Anaphylactic/anaphylactoid reactions may 
occur within minutes of oxaliplatin administration; symptoms may be managed 
with epinephrine, corticosteroids, and antihistamines. Grade 3 or 4 
hypersensitivity has been observed. Allergic reactions may occur with any cycle and 
may include bronchospasm (rare), erythema, hypotension (rare), pruritus, rash, 
and/or urticaria. 
•
Neuropathy: Two different types of peripheral sensory neuropathy may occur: First, 
an acute (within first 2 days), reversible (resolves within 14 days), with primarily 
peripheral symptoms that are often exacerbated by cold (may include 
pharyngolaryngeal dysesthesia); avoid mucositis prophylaxis with ice chips during 
oxaliplatin infusion; may recur with subsequent doses. Secondly, a more persistent 
(>14 days) presentation that often interferes with daily activities (e.g., writing, 
buttoning, swallowing), these symptoms may improve in some patients upon 
discontinuing treatment.
•
Hepatotoxicity: Hepatotoxicity (including rare cases of hepatitis and hepatic failure) 
has been reported. Liver biopsy has revealed peliosis, nodular regenerative 
hyperplasia, sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive 
lesions. The presence of hepatic vascular disorders (including veno-occlusive 
disease) should be considered, especially in individuals developing portal 
hypertension or who present with increased liver function tests. 
•
Pulmonary fibrosis: May cause pulmonary fibrosis; withhold treatment for 
unexplained pulmonary symptoms (e.g., crackles, dyspnea, nonproductive cough, 
pulmonary infiltrates) until interstitial lung disease or pulmonary fibrosis are 
excluded. 
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Table 5:  Frequency of Toxicities Associated with Oxaliplatin Monotherapy by Body System
Body System
>10%
1%-10%
<1%
Cardiovascular
• Edema (10%)
• Chest pain (5%)
• Peripheral edema (5%)
• Flushing (3%)
• Thromboembolism 
(2%)
• Hypertension
Central Nervous 
System
• Fatigue (61%)
• Fever (25%)
• Pain (14%)
• Headache (13%)
• Insomnia (11%)
• Dizziness (7%)
• Aphonia
• Ataxia
• Cranial nerve palsies
• Deep tendon reflex 
loss
• Deafness
• Dysarthria
• Fasiculations
• Gait abnormal
• Intracerebral bleeding
• Lhermittes' sign
• Myoclonus
• Seizure
• Trigeminal neuralgia
Dermatologic
• Rash (5%), alopecia 
(3%), hand-foot 
syndrome (1%)
Endocrine & 
Metabolic
• Dehydration (5%)
• Hypokalemia (3%)
• Hypomagnesaemia
• Metabolic acidosis
Gastrointestinal
• Nausea (64%)
• Diarrhea (46%)
• Vomiting (37%)
• Abdominal Pain 
(31%)
• Constipation (31%)
• Anorexia (20%)
• Stomatitis (14%)
• Dyspepsia (7%)
• Taste perversion (5%)
• Flatulence (3%)
• Mucositis (2%)
• Gastroesophageal 
reflux (1%)
• Dysphagia (acute 1% -
2%)
• Colitis
• Ileus
• Intestinal obstruction
• Pancreatitis
• Rectal hemorrhage
Genitourinary
• Dysuria (1%)
Hematologic
• Anemia (64%; 
Grades 3/4: 1%)
• Thrombocytopenia 
(30%; Grades 3/4 
3%)
• Leukopenia (13%)
• Neutropenia (7%)
• Hemolysis
• Hemolytic anemia 
(immuno-allergic)
• Hemolytic uremia 
syndrome
• Hemorrhage
• INR increased
• Neutropenic fever
• Neutropenic sepsis
• Prothrombin time 
increased
• Thrombocytopenia 
(immuno-allergic)
Hepatic
• AST increased 
(54%; Grades 3/4: 
4%)
• Hepatic failure
• Hepatitis
• Hepatotoxicity
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• ALT increased 
(36%; grades 3/4: 
1%)
• Total bilirubin 
increased (13%; 
grades 3/4: 5%)
• Nodular regenerative 
hyperplasia
• Peliosis
• Veno-occlusive liver 
disease (sinusoidal 
obstruction syndrome 
and perisinusoidal 
fibrosis)
Neuromuscular & 
Skeletal
• Peripheral 
neuropathy (may be 
dose limiting; 76%-
92%; acute 65%; 
grades 3/4: 5%; 
persistent 43%; 
grades 3/4: 3%)
• Back pain (11%)
• Rigors (9%)
• Arthralgia (7%)
• Muscle spasm
• Rhabdomyolysis
Ocular
• Abnormal lacrimation 
(1%)
• Diplopia
• Optic neuritis
• Ptosis
• Visual disturbance 
(acuity decreased, 
field disturbance, 
transient loss)
Renal
• Serum creatinine 
increased (5%-10%)
• Acute renal failure
• Hematuria
• Interstitial nephritis 
(acute)
• Tubular necrosis 
(acute)
Respiratory
• Dyspnea (13%)
• Cough (11%)
• URI (7%)
• Rhinitis (6%)
• Epistaxis (2%)
• Pharyngitis (2%)
• Pharyngolaryngeal 
dysesthesia (grades 
3/4: 1%-2%)
• Dysphonia
• Eosinophilic 
pneumonia
• Hypoxia
• Interstitial lung 
diseases
Miscellaneous
• Injection site reaction 
(9%; 
redness/swelling/pain)
• Allergic reactions 
(3%)
• Hypersensitivity 
(includes urticaria, 
pruritus, facial 
flushing, shortness of 
breath, bronchospasm, 
diaphoresis, 
hypotension, syncope: 
grades 3/4: 2%-3%)
• Hiccup (2%)
• Alkaline phosphatase 
increased
• Anaphylactic/ 
anaphylactoid 
reactions
• Anaphylactic shock
• Angioedema
• Extravasation 
(including necrosis)
• Sepsis
              
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Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment; increased 
toxicity may occur
6.1.4      Capecitabine:
             Concerns related to adverse effects:
• Cardiotoxicity: There has been cardiotoxicity associated with fluorinated pyrimidine 
therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, 
sudden death, ECG changes, and cardiomyopathy. These adverse events may be 
more common in patients with a history of coronary artery disease.
• Diarrhea: Can cause severe diarrhea; median time to first occurrence is 34 days; 
subsequent doses should be reduced after grade 3 or 4 diarrhea or recurrence of 
grade 2 diarrhea.
• Hand-and-foot syndrome: May cause hand-and-foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy-induced acral erythema) is characterized by 
numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, 
desquamation, blistering, and severe pain. If grade 2 or 3 hand-and-foot syndrome 
occurs, interrupt administration of capecitabine until the event resolves or decreases 
in intensity to grade 1. Following grade 3 hand-and-foot syndrome, decrease 
subsequent doses of therapy.
• Necrotizing enterocolitis (typhlitis): Has been reported.
              Disease-related concerns:
Bone marrow suppression: Use with caution in patients with bone marrow 
suppression.
Dihydropyrimidine dehydrogenase (DPD) deficiency: Rare and unexpected severe 
toxicity (stomatitis, diarrhea, neutropenia, neurotoxicity) may be attributed to 
Dihydropyrimidine dehydrogenase (DPD) deficiency.
Hepatic impairment: Use with caution in patients with hepatic impairment.
Renal impairment: Use with caution in patients with renal impairment; reduce dose 
with moderate impairment and carefully monitor and reduce subsequent dose (with 
any grade 2 or higher adverse effect) with mild-to-moderate impairment.
          
 Concurrent drug therapy issues:
Alkylating therapy: Use with caution in patients who have received alkylating 
therapy.
Fluorouracil/leucovorin (FU/LV): In patients with colorectal cancer, treatment with 
capecitabine immediately following 6 weeks of FU/LV therapy has been associated 
with an increased incidence of grade ≥3 toxicity, when compared to patients 
receiving the reverse sequence, capecitabine (two 3-week courses) followed by 
FU/LV (Hennig, 2008). 
Warfarin: [U.S. Boxed Warning]: Capecitabine may increase the anticoagulant 
effects of warfarin; monitor closely.
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Table 6:  Frequency of Toxicities Associated with Capecitabine Monotherapy by Body System
Body System
>10%
5%-10%
<5%
Cardiovascular
Edema (9%-15%)
Venous thrombosis 
(8%)
Chest pain (6%)
Angina
Atrial fibrillation
Bradycardia
Cardiac arrest
Cardiac failure
Cardiomyopathy
Dysrhythmia
ECG changes
Hyper-/hypotension
MI
Myocardial ischemia
Myocarditis
Pericardial effusion
Tachycardia
Ventricular extrasystoles
Central 
Nervous 
System
Fatigue (16%-42%)
Fever (7%-18%)
Pain (12%)
Headache (5%-10%)
Lethargy (10%)
Dizziness (6%-8%)
Insomnia (7%-8%)
Mood alteration (5%)
Depression (5%)
Ataxia
Cerebral vascular accident
Confusion
Dysarthria
Encephalopathy
Impaired balance
Irritability
Loss of consciousness
Sedation
Tremor
Vertigo
Dermatologic
Palmar-plantar 
erythrodysesthesia 
(hand-and-foot 
syndrome) (54%-
60%; Grade 3: 11%-
17%; may be dose 
limiting)
Dermatitis (27%-37%)
Nail disorder (7%)
Rash (7%)
Skin discoloration 
(7%)
Alopecia (6%)
Erythema (6%)
Ecchymosis
Thrombocytopenic purpura
Pruritus
Radiation recall syndrome
Skin ulceration
Endocrine & 
Metabolic
Dehydration (7%)
Cachexia
Diaphoresis
Hypokalemia
Hypomagnesemia
Hypertriglyceridemia
Thirst
Weight gain
Gastrointestinal Diarrhea (47%-57%; 
may be dose limiting; 
Grade 3: 12%-13%; 
Grade 4: 2%-3%)
Nausea (34%-53%)
Vomiting (15%-
37%)
Abdominal pain 
(7%-35%)
Stomatitis (22%-
Motility disorder 
(10%)
Oral discomfort 
(10%)
Dyspepsia (6%-8%)
Upper GI 
inflammatory 
disorders (colorectal 
cancer: 8%)
Hemorrhage (6%)
Abdominal Distension
Appetite increased
Ascites
Colitis
Duodenitis
Dysphagia
Esophagitis
Gastric ulcer
Gastritis
Gastroenteritis
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25%)
Appetite decreased 
(26%)
Anorexia (9%-23%)
Constipation (9%-
15%)
Ileus (6%)
Taste perversion 
(colorectal cancer: 
6%)
Ileus
Intestinal obstruction (~1%)
Necrotizing enterocolitis 
(typhlitis)
Proctalgia
Toxic megacolon
Hematologic
Lymphopenia (94%; 
grade 4: 14%)
Anemia (72%-80%; 
grade 4: <1%-1%)
Neutropenia (2%-
26%; grade 4: 2%)
Thrombocytopenia 
(24%; grade 4: 1%)
Coagulation disorder
Idiopathic thrombocytopenia 
purpura
Leukopenia
Pancytopenia
Hepatic
Bilirubin increased 
(22%-48%; grades 
3/4: 11%-23%)
Cholestasis
Hepatic fibrosis
Hepatitis
Neuromuscular 
& skeletal
Paresthesia (21%)
Back pain (10%)
Weakness (10%)
Neuropathy (10%)
Myalgia (9%)
Arthralgia (8%)
Limb pain (6%)
Arthritis
Bone pain
Joint stiffness
Ocular
Eye irritation (13%-
15%)
Abnormal vision 
(colorectal cancer: 5%)
Conjunctivitis (5%)
Keratoconjunctivitis
Renal
Nocturia
Renal impairment
Respiratory
Dyspnea (14%)
Cough (7%)
Asthma
Bronchitis
Bronchopneumonia
Bronchospasm
Epistaxis
Hematemesis
Hemoptysis
Hoarseness
Laryngitis
Pneumonia
Pulmonary embolism
Respiratory distress
Sore throat
Miscellaneous
Viral infection 
(colorectal cancer: 5%)
Deep vein thrombosis
Fibrosis
Fungal infection
Hot flushes
Hypersensitivity
Infection
Influenza-like illness
Lymphedema
Oral candidiasis
Photosensitivity reaction
Sepsis
Thrombophlebitis
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Postmarketing and/or case reports: Fingerprint distortion, hepatic failure, lacrimal duct 
stenosis, multifocal leukoencephalopathy.
A list of the adverse events and potential risks associated with the agents administered in 
this study appear below and will determine whether dose delays and modifications will 
be made or whether the event requires expedited reporting in addition to routine 
reporting. 
6.2   Toxicity Management
[For management of adverse infusion reaction refer to section 5.2.1 (trastuzumab), 5.2.2 
(bevacizumab), and 5.2.3 (oxaliplatin)].
 6.2.1      Trastuzumab Toxicity Management
There are no dose reductions for trastuzumab.  If adverse events occur that require 
holding trastuzumab, the dose will remain the same once treatment resumes.   
LVEF is to be determined by echocardiogram or MUGA scan.  The same method of 
evaluation should be used for an individual throughout the study.
If trastuzumab is held for any reason, bevacizumab, oxaliplatin and capecitabine 
may be given if parameters are met for administration of these agents.  Once the 
criteria to resume trastuzumab is met, it will be given on day 1 of the next cycle. 
Table 7:  Trastuzumab: Guidelines for LVEF
LVEF
Check prior to C4D1 and then every 4 cycles
≥50% 
Administer trastuzumab 
< 50 %
Hold trastuzumab
Recheck MUGA or echocardiogram every 3 weeks  
May resume at current dose when LVEF returns to ≥ 50%
If LVEF remains < 50% for greater than 12 weeks, may 
discontinue trastuzumab permanently. 
           
 6.2.2      Bevacizumab 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.
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Any toxicity associated or possibly associated with bevacizumab treatment should be 
managed according to standard medical practice. Discontinuation of bevacizumab will 
have no immediate therapeutic effect. Bevacizumab has a terminal half-life of 21 days; 
therefore, its discontinuation results in slow elimination over several months. There is 
no available antidote for bevacizumab. 
Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion. If unmanageable toxicity occurs because of bevacizumab at any time during 
the study, treatment with bevacizumab should be discontinued. 
Regardless of the reason for holding bevacizumab, the maximum allowable length 
of treatment interruption is 9 weeks.  Bevacizumab will be permanently 
discontinued if held for greater than 9 weeks.
If bevacizumab is held for any reason, trastuzumab, oxaliplatin and capecitabine 
may be given if parameters are met for administration of these agents.  Once the 
criteria to resume bevacizumab is met, it will be given on day 1 of the next cycle.
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Table 8 (table 1 of 3):
Bevacizumab Dose Management due to Adverse Events
CTCAE Version: 4.0                                         
Event
Action to be taken
Hypertension
Grade 1 or 2
            
Grade 3
Grade 4 (including hypertensive 
encephalopathy)
No action
If not controlled to ≤160/100 within 3 weeks of starting 
antihypertensive medication, discontinue permanently
Discontinue bevacizumab
Hemorrhage (non-pulmonary 
or non-CNS event)
Grade 1 or 2
Grade 3
Grade 4
No action
Hold bevacizumab until all of the following are met:

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 hemorrhagic 
recurrence
If there is a second Grade 3 hemorrhagic event the 
bevacizumab will be discontinued permanently
Discontinue bevacizumab
Hemorrhage (Pulmonary or 
CNS)
Any grade
Hold bevacizumab until all of the following are met:

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 hemorrhagic recurrence 
(not including brain metastases)
All CNS hemorrhage events must be reported directly to the 
PI within 24 hours of occurrence.
If CNS hemorrhage, perform brain MRI prior to next 
planned cycle of therapy.  If stable or resolved, dosing may 
proceed.  If there is progression of CNS hemorrhage, the 
bevacizumab will be permanently discontinued.
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Table 8 (table 2 of 3):
Bevacizumab Dose Management due to Adverse Events
CTCAE Version: 4.0                                          
Event
Action to be taken
Venous Thrombosis including 
pulmonary embolism and 
vascular access devise related 
thrombosis
Grade 1 or 2
Grade 3 or 4
No action
Anti-coagulate as clinically indicated with low molecular 
weight heparin (warfarin is not allowed on this study).   
Bevacizumab may be administered when anticoagulant 
dosing is stable, provided the patient has not had any Grade 
3 or 4 hemorrhagic events while on anticoagulation
Arterial thromboembolic 
Event (new onset, worsening, or 
unstable angina, MI, TIA, CVA 
or any other arterial 
thromboembolic event)
Any Grade
Discontinue bevacizumab 
Congestive Heart Failure
Grade 1 or 2
Grade 3
Grade 4
No action
Hold bevacizumab until resolution of symptoms
Discontinue bevacizumab
Proteinuria or Nephrotic 
Syndrome
Grade 1  
1+proteinuria; Urinary Protein 
<1.0 g/24 hours
Grade 2 
 2+proteinuria; Urinary Protein 
>1.0- 3.4g/24 hours
(UPCR is collected every other cycle, treatment decision 
will be based on results of UPCR)
Continue bevacizumab
UPCR <1.9 Continue bevacizumab
UPCR >1.9 Hold bevacizumab and obtain 24 hour urine 
sample for protein prior to next visit.
Resume bevacizumab when UPCR is <1.9 or 24 hour 
urine protein is < 2gms/24 hours
Hold for a maximum of 9 weeks.  Discontinue 
bevacizumab if no improvement in 9 weeks.
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Grade 3  
Urinary Protein >3.5g/24 hours
Nephrotic Syndrome
Hold bevacizumab 
Obtain 24 hour urine sample for protein prior to next visit.
Resume bevacizumab when UPCR is <1.9 or 24 hour 
urine protein is < 2gms/24 hours
Hold for a maximum of 9 weeks.  Discontinue 
bevacizumab if no improvement in 9 weeks.
Suggest nephrology consult
Discontinue bevacizumab 
Suggest nephrology consult
GI perforation
Discontinue bevacizumab
Fistula
Any Grade 
Discontinue bevacizumab
Table 8 (table 3 of 3):
Bevacizumab Dose Management due to Adverse Events
CTCAE Version: 4.0
Event
Action to be taken
Bowel Obstruction
Grade 1
Grade 2
Grade 3 or 4
Continue bevacizumab if intervention is not indicated
Hold bevacizumab.  Resume at investigators discretion
Hold bevacizumab.  If surgical intervention is indicated, 
may restart after full recovery at investigators discretion
Wound Dehiscence
Any grade
Discontinue bevacizumab
Reversible Posterior 
Leukoencephalopathy
Any Grade (confirmed by MRI)
Discontinue bevacizumab
Pneumatosis Intestinalis
Hold bevacizumab until no radiographic evidence of this.
Resume at investigator’s discretion
Other unspecified 
Bevacizumab related Adverse 
Events
Grade 1 or 2
Grade 3
Grade 4
No action
Hold bevacizumab until recovery to ≤Grade 1 or baseline
Discontinue bevacizumab
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6.3   Dose Modifications/Delays
There will be no dose reductions of bevacizumab and trastuzumab.  Criteria for holding 
bevacizumab and trastuzumab are noted in table 3 (pg 51) and table 4 (pg 53).  
Doses of capecitabine or oxaliplatin (chemotherapy agents) that have been reduced for treatment 
related toxicity are permanent and will not be re-escalated.
If it is necessary to hold any of the study agents, treatment may continue with other agents at the 
discretion of the treating investigator providing re-treatment parameters are met.  A maximum 
of 3 dose reductions for each of the chemotherapy agents will be allowed.  
Table 9:   Dose Modification
Chemotherapy 
Agent
Starting dose
Dose level -1
Dose level -2
Dose level -3
Oxaliplatin
130mg/m2
25% reduction 
of starting dose
25% reduction 
of dose level -1
25% reduction 
of dose level -2
Capecitabine
1200mg/m2 in 
divided dose
↓ starting dose 
by one 500 mg 
tablet
↓ previous dose 
by one 500 mg 
tablet
↓ previous dose 
by one 500 mg 
tablet
6.3.1       Hematological Toxicity:
Table 10:   Hematological Toxicity
Hematologic Toxicity on Day 1 of Cycle:
ANC (Absolute 
Neutrophil Count)
Platelets
Dose Modification (if both ANC and platelet toxicity, 
dose modification for the more severe toxicity will 
apply)
> 1,000/mm3
> 75 x 109/L
Maintain current dose
<1,000/mm3
<75 x 109/L
  
HOLD all study agents
When ANC > 1,000/mm3 and Plts > 75 x 109/L, initiate 
a new cycle and reduce both capecitabine and 
oxaliplatin one dose level
If not recovered in 3 weeks, or if more than 3 dose 
reductions are required for this toxicity, the patient 
will be removed from the study.
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6.3.2      Febrile Neutropenia: 
In the event of febrile neutropenia, defined for this protocol as temperature above 100.4 
with ANC less than 1000/mm³, capecitabine and oxaliplatin will be held.  The use of 
leukocyte growth factors may be indicated during this period and should be given as per 
ASCO guidelines at the discretion of the treating investigator.   Prophylactic antibiotics 
may also be offered at the discretion of the treating investigator.
Upon recovery, including resolution of fever or infection, and recovery of ANC to 
greater than 1000/mm³, the dose modifications and recovery times noted in table 
(Hematologic Toxicity) will apply.  
6.3.3      Non Hematological Dose Modifications
These criteria apply only to treatment-related, clinically relevant toxicity as determined 
by the investigator.  There will be no dose modifications for grade 1 events.
Non hematological dose modifications will be based on the worst toxicity experienced at 
any time in the cycle.   Refer to table 7 (pg 58).
Table 11: Non-Hematological Toxicity
CTCAE 
version 4.0
Non 
hematological 
toxicity 
Other than those 
noted elsewhere 
in this table
Diarrhea
Creatinine
Bilirubin
(related to study 
drug and not  
biliary obstruction)
Palmar/plantar 
erythrodysesthesia 
syndrome 
(Hand /foot 
syndrome)
Sensory or 
motor 
peripheral 
neuropathy
Grade 2
Maintain dose 
if  tolerable to 
patient 
If intolerable 
HOLD 
capecitabine 
and oxaliplatin 
until recovery 
to ≤grade 1 
Reduce dose of 
most likely 
causative agent 
one dose level 
when treatment 
is resumed.
HOLD 
capecitabine 
until recovery to 
≤grade 1 
If diarrhea was 
not optimally 
treated, continue 
at current dose 
when treatment 
is resumed.
If grade 2 
diarrhea despite 
optimal 
treatment, 
reduce dose of  
capecitabine one 
dose level when  
treatment is 
resumed
HOLD 
capecitabine 
and 
oxaliplatin 
Upon 
recovery to 
normal 
limits or 
baseline 
resume at 
current dose 
level. 
HOLD 
capecitabine 
until recovery to 
≤grade 1
For first 
occurrence, 
continue at 
current dose 
when treatment 
is resumed.
For any 
subsequent 
occurrence, 
reduce dose of  
capecitabine one 
dose level when  
treatment is 
resumed 
HOLD 
capecitabine 
until recovery to 
≤grade 1
Reduce dose of  
capecitabine one 
dose level when  
treatment is 
resumed 
HOLD 
oxaliplatin 
until 
recovery to 
≤grade 1
Resume at 
same dose if 
recovered by 
next cycle.  
Dose 
reduction at 
the 
investigators 
discretion.
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Grade 3
HOLD 
capecitabine 
and oxaliplatin 
until recovery 
≤grade 1.
Reduce dose of 
most likely 
causative agent 
one dose level 
when treatment 
is resumed.
HOLD 
capecitabine 
until recovery to 
≤grade 1 
Reduce dose of  
capecitabine one 
dose level when  
treatment is  
resumed
HOLD 
capecitabine 
and 
oxaliplatin 
Upon 
recovery to 
normal 
limits or 
baseline 
resume at 
current dose 
level.
HOLD 
capecitabine 
until recovery to 
≤grade 1
Reduce dose of  
capecitabine one 
dose level when  
treatment is 
resumed 
HOLD 
capecitabine 
until recovery to 
≤grade 1
Reduce dose of  
capecitabine one 
dose level when  
treatment is 
resumed 
Permanently 
discontinue
oxaliplatin
Grade 4
HOLD 
capecitabine 
and oxaliplatin 
until recovery 
≤grade 1.
Reduce dose of 
most likely 
causative agent 
by one to two 
dose levels 
when treatment 
is  resumed
HOLD 
capecitabine 
until recovery to 
≤grade 1 
Reduce dose of  
capecitabine one 
to two dose 
levels when  
treatment is 
resumed 
HOLD 
capecitabine 
and 
oxaliplatin 
Upon 
recovery to 
normal 
limits or 
baseline 
resume 
capecitabine 
and 
oxaliplatin 
at current 
dose.
HOLD 
capecitabine 
until recovery to 
≤grade 1
Reduce dose of  
capecitabine one 
to two dose 
levels when  
treatment is 
resumed 
HOLD 
capecitabine 
until recovery to 
≤grade 1
Reduce dose of  
capecitabine one 
to two dose 
levels when  
treatment is 
resumed 
Permanently 
discontinue
oxaliplatin
7.  DRUG FORMULATION 
Qualified personnel, familiar with procedures that minimize undue exposure to    themselves 
and the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.            
            
7.1    Ordering & Accountability:
Oxaliplatin and Capecitabine will be obtained from commercial supply.   Bevacizumab and 
Trastuzumab will be supplied by Genentech and provided free of charge to patient.  
Before an initial supply of Bevacizumab and Trastuzumab may be ordered from Genentech, up 
to two designated pharmacists responsible for requesting Bevacizumab and Trastuzumab must 
be identified using the Genentech BioOncology Avastin Approval Signatures for Drug Re-
supply form and Genentech BioOncology Herceptin Approval Signatures for Drug Re-supply 
form. Fax the completed forms to Genentech and an email to notify that the fax has been sent 
using the following information:  
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Bevacizumab (Avastin) Drug Orders
Fax to: 650-745-0978
Avastin-gsur@gene.com
 
Trastuzumab (Herceptin) Drug Orders
Fax to: 650-360-6908
herceptin-gsur@gene.com
Bevacizumab and Trastuzumab will be ordered by the responsible pharmacist(s) using the 
Genentech BioOncology Avastin Drug Request Form and Genentech BioOncology Herceptin 
Drug Request Form. The pharmacist(s) will fax the completed form to Genentech and confirm 
the request by email using the following information:
Bevacizumab (Avastin) Drug Orders
Fax to: 650-745-0978
Avastin-gsur@gene.com
 
Trastuzumab (Herceptin) Drug Orders
Fax to: 650-360-6908
herceptin-gsur@gene.com
Bevacizumab and Trastuzumab will be shipped directly from Genentech.  Please allow at least 
two weeks for drug to arrive on site. Drug deliveries are made only on Tuesday, Wednesday, 
Thursday and Friday. 
The responsible pharmacist will follow institutional guidelines for receipt and product 
accountability of the study agents.
7.1.1      Destruction and Return:
At the end of the study, unused supplies of bevacizumab and trastuzumab will be 
either destroyed per institutional policy or returned to Genentech as directed. 
7.2    Bevacizumab 
Bevacizumab will be provided by Genentech. See Section 7.1 for instruction on requesting re-
supply.
Bevacizumab is a recombinant, humanized monoclonal antibody which binds to, and neutralizes, 
vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors, 
Flt-1 and KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the formation 
of new blood vessels). The inhibition of microvascular growth is believed to retard the growth of 
all tissues (including metastatic tissue).
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Pharmacodynamics/Kinetics 
Distribution: Vd: 46 mL/kg 
Half-life elimination: ~20 days (range: 11-50 days) 
Excretion: Clearance: 2.75-5 mL/kg/day 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium Chloride Injection, 
USP.  Administration will be as an IV infusion.  
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.
7.3 Trastuzumab 
Trastuzumab will be provided by Genentech.  See Section 7.1 for instruction on requesting re-
supply.
Trastuzumab is a monoclonal antibody which binds to the extracellular domain of the human 
epidermal growth factor receptor 2 protein (HER-2); it mediates antibody-dependent cellular 
cytotoxicity by inhibiting proliferation of cells which overexpress HER-2 protein.
Pharmacodynamics/Kinetics 
Distribution: Vd: 44 mL/kg; not likely to cross the (intact) blood brain barrier (due to the large 
molecule size) 
Half-life elimination: Weekly dosing: Mean: 6 days (range: 1-32 days); every 3 week regimen: 
Mean: 16 days (range: 11-23 days) 
Trastuzumab intravenous powder for solution: 150mg.  Refer to package insert and/or 
institutional guidance for preparation, dispensing instructions and storage conditions.  The 
trastuzumab 150mg vial will be used as a single dose vial only.  Please note that the 440mg vials 
of trastuzumab can be used until they are depleted.
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7.4 Oxaliplatin 
Oxaliplatin is commercially available, and will not be provided by study.  
Oxaliplatin is a platinum derivative, an alkylating agent. Following intracellular hydrolysis, the 
platinum compound binds to DNA forming cross-links which inhibit DNA replication and 
transcription, resulting in cell death. Cytotoxicity is cell-cycle nonspecific.
Pharmacodynamics/Kinetics 
Distribution: Vd: 440 L 
Protein binding: >90% primarily albumin and gamma globulin (irreversible binding to platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive derivatives 
Half-life elimination: Terminal: 391 hours
Excretion: Urine (~54%); feces (~2%)
Administration: I.V. 
Administer as I.V. infusion over 2 hours. The infusion time may be lengthened to 6 hours if the 
evidence of hypersensitivity or laryngeal dysesthesia.   Flush infusion line with D5W prior to 
administration of any concomitant medication. 
Storage 
Store intact vials at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F); do not freeze. Protect concentrated solution from light (store in original outer 
carton). According to the manufacturer, solutions diluted for infusion are stable up to 6 hours at 
room temperature of 20°C to 25°C (68°F to 77°F) or up to 24 hours under refrigeration at 2°C to 
8°C (36°F to 46°F). Oxaliplatin solution diluted with D5W to a final concentration of 0.7 mg/mL 
(polyolefin container) has been shown to retain >90% of it’s original concentration for up to 30 
days when stored at room temperature or refrigerated; artificial light did not affect the 
concentration (Andre, 2007). As this study did not examine sterility, refrigeration would be 
preferred to limit microbial growth. Solutions diluted for infusion do not require protection from 
light.
Reconstitution 
Oxaliplatin is supplied in vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, 
preservative-free, aqueous solution at a concentration of 5 mg/ml. Water for Injection, USP is 
present as an inactive ingredient.  Dilution in D5W (250 or 500 mL) is required prior to 
administration.
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Do not prepare using a chloride-containing solution such as NaCl, due to rapid conversion to 
monochloroplatinum, dichloroplatinum, and diaquoplatinum; all highly reactive in sodium 
chloride.  Do not use needles or administration sets containing aluminum during preparation. 
Oxaliplatin has vesicant and irritant properties.  There have been reported cases of extravasation 
induced necrosis to skin and surrounding tissues.  Cool compress may be used for immediate 
management of extravasation, with consideration of potential for peripheral neuropathic 
discomfort exacerbated by cold. Warm compresses may avoid peripheral neuropathic discomfort, 
however, while possibly increasing drug removal through local vasodilation may increase 
cellular uptake and injury.
7.5    Capecitabine
Capecitabine is available commercially and will not be supplied by the study.  Treating 
investigator will write prescription, and give to patient during cycle 1.  The patient will fill 
through either local or mail order pharmacy depending on insurance carrier.  150 MG or 500 MG 
tablets of capecitabine are commercially available; however, for this study only 500 mg tablets 
will be used.
  Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues to form 
fluorouracil which is the active moiety. Fluorouracil is a fluorinated pyrimidine antimetabolite 
that inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to 
thymidylic acid, interfering with DNA, and to a lesser degree, RNA synthesis. Fluorouracil 
appears to be phase specific for the G1 and S phases of the cell cycle.
Pharmacodynamics/Kinetics 
Absorption: Rapid and extensive 
Protein binding: <60%; ~35% to albumin 
Metabolism:
Hepatic: Inactive metabolites: 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine
Tissue: Active metabolite: Fluorouracil 
Half-life elimination: 0.5-1 hour 
Time to peak: 1.5 hours; Fluorouracil: 2 hours 
Excretion: Urine (96%, 57% as α-fluoro-β-alanine); feces 
Administration: Oral 
Administered in 2 divided doses taken approximately 12 hours apart. Doses should be taken with 
water and within 30 minutes after a meal.
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Dietary Considerations 
Because current safety and efficacy data are based upon administration with food, it is 
recommended that capecitabine be administered with food. In all clinical trials, patients were 
instructed to take with water within 30 minutes after a meal.
Storage 
Store at room temperature of 25°C (77°F); excursions permitted between 15°C and 30°C (59°F 
and 86°F).
8. CORRELATIVE/SPECIAL STUDIES 
8.1   General
The purpose of the samples is to further understand the mechanism of the mode of action of 
trastuzumab and bevacizumab in esophageal and gastric cancer, and/or potentially identify a 
marker to monitor or predict treatment results.  All subjects will sign the informed consent form 
for the correlative science portion of this study.
Samples for the correlative science portion of the study will be analyzed after the completion of 
the clinical portion of this study in order to better understand biologic correlates of the clinical 
activity of trastuzumab and bevacizumab in the subject population. The analysis will be 
performed at a laboratory designated by the principal investigator.
All samples (tumor, plasma and whole blood) will be labeled according to directions noted 
below.  
Fresh biopsy samples may also be used for the generation of cell lines.  Any remaining samples, such 
as unstained slides, tumor blocks, plasma, and whole blood will be retained at the testing 
laboratory until completion of the trial.  All samples will be destroyed after a maximum of 10 
years.
An additional tube of blood will be collected at baseline and will be stored for future studies of 
other factors that may prove useful at that time. Permission for future research will be included 
separately in the informed consent form. 
The analysis of results will not be made available to either the subject or the treating physician; 
however, group results from this trial will be published. 
               Contact person at DFCI for correlative science labs:
Katharine Straw, CRC   617 632 6316 or Katharine_Straw@dfci.harvard.edu
8.2   Collection of tumor blocks/slides
 For all patients (Part I and II), a sample of tumor from primary biopsy that was obtained at the 
time of diagnosis (either paraffin block or 15 freshly cut unstained slides) must be obtained from 
all participants. This sample must have been taken prior to first loading dose of trastuzumab.   
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The participating investigator will request the tumor block or slides during the screening period, 
they need to be en route, but do not have to be received by the site to begin treatment.               
Patients in Part II of the study, must be willing to consent to two mandatory biopsies.  The first 
sample will be obtained anytime within two weeks of loading dose of trastuzumab; the second 
sample will be obtained on Cycle 1 Day 7, one week after the loading dose of trastuzumab.  We 
do not intend to send this sample for processing in the clinical pathology laboratory, unless there 
is a concern about any findings during this biopsy procedure as determined by the MD 
performing the biopsy.
8.2.1      Rationale
A key to the success of any targeted agent is to identify which patients benefit most from 
its use.  Therefore, in addition to clinical response, we would propose correlative 
scientific studies to identify this population to inform future therapeutic initiatives.  
All patients (Part I and Part II) will have blood samples drawn at designated time points 
throughout the study.  In addition, mandatory biopsy of tumor will be obtained from 
patients in Part II of this study at two time points.   The first will be obtained within one 
week prior to loading dose of trastuzumab, the second will be obtained 7 days post 
loading dose of trastuzumab.  
8.3.    Evaluation of signaling pathways 
8.3.1       Rationale
It has been demonstrated in preclinical models that trastuzumab exerts its anti-
proliferative effects through multiple mechanisms.  A principle pathway that is 
attenuated by trastuzumab, leading to growth arrest, is the PI3K/AKT pathway (Fujita, 
T et al.  Br J Cancer. 2006 Jan 30;94(2):247-52; Fabi, A et al. Oncology. 
2010;78(2):141-9).  Additionally, the status of this pathway in human patient samples 
(measured by PTEN status and other components of the PI3K pathway) has been shown 
to significantly correlate with multiple different clinical endpoints in breast cancer 
patients treated with trastuzumab. (Fujita.  Br J Cancer. 2006 Jan 30;94(2):247-52; 
Singer, CF et al.  Biochim Biophys Acta. 2008 Dec;1786(2):105-13; Fabi, A et al. 
Oncology. 2010;78(2):141-9;)
It has recently been shown that trastuzumab has activity in esophagogastric cancer.  In 
the ToGA study, reported at ASCO in June of 2009 (van Cutsem.  J Clin Oncol 27:18s, 
2009 (suppl; abstr LBA4509), patients with HER2/neu positive tumors were 
randomized to cisplatin/fluorouracil (or cisplatin/capecitabine) with or without 
trastuzumab.  Patients who received trastuzumab had a higher response rate (47% vs. 
35%; p=0.0017) and a longer overall survival (13.8mos vs. 11.1 mos; p=0.0046)
To date the molecular mechanism of this response and survival benefit has not been 
well studied in esophagogastric cancer, nor has the ability of trastuzumab to inhibit the 
PI3K pathway in esophagogastric tumors been well explored.  We hypothesize that the 
PI3K pathway, as in breast cancer, may be predictive of response to this agent.  
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Therefore, demonstrating the ability of trastuzumab to inhibit this pathway in patient 
samples will be informative in understanding its mechanism of action in these cancers. 
The first 20 patients will NOT undergo biopsy for this study.  These patients will 
demonstrate the safety and tolerability of this regimen. Once safety and tolerability has 
been established, the subsequent 16 patients will undergo a mandatory baseline 
research biopsy no more than 2 weeks before initiation of trastuzumab therapy and a 
second mandatory research biopsy on day 7 after their first trastuzumab treatment. 
Seven days is the maximum time that patients are typically willing to wait before 
initiating palliative chemotherapy and, based on pre-clinical data (Mohsin, SK et al.  J 
Clin Oncol. 2005 Apr 10;23(11):2460-8; Dasari VR et al. PLoS One. 2010 Apr 
26;5(4):e10350.), this period of time should be sufficient to document downregulation 
of signal transduction pathways.  We believe that 16 pre- and post-treatment patient 
samples should be sufficient to detect a clinically meaningful inhibition of the PI3K 
pathway.  A sample size of 16 matched samples achieves an 80% power to detect a 
difference of at least 20% using a binomial test, with one-sided type I error 5% and 
assuming the population proportion under the null hypothesis is at least 5%."
We will utilize Immunohistochemistry (IHC) for the following surrogates of PI3K 
activation in the tumors (phopho-AKT and phosphor-S6) and pretreatment biopsies will 
be assessed for PTEN status (which may indicate hyperactivation of the PI3K 
pathway).  IHC will be performed using standard methods.  In brief, samples will be 
immediately placed in formalin to minimize artifacts of devascularized tissue, such as 
loss of phosphorylation events.  Importantly, the processing of the pre-treatment and 
post-treatment biopsies will be performed in an identical fashion allowing for more 
robust comparisons of treatment effect. Antigen retrieval of formalin fixed, paraffin 
embedded tissue will be performed in a standard citrate buffer and heat in a pressure 
cooker.  The primary antibodies used in this study include PTEN (Cell 
Signalling#9559), phospho-Akt Ser-473 (Cell signaling# 3787), and phospho-S6 
Ser235/236 (Cell Signaling#4857).  
These antibodies have been well characterized and used in multiple tumor tissue types: 
PTEN – Saal et al. Nat Genet. 2008 Jan;40(1):102-7
pAKT – Kinkade et al. J Clin Invest. 2008 Sept; 118(9):3051-3064.
pS6 -  Iwenofu et al. Modern Pathology. 2008 Dec; 21:231-237.
            Secondary antibodies conjugated to HRP and the chromogenic substrate DAB, used for 
visualization of the antigen.  Adjacent sections will be stained with H&E to validate the 
presence of tumor.  Staining will be scored and quantitated using an iCys Laser 
Scanning Cytometer, through an ongoing collaboration with pathologist Dr. Gerry Chu.
8.4.   Sample Management of tumor blocks and slides.
8.4.1      Biopsy Specimens (Part II) and preparation of slides from paraffin-embedded tumor 
blocks (Part I and Part II)         
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Part II: Fresh Biopsy specimens:
            Two samples of tumor will be obtained during each biopsy procedure.   One sample will 
be immediately placed in formalin, a second sample will be snap frozen according to 
instructions below.
            The CRC will be responsible for collecting and delivery of this sample to the laboratory 
of Dr Alec Kimmelman.  Every effort should be made to obtain tissue that contains cells 
representative of the tumor. Each specimen should contain sufficient non-necrotic tumor 
tissue.
Instructions for Formalin Specimen:
1. Pre-label one large cryovial (at least 3 ml) with protocol # (09-457), study subject # 
and date of collection 
2. Fill each cryovial about halfway with Formalin
3. At time of biopsy collection, immediately place tumor specimen in cryovials, make 
sure specimen is immersed in formalin.
4. Deliver specimen as soon as possible to laboratory of Dr Alec Kimmelman, where 
specimen will be processed into paraffin block.
Instructions for Frozen Specimen:
1. Pre-label plastic block cryomold with protocol # (09-457), study subject #, and date 
of collection.
2. Place a few drops of OCT tissue compound into the cryomolds.
3. At the time of biopsy, immediately place tumor sample in cryomold, cover sample 
completely with OCT, wrap in aluminum foil, and place on dry ice.
4. Deliver specimen as soon as possible to the laboratory of Dr Alec Kimmelman for 
further processing.      
Part I and Part II: Preparation of slides from paraffin-embedded tumor biopsies:
A minimum of ten and preferably fifteen unstained slides will be prepared as follows 
from the paraffin-embedded tumor (unstained and 1 stained with hematoxylin and 
eosin).
Cut sections at 5 microns.
Apply sections to positively-charged (also called “plus”) glass slides.
Apply 1 section per slide.
A minimum of 10 unstained slides are required.   
One hematoxylin and eosin-stained slide from the tumor block used for diagnosis   
should also be sent.    
Label the glass slides with the protocol # (09-457), study subject #, and date of 
collection.
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Do not treat the cut section in the oven before storage in the refrigerator.
Store slides in a refrigerator at 4°C, and protect from light until shipped.
Labeling of slides:
       All slides/ tumor blocks must be labeled with:
1. Protocol Number:   09-457
2. Unique subject identifier: (initials of patient and study subject  #) 
3. Collection date.
Every effort should be made to obtain slides or blocks that contain cells representative of 
the tumor. The specimen should contain sufficient non-necrotic tumor tissue. In addition 
to the slides or block, one hematoxylin/eosin stained slide must be collected from the 
block that was used for diagnosis. The paraffin block could be a biopsy, or be part of a 
larger sample obtained at surgery. The minimum size paraffin block should be 3 mm x 3 
mm of tumor tissue.
8.5   Blood sample management 
Samples will be drawn by an experienced phlebotomist or nurse.   Blood samples may be drawn 
either peripherally or via a central line.
Each site will be responsible for ordering their own laboratory supplies and shipping materials 
for the specimens.  Shipping costs and supplies will be covered by the protocol budget.  
Specimens will be stored at the site until arrangements have been made to store at DF/HCC.  
8.5.1      Plasma specimens:
Approximately 5-7 ml of blood for plasma-based studies will be collected in EDTA 
(purple top) tubes. 
Blood samples will be drawn as follows:

Within 2 weeks prior to initiation of therapy (may be done on C1D1) 

Day 1 cycle 2, 0-24 hours prior to initiation of therapy.

Day 1 cycle 4, 0-24 hours prior to initiation of therapy

Every 2 cycles thereafter, on Day 1, 0-24 hours prior to initiation of therapy

End of study
Instructions for plasma samples:
Invert tube several times to assure complete mixing of anticoagulant (EDTA) and 
immediately centrifuge in a clinical centrifuge at 3,000 r.p.m. for 10 minutes at room 
temperature. Plasma should be aspirated without disturbing cells, aliquoted in 3 
cryogenic vials, and frozen at –70C.  
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All cryovials will be labeled as follows: 
1. Protocol Number: 09-457
2. Unique subject identifier (initials of patient and study subject #) 
3. Collection date
4. Tube # (there should be 3 cryovials)/ contents (plasma)
Instruction for Whole Blood sample:
An additional tube of whole venous blood will be collected at baseline and will be 
stored for future studies of other factors that may prove useful at that time. Venous 
blood will be collected into a 6 ml purple-top EDTA tube. After collection of the 
sample, the tube should be gently inverted to ensure mixing with the anticoagulant.  
Whole blood should be transferred from EDTA tube into 2 labeled cryotubes and 
frozen at –80C. 
The cryovials will be labeled as follows: 
1. Protocol Number: 09-457
2. Unique subject identifier (initials of the patient and subject study #) 
3. Collection date
4. Tube # (there should be 2 cryovials) / contents (whole blood)
       
8.5.2      Sample Management – CECs:  Obtained at the following time   points:

Within 2 weeks of initiation of therapy (may be done on C1D1)

Day 1 cycle 2, 0-24 hours prior to initiation of therapy.

Day 1 cycle 4, 0-24 hours prior to initiation of therapy

Every 2 cycles thereafter, on Day 1, 0-24 hours prior to initiation of therapy

End of Study
Sample Management – Handling Instructions for CEC specimens
1.   Approximately 7 cc of venous blood will be collected into a BD Vacutainer 
CPT™ tube with Sodium Citrate (Becton Dickinson product #362761). The tube 
should be gently inverted several times to ensure mixing with the anticoagulant.
2.   Within two hours the CPT tube should be centrifuged at room temperature in a 
horizontal rotor for 25 minutes at 1600g. After centrifugation, the mononuclear 
cells will be visible in a whitish layer just under the plasma (refer to picture 
below).  
3.   500-900 µL aliquot should be taken from the mononuclear layer (we are not 
collecting plasma from this tube) and transferred to a cryotube (designated tube 
#1/mononuclear), to which an equal volume of freezing media (RPMI-1640 
media with 20% dimethyl sulfoxide) should be added.
4.   Tube #1 should immediately be placed in a –80C degree freezer. All cryotubes 
should be labeled as noted above.
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9. STUDY 
CALENDAR
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1 All labs must be done within 14 days of start and do not need to be repeated on day 1
2 Part II study participants: C1D1 must be on Tuesday, Wednesday, Thursday or Friday
3 Part I: C2D1 will begin one week after loading dose of trastuzumab; Part II: C2D1 will be 9-11 days after loading 
dose of trastuzumab in Part II. 
4 UPCR every other cycle. Not required if Bevacizumab discontinued.
5 Screening CT scan of chest, abdomen and pelvis within 28 days of C1D1
6First restaging scans within 1 week of C4D1 and then every 2 cycles until C24D1. Scans after cycle 24 will be 
every 3 cycles.
7 MUGA scan or Echocardiogram within 28 days of C1D1.  Please use the same modality each time.
8 MUGA or Echocardiogram to be performed anytime prior to cycle 4, then prior to every 4th cycle while on study 
(i.e. prior to Cycle 8, Cycle 12, etc.)
9 EKG within 28 days
10 For women of childbearing potential  
11 Tumor block or 15 freshly cut unstained slides are required for eligibility and are to be requested for delivery to 
study team, however do not have to be on site to begin cycle 1
12 Part II DF/HCC study participants: Cycle 1 Day 7 Biopsy
13 Study blood with screening labs (or just prior to C1D1 infusion)
14 Study blood only C2D1
15 Study bloodC4D1; then every other cycle; and Off study
16 Give patient prescription for capecitabine to be filled at local pharmacy prior to C2D1
After cycle one, each cycle is 21 days +/- 1 day
  Screening Assessments will be performed 
within 14 days of C1D1 unless otherwise 
noted below.  Informed consent  may be 
within 28 days of study entry1
Screening Assessments
C1D12  C1D7 C2D13
and
C3D1 
C4D1
 (and all 
subsequent cycles)
Off 
study
Informed consent
X
History
X
Physical exam
X
X
X
X
X
Height/weight/BSA
X
X
X
Concomitant medications
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Toxicity Assessment
X
X
X
X
X
CBC with differential
X
X
X
X
Comprehensive metabolic panel
X
X
X
X
PT/PTT/INR
X
U/A
X
Urine Protein/Creatinine ratio (UPCR)
X
X4
CT scan of chest, abdomen, pelvis
X5
X6
MUGA scan or echocardiogram
X7
X8
EKG
X9
Urine or serum pregnancy test10
X
Biopsy of tumor (Part II only)
X11
X12
Study bloods
X13
 X14
X15
X
Trastuzumab loading dose
X
Bevacizumab/Trastuzumab/oxaliplatin
administration
X
X
Capecitabine  days 1-14
X16
X
X
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10. MEASUREMENT OF EFFECT. 
Response will be assessed using RECIST version 1.1 criteria
10.1   Antitumor Effect– Solid Tumors
For the purposes of this study, participants should be evaluated for response after the first 3 
cycles and then every 2 cycles (6 weeks) until cycle 24, after which participants should be 
evaluated after every 3 cycles.
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer 
et al, 2009) guideline. Changes in the diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST 1.1 criteria 
10.1.1     Definitions
Evaluable for toxicity.  All participants who have received all intravenous study 
agents in cycle 1 and cycle 2 and at least one dose of capecitabine during cycle 2 
will be evaluable for toxicity.
Evaluable for objective response. Only those participants who have measurable disease 
present at baseline, have received at least two cycles of therapy (all IV therapy and at 
least one dose of capecitabine), and have had their disease re-evaluated will be 
considered evaluable for response. These participants will have their response 
classified according to the definitions stated below. 
                        
10.1.2      Disease Parameters
Measurable disease. Measurable disease is the presence of at least one (1) lesion that 
can be accurately measured in at least one dimension with longest diameter >20 
millimeters (mm) using conventional techniques (CT, MRI, x-ray) or >10 mm with 
spiral CT scan. Measurable lesions must be at least 2 times the slice thickness in 
mm. All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters).
Malignant lymph nodes. To be considered pathologically enlarged and measurable, 
a lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed.
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with > 10 to < 15mm 
short axis, are considered non-measurable disease. Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, abdominal masses identified by physical exam that are 
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not measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Lesions must be accurately 
measured in 1 dimension with a minimum size of 10 mm by CT or MRI (slice 
thickness no greater than 5 mm), 20 mm by chest x-ray. Nodes must have a short 
axis > 15 mm. The short axis should be included in the sum of the lesions in the 
calculation of response. Nodes that shrink to < 10 mm are considered normal. 
Target lesions should be selected on the basis of their size, be representative of all 
the involved organs, and should be lesions that can be followed with reproducible 
repeated measurements. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered target lesions if the soft tissue component meets the 
definition of measurability as defined above. Cystic lesions thought to represent cystic 
metastases can be considered as target lesions. However, if non-cystic lesions are 
present, these are preferred for selection as target lesions. Lesions in previously 
irradiated areas or areas subject to other loco-regional therapy are usually not 
considered measurable unless there has been demonstrated progression of that lesion. 
Non-target lesions. All other lesions, including small lesions < 10 mm or pathological 
lymph nodes measuring > 10 mm to < 15 mm in short axis, as well as truly non-
measurable lesions, which include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging technique
 10.1.3      Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. All baseline evaluations should be performed as 
closely as possible to the beginning of treatment and never more than 4 weeks before the 
beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the anti-tumor effect of a treatment.
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended.
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Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung; however, CT is preferable.
Conventional CT and MRI. These techniques should be performed with cuts of 10 
mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm. This applies to tumors of the chest, 
abdomen, and pelvis. Head and neck tumors and those of extremities usually 
require specific protocols.
Ultrasound (US). When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions. It is, however, a 
possible alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions, and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination.
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should 
follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response 
(L.K. Shankar, J.M. Hoffman, S. Bacharach, M.M. Graham, J. Karp, A.A. 
Lammertsma, S. Larson, D.A. Mankoff, B.A. Siegel, A. Van den Abbeele, J. Yap, D. 
Sullivan. Consensus recommendations for the use of 18F-FDG PET as an indicator of 
therapeutic response in patients in National Cancer Institute Trials. J Nucl Med, 
47(6):901-903, 2006). Patients should avoid strenuous exercise and be on a low 
carbohydrate diet for 24 hours prior to the scan. Patients should fast for 4 hours or 
longer prior to the FDG injection and should have a serum glucose of less than 200 
mg/dL at the time of FDG injection. A 10-20 mCi dose of FDG should be injected for 
typical adult patients. For longitudinal studies with multiple scans, particular attention 
should be paid to ensure consistent patient preparation and acquisition parameters 
between the follow-up scan and the baseline scan. When designing a study where PET 
scans are going to be utilized as one of the modalities to evaluate efficacy, it is 
important to consult with physicians in nuclear medicine in designing the appropriate 
criteria to be utilized.
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only 
be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in reference 
centers. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained.
Tumor markers. Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a subject to be 
considered in complete clinical response. Specific additional criteria for 
standardized usage of prostate-specific antigen (PSA) and CA-125 response in 
support of clinical trials are being developed.
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Cytology/Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain).
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease.
10.1.4      Response Criteria 
10.1.4.1         Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph node must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study with at least a 5 mm 
absolute increase in the sum of all lesions. The appearance of one or more new 
lesions* denotes disease progression. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
Unknown (UN): Assessment of target lesions cannot be made due to insufficient 
or unevaluable data. In this case, a concise explanation must be given.
Note: If tumor response data is missing for target lesions, the overall assessment 
must be UN unless there is new disease that would result in an overall assessment 
of PD. However, if there is missing or unevaluable data for non-target lesions, but 
data is available for all target lesions, the overall response for that time point will 
be assigned based on the sum LD of all target lesions. Additionally, the 
assessment of CR cannot be made if there is missing or unevaluable data for non-
target lesions. In this case, the overall assessment would be PR.
 *Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a follow-
up scan in an anatomical location that was not scanned at baseline is considered 
new and will indicate PD. If a new lesion is equivocal (because of small size, 
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etc.), follow-up evaluation will clarify if it truly represents new disease and if PD 
is confirmed, progression should be declared using the date of the initial scan on 
which the lesion was discovered. 
10.1.4.2         Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.   All lymph nodes must be non-pathological 
in size (less than 10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response.
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesions and/or maintenance of tumor marker level above the 
normal limits.
Progressive Disease (PD): Appearance of one or more new lesions* (new 
lesions must be > slice thickness) and/or unequivocal progression of 
existing non-target lesions.
Overall level of substantial worsening that merits discontinuation of 
therapy. A useful test that can be applied when assessing non-targets for 
unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for 
measurable disease.
Unknown (UN): Assessment of non-target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be given.
*Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a follow-
up scan in an anatomical location that was not scanned at baseline is considered 
new and will indicate PD. If a new lesion is equivocal (because of small size, 
etc.), follow-up evaluation will clarify if it truly represents new disease and if PD 
is confirmed, progression should be declared using the date of the initial scan on 
which the lesion was discovered. 
10.1.4.3         Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
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started). The participant's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target
Lesions
New
Lesions
Overall 
Response
Best Overall Response 
for when 
Confirmation is 
CR
CR
No
CR
>4 wks confirmation
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/Not 
evaluated
No
PR
>4 wks confirmation
SD
Non-CR/Non-
PD/Not 
evaluated
No
SD
Documented at least 
once >4 wks from 
baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
No prior SD, PR or CR
*
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
Note:   Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as "symptomatic 
deterioration". Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target 
Lesions
New
Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
Not all evaluated
No
Not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Non-CR/non-PD is preferred over stable disease for non-target disease since 
SD is increasingly used an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised. 
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10.1.5     Duration of Response
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrence or PD is objectively documented, taking as reference for PD 
the smallest measurements recorded since the treatment started.
Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.
10.1.6      Progression-Free Survival
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment 
to time of objective disease progression. 
Response Review
Dana-Farber Harvard Cancer Center Tumor Metrics Imaging Core (TIMC) will 
conduct central review of all radiological assessments for this study.
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1
General 
In the event of any adverse event the first concern will be for the safety of the patient.  
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE v4.0) that is available at http://ctep.cancer.gov/reporting//ctc.html. 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections. 
Adverse events experienced by participants will be collected and reported from initiation of 
study medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event or related to a study procedures and/or 
study medication beyond 30 days will continue to be contacted by a member of the study team 
until the event is resolved, stabilized, or determined to be irreversible by the participating 
investigator. 
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Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study. 
11.2
Definitions 
11.2.1       Adverse Event (AE)
An adverse event is any undesirable sign, symptom or medical condition or experience 
that develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be 
related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests. 
11.2.2
  Serious adverse event (SAE) 
An SAE is any sign, symptom or medical condition that emerges during capecitabine, 
oxaliplatin, bevacizumab or trastuzumab treatment or post-treatment during the follow 
up period that (1) was not present at the start of treatment or is not a chronic condition 
that is part of the patient’s medical history or (2) was present at the start of treatment 
or was part of the patients history but worsened in severity and/or frequency during 
therapy, and meets any of the following criteria: 
A serious adverse event is an undesirable sign, symptom, or medical condition which:

is fatal or life-threatening;

requires or prolongs inpatient hospitalization;

results in persistent or significant disability/incapacity;

constitutes a congenital anomaly or birth defect; or

jeopardizes the participant and requires medical or surgical intervention to 
prevent one of the outcomes listed above. 
Events not considered to be serious adverse events are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not 
worsen

emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

respite care
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11.2.3
   Expectedness 
 Adverse events can be 'Expected' or 'Unexpected.' 
11.2.3.1           Expected adverse event
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk.  
Refer to Section 6.1 for a listing of expected adverse events associated with the 
study agent(s).  
11.2.3.2
Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
adverse event list, the Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk.  
11.2.4
    Attribution 
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows:

Definite – The AE is clearly related to the study treatment.

Probable – The AE is likely related to the study treatment.

Possible – The AE may be related to the study treatment. 

Unlikely - The AE is doubtfully related to the study treatment.

Unrelated - The AE is clearly NOT related to the study treatment.
11.3
Recording Adverse Events
Adverse event information will be obtained at each contact with the participant. All adverse 
events will be recorded on the appropriate study-specific case report forms (CRFs). 
11.4
Reporting Adverse Events 
 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
on the local institutional SAE form. 
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For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each 
participating investigator must abide by the reporting requirements set by the DF/HCC.  This 
applies to any medical event equivalent to an unexpected grade 2 or 3 with a possible, probable 
or definite attribution, grade 4 toxicities, and grade 5 (death) regardless of study phase or 
attribution.
Additionally, other investigative sites will also report SAEs to their respective IRB according to 
the local IRB policies and procedures in reporting adverse events. The study must be conducted 
in compliance with FDA regulations, local safety reporting requirements, and reporting 
requirements of the principal investigator.
11.4.1      SAE Reporting to Genentech Drug Safety 
Med Watch 3500a Forms 
http://www.fda.gov/medwatch/REPORT/Mfg.htm[for drugs/biologics]
All SAEs must be reported to Genentech Drug Safety within 24 hours of learning of 
the event. Reporting will be done on the Med Watch 3500a Form and should include 
the following information:

Appropriate patient demographic information

Suspect products information

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 

Relevant history/preexisting medical conditions

Concomitant medications

Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication per protocol section 11.2.4.
Med Watch 3500a Forms must be faxed to:
Genentech Drug Safety:
(650) 225-4682 or (650) 225-5288
Copies of SAE submission to Genentech Drug Safety must be simultaneously copied 
to the study sponsor by fax or email:
Peter C. Enzinger, MD
Fax: 617-582-7988
Peter_enzinger@dfci.harvard.edu
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Follow-up information:  
Within 24-48 hours, the participating investigator must provide follow-up information 
on the SAE. Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will continue 
or discontinue study participation.
Additional information may be added to a previously submitted report by any of the 
following methods:

Adding to the original Med Watch 3500a report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with 
the original Med Watch 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 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. 
11.4.2       Notification by Investigator to Overall PI & DFCI IRB
All adverse events that occur after the initial dose of study treatment, during treatment, 
or within 30 days of the last dose of treatment that meet the criteria outlined in the 
DFCI IRB Adverse Event Reporting Policy (outlined below) must be reported to the 
DF/HCC IRB using the DFCI Adverse Event Reporting Form. 
The DFCI IRB requires the following Adverse Events (AE) be reported for all 
subjects enrolled and actively participating in the trial or when the AE occurs 
within 30 days of the last study intervention (e.g. drug administration):

Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
Unexpected and Possibly, Probably or Definitely Related / Associated with the 
Intervention.

ALL Grade 4 (life threatening or disabling) Events – Unless expected AND 
specifically listed in protocol as not requiring reporting.

ALL Grade 5 (fatal) Events
Note: If the participant is in long term follow up, report the death at the time of 
continuing review. 
Investigative sites within DF/HCC and DF/PCC will notify the Overall PI within 1 
business day of the event or within 1 business day of learning of the event. Sites within 
DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for Human 
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Research Studies (OHRS) per the DFCI IRB reporting policy. A copy of the 
submission must be sent to the Overall PI.
Other participating sites must report each serious adverse event to the DF/HCC 
Principal Investigator within 1 business day of learning of the occurrence. In the event 
that the participating investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 1 business day after learning of it and 
document the time of his or her first awareness of the adverse event. Report serious 
adverse events by email or facsimile to:
Peter C. Enzinger, MD
Fax: 617-582-7988
Peter_enzinger@dfci.harvard.edu
Within the following 24-48 hours, the participating investigator must provide follow-
up information on the serious adverse event. Follow-up information should describe 
whether the event has resolved or continues, if and how the event was treated, and 
whether the participant will continue or discontinue study participation. 
11.4.3       Non-Serious Adverse Event Reporting Requirements
Non-serious adverse events will be reported to the Principal Investigator on the 
toxicity Case Report Forms.  
11.5   Hospital Risk Management Notification by Investigator
The participating investigator will report to the Principal Investigator and to local Risk 
Management any subject safety reports or sentinel events that require reporting according to 
institutional policy.
12. DATA AND SAFETY MONITORING
12.1
Data Reporting 
12.1.1      Method 
The QACT will collect, manage, and monitor data for this study. 
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12.1.2      Data Submission 
The schedule for completion and submission of case report forms (paper or electronic) 
to the QACT is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with QACT
On Study Form
Within 14 days of registration
Baseline Assessment Form
Within 14 days of registration
Treatment Form
Within 10 days of the last day of the cycle
Adverse Event Report Form
Within 10 days of the last day of the cycle
Response Assessment Form
Within 10 days of the completion of the cycle 
required for response evaluation
Off Treatment/Off Study Form
Within 14 days of completing treatment or 
being taken off study for any reason
Follow up/Survival Form
Within 14 days of the protocol defined follow 
up visit date or call
12.2
Safety Meetings
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Principal Investigator and study team.
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current 
dose level information; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring within 30 days for Phase I or II protocols; Other information 
(e.g. scans, laboratory values) will be provided upon request. 
12.3 
Monitoring
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator or DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported in accordance with the protocol, institutional policy, 
and any applicable regulatory requirements. 
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All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue 
during protocol performance and completion. Please refer to Section 5.0 of the Dana-Farber/ 
Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (Appendix D) for further 
detail.
12.4   Multicenter Guidelines
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix D.
The Overall PI/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports to all participating institutions for submission to their 
individual IRBs for action as required.
Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.
Except in very unusual circumstances, each participating institution will order the study agent(s) 
directly from supplier.  A participating site may order the agent(s) only after the initial IRB 
approval for the site has been forwarded to the Coordinating Center.
13. REGULATORY CONSIDERATIONS
13.1   Protocol Review and Amendments
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location. 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The Principal Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators. 
All decisions of the IRB concerning the conduct of the study must be made in writing.
13.2   Informed Consent
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this 
study. The formal consent of a participant, using the IRB approved consent form, must be 
obtained before the participant is involved in any study-related procedure. The consent form 
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must be signed and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The participant must be given a copy 
of the signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 
13.3   Ethics
This study is to be conducted according to the following considerations, which represent 
good and sound research practice:

US Code of Federal Regulations (CFR) governing clinical study conduct 
and ethical principles that have their origin in the Declaration of Helsinki

Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 

Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 

Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 

Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 

State laws

Institutional research policies and procedures 
www.dfhcc.harvard.edu/clinical-research-support/clinical-research-
operations-cro/policies-and-procedures
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must 
be reported to the IRB according to the local reporting policy. 
13.4   Study Documentation
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified.
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays. 
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13.5 Records Retention
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
14. STATISTICAL CONSIDERATIONS 
14.1 Statistical Design
This study will have a 3 stage design.  Part I of the study will have two stages and will enroll the 
first 20 patients.  Part II will enroll 16 additional patients if criteria for study continuation is met.  
To be considered evaluable for this study, (for both toxicity and response), patients must have 
received all of the intravenous study agents in cycle 1 and 2 and at least one dose of capecitabine 
in cycle 2.  Any patient that does not complete this period of evaluation will be replaced.
In the first stage of Part I of the study, 5 patients will be enrolled and evaluated through 2 cycles 
of therapy.    Safety and tolerability criteria are defined below.
Safety and tolerability for the first 5 patients will be defined as:
1. No clinically significant, treatment related grade 3-5toxicity occurring in 4 or more 
patients.
If 4 or more patients have grade 3-5 toxicity, the study will be put on hold and the treatment 
will be either modified with IRB approval or will close.   If the study is modified for safety 
and tolerability, upon reopening, 5 new patients will be enrolled and evaluated using the 
same toxicity criteria noted above. 
This is based on the following calculation:  Let X denote the number of subjects experiencing 
grade 3-5 toxicity.  Let p denote the true underlying rate for this safety endpoint.
The table below gives the probability of stopping associated with this stopping rule when p=p0: 
p0      P(X >/= 4 | p = p0)
-----------------------------
0.50      0.19
0.55      0.26
0.60      0.34
0.65      0.43
0.70      0.53
0.75      0.63
0.80      0.74
0.85      0.84
          
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Once the PI has determined that the regimen is safe and tolerable, an additional 15 patients will 
be enrolled for further evaluation of safety, tolerability and response to complete Part I of the 
study.
Safety and tolerability for the first 20 patients will be defined as:
1.
No clinically significant, treatment related grade 3-5 toxicity occurring in 13 or more 
patients.
Let X denote the number of subjects experiencing grade 3-5 toxicity. Let p denote the true 
underlying rate for this safety endpoint.
Based on 20 subjects, the trial would stop if 13 or more out of these 20 subjects experience 
clinically significant, treatment related grade 3-5 toxicity. 
The table below gives the probability of stopping associated with this stopping rule when p = p0: 
 p0      P(X >/= 13 | p = p0)
-----------------------------
0.50       0.13
0.55       0.25
0.60       0.42
0.65       0.60
0.70       0.77
0.75       0.90
0.80       0.97
0.85       0.99
If the true grade 3-5 toxicity rate is 75%, we would have 90% chance to stop the trial based on 
the first 20 subjects. We consider a 75% rate or higher for this safety endpoint to be unacceptable 
because in the recent randomized CALGB 80403/ECOG 1206 trial, reported at ASCO 2010 in 
Chicago, the Grade 3-5 toxicity for the 3 treatment arms was 75%, 79%, and 86%, respectively.  
Further support for this toxicity threshold is given in the only trial that has led to FDA 4approval 
of a chemotherapeutic agent for esophagogastric cancer.  In the V325 study (van Cutsem. J Clin 
Oncol 2006), the grade 3-4 non-hematologic toxicity rate was 81.4% for the DCF arm that led to 
approval of docetaxel in esophagogastric cancer.  Furthermore, this DCF regimen had a 82.3% 
grade 3-4 neutropenia rate (and lesser rates of anemia and thrombocytopenia).
Efficacy for the first 20 patients will be defined as:
 If ≤6 responses are noted in the initial group of 20 evaluable patients (early termination 
probability 0.61), the trial will be terminated.  If there are ≥ 7 patients with a major 
response, another 16 patients will be accrued to a total of 36 evaluable patients.  
 This regimen will be considered promising if 15 or more evaluable patients have a major 
response by RECIST 1.1 criteria in the final analysis.  This is based on a hypothetical 
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historical response rate of less than or equal to 30% for the CAPOX combination versus the 
new response rate of at least 50% in this combination plus bevacizumab and trastuzumab, 
using a type I error of 10% (one sided) and power of 86%.
For correlative science, we believe that 16 pre-and post-treatment samples should be 
sufficient to detect a clinically meaningful inhibition of the P13K pathway.  A sample size 
of 16 matched samples achieves an 80% power to detect a difference of at least 20% using a 
binomial test, with one-sided type I error 5% and assuming the population proportion under 
the null hypothesis is at most 5%.  
Update:
As of 4.4.13, 16 patients have met eligibility requirements and have received study drug.  
Of these 16 patients, all are evaluable for toxicity and 15 are evaluable for efficacy (1 too 
early). There have been no grade 5 toxicities.  Only one patient has had grade 4 toxicity 
(hypertriglyceridemia, a rare but documented toxicity of capecitabine).  Clinically relevant 
grade 3 toxicities have occurred in only 5 patients.  These include diarrhea:  5pts; dehydration:  
2pts; GI disorder, other:  1pt; hypokalemia: 2pts; hypophosphatemia:  1pt; and thromboembolic 
event:  1pt.  Additionally, 2 patients have had grade 3 lymphopenia.  Thus, 10 of 16 patients have 
had no clinically relevant grade 3-5 toxicity.  This exceeds the requirement that a minimum of 7 
patients out of 20 patients must have no clinically significant, treatment related grade 3-5 toxicity 
to move forward with Part II of the study.
Of 15 patients evaluable for efficacy, 11 have had a confirmed PR and 1 has had a 
confirmed CR by RECIST version 1.1 for a major response rate of 80%.  This is double the 
efficacy requirement of > 6 of 20 patients with major response to move forward with Part II 
of the study.
We have thus fulfilled the toxicity and efficacy criteria for Part I of the study and would like 
to move forward now with Part II.  The reason that this is important is that patients meeting 
the HER2/neu eligibility requirements are fewer than previously expected. We would like to 
start requiring biopsies of the DF/HCC patients immediately (rather than waiting until 
patient #20) since we may otherwise not enroll sufficient biopsy eligible patients to reach 
the 16 paired biopsies that we have proposed.
14.2   Endpoints
14.2.1       Primary endpoint
To determine the response rate (based on RECIST version 1.1) for the combination of 
CAPOX + bevacizumab + trastuzumab in patients with metastatic or unresectable 
esophagogastric cancer.  
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14.2.2       Secondary endpoints
To determine the safety and tolerability of the CAPOX + bevacizumab + 
trastuzumab combination in patients with metastatic or unresectable esophagogastric 
cancer.
To determine the overall survival for the combination of CAPOX + bevacizumab + 
trastuzumab in patients with unresectable esophagogastric cancer.
To determine the time to progression for the combination of CAPOX + bevacizumab 
+ trastuzumab in patients with unresectable esophagogastric cancer.
14.2.3       Exploratory analyses:
Using a baseline biopsy and day 7 biopsy, we will seek to determine if certain signal 
transduction pathways (using the following antibodies:  pAKT, pERK, pEGFR, 
pMET, pPDGFR, HER2) in esophagogastric cancers are up regulated or down 
regulated after a single dose of trastuzumab.
To correlate expression of serum VEGF with response and survival in metastatic 
esophageal and gastric patients treated with CAPOX+ bevacizumab+ trastuzumab.
14.3
Sample Size/Accrual Rate
Due to the restrictive enrollment criteria, we expect only 1-2 patients to be enrolled per 
month.  Thus, we expect to reach sufficient enrollment for the primary endpoint in 
approximately 1 year (20 evaluable patients as defined in 14.0).   Patients who are not 
evaluable as defined in 14.0 will be replaced.  
14.4    Analysis of Secondary Endpoints
Overall survival and time to progression will include all evaluable patients, will be 
measured from the date of enrollment, and will be calculated using the method of Kaplan 
and Meier.
14.5 
Reporting and Exclusions
14.5.1 
    Evaluation of toxicity
To be considered evaluable, patients must have received all intravenous study 
agents in cycle 1 and cycle 2 and at least one dose of capecitabine during cycle 
2.
  
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14.5.2 
   Evaluation of response
All participants who received all intravenous study agents in cycle 1 and cycle 2 
and at least one dose of capecitabine during cycle 2 will be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they are 
determined to be ineligible. Each participant will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database.
          
15. PUBLICATION PLAN
A full report of the outcomes should be made public no later than three (3) years after the end of 
data collection. 
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16. REFERENCES /BIBLIOGRAPHY
American Cancer Society: Cancer Reference Information 5/28/2009
Barnholtz-Sloan JS, Sloan AE, Davis FG, et al: Incidence proportions of brain metastases in 
patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance 
System. J Clin Oncol 22:2865-72, 2004
Batchelor TT, Sorensen AG, DiTomaso E, et al: AZD2171, a pan-VEGF receptor tyrosine kinase 
inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. 
Cancer Cell 11:83-95, 2007
Bendell JC, Domchek SM, Burstein HJ, et al: Central nervous system metastases in women who 
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patients with HER2-positive metastatic breast cancer – the TBP study (BDB26/GIB 3-05). 
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17. APPENDICES 
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Appendix A: Patient Diary
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Patient initials________        Cycle___________
MRN________________
Take capecitabine (xeloda) tablets twice a day 30 minutes after eating.  Take with at least 8 oz of 
water.  Try to take 12 hours apart.  If you vomit or miss a dose, please note it on diary and do not 
make up the dose.  
***If day 1 start is delayed until the afternoon, take only one dose on day 1 and take the final 
dose on day 15 in the morning.
The use of a daily moisturizer to hands, feet and face are recommended.  Please use sunscreen 
when going outdoors.
Your dose will be ________tablets in the morning and _________tablets in the evening
Day/Date
Capecitabine
Check box and note time taken 
below:
           AM                     PM
Comments
1
□    __:__
□    __:__
2
□    __:__
□    __:__
3
□    __:__
□    __:__
4
□    __:__
□    __:__
5
□    __:__
□    __:__
6
□    __:__
□    __:__
7
□    __:__
□    __:__
8
□    __:__
□    __:__
9
□    __:__
□    __:__
10
□    __:__
□    __:__
11
□    __:__
□    __:__
12
□    __:__
□    __:__
13
□    __:__
□    __:__
14
□    __:__
□    __:__
15
***  □    __:__
***only if day 1 start was delayed
16
17
18
19
20
21
Patient Signature: ______________________________Date: ________________
Research Team Signature: _______________________ Date: ________________
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Appendix B:
Performance Status Criteria:
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
100
Normal, no complaints, no evidence of disease.
0
Normal activity. Fully active, able to carry on all 
pre-disease performance without restriction.
90
Able to carry on normal activity; minor signs or 
symptoms of disease.
80
Normal activity with effort; some signs or 
symptoms of disease.
1
Symptoms, but ambulatory. Restricted in physically 
strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on normal activity 
or to do active work.
60
Requires occasional assistance, but is able to 
care for most of his/her needs.
2
In bed < 50% of the time. Ambulatory and capable 
of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking 
hours.
50
Requires considerable assistance and frequent 
medical care.
40
Disabled, requires special care and assistance.
3
In bed >50% of the time. Capable of only limited 
self-care, confined to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization indicated. 
Death not imminent.
20
Very sick, hospitalization indicated. Death not 
imminent.
4
100% bedridden. Completely disabled. Cannot carry 
on any self-care. Totally confined to bed or chair.
10
Moribund, fatal processes progressing rapidly. 
5
Dead.
0
Dead.
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Appendix C: Urine Protein/Creatinine Ratio (UPCR):
Procedure for Obtaining Urine Protein / Creatinine Ratio (UPCR)

Obtain at least 4 ml of a random urine sample (does not have to be a 24 hour urine) 

Determine protein concentration (mg/dL) 

Determine creatinine concentration (mg/dL) 

Divide results of protein concentration by creatinine concentration.  

(Urine protein / creatinine ratio = protein concentration (mg /dL) / creatinine 
concentration (mg /dL))
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DFCI IRB Protocol #: 09-457
APPENDIX D
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan
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TABLE OF CONTENTS
1.0
INTRODUCTION .......................................................................................74
1.1
Purpose
74
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
74
2.0
GENERAL ROLES AND RESPONSIBILITIES .........................................74
2.1
DF/HCC Sponsor
74
2.2
Coordinating Center
74
2.3
DF/HCC Quality Assurance Office for Clinical Trials (QACT)
74
2.4
Participating Institution
74
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ..........74
3.1
Protocol Distribution
74
3.2
Protocol Revisions and Closures
74
3.3
Informed Consent Requirements
74
3.4
IRB Documentation
74
3.5
IRB Re-Approval
74
3.6
Participant Confidentiality and Authorization Statement
74
3.6.1
DF/HCC Multi-Center Protocol Confidentiality.................................................................74
3.7
DF/HCC Multi-Center Protocol Registration Policy
74
3.7.1
Initiation of Therapy
74
3.7.2
Eligibility Exceptions
74
3.7.3
Verification of Registration, Dose Levels, and Arm Designation
74
3.8
DF/HCC Protocol Case Number
74
3.9
Protocol Deviations, Exceptions and Violations
74
3.9.1
Definitions
74
3.9.2
Reporting Procedures
74
3.10
Safety Assessments and Toxicity Monitoring
74
3.10.1
Guidelines for Reporting Serious Adverse Events
74
3.10.2
Guidelines for Processing IND Safety Reports
74
3.11
Data Management
74
3.11.1
Data Forms Review
74
4.0
REQUISITIONING INVESTIGATIONAL DRUG......................................74
5.0
MONITORING: QUALITY CONTROL .....................................................74
5.1
Ongoing Monitoring of Protocol Compliance
74
5.2
Evaluation of Participating Institution Performance
74
5.2.1
Monitoring Reports
74
6.0
AUDITING: QUALITY ASSURANCE .......................................................74
6.1
NCI Sponsored Trials
74
6.2
DF/HCC Sponsored Trials
74
6.3
Participating Institution
74
6.4
DF/HCC Sponsor and Coordinating Center
74
6.5
Sub-Standard Performance
74
6.5.1
Corrective Actions
74
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1.0
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that 
will be participating in the research protocol.
1.1   Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures, and Cancer 
Therapy Evaluation Program (CTEP) Multi-Center Guidelines.       
1.2 Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-center Protocol:  A research protocol in which one or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Children’s Hospital Boston (CHB), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol 
as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines 
(CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  
The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also 
typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol.  
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, 
management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (i.e. CTEP 
Protocol and Information Office (PIO), FDA, OBA etc.). The DF/HCC Sponsor has ultimate 
authority over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Principal Investigator; however, both roles can be filled by two different people. For CTEP 
Protocols this person is called the Protocol Chair.
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.   
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
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Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order 
that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. Should the 
DF/HCC Sponsor decide to use a CRO, the CRO will be deemed the Coordinating Center.  
DF/HCC Quality Assurance Office for Clinical Trials: A unit within DF/HCC developed to 
computerize and manage data, and to provide a Quality Control and Quality Assurance function 
for DF/HCC trials.  
2.0
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities: 
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, Peter C. Enzinger, MD will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 

Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments. 

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.  

Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.

Assure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team receives adequate protocol 
training and/or a Site Initiation Visit prior to enrolling participants and throughout trial’s 
conduct as needed.

Ensure the protocol will be provided to each participating site in a language 
understandable to all site personnel when English is not the primary language. 

Monitor progress and overall conduct of the study at all Participating Institutions. 

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. 
CTEP, FDA, OBA) reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with CTEP/PIO Office (CTEP trials) or FDA (investigator-held 
IND trials) or OBA (gene therapy trials), as applicable.

Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 
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2.2
Coordinating Center 
The Coordinating Center, Dana-Farber Cancer Institute, will assume the following general 
responsibilities:

Assist in protocol development 

Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all Participating Institutions.

Maintain CTEP, FDA or OBA correspondence, as applicable.

Maintain updated roster of participants. 

Verify eligibility.

Verify response.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.  

Distribute adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting Policy to all participating investigators.

Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with.

Monitor Participating Institutions either by on-site or virtual monitoring. 

Maintain Regulatory documents of all Participating Institutions. 

Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc). 

Maintain documentation of all communications.

Ensure that each Participating Institution has the appropriate assurance on file with the 
Office of Human Research Protection (OHRP).    
2.3
DF/HCC Quality Assurance Office for Clinical Trials (QACT)
In addition to the Coordinating Center, the DF/HCC QACT provides the following support 
services to assist the DF/HCC Sponsor:

Develop protocol specific case report forms (CRF/eCRFS).

QA/QC data of protocol specific CRFs. 

Provide a central participant registration, which includes review of consent and 
eligibility.

Provide auditing services (funding and QACT approval required).
2.4
Participating Institution
Each Participating Institution is expected to comply with all applicable Federal Regulations and 
DF/HCC requirements, the protocol and HIPAA requirements. All Participating Institutions will 
provide a list of personnel assigned to the role for oversight of data management at their site to 
the Coordinating Center. 
The general responsibilities for each Participating Institution are as follows:

Commit to the accrual of participants to the protocol.
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
Submit protocol and/or amendments to their local IRB.

Maintain a regulatory binder in accordance with DF/HCC requirements.

Provide the Coordinating Center with regulatory documents as requested.

Participate in protocol training prior to enrolling participants and throughout the trial as 
needed (i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center. 

Submit source documents, research records, and CRFs per protocol specific submission 
guidelines to the Coordinating Center.

Submit Serious Adverse Event (SAE) reports to local IRB per local requirements and to 
the Coordinating Center, in accordance with DF/HCC requirements. For CTEP trials, 
submit SAE reports directly to CTEP and provide copies to the Coordinating Center 

Submit protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements.

Secure and store investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.

For protocols using investigational agents, the Participating Institution will order their 
own investigational agents regardless of the supplier (i.e. National Cancer Institute (NCI), 
pharmaceutical company). [This is the preferred method of ordering investigational 
agent. Some pharmaceutical companies may require the Coordinating Center to order 
study drug for external sites. Contact pharmacy to confirm this is feasible. Revise as 
necessary.]
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.   
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions.

Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 
90 days from receipt of the notification.

Revisions for life-threatening causes: Participating Institutions will receive immediate 
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notification from the Coordinating Center concerning protocol revisions required to 
protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions 
will be implemented immediately followed by IRB request for approval.

Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating Center, 
will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures.
3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the 
DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols.  This document will be provided separately to each Participating Institution.
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB.
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent to interventional trials 
(i.e. drug and/or device trials).  
3.4
IRB Documentation
The following must be on file with the Coordinating Center:

Approval letter of the Participating Institution's IRB 

Copy of the Informed Consent Form approved by the Participating Institution’s IRB 

Participating IRB’s approval for all amendments
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the Coordinating Center their 
IRB approval for amendments to a protocol.   
3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals.
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The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.  
3.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known 
as the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to 
the physical or mental health of an individual is called Protected Health Information (PHI). 
HIPAA outlines how and under what circumstances PHI can be used or disclosed. 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an Authorization.  This Authorization may or may not be 
separate from the informed consent document.  The Coordinating Center, with the approval from 
the DFCI IRB and if applicable NCI/CTEP, will provide a consent template, which covered 
entities (Participating Institutions) must use. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its 
trials.  However, because of the nature of these trials, certain protected health information must 
be collected per NCI requirements. These are the primary reasons why DF/HCC has chosen to 
use Authorizations, signed by the participant in the trial, rather than limited data sets with data 
use agreements.
3.6.1
    DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are 
strictly confidential. Whenever reasonably feasible, any participant specific reports 
(i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the 
Coordinating Center must have the participant’s full name & social security number 
“blacked out” and the assigned DF/HCC QACT case number (as described below) and 
DF/HCC protocol number written in (with the exception of the signed informed 
consent document). Participant initials may only be included or retained for cross 
verification of identification
3.7
DF/HCC Multi-Center Protocol Registration Policy
Refer to protocol section 4.0 for protocol registration procedures.
3.7.1
    Initiation of Therapy
Participants must be registered with the DF/HCC QACT and according to local 
institution guidelines before receiving treatment.  Treatment may not be initiated until 
the Participating Institution receives a faxed or e-mailed copy of the participant’s 
registration confirmation memo from the Coordinating Center. Therapy must be 
initiated per protocol guidelines.  The DF/HCC Sponsor and DFCI IRB must be 
notified of any exceptions to this policy.
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3.7.2
    Eligibility Exceptions
The DF/HCC QACT will make no exceptions to the eligibility requirements for a 
protocol without DFCI IRB approval. The DF/HCC QACT requires each institution to 
fully comply with this requirement.
3.7.3
    Verification of Registration, Dose Levels, and Arm Designation
A registration confirmation memo for participants registered to DF/HCC Multi-Center 
Protocol will be faxed or emailed to the registering institution within one business day 
of the registration. Treatment may not be initiated until the site receives a faxed or e-
mailed copy of the registration confirmation memo and once the participant has been 
registered according to local requirements.
3.8
DF/HCC Protocol Case Number
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for QACT CRF/eCRF completion and correspondence, and correspondence 
with the Coordinating Center.  
3.9
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe derivations from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB.
3.9.1
Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation. 
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3.9.2
Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in 
the medical record and/or regulatory documents to describe all protocol exceptions, 
deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring 
that all protocol violations/deviations are promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the 
DFCI IRB. The Participating Institution must submit the deviation request to the 
Coordinating Center who will then submit the deviation request to the DFCI IRB. 
Upon DFCI IRB approval the deviation is submitted to the Participating Institution 
IRB, per institutional policy. A copy of the Participating Institution’s IRB report and 
determination will be forwarded to the Coordinating Center within 10 business days 
after the original submission. 
All protocol violations must be sent to the Coordinating Center in a timely manner. 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the Coordinating Center will submit the report to the 
DF/HCC Sponsor for review. Subsequently, the Participating Institution’s IRB 
violation/deviation report will be submitted to the DFCI IRB for review per DFCI IRB 
reporting guidelines. DF/HCC will forward all violation reports to CTEP via an 
internal DF/HCC process, as applicable.
3.10
Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights 
and well-being of study participants. Recording and reporting of adverse events that occur during 
the course of a study help ensure the continuing safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety.   The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center. Protocols using CTEP supplied agents must 
also report these toxicities via the AdEERS system.
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
3.10.1      Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) 
are detailed in protocol section 11.4.
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Participating Institutions must report the AEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB SAE Reporting Requirements. 
The Coordinating Center will maintain documentation of all Participating Institution 
Serious Adverse Event reports and be responsible for communicating to all 
participating investigators, any observations reportable under the DFCI IRB Reporting 
Requirements.  The Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures.
3.10.2
Guidelines for Processing IND Safety Reports 
FDA regulations require sponsors of clinical studies to notify the FDA and all 
participating investigators of any adverse experience associated with the use of the 
investigational agent that is both serious and unexpected. The DF/HCC Sponsor will 
review all IND Safety Reports and ensure that all IND Safety Reports are distributed 
to the Participating Institutions.  The Participating Investigators are to review, send a 
copy to their IRB according to their local IRB’s policies and procedures, and file a 
copy with their regulatory documents.
3.11
Data Management
The DF/HCC QACT develops a set of electronic case report forms (CRF/eCRFs), for use with 
the protocol.  These forms are designed to collect data for each study. The DF/HCC QACT 
provides a web based training for eCRF users. Refer to protocol section 12.1.2 for the schedule 
for completion and submission of case report forms (paper or electronic) to the QACT.
  
3.11.1      Data Forms Review
When data forms arrive at the DF/HCC QACT, they are reviewed for completeness, 
protocol treatment compliance, adverse events (toxicities) and response. Data 
submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in 
accordance with the following:
Incomplete or Questionable Data
If study forms are received with missing or questionable data, the submitting 
institution will receive a written or electronic query from the DF/HCC QACT Data 
Analyst or study monitor.  Responses to all queries should be completed and submitted 
within 14 calendar days.  Responses may be returned on the written query or on an 
amended paper case report form, or in the case of electronic queries, within the 
electronic data capture (eDC) system. In the case of a written query for data submitted 
on a paper case report form, the query must be attached to the specific data being re-
submitted in response.  
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Missing Forms
If study forms are not submitted on schedule, the Participating Institution will receive 
a Missing Form Report from the Coordinating Center noting the missing forms.  These 
reports are compiled by the DF/HCC QACT and distributed a minimum of four times 
a year. 
4.0
REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in protocol section 7.1. 
5.0
MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the QACT provides quality control 
oversight for the protocol.
5.1 Ongoing Monitoring of Protocol Compliance
 
The Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution will also be subject to at least one 
on-site monitoring conducted by the Coordinating Center’s Clinical Trial Specialist. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring will occur before the clinical phase of the protocol begins, 
continue during protocol performance and through study completion. Additional monitoring 
practices may include but are not limited to; source verification, review and analysis of the 
following: eligibility requirements of all participants, informed consent procedures, adverse 
events and all associated documentation, study drug administration/treatment, regulatory files, 
protocol deviations, pharmacy records, response assessments, and data management. 
The DF/HCC Lead Institution will maintain regular and ongoing communication to Participating 
Institutions about study related information. 
On-Site Monitoring will occur at least once per non DF/HCC site. Initial site visit to occur after 
first participant is enrolled or after study has been activated for 9 months, whichever comes first. 
Additional on-site monitoring may occur at the request of the DF/HCC Sponsor.  Participating 
Institutions will be required to provide access to participants’ complete medical record and 
source documents for source documentation verification and Site Regulatory Binder.
Virtual Monitoring will take place for verification of informed consent and eligibility, study visit 
source documents and CRF, investigational product accountability, CRF review for missing data 
and query resolution, AEs, SAEs, and protocol endpoints unless on-site monitoring is requested 
by the DF/HCC Sponsor. Participating Institutions will be required to forward de-identified 
copies of participants’ medical record and source documents to the Coordinating Center.
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All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Coordinating Center and if 
applicable, QACT Data Analysts assigned to the protocol, will perform the ongoing protocol 
data compliance monitoring.
5.2 Evaluation of Participating Institution Performance
5.2.1
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports for on-site and virtual 
monitoring of Participating Institutions to ensure protocol compliance and ability to 
fulfill responsibilities of participating in the study. The DF/HCC Sponsor may increase 
the monitoring activities at Participating Institutions that are unable to comply with the 
protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating 
Institutions may also be subject to an audit as determined by the DF/HCC Sponsor.
6.0
AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial 
related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per 
the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations 
(CFR).
6.1 DF/HCC Sponsored Trials
Auditing of this protocol will take place as determined by DFCI QACT. One on-site audit will be 
scheduled by the QACT, assuming at least three participants have been treated on protocol at the 
site. Approximately 3-4 participants would be audited at the site over a 2 day period.  If 
violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 
6.2 Participating Institution
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and corrective 
action plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date. 
6.3 DF/HCC Sponsor and Coordinating Center 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. 
The Coordinating Center, must forward these reports to the DF/HCC QACT per DF/HCC policy 
for review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC 
Audit Committee could accept or conditionally accept the audit rating and final report. 
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Conditional approval could require the DF/HCC Sponsor to implement recommendations or 
require further follow-up.  For unacceptable audits, the DF/HCC Audit Committee would 
forward the final audit report and corrective action plan to the DFCI IRB as applicable.
6.4 Sub-Standard Performance
The DF/HCC Sponsor, DFCI IRB and the NCI for CTEP trials, is charged with considering the 
totality of an institution’s performance in considering institutional participation in the protocol.
6.4.1
Corrective Actions
Participating Institutions that fail to meet the performance goals of accrual, submission 
of timely accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, will be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during 
the probation period that deficiencies have been corrected, as evidenced by the 
improved performance measures. Participating Institutions that fail to demonstrate 
significant improvement will be considered by the DF/HCC Sponsor for revocation of 
participation. 
Dana Farber
IRB NUMBER: 09-457
IRB APPROVAL DATE: 11/25/2019