Clinical trial NCT01208103
Conditions: Ampulla of Vater Adenocarcinoma Small Intestinal Adenocarcinoma Stage III Ampulla of Vater Cancer AJCC v8 Stage III Small Intestinal Adenocarcinoma AJCC v8 Stage IIIA Ampulla of Vater Cancer AJCC v8 Stage IIIA Small Intestinal Adenocarcinoma AJCC v8 Stage IIIB Ampulla of Vater Cancer AJCC v8 Stage IIIB Small Intestinal Adenocarcinoma AJCC v8 Stage IV Ampulla of Vater Cancer AJCC v8 Stage IV Small Intestinal Adenocarcinoma AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-05-06; Completion date: 2018-03-07
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well bevacizumab given with capecitabine and oxaliplatin work in treating participants with small bowel or ampulla of Vater adenocarcinoma that has spread to other places in the body. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Drugs using in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bevacizumab, capecitabine, and oxaliplatin may work better in treating participants with small intestinal or ampulla of Vater adenocarcinoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the progression-free survival (PFS) at six months for patients with advanced adenocarcinoma of the small bowel (small intestine) or ampulla of Vater treated with capecitabine, oxaliplatin (CAPOX) and bevacizumab.

SECONDARY OBJECTIVES:

I. To determine the response rate (RR) for CAPOX and bevacizumab. II. To determine the overall progression free survival for CAPOX and bevacizumab.

III. To determine the overall survival (OS) for CAPOX and bevacizumab. IV. To determine the toxicity of CAPOX and bevacizumab.

OUTLINE:

Participants receive oxaliplatin via central venous catheter (CVC) over 2 hours and bevacizumab intravenously (IV) over 30-90 minutes on day 1. Participants also receive capecitabine orally (PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 10 and 30 days, and then every 3 months thereafter.

Arms: arm 1: Participants receive oxaliplatin via CVC over 2 hours and bevacizumab IV over 30-90 minutes on day 1. Participants also receive capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bevacizumab intervention 2: Capecitabine intervention 3: Oxaliplatin
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given CVC

Protocol documents:
Prot_SAP_000.pdf: 
2009-0626 
May 6, 2014  
 
The University of Texas M. D. Anderson Cancer Center 
Division of Cancer Medicine 
 
Title:  Phase II Study of Bevacizumab Combined with Capecitabine and 
Oxaliplatin (CAPOX) in Patients with Advanced Adenocarcinoma of the 
Small Bowel or Ampulla of Vater 
 
Study Drugs 
Bevacizumab (Avastin®) 
Capecitabine 
Oxaliplatin 
 
Support Provided By 
Genentech, Inc. 
 
Principal Investigator 
Michael J. Overman, MD 
Assistant Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-745-4317 (phone) 
713-745-1163 (fax) 
moverman@mdanderson.org 
 
 
Sub-Investigators 
Robert A. Wolff, MD 
Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-745-5476 (phone) 
713-745-1163 (fax) 
rwolff@mdanderson.org 
 
Gauri Varadhachary, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
gvaradha@mdanderson.org 
 


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Christopher Garrett, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
cgarrett@mdanderson.org 
 
Bryan Kee, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
bkee@mdanderson.org 
 
 
David Fogelman, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
dfogelman@mdanderson.org 
 
Rachna Shroff, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
rshroff@mdanderson.org 
 
 
Scott Kopetz, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
skopetz@mdanderson.org 


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Milind Javle, MD 
Associate Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX 77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
mjavle@mdanderson.org 
 
Kanwal P. Raghav, MBBS 
Assistant Professor, Department of Gastrointestinal Medical Oncology 
The University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 426 
Houston, TX  77030 
713-792-2828 (phone) 
713-745-1163 (fax) 
kpraghav@mdanderson.org 
 
 
Statistician 
Jeffrey Morris, PhD 
Associate Professor, Department of Biostatistics 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
713/563-4284 (phone)  
jefmorris@mdanderson.org 
 
 
Pathologist 
Huamin Wang, MD, PhD 
Associate Professor, Department of Pathology 
The University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 0085 
Houston, TX  77030 
713-563-1846 (phone) 
hmwang@mdanderson.org 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
 
 
1.0 BACKGROUND ........................................................................................... 1 
1.1 Adenocarcinoma of the Small Bowel and Ampulla of Vater  ................... 1 
1.2 
Treatment for Adenocarcinoma of the Small Bowel and Ampulla 
of Vater  .......................................................................................... 2 
1.3 Vascular Endothelial Growth Factor  ...................................................... 5 
1.4 Bevacizumab .......................................................................................... 5 
1.5 CAPOX Combined with Bevacizumab .................................................... 6 
1.6 Bevacizumab Clinical Experience ........................................................... 7 
1.7 Oxaliplatin ............................................................................................... 15 
1.8 Capecitabine .......................................................................................... 17 
1.9 Capecitabine plus Oxaliplatin (CAPOX) ................................................. 20 
1.10 
CAPOX Safety Profile ..................................................................... 22 
1.11 
Study Rationale .............................................................................. 22 
2.0 OBJECTIVES .............................................................................................. 23 
2.1  
Primary ........................................................................................... 23 
2.2  
Secondary ...................................................................................... 23 
3.0 STUDY DESIGN .......................................................................................... 23 
3.1 
Description of the Study .................................................................... 23 
3.2 
Outcome Measures ........................................................................... 23 
4.0 SAFETY PLAN ............................................................................................ 24 
4.1 
General Plan to Manage Safety.......……………………………………24 
5.0 STUDY SUBJECTS ..................................................................................... 25 
5.1 
Subject Selection ............................................................................ 25 
5.2 
Inclusion Criteria ............................................................................. 25 
5.3 
Exclusion Criteria............................................................................ 26 
6.0 STUDY DESIGN .......................................................................................... 29 
6.1 
Treatment Plan ............................................................................... 29 
7.0 STUDY MEDICATION ................................................................................. 30 
7.1 
Bevacizumab  .................................................................................... 30 
7.2 
Oxaliplatin  ........................................................................................ 32 
7.3 
Capecitabine ..................................................................................... 34 
7.4 
Dose Modifications and/or Delays Due to Toxicity ............................ 35 


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7.5 
Bevacizumab plus CAPOX................................................................ 46 
7.6 
Concomitant Medications .................................................................. 47 
8.0 CLINICAL AND LABORATORY EVALUATIONS ......................................... 50 
8.1 
Pre-treatment Evaluations ................................................................. 51 
8.2 
Evaluations During Treatment ........................................................... 53 
8.3 
End of Treatment Evaluations ........................................................... 54 
8.4 
Follow-up (Off Treatment) ................................................................. 54 
9.0  SUBJECT DISCONTINUATION .................................................................. 55 
10.0 RESPONSE EVALUATION ......................................................................... 56 
10.1 Measurement of Effect ...................................................................... 56 
10.2 Definitions ......................................................................................... 56 
10.3 Measurable Disease ......................................................................... 57 
10.4 Non-Measurable Disease .................................................................. 57 
10.5 Target Lesions .................................................................................. 58 
10.6 Non-Target Lesions ........................................................................... 58 
10.7 Guidelines for Evaluation of Measurable Disease ............................. 58 
10.8 Response Criteria ............................................................................. 59 
10.9 Time Point Evaluation ....................................................................... 61 
10.10 Evaluation of Best Overall Response ................................................ 63 
10.11 Confirmation ...................................................................................... 64 
10.12 Duration of Overall Response ........................................................... 64 
10.13 Duration of Stable Disease ............................................................... 64 
11.0 STUDY DISCONTINUATION ...................................................................... 65 
12.0 STATISTICAL METHODS ........................................................................... 65 
12.1Study Design and Sample Size............................................................. 65 
 
12. 2 Planned Efficacy Evaluations .............................................................. 65 
       12.3 Statistical Analysis ............................................................................... 66 
13.0 DATA AND PROTOCOL MANAGEMENT ................................................... 67 
14.0 OPTIONAL TISSUE COLLECTION FOR FUTURE RESEARCH ................ 68 
15.0 SAFETY REPORTING OF ADVERSE EVENTS ......................................... 69 
15.1 Adverse Events Reporting and Definitions ........................................ 69 
15.2 Reporting of Serious Treatment Emergent Adverse Events .............. 69 
15.3 Safety Reporting Requirements for IND Exempt Studies  ................. 71 
16.0 RETENTION OF RECORDS ....................................................................... 71  
 
 


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APPENDICES 
 
 
 
Appendix 1 – ECOG Performance Status 
Appendix 2 – Calculated creatinine clearance (CrCl) calculated 
using the Cockcroft and Gault formula 
Appendix 3 - Capecitabine Dosing 
Appendix 4 - FDA MedWatch 3500a Form 
Appendix 5 - NYHA Guidelines 
Appendix 6 - Procedure for Obtaining a Urine Protein / Creatinine Ratio 
Appendix 7 – Safety Reporting FAX Cover Sheet


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Page 1 
 
 
1. BACKGROUND 
 
1.1. ADENOCARCINOMA OF THE SMALL BOWEL AND AMPULLA OF 
VATER 
Small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC) are 
rare tumors that commonly present with late stage disease and have an overall 
poor outcome.  The estimated incidence of small bowel cancer for 2007 is 5,640 
patients with the vast majority presenting with late stage disease.[1]  Because of 
its infrequency, knowledge of its clinical and pathological characteristics is 
limited.  However, considering that the small bowel constitutes 75% of the length 
and over 90% of the mucosal surface area of the gastrointestinal tract, it is 
interesting that only 1% to 2% of gastrointestinal malignancies occur in this 
segment. [2] Unfortunately, most of these tumors produce nonspecific signs and 
symptoms, making them difficult to diagnose.  Indeed, the lethality of small bowel 
tumors appears to be related in large part to the delay in diagnosis and 
treatment. 
Risk factors for small bowel malignancy include Crohn’s disease, familial 
adenomatous polyposis, celiac disease, cigarette smoking, alcohol consumption, 
prior peptic ulcer disease, prior colon cancer, and cystic fibrosis.  It also appears 
to be associated with cholecystectomy, immunosuppressive states, ileostomy, 
duplications of the small bowel, and high fat and protein intake. 
The prognosis of patients with SBA is grim.  The overall 5 year survival rates 
range from 5% to 32%.[3-5]  Even in the series of Ouriel and Adams, who 
reported some of the best results, 70% of those with node-negative disease were 
alive at 5 years, whereas only 13% with node-positive disease were alive at 5 
years.[5] 
When analyzed stage for stage, survival of patients with SBA is remarkably 
similar to that of patients with colonic carcinoma.[6]  There are other striking 
similarities between adenocarcinomas of the small and large bowel as well.  For 
example, the incidence of the two diseases is similar from country to country.[7]  
There are multiple genetic disorders that lead to varying degrees of increased 
likelihood of developing adenocarcinoma not only in the small bowel and ampulla 
of Vater, but also in the colon, stomach, and esophagus (i.e., Peutz-Jeghers 


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Syndrome, familial adenomatous polyposis, attenuated familial adenomatous 
polyposis, hereditary non-polyposis colorectal cancer).   In addition, 
adenomatous polyps appear to be precursor lesions for adenocarcinomas in both 
regions of the gastrointestinal tract.[8]  Furthermore, patients with SBA are at 
greater risk of large bowel adenocarcinoma, and vice versa.  Moreover, 
researchers who have identified many of the molecular and genetic changes that 
occur at various stages in the development and progression of adenoma-
carcinoma sequence have noted that the molecular genetic changes, 
frequencies, and order of appearances of several important oncogenes that 
occur in colorectal cancer are also seen in small bowel carcinoma.[9, 10]  In 
particular, abnormalities in cyclin D1, p53, MLH-1, MSH-2, APC, CTNNB1 and 
KRAS are present in both cancers.[11]  More specifically, the activating 
mutations in the KRAS oncogene occur in about 40% of both small bowel and 
large bowel adenocarcinoma.[12, 13] The level of the p53 protein is also 
increased in up to 70% of tumors at both sites, with higher levels in 
adenocarcinomas than adenomatous polyps.  The level of the p53 protein is also 
increased during adenoma-to-carcinoma transition in both large bowel and small 
bowel adenocarcinoma.   
In support of the similarities between small bowel and large bowel 
adenocarcinoma we have recently demonstrated similar outcomes with the use 
of capecitabine plus oxaliplatin (CAPOX) chemotherapy. Our response rate of 
52% is nearly identical to the expected response rate seen with CAPOX in the 
treatment of colorectal adenocarcinoma. 
1.2 
TREATMENT FOR ADENOCARCINOMA OF THE SMALL BOWEL AND 
AMPULA OF VATER 
Systemic chemotherapy has been known to be active in SBA for a number of 
years. However because of the low incidence of small bowel adenocarcinoma, 
the literature on the use of chemotherapy in this cancer is sparse.  A review of 
the literature regarding the use of chemotherapy in adenocarcinoma of the small 
bowel is presented in table 1.  The benefit of chemotherapy in advanced small 
bowel adenocarcinoma has recently been demonstrated.  A statistical overall 
survival benefit with chemotherapy versus no chemotherapy was shown in the 
MD Anderson Cancer Center retrospective review by Dabaja et. al.[4]  Both 
retrospective studies by Czykowski et. al. and Oriel et. al. demonstrated a trend 


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Page 3 
 
to benefit with 5-fluorouracil (5-FU) based chemotherapy but given the small 
numbers no statistical significance was obtained.[5, 14]   
Table 1: Prior studies of Chemotherapy treatment for small bowel 
adenocarcinoma 
Author 
Year study 
No. of 
patients Chemotherapy 
RR 
OS 
(m) 
Overman et 
al.[15]  
2009 phase II 
30 
CAPOX 
52% 
20.4 
Fishman et 
al.[16] 
2006 Retrospective 44 
Various agents 
29% 
18.6 
Locher et 
al.[17] 
2005 Retrospective 20 
5-FU and platinum 
21% 
14 
Gibson et 
al.[18] 
2005 phase II 
38 
FAM 
18% 
8 
Czaykowski 
et al.[14] 
2004 retrospective 
37 
5-FU based 
5% 
16 
Crawley et 
al.[19] 
1998 retrospective 
8 
ECF/5-FU 
37% 
13 
Jigyasu et 
al.[20] 
1984 retrospective 
14 
5-FU based 
7% 
9 
Rochlin et 
al.[21] 
1965 retrospective 
11 
5-FU 
36% 
NR 
Abbreviations: No. (number); 5-FU (5-fluorouracil); RR (response rate); OS (overall 
survival in months); NR (not reported) 
 
5-FU, as in colorectal cancer, has remained the backbone chemotherapy agent 
studied in adenocarcinoma of the small bowel.  Response rates observed with 
primarily single agent 5-FU have varied from 0% to 36%.   
Two prospective phase II studies have been conducted in SBA.  The first study, 
conducted by the Eastern Cooperative Oncology Group (ECOG) was reported in 
2005.  This study defined SBA as adenocarcinoma of duodenum, jejunum, ileum, 
and ampulla of Vater.  The combination of 5-FU, doxorubicin, and mitomycin C 
(FAM) resulted in an overall response rate of 18.4% and complete response rate 
of 5%.[18]   We have recently completed a phase II study of capecitabine 
combined with oxaliplatin (CAPOX) in the treatment of SBA and AAC.[15]  
CAPOX was administered as a 21 day cycle with oxaliplatin 130 mg/m2 IV 
administered on day 1 and capecitabine 750 mg/m2 PO BID administered on 
days 1-14.   This single institution study conducted at M.D. Anderson Cancer 


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Center enrolled 30 patients with metastatic or unresectable disease over a 31 
month time period (11/04 to 7/07). For the 25 patients with metastatic disease the 
overall response rate was 52%, median progression-free survival (PFS) was 6.6 
months and median overall survival was 15.5 months.  The six month PFS  was 
52% (figure 1).  Treatment was well tolerated with the most common adverse 
events being nausea/vomiting, fatigue, and peripheral neuropathy.  The most 
common grade 3/4 toxicities included fatigue in 7 patients (23%), neuropathy in 2 
patients (7%), granulocytopenia in 3 patients (10%), vomiting in 3 patients (10%), 
diarrhea in 3 patients (10%), thrombocytopenia in 2 patients (7%), and 
hypokalemia in 2 patients (7%).  The results of this study have made CAPOX 
chemotherapy the new standard first-line chemotherapy combination for 
advanced SBA and AAC. 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. PFS for CAPOX in adenocarcinoma of the small bowel and 
ampulla of Vater 
 
1.3 
VASCULAR ENDOTHELIAL GROWTH FACTOR 
 


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Vascular endothelial growth factor (VEGF) plays a key role in tumor-associated 
neo-angiogenesis, which contributes to providing a tumor with oxygen, nutrition, 
and supports the development of metastases.  Binding of VEGF-A to the VEGF 
receptor (VEGFR) leads to survival, proliferation, and migration of endothelial 
cells. [22]  In addition recent studies have demonstrated the presence of 
VEGFRs on multiple tumor cells. [23]   Increased expression of VEGF has been 
seen in most human tumors, such as lung, breast, thyroid, colon, and kidney. [24]  
In xenograft models the inhibition of VEGF signaling results in tumor shrinkage in 
a wide variety of human cancer cell lines.   When inhibition of VEGF signaling is 
combined with chemotherapy, increased antitumor effects are seen in xenograft 
models when compared to chemotherapy alone. [25] 
1.3.1 VEGF In small bowel adenocarcinoma 
No published data exists on the expression of VEGF in small bowel 
adenocarcinoma.  At MD Anderson we have conducted immunohistochemical 
staining for VEGF-A on 54 SBA tumor samples (unpublished data).  In these 54 
samples we found VEGF-A to be expressed in 91% of patients.    An additional 
study has also noted universal expression of VEGF-A RNA in a small group of 
SBA samples.[26] No clinical study has investigated the role of VEGF signaling 
inhibition in SBA or AAC. 
1.4 
BEVACIZUMAB 
Bevacizumab is an FDA approved recombinant humanized monoclonal IgGF1 
antibody that binds to VEGF and prevents the interaction of VEGF to its 
receptors on endothelial and tumor cells.  
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials 
in more than 5000 patients and in multiple tumor types. In addition, data are 
available from 3,863 patients enrolled in two postmarketing studies in metastatic 
colorectal cancer (CRC).  Approximately 130,000 patients have been exposed to 
bevacizumab as a marketed product or in clinical trials.   
1.5 
CAPOX COMBINED WITH BEVACIZUMAB 
The combination of CAPOX and bevacizumab has been extensively studied in 
CRC and has a well defined side effect profile.  The randomized phase II TREE 


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study compared two successive cohorts of patients.  In TREE-1 (n=150) patients 
were treated with either FOLFOX or bolus 5-FU or CAPOX and in TREE-2 
(n=223) patients were treated with the same regiments but also received 
bevacizumab.[27]  Capecitabine dosing in TREE-2 was lower than in TREE-1 
with capecitabine reduced from 2000mg/m2/day to 1700mg/m2/day.  The addition 
of bevacizumab to CAPOX improved outcomes with RR of 46% vs. 27%, median 
TTP of 10.3 months vs. 5.9 months, and median OS of 24.6 months vs. 17.2 
months. 
The phase III XELOX-1/NO16966 study, which compared CAPOX to FOLFOX in 
untreated metastatic colorectal cancer patients, has recently been reported.[28]  
This was a 1401 patient study in which 654 of the patients also received the 
addition of bevacizumab to either CAPOX or FOLFOX.  The study demonstrated 
equivalency for these two combinations of fluorinated pyrimidines and oxaliplatin.  
The primary endpoint was reached with CAPOX demonstrating non-inferiority to 
FOLFOX for PFS.  Both regiments demonstrated good tolerance.  Grade 4 
toxicities occurred in 12% of the CAPOX arm and 25% of the FOLFOX arm.  This 
difference primarily reflected a difference relating to increased grade 4 
neutropenia with FOLFOX.   For the FOLFOX arm the most common grade 3-4 
toxicities were neutropenia in 43%, diarrhea in 12%, fatigue in 9%, nausea in 5%, 
and abdominal pain in 5%.   The most common grade 3-4 toxicities for the 
CAPOX arm were diarrhea in 20%, thrombocytopenia in 7%, neutropenia in 7%, 
hand-foot syndrome in 6%, and fatigue in 6%, and nausea in 5%.  The 
comparison between bevacizumab plus FOLFOX/CAPOX and placebo plus 
FOLFOX/CAPOX demonstrated similar rates of grade 3-4 toxicity with 21% and 
15%, respectively.  Grade 3-4 adverse events that were higher with bevacizumab 
were venous thromboembolism (8% vs. 5%), hypertension (4% vs. 1%), bleeding 
(2% vs. 1%), and arterial thromboembolic events (2% vs. 1%).  The addition of 
bevacizumab improved outcomes with median PFS of 9.4 months with 
bevacizumab compared to 8 months with placebo. 
1.6 
BEVACIZUMAB CLINICAL EXPERIENCE     
  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. 


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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 26 
February 2004 in the United States for first-line treatment in combination with IV 
5-FUbased chemotherapy for subjects with metastatic colorectal cancer.  
Additional data from Phase III trials in metastatic CRC (E3200), nonsmall cell 
lung cancer (NSCLC; E4599), and metastatic breast cancer (E2100) have also 
demonstrated clinical benefit from bevacizumab when added to chemotherapy.  
In Study E3200, the addition of bevacizumab to FOLFOX chemotherapy resulted 
in improved overall survival compared with FOLFOX alone (13.0 vs. 
10.8 months, respectively, HR  0.75; p  0.01) in a population of previously 
treated CRC patients.   
There was also improved overall survival in first-line NSCLC patients (E4599) 
treated with carboplatin/paclitaxel  bevacizumab compared with chemotherapy 
alone (12.3 vs. 10.3 months, respectively; HR  0.80; p = 0.003).  The results 
from this trial were the basis for FDA approval of bevacizumab for use in 
combination with carboplatin  paclitaxel as first-line treatment of patients with 
unresectable, locally advanced, recurrent or metastatic, non-squamous NSCLC 
in October 2006.  Finally, patients with untreated metastatic breast cancer 
(E2100) who received bevacizumab in combination with weekly paclitaxel had a 
marked improvement in PFS compared with chemotherapy alone (13.3 vs. 
6.7 months, respectively; HR  0.48; p  0.0001) (see the Bevacizumab 
Investigator Brochure for additional details). 
 


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a. Safety Profile 
In the initial Phase I and II clinical trials, four potential bevacizumab-associated 
safety signals were identified: hypertension, proteinuria, thromboembolic events, 
and hemorrhage.  Additional completed Phase II and Phase III studies of 
bevacizumab as well as spontaneous reports have further defined the safety 
profile of this agent. Bevacizumab-associated adverse events identified in phase 
III trials include congestive heart failure (CHF) 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 
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 


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nephrotic syndrome; the majority of proteinuria events have been grade 1. NCI-
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 proteinuria 
was reported in up to 3% of bevacizumab-treated patients, and Grade 4 in up to 
1.4% of bevacizumab-treated patients.  The proteinuria seen in bevacizumab 
clinical trials was not associated with renal impairment and rarely required 
permanent discontinuation of bevacizumab therapy.  Bevacizumab should be 
discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome) 
Patients with a history of hypertension may be at increased risk for the 
development of proteinuria when treated with bevacizumab.  There is evidence 
from the dose-finding, Phase II trials (AVF0780g, AVF0809s, and AVF0757g) 
suggesting that Grade 1 proteinuria may be related to bevacizumab dose. 
Proteinuria will be monitored by urine protein:creatinine (UPC) ratio at least every 
9 weeks.  If the UPC ratio is not available, a dipstick urinalysis may be used to 
allow treatment to proceed. 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) 
events, ranging in severity from catheter-associated phlebitis to fatal, have been 
reported in patients treated with bevacizumab in the colorectal cancer trials and, 
to a lesser extent, in patients treated with bevacizumab in NSCLC and breast 
cancer trials.  
Venous thromboembolism (including deep venous thrombosis, pulmonary 
embolism, and thrombophlebitis:  In the phase III pivotal trial in metastatic 
CRC, there was a slightly higher rate of venous TE events in patients treated with 
bevacizumab plus chemotherapy compared with chemotherapy alone (19% vs. 
16%).  
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, 
including deep venous thrombosis, pulmonary embolism, and thrombophlebitis, 
occurred in 15.2% of patients receiving chemotherapy alone and 16.6% of 
patients receiving chemotherapy  bevacizumab.  
The incidence of NCI-CTCAE 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; no fatal events were reported in the 
carboplatin/paclitaxel arm (see Bevacizumab Investigator Brochure).  


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


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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 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. 
Permanently discontinue bevacizumab in patients with tracheoesophageal 
fistulae or any Grade 4 fistula.  Limited information is available on the continued 
use of bevacizumab in patients with other fistulae.  In cases of internal fistula not 
arising in the GI tract, discontinuation of bevacizumab should be considered. 
Wound healing complications: Wound healing complications such as wound 
dehiscence have been reported in patients receiving bevacizumab. In an analysis 


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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, and III clinical trials in multiple tumor types (bevacizumab Investigator 
Brochure, October 2005). The hemorrhagic events that have been observed in 
bevacizumab clinical studies were predominantly tumor-associated hemorrhage 
(see below) and minor mucocutaneous hemorrhage.  
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC.  
Life-threatening and fatal hemoptysis was identified as a bevacizumab-related 
adverse event in NSCLC trials.  These events occurred suddenly and presented 
as major or massive hemoptysis.  Among the possible risk factors evaluated 
(including squamous cell histology, treatment with 
anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, 
central tumor location, and cavitation of tumors during therapy), the only 
variables that showed statistically significant correlations with bleeding were 
bevacizumab therapy and squamous cell histology. 


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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. 
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-CTCAE 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.  
Reversible Posterior Leukoencephalopathy Syndrome:  There have been 
rare reports of bevacizumab-treated patients developing signs and symptoms 
that are consistent with RPLS, a rare neurologic disorder that can present with 
the following signs and symptoms (among others):  seizures, headache, altered 
mental status, visual disturbance, or cortical blindness, with or without associated 
hypertension.  Brain imaging is mandatory to confirm the diagnosis of RPLS.  In 
patients who develop RPLS, treatment of specific symptoms, including control of 
hypertension, is recommended along with discontinuation of bevacizumab.  The 
safety of reinitiating bevacizumab therapy in patients previously experiencing 
RPLS is not known (Glusker et al. 2006; Ozcan et al. 2006).   
Congestive heart failure:  In clinical trials CHF was observed in all cancer 
indications studied to date, but predominantly in patients with metastatic breast 
cancer.  In the Phase III clinical trial of metastatic breast cancer (AVF2119g), 7 
(3%) bevacizumab-treated patients experienced CHF, compared with two (1%) 
control arm patients.  These events varied in severity from asymptomatic 
declines in left ventricular ejection fraction (LVEF) to symptomatic CHF requiring 
hospitalization and treatment.  All the patients treated with bevacizumab were 
previously treated with anthracyclines (doxorubicin cumulative dose of 
240360 mg/m2).  Many of these patients also had prior radiotherapy to the left 


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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-CTCAE 
Grade 3 or 4) in the paclitaxel  bevacizumab arm was 0.3% versus 0% for the 
paclitaxel alone arm. 
No information is available on patients with preexisting CHF of New York Heart 
Association (NYHA) Class IIIV at the time of initiating bevacizumab therapy, as 
these patients were excluded from clinical trials. 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall may be 
possible risk factors for the development of CHF.  Caution should be exercised 
before initiating bevacizumab therapy in patients with these risk factors. 
A Phase II trial in patients with refractory acute myelogenous leukemia reported 
5 cases of cardiac dysfunction (CHF or LVEF decrease to  40%) among 
48 patients treated with sequential cytarabine, mitoxantrone, and bevacizumab.  
All but 1 of these patients had significant prior exposure to anthracyclines as well 
(Karp et al. 2004).  
Other studies in patients with various tumor types and either a history of 
anthracycline exposure or concomitant use with bevacizumab are ongoing.  
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or 
infection with severe neutropenia (including some fatalities) have been observed 
in patients treated with some myelotoxic chemotherapy regimens plus 
bevacizumab in comparison to chemotherapy alone (Sandler et al. 2006). 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for 
additional details regarding the safety experience with bevacizumab. 
 
1.7 
OXALIPLATIN  
Oxaliplatin is a diaminocyclohexane (DACH)-platinum compound, active in 
several solid tumor types, including some cisplatin/carboplatin refractory 
diseases. The mechanism of action of oxaliplatin is similar to that of cisplatin as 
well as other platinum (Pt) compounds.  Oxaliplatin forms intrastrand Pt-DNA 
adducts/crosslinks between two adjacent or close guanines (GG or GNG) or 


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adjacent guanine-adenine (GA) base pairs.  The formation of these Pt-DNA 
crosslinks inhibits DNA replication and transcription, resulting in cell death in 
actively dividing cells.  In addition to intrastrand DNA crosslinks, use of 
oxaliplatin, like other Pt compounds, can result in Pt-DNA interstrand crosslinks.  
Oxaliplatin can also cause Pt-DNA-protein crosslinks, although to a lesser extent. 
Studies indicate that the types and percentages of Pt-DNA adducts formed by 
oxaliplatin are qualitatively similar to those formed by cisplatin.  However, the 
following preclinical data with oxaliplatin suggest several unique attributes related 
to the cytotoxic/antitumor activity of oxaliplatin compared to cisplatin: 
1) DACH-Pt DNA adducts are bulkier and more hydrophobic than cis-diammine-
Pt DNA adducts and may be more effective in DNA synthesis inhibition. 
2) DNA mismatch-repair complexes do not recognize DACH-Pt DNA adducts. 
3) Experimental data on naked and intracellular DNA suggest that oxaliplatin Pt-
DNA adducts have higher cytotoxic efficacy than cisplatin Pt-DNA adducts. 
Oxaliplatin demonstrates a broad spectrum of in vitro cytotoxic and in vivo 
antitumor activity that differs from that of either cisplatin or carboplatin.  
Oxaliplatin is active against several cisplatin-resistant cell lines, colon carcinoma, 
and other solid tumors that are not responsive to cisplatin.  In addition, oxaliplatin 
in combination with 5-FU leads to synergistic antiproliferative activity in vitro, as 
well as in vivo in several tumor models. 
 
 
a. Oxaliplatin Safety Profile 
 
Neurotoxicity is the dose-limiting toxicity of oxaliplatin. The most common acute 
side effect is a transient peripheral neurotoxicity characterized by paresthesia 
and dysesthesia in hands, feet and the peri-oral area, triggered and/or enhanced 
by contact with cold. Some patients report laryngopharyngeal dysesthesia when 
swallowing cold food or drink. The intensity is generally mild to moderate. These 
symptoms are often observed during oxaliplatin infusion, lasting for a few 
minutes to a few days, and are fully reversible. This toxicity, already observed at 


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doses of 90 mg/m², increases with dose, to affect 75% of patients treated at 200 
mg/m². 
The incidence and intensity of symptoms increase with the number of cycles, 
with a median time of evolution to grade 3 of 23 weeks when administered as a 
single agent at 130 mg/m2 every 3 weeks.[29] Women seem more likely than 
men to experience severe neurotoxicity. Interestingly, these symptoms disappear 
within 3 months of stopping treatment in 50% of patients and in 90% of patients 
by one year. 
At doses higher than 45 mg/m², oxaliplatin induces nausea and vomiting with 
rapid onset in the majority of patients; this can last for 24 to 48 hours and is 
generally controlled by the standard anti-emetic measures used for all platinum 
derivatives. Gastrointestinal toxicity, such as diarrhea, is less common (up to 
25% of cycles) and rarely severe.  
Hematological toxicity is minor and sporadic. In monotherapy studies, 2% of 
patients experienced grade 3-4 anemia and neutropenia.[29]  No grade 3-4 
thrombocytopenia occurred, but grade 2 thrombocytopenia was seen in 14%.  No 
significant renal toxicity and ototoxicity were reported with oxaliplatin although no 
studies were performed which included patients with severe renal impairment. 
Allergic reactions to oxaliplatin are rare: 1.5% purely cutaneous and <0.5% 
anaphylactic. 
1.8 
CAPECITABINE    
Capecitabine is an oral fluoropyrimidine carbamate rationally designed to 
generate 5-FU preferentially in tumor tissue through exploitation of high 
intratumoral concentrations of thymidine phosphorylase [39;40].  Human 
pharmacokinetic studies have shown that after oral administration, capecitabine 
is rapidly and almost completely absorbed through the gastrointestinal wall, thus 
avoiding direct intestinal exposure to 5-FU. Capecitabine is then metabolized to 
5-FU via a three-step enzymatic cascade.  After oral administration, capecitabine 
is absorbed unchanged from the gastrointestinal tract, and is sequentially 
converted to the cytotoxic moiety, 5-FU in a series of metabolic steps. First, 
capecitabine is metabolized primarily in the liver by the 60kDa carboxylesterase 
to 5’-deoxy-5-fluorocytidine (5’-DFCR). 5'-DCFR is then converted to 5’-DFUR by 
cytidine deaminase, which is principally, located in the liver and tumor tissues 


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(Figure 2). Metabolism of 5’-DFUR to the pharmacologically active agent 5-
fluorouracil (5-FU) occurs preferentially at the tumor site by the tumor-associated 
angiogenic factor, thymidine phosphorylase (dThdPase). Concentrations of 
dThdPase are higher in colorectal tumor tissues than in normal tissues, 
accounting for the preferential activation of 5-FU in tumor.[30] 
 
 
 
 
 
Figure 2:  Metabolism of Capecitabine 
 
 
 
 
 
 
a. Capecitabine Safety Profile 
 
The main toxicities of capecitabine included diarrhea, mucositis, and palmar-
plantar erythrodysesthesia (hand-foot syndrome).  Overall, the clinical safety 
profile of capecitabine is similar to that of fluoropyrimidines. Important differences 
however are noted: patients who receive capecitabine experience a lower 
incidence of grade 3/4 stomatitis and grade 3/4 neutropenia leading to a 
significantly lower incidence of neutropenic fever and sepsis, a similar incidence 
of grade 3/4 diarrhea and a higher incidence of grade 3 hand-foot syndrome [41]. 
2
O
H
H
 (5'-DFUR)
(5-FU)
(5'-DFCR)
Capecitabine
(Ro 09-1978)
(Liver)
(Tumor,
Liver)
(Tumor)
Cytidine
Deaminase
Carboxylesterase
PyNPase


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Severe myelosuppression is uncommon with capecitabine. Grade 3/4 
neutropenia occurred in 2.2% of patients. Neutropenia and neutropenic fever as 
a serious clinical adverse event occurred at 0.5% and 0.2% of patients, 
respectively. Sepsis and septicemia as a serious clinical adverse event occurred 
at 0.2% and 0.2% of patients. 
Hyperbilirubinemia was observed. Elevations higher than three times the upper 
limit of normal (ULN) (grade 4 according to NCI-CTCAE) were reported in 4.5% 
of patients. The incidence of patients with grade 3 hyperbilirubinemia (elevations 
higher than 1.5 x ULN) was 18.3%. Grade 3 or 4 hyperbilirubinemia was usually 
not associated with other signs of liver disturbance. Persistence of 
hyperbilirubinemia tended to be associated with liver metastases. There was no 
evidence of a cumulative effect.  
The incidence of hospitalization due to treatment-related adverse events was 
11.6%. Of these, hospitalizations due to treatment-related events associated with 
neutropenia (infection, neutropenia, neutropenic fever, and sepsis) were low 
(incidence of 0.2% per event).  Diarrhea led to hospitalization in 4.2% of patients. 
The incidence of hospitalizations due to dehydration and stomatitis was 2.2% 
and 0.2%, respectively. Hand-foot syndrome rarely required hospitalization.  
Based on a pharmacokinetic study in cancer patients with mild to severe renal 
impairment treated with capecitabine 1250 mg/m2 twice-daily (monotherapy), 
there is no evidence for an effect of creatinine clearance on the pharmacokinetics 
of intact drug and 5-FU.  Creatinine clearance was found to influence the 
systemic exposure to 5’-DFUR (35% increase in AUC when creatinine clearance 
decreases by 50%) and to FBAL (114% increase in AUC when creatinine 
clearance decreases by 50%) [47,48].  5’-DFUR is the direct precursor of 5-FU, 
and FBAL is a metabolite without antiproliferative activity. 
Analyses of the pharmacokinetic study in cancer patients with mild to severe 
renal impairment and overall clinical safety data from capecitabine clinical trials 
[48] indicated that:   Patients with severe renal impairment at baseline (calculated 
creatinine clearance <30 mL/min) had a high rate of grade 3-4 toxicity and 
serious adverse events and shorter treatment duration and as a consequence 
capecitabine was contraindicated in this population.  Patients with moderate 
renal impairment at baseline (calculated creatinine clearance 30-50 mL/min) had 
a greater overall incidence of treatment-related grade 3-4 toxicity and serious 


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adverse events relative to patients with normal renal function.  Patients with mild 
renal impairment at baseline (calculated creatinine clearance 51-80 mL/min) 
experienced slightly more serious adverse events and withdrawals due to 
adverse events than the patients with normal renal function and maintained their 
overall benefit/risk ratio.  As a consequence, careful monitoring during 
capecitabine treatment is advised.  
Altered coagulation parameters and/or bleeding have been reported in patients 
taking capecitabine concomitantly with coumarin-derivative anticoagulants such 
as warfarin and phenprocoumon. These events occurred within several days and 
up to several months after initiating capecitabine therapy and, in a few cases, 
within one month after stopping capecitabine and occurred in patients with and 
without liver metastases. In a drug interaction study with single dose warfarin 
administration, there was a significant increase in the mean AUC of S-warfarin. 
The maximum observed INR value increased by 91%. This interaction is 
probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its 
metabolites. 
1.9 
CAPECITABINE PLUS OXALIPLATIN (CAPOX) 
An initial phase II study of the combination of oral capecitabine and intravenous 
oxaliplatin (oral capecitabine 1000 mg/m2 twice daily days 1-14, intravenous 
oxaliplatin 130 mg/m2 day 1) administered every 3 weeks was conducted as first 
line therapy in metastatic colorectal cancer patients [31].  Ninety-six patients 
received CAPOX and were assessable.  The most frequent related grade 3-4 
adverse reactions were sensory neuropathy (14%), diarrhea (14%), 
nausea/vomiting (13%), asthenia (9%), stomatitis (6%), neutropenia (5%), 
thrombocytopenia (4%) and hand-foot syndrome (3%).    Despite the long 
treatment duration in this trial (median of 10 cycles of CAPOX or capecitabine 
alone), approximately half the patients (47%) did not require any dose 
reductions.  Eighteen percent required only capecitabine dose reduction, 14% 
required only oxaliplatin dose reduction and 22% had a reduction of both agents. 
Since this initial phase II trial, a number of studies have utilized the CAPOX 
regimen in various schedules.   A recent large phase III study, NO16966, 
evaluated CAPOX versus FOLFOX4 in 1401 patients.  CAPOX (oxaliplatin 
130mg/m2 IV, capecitabine 1000mg/m2 BID D1-14 q21d) was administered with 
or without bevacizumab.[32]   Grade 3-4 diarrhea was higher with CAPOX, 20% 


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vs. 11%, and hand-foot syndrome was higher with CAPOX, 6% vs. 1%.  Grade 
3/4 neutropenia was markedly lower in the CAPOX arm, 7% vs. 43%.  
Tolerance to CAPOX has been demonstrated to relate to geographical location 
with higher toxicity seen at the same dosing in the United States and Canada 
versus Europe. A retrospective review of data from treatment with either 
capecitabine or intravenous 5-FU in 1189 metastatic patients and 1861 adjuvant-
treated patients demonstrated that grade 3/4 toxicity was higher in the USA 
cohort in comparison to the non-USA cohort.  This occurred for both capecitabine 
and intravenous 5-FU.[33]  In addition data from the TREE-1 and TREE-2 studies 
also support a lower capecitabine dose when administered in the United States.  
The TREE studies were conducted in metastatic colorectal cancer and each 
study had three arms, CAPOX, FOLFOX or bolus 5-FU with oxaliplatin.  In 
TREE-2 study bevacizumab was added to these three combinations.  Due to 
toxicity in the TREE-1 CAPOX arm with capecitabine at 2000mg/m2/day the dose 
was reduced to 1700mg/m2/day for TREE-2.  With this reduction in dose, toxicity 
decreased, tolerance improved, and activity markedly improved.  When 
comparing CAPOX in TREE-1 vs. TREE-2 grade 3-4 adverse events were: 
vomiting 19% vs. 7%, dehydration 21% vs. 8%, diarrhea 27% vs. 17%, and 
neutropenia 21% vs. 8%.  While the response rate improved with the addition of 
bevacizumab in the FOLFOX arm from 41% to 52%, the response rate in the 
CAPOX arm dramatically improved from 27% to 46%.[34]  Thus, in the United 
States, in general, the standard dose of capecitabine in the CAPOX regimen 
varies from 750mg/m2 twice daily to 850mg/m2 twice daily. 
Our recently completed study of CAPOX (oxaliplatin 130mg/m2 administered 
intravenously on Day 1 and capecitabine 750mg/m2 administered orally twice a 
day on Days 1-14, repeated every 3weeks) in SBA and AAC utilized a well-
tolerated capecitabine dose of 750mg/m2 twice daily.  This study demonstrated 
grade 3-4 non-hematologic toxicity in 29% of patients and grade 3-4 hematologic 
toxicity in 13%.[15]  The most common grade 3-4 non-hematologic toxicity was 
fatigue, which was observed in 20% of the patients.  Grade 3-4 diarrhea was 
seen in 5% of patients.  This well-tolerated dosing of CAPOX will be the 
equivalent dosing utilized in the study described in this protocol. 
Due to safety concerns from the use of an oral chemotherapy medication, 
patients will be educated to stop capecitabine at the first signs of grade 2 toxicity, 


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and only to restart with the agreement of the physician, when toxicity has 
subsided to grade 1 or less.   
 
 
 
1.10 CAPOX PLUS BEVACIZUMAB SAFETY PROFILE 
A number of studies have evaluated the combination of CAPOX and 
bevacizumab.  In general the addition of bevacizumab to CAPOX results in 
additional toxicities related to the use of bevacizumab but does not alter the side 
effect profile of CAPOX.  The randomized phase II TREE study compared two 
successive cohorts of patients.  In TREE-1 (n=150) patients were treated with 
either FOLFOX or bolus 5-FU or CAPOX and in TREE-2 (n=223) patients were 
treated with the same regiments but also received bevacizumab.[27]  
Capecitabine dosing in TREE-2 was lower than in TREE-2 with capecitabine 
reduced from 2000mg/m2/day to 1700mg/m2/day.  Toxicity with 
CAPOX/bevacizumab compared to CAPOX was improved with a reduction in 
grade 3-4 adverse events from 67% to 51%, and in particular a reduction in 
diarrhea (31% vs. 19%), nausea/vomiting (38% vs. 21%), dehydration (27% vs. 
8%), and hand-foot syndrome (21% vs. 10%).  Grade 3-4 adverse events that 
were higher in the bevacizumab treated patients were hypertension (15% vs. 2%) 
and deep vein thrombosis (3% vs. 0%).   
The phase III XELOX-1/NO16966 study, evaluated 1401 patients treated with 
CAPOX or FOLFOX with or without bevacizumab.[28]    Similar rates of grade 3-
4 toxicity were seen between the two arms with the placebo arm demonstrating a 
rate of 15% and the bevacizumab arm demonstrating a rate of 21%.  Grade 3-4 
adverse events that were higher with bevacizumab were venous 
thromboembolism (8% vs. 5%), hypertension (4% vs. 1%), bleeding (2% vs. 1%), 
and arterial thromboembolic events (2% vs. 1%).   
1.11 STUDY RATIONALE 
 
Adenocarcinoma of the small bowel is a rare cancer that has many molecular, 
genetic, and epidemiological similarities with adenocarcinoma of the large bowel.  
In particular both cancers demonstrate a similar frequency of expression of 
VEGF-A. The use of anti-VEGF antibodies, such as bevacizumab, has 


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demonstrated clear anti-cancer activity in the treatment of adenocarcinoma of the 
colorectum.   
Thus, given these known facts, we hypothesize that the addition of bevacizumab 
to CAPOX chemotherapy will result in improved anti-cancer activity and improved 
outcomes for patients with metastatic adenocarcinoma of the small bowel and 
ampulla of Vater.  We now propose a study to test this hypothesis by evaluating 
the addition of bevacizumab to the standard of care chemotherapy treatment, 
CAPOX, for metastatic SBA and AAC.  
 
2.0 
OBJECTIVES 
 
2.1 
PRIMARY 
 
 To determine the progression-free survival (PFS) at six months for patients 
with advanced adenocarcinoma of the small bowel or ampulla of Vater treated 
with capecitabine, oxaliplatin (CAPOX) and bevacizumab  
 
2.2 
SECONDARY 
 
 To determine the response rate (RR) for CAPOX and bevacizumab 
 To determine the overall PFS for CAPOX and bevacizumab  
 To determine the overall survival (OS) for CAPOX and bevacizumab 
 To determine the toxicity of CAPOX and bevacizumab 
 
3.0 
STUDY DESIGN  
3.1 
DESCRIPTION OF THE STUDY 
This is a single-center open-label single arm phase II study.  All patients must be 
registered on the M. D. Anderson Cancer Center Clinical Oncology Research 
(CORe) system prior to initiation of treatment. 
 
3.2  
OUTCOME MEASURES  
3.2.1 Primary Outcome Measure 
Progression-free survival at six months is the primary outcome measure.  
3.2.2 Secondary Outcome Measures 
Response rate as per RECIST 1.1, overall PFS, OS, and safety.  


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4.0 
SAFETY PLAN 
See Section 4.1 for complete details of the safety evaluation for this study.  
4.1 
GENERAL PLAN TO MANAGE SAFETY  
a. Bevacizumab-Specific 
A number of measures will be taken to ensure the safety of patients participating 
in this trial.  These measures will be addressed through exclusion criteria (see 
Section 5.3) and routine monitoring as follows. 
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this 
study.  Safety evaluations will consist of medical interviews, recording of adverse 
events, physical examinations, blood pressure, and laboratory measurements.  
Patients will be evaluated for adverse events (all grades), serious adverse 
events, and adverse events requiring study drug interruption or discontinuation at 
each study visit for the duration of their participation in the study.  Patients 
discontinued from the treatment phase of the study for any reason will be 
evaluated ~30 days (28–35 days) after the decision to discontinue treatment (see 
Section 9).   
Specific monitoring procedures are as follows: 
 Hypertension will be monitored through routine evaluation of blood pressure 
prior to each bevacizumab treatment.  Optimal control of blood pressure 
according to standard public health guidelines is recommended for patients 
on treatment with or without bevacizumab. 
 Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or dipstick 
at least every 9 weeks.  
 If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical 
procedure. Patients undergoing a major surgical procedure should not 
begin/restart bevacizumab until 4 weeks after that procedure (in the case of 
high risk procedures such as liver resection, thoracotomy, or neurosurgery, it 


2009-0626 
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is recommended that chemotherapy be restarted no earlier than 6 weeks and 
bevacizumab no earlier than 8 weeks after surgery). 
Please see Section 7.4 for detailed instructions for the management of other 
study drug–related toxicities. 
 
5.0 
STUDY SUBJECTS 
5.1 
SUBJECT SELECTION 
Patients will be included in the study based on the following inclusion and 
exclusion criteria.    
5.2 
INCLUSION CRITERIA 
 Patients must have histologically confirmed adenocarcinoma of the small 
bowel or ampulla of Vater. 
 
 Prior adjuvant chemotherapy (including 5-FU, capecitabine, and 
oxaliplatin) for the treatment of adenocarcinoma of the small bowel or 
ampulla of Vater is allowed if completed ≥ 52 weeks prior to first dose of 
study treatment. 
 
 Prior capecitabine or 5-FU administered as a radiosensitizing agent 
concurrently with external beam radiotherapy is allowed. 
 
 Patients must have metastatic disease 
 
 A minimum of 4 weeks must have elapsed from completion of any prior 
chemotherapy or radiotherapy or surgery and the start date of study 
therapy.  
 
 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 
2 (Appendix 1).   
 
 Adequate organ function including: 
 
Absolute neutrophil 
count (ANC)  
≥1,500/ul 
Platelets 
 
≥100,000/ul 
Total bilirubin $ 
≤1.5 x ULN 


2009-0626 
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AST (SGOT) and 
ALT (SGPT) 
< 3 x ULN 
Calculated # 
creatinine 
clearance (CrCL) 
> 50 cc/min 
$ In patients with known Gilbert’s syndrome direct bilirubin ≤1.5 x ULN will 
be used as organ function criteria, instead of total bilirubin  
# Calculated creatinine clearance (CrCl) calculated using the Cockcroft 
and Gault formula (Appendix 2).   
 Negative serum or urine pregnancy test in women with childbearing potential 
(defined as not post-menopausal for 12 months or no previous surgical 
sterilization), within one week prior to initiation of treatment. 
 Patients must sign an Informed Consent and Authorization indicating that they 
are aware of the investigational nature of this study and the known risks 
involved.  
 The effects of the combination of CAPOX and bevacizumab on the 
developing fetus are unknown. For this reason, women of childbearing 
potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control) prior to study entry, for the duration of study 
participation, and for six months following the completion of therapy.  Should 
a woman become pregnant while participating in this study, she should inform 
her treating physician immediately. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of 
the mother with oxaliplatin or capecitabine or bevacizumab, breast feeding 
must be discontinued. 
 
5.3 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria are ineligible for study entry:   
 Patients who have received prior chemotherapy for their metastatic disease 
are excluded. Chemotherapy if given as a radiation-sensitizer is allowed. 
 Patients may not be receiving any other investigational agents nor have 
received any investigational drug 28 days prior to enrollment. 


2009-0626 
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 Known history of dihydropyrimidine (DPD) deficiency.  
 Peripheral neuropathy of grade 3 or greater by Common Terminology Criteria 
for Adverse Events (CTCAE) 4.0. 
 Gastrointestinal tract disease resulting in an inability to take oral medication 
or a requirement for IV alimentation.  
 Because of the interaction between coumadin and capecitabine, patients 
taking therapeutic doses of coumarin-derivative anticoagulants, are not 
eligible. Low-dose Coumadin (e.g. 1 mg PO per day) in patients with in-
dwelling venous access devices is allowed but frequent INR monitoring is 
recommended. 
 Prior treatment with bevacizumab or known hypersensitivity to any 
component of bevacizumab. 
 Inadequately controlled hypertension (defined as systolic blood pressure 
>140 mmHg and/or diastolic blood pressure > 90 mmHg) 
 Prior history of hypertensive crisis or hypertensive encephalopathy 
 Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
 New York Heart Association (NYHA) Grade II or greater congestive heart 
failure (see Appendix 5) 
 History of myocardial infarction or unstable angina within 6 months prior to 
Day 1  
 History of stroke or transient ischemic attack within 6 months prior to Day 1  
 Significant  vascular disease (e.g., aortic aneurysm requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to Day 1 
 History of hemoptysis ( 1/2 teaspoon of bright red blood per episode) within 
1 month prior to Day 1 
 History of abdominal fistula or gastrointestinal perforation which must have 
resolved at least 6 months prior to Day 1 


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Page 27 
 
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 
days prior to Day 1 or anticipation of need for major surgical procedure during 
the course of the study. 
 Core biopsy or other minor surgical procedure excluding placement of a 
vascular access device, within 7 days prior to Day 1.  
 Serious, non-healing wound, active ulcer, or untreated bone fracture 
 Proteinuria at screening as demonstrated by either (1) urine protein:creatinine 
(UPC) ratio of ≥ 1.0 or (2) urine dipstick for proteinuria ≥ 2+ (patients 
discovered to have ≥2+ proteinuria on dipstick urinalysis should undergo a 24 
hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be 
eligible). 
 Known CNS disease, except for treated brain metastasis.  Treated brain 
metastases are defined as having no evidence of progression or hemorrhage 
after treatment and no ongoing requirement for dexamethasone, as 
ascertained by clinical examination and brain imaging (MRI or CT) during the 
screening period.  Anticonvulsants (stable dose) are allowed.  Treatment for 
brain metastases may include whole brain radiotherapy (WBRT), radiosurgery 
(RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed 
appropriate by the treating physician.  Patients with CNS metastases treated 
by neurosurgical resection or brain biopsy performed within 3 months prior to 
Day 1 will be excluded 
 
 Current, recent (within 4 weeks of the first infusion of this study), or planned 
participation in an experimental drug study other than this  study 
 Pregnancy (positive pregnancy test) or lactation.  
 Active malignancy, other than superficial basal cell and superficial squamous 
(skin) cell, or carcinoma in situ of the cervix, within last five years  
 Inability to comply with study and/or follow-up procedures 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, or psychiatric illness/social 
situations that would limit adherence with study requirements. 


2009-0626 
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 Age <18 years. Because no dosing or adverse event data are currently 
available on the use of CAPOX and bevacizumab in patients <18 years of 
age, children are excluded from this study.  
 
6.0 
STUDY DESIGN 
 
6.1 
TREATMENT PLAN 
 
 
This is a single-center open-label single arm phase II study.  All patients must be 
registered on the M. D. Anderson Cancer Center Clinical Oncology Research 
(CORe) system prior to initiation of treatment. 
 
A maximum of thirty patients will be accrued to this study. Accrual is projected to 
be 1 to 1.5 subjects per month, with accrual completion within 24 months of study 
activation.  The last study visit is projected to be 36 months from study activation.   
 
Treatment will consist of intravenous oxaliplatin administered on Day 1, 
intravenous bevacizumab administered on Day 1, and oral capecitabine 
administered twice daily on Days 1-14.  A cycle of therapy is defined as 21 days.  
Restaging will be done every 3 cycles (+/- 1week allowance is made for 
scheduling).  Treatment will be continued until progression unless other reasons 
for study discontinuation occur as listed in section 9 “Study Discontinuation.” 
 
Table 2:    Starting Dose Level 
Drugs 
Dose 
Schedule 
Oral 
Capecitabine: 
750 mg/m2 BID 
(total daily dose 1500 
mg/m2) 
Days 1-14 with first dose to begin the 
morning or evening of Day 1* 
IV Oxaliplatin: 
130 mg/m2 
Day 1 over 2 hours (administer prior to 
bevacizumab) 
IV 
Bevacizumab: 
7.5 mg/kg 
Day 1 over 90 minutes (if well-
tolerated, subsequent infusion time 
can be decreased to 60 and then 30 
minutes) 


2009-0626 
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*On Day 1 of any cycle, the first dose of capecitabine may be administered in the 
evening.  If this occurs, the last dose of capecitabine for the cycle would be taken 
on the morning of Day 15. 
 
 
7.0 
STUDY MEDICATION  
 
Dose modifications and treatment delays based on observed drug-related toxicity 
will be performed as described below. A cycle of therapy may be delayed up to 2 
weeks to allow for weather events, patient’s personal emergencies, observation 
of holidays, or other unforeseen delays that the Investigator deems to be in the 
best interest of the patient. 
 
All doses of oxaliplatin and capecitabine will be calculated on the basis of 
milligrams of each drug per square meter (mg/m2) of body surface area (BSA).  
BSA will be recalculated prior to each cycle.  Refer to Appendix 3 for the rounded 
total daily dose of capecitabine in mg each patient should receive.  Doses of 
bevacizumab will be calculated based on the patient’s actual body weight in 
kilograms prior to each cycle. 
 
7.1 
BEVACIZUMAB 
7.1.1 Bevacizumab dosage and formulation 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile 
liquid concentrate for solution for intravenous (IV) infusion.  Bevacizumab will be 
supplied in 20-cc (400-mg) glass vials containing 16 mL bevacizumab (25 
mg/mL).  Vials contain bevacizumab with phosphate, trehalose, polysorbate 20, 
and Sterile Water for Injection (SWFI), USP.  Vials contain no preservative and 
are suitable for single use only. 
For further details and molecule characterization, see the bevacizumab 
Investigator Brochure. 
7.1.2 Bevacizumab Administration 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium Chloride 
Injection, USP.  Administration will be as a continuous IV infusion.  Anaphylaxis 


2009-0626 
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precautions should be observed during study drug administration.   It is not 
necessary to correct dosing based on ideal weight. 
The initial dose will be delivered over 9015 minutes.  If the first infusion is 
tolerated without infusion-associated adverse events (fever and/or chills), the 
second infusion may be delivered over 6010 minutes.  If the 60-minute infusion 
is well tolerated, all subsequent infusions may be delivered over 3010 minutes.   
If a subject experiences an infusion–associated adverse event, he or she may be 
premedicated for the next study drug infusion; however, the infusion time may 
not be decreased for the subsequent infusion.  If the next infusion is well 
tolerated with premedication, the subsequent infusion time may then be 
decreased by 3010 minutes as long as the subject continues to be 
premedicated.  If a subject experiences an infusion-associated adverse event 
with the 60-minute infusion, all subsequent doses should be given over 
9015 minutes.  Similarly, if a subject experiences an infusion-associated 
adverse event with the 30-minute infusion, all subsequent doses should be given 
over 6010 minutes. 
7.1.3 Bevacizumab Storage 
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C  
(36F–46F) and should remain refrigerated until just prior to use.  DO NOT 
FREEZE.  DO NOT SHAKE.   Vials should be protected from light. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE USE 
ONLY.  Vials used for 1 subject may not be used for any other subject.  Once 
study drug has been added to a bag of sterile saline, the solution must be 
administered within 8 hours. 
7.1.4 How Supplied 
Bevacizumab will be supplied by Genentech.  Unused or expired medication will 
be returned to Genentech.    
7.2 
OXALIPLATIN 
7.2.1 Active Ingredient 
Oxaliplatin or Eloxatin® has the chemical name of Trans-/-diaminocyclohexane 
oxalatoplatinum cis-[oxalato(trans-/-1,2-diaminocyclohexane) platinum(II)].  


2009-0626 
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Oxaliplatin has a molecular weight of 397.3 D.  It is slightly soluble in water and 
an aqueous solution of 2mg/ml has a pH between 4.8 and 5.7.  
7.2.2 Finished Product 
Oxaliplatin is presented in the form of a white to off-white cake or powder 
contained in clear glass vials sealed with a rubber stopper and an aluminum seal 
with a flip-off cover. 
 
Table 3: Oxaliplatin composition 
 
50 mg 
vials 
100 
mg 
vials 
Oxaliplatin 
50 mg 
100 
mg 
Lactose monohydrate 
450 
mg 
900 
mg 
Nominal volume of vial 
36 ml 
50 ml 
 
7.2.3 Route of Administration 
Intravenous 
7.2.4 Reconstitution 
The freeze-dried powder is reconstituted by adding 10 (for the 50 mg vials) or 20 
(for the 100 mg vials) ml of water for injection or 5% dextrose solution and then 
by diluting in an infusion solution of 250 to 500 ml of 5% dextrose solution. 
Dispose of any reconstituted solution that shows evidence of precipitation. 
Always use the recommended solvents. Never administer undiluted solution.  
Reconstitution or final dilution must never be performed with sodium chloride 
solution. 


2009-0626 
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Page 32 
 
Oxaliplatin must be infused by central venous line over 2 hours.  If acute 
(occurring during or after the 2 hour infusion) laryngopharyngeal dysesthesias 
occur, increase duration of the infusion to 6 hours.  Ensure the infusion lines are 
adequately flushed with 5% dextrose solution between the administration of any 
other drug.  The administration of oxaliplatin does not require pre-hydration. 
7.2.5 Incompatibilities/Precautions 
Do not mix or administer with saline or other chloride containing solutions.  
Oxaliplatin is unstable in the presence of chloride. Do not simultaneously 
administer other drugs by the same infusion line. Do not combine with alkaline 
solutions.  Oxaliplatin is unstable under alkaline conditions. Do not use 
components containing aluminum (i.e. needles or intravenous sets) for the 
preparation or administration of oxaliplatin.  There is risk of degradation when in 
contact with aluminum 
Flush line after oxaliplatin administration.  Flush lines with a 5% dextrose solution 
after oxaliplatin is given and before administration of supportive care 
medications. 
7.2.6 How Supplied 
Commercial drug supply will be used.  
7.2.7 Storage and Handling 
Unreconstituted vials may be stored for 3 years at room temperature up to 30°C 
(86°F).  Reconstituted solution, in 5% dextrose solution or water for injection and 
in the original vial, should not be stored for more than 24 hours between 2°C and 
8°C. Solution for infusion, after dilution in 250 to 500 ml of 5% dextrose solution, 
should be used immediately. 
All cancer chemotherapeutic agents should be handled with utmost care during 
preparation and administration. They should not be prepared by pregnant or 
breast-feeding women or by persons allergic to that agent. To avoid any form of 
physical contact with the drug by the health care provider, gown, gloves and 
masks should be worn when appropriate. As a parenteral agent, oxaliplatin 
should be prepared in a vertical-flow biologic safety cabinet. All equipment used 
to prepare and administer the drug should be destroyed according to standard 


2009-0626 
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Page 33 
 
hospital procedures for disposal of cytotoxic waste. Refer to hospital guidelines 
for any additional precautions that may apply. 
 
7.3 
CAPECITABINE  
7.3.1 Active Ingredient 
Capecitabine is a fluoropyrimidine carbamate.  It is an orally administered 
systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-
fluorouracil via three enzymatic steps carried out by the enzymes, 5’deoxy-5-
fluorocytidine, 5’-deoxy-5-fluorouridine, and thymidine phosphorylase. 
7.3.2 Finished Product 
Capecitabine is supplied as biconvex, oblong film-coated tablets for oral 
administration. Each light peach-colored tablet contains 150 mg capecitabine and 
each peach-colored tablet contains 500 mg capecitabine.  For dosing 
convenience, only the 500 mg tablet will be used in this study. 
7.3.3 Route of Administration 
Oral 
7.3.4 Drug Interactions 
A drug interaction between capecitabine and coumarin anticoagulants has been 
reported.  Altered coagulation parameters and/or bleeding have been reported in 
patients taking capecitabine concomitantly with coumarin-derivative 
anticoagulants such as warfarin and phenprocoumon. These events occurred 
within several days and up to several months after initiating capecitabine therapy 
and, in a few cases, within one month after stopping capecitabine and occurred 
in patients with and without liver metastases. In a drug interaction study with 
single dose warfarin administration, there was a significant increase in the mean 
AUC of S-warfarin. The maximum observed INR value increased by 91%. This 
interaction is probably due to an inhibition of cytochrome P450 2C9 by 
capecitabine and/or its metabolites. 
Antivirals, Sorivudine, also called BV-araU or brovavir or Usevir, or its chemically 
related analogues, such as brivudine, approved in Europe only, interact with 
capecitabine.  A clinically significant drug-drug interaction between sorivudine 


2009-0626 
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and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase 
(DPD) by sorivudine, has been described.  This interaction leads to increased 
fluoropyrimidine toxicity and is potentially fatal. 
Patients taking phenytoin concomitantly with capecitabine should be regularly 
monitored for increased phenytoin plasma concentrations and associated clinical 
symptoms.   Increased phenytoin plasma concentrations have been reported 
during concomitant use of capecitabine with phenytoin, suggesting a potential 
interaction.   
7.3.5 How Supplied 
Commercial drug supply will be used.  
7.3.6 Storage and Handling 
Store at 25° C (77°F); excursions permitted to 15° C to 30°C (59° C-86°F), keep 
tightly closed. 
 
7.4 
DOSE MODIFICATIONS AND/OR DELAYS DUE TO TOXICITY 
Toxicity will be graded according to the NCI CTCAE, Version 4.0 (which is available 
at: http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm) except for 
neurosensory and skin toxicity.  Neurosensory toxicity will be graded according to 
the Neurologic Toxicity Scale for Oxaliplatin Dose Adjustments, Table 5 below.   
For any CTCAE toxicity thought to be at least possibly related to therapy, further 
treatment will be guided by the dose adjustment tables 4, 5, and 6. 
For any event which is apparent at baseline, the dose modification will apply 
according to the corresponding shift in toxicity grade if the investigator feels this 
is appropriate, (e.g. if a patient has grade 1 asthenia at baseline which increases 
to grade 2 during treatment, this will be considered as a shift of 1 grade and 
treated as a grade 1 toxicity for dose modification purposes).  Neurosensory 
toxicity does not result in dose reduction for capecitabine or bevacizumab.  If 
creatinine clearance declines to <50 ml/min during the study, no capecitabine 
dose reduction is required unless there are concomitant AEs requiring reduction. 
In patients with known Gilbert’s syndrome, direct bilirubin will be used to assess 
organ function instead of total bilirubin. 


2009-0626 
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Page 35 
 
 
Capecitabine treatment interruptions are regarded as lost treatment days and 
missed doses should not be replaced; the planned treatment schedule should be 
maintained.   Once a dose of capecitabine or oxaliplatin has been reduced, it 
should not be increased at a later time.  Reasons for dose modifications or 
delays, the supportive measures taken, and the outcome will be documented in 
progress notes.  Radiographic tumor evaluation should be performed every 3 
cycles.  Scheduling flexibility of +/- 1 week is allowed for radiographic imaging.  
Evaluations earlier than every 3 cycles are allowed if,  in the investigator’s 
opinion, this evaluation is in the patient’s best interest.  
A new cycle of chemotherapy with capecitabine, oxaliplatin, and bevacizumab 
will be delayed until: 
 Absolute neutrophil count ≥ 1000/mm3 and platelet count ≥ 75,000/mm3 
 Recovery from any treatment-related non-hematological toxicity (except 
alopecia, and oxaliplatin-related neurosensory toxicity) to baseline or ≤ grade 
1.  At the treating physician’s discretion a new cycle may be started with a 
grade 2 toxicity, if the toxicity is not felt to be clinically meaningful and is in the 
best interest of the patient. 
If toxicity requires a dosing delay for more than four weeks from the planned 
cycle, study treatment will be discontinued.  If capecitabine or bevacizumab must 
be discontinued permanently due to toxicity, study treatment will be discontinued. 
If oxaliplatin must be discontinued permanently due to either neurological toxicity 
or hypersensitivity reaction, then treatment with capecitabine and bevacizumab 
may continue on protocol.  In addition oxaliplatin may be discontinued 
permanently for recurrent thrombocytopenia (Grade 3 or Grade 2 
thrombocytopenia that is not recovered to grade ≤1 by Day 28) despite two 
oxaliplatin dose reductions and for persistent fatigue in patients who have been 
on treatment for over six months.   Persistent fatigue is defined as grade 2 or 
more fatigue on two sequential cycles in a patient who has been on study for 
greater than six months from the first dose of study drug.  If the reason for 
oxaliplatin discontinuation is due to any other toxicity then study treatment will be 
discontinued.  Two dose reductions are allowed for capecitabine and oxaliplatin 
(see table 7).  If a third reduction is required then that patient will be removed 


2009-0626 
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Page 36 
 
from the study. If the treating physician feels that the given toxicity requiring dose 
adjustment is only due to one study drug, oxaliplatin or capecitabine, than dose 
adjustment for only that one study drug may be done. There are no dose 
adjustments for bevacizumab. For management of adverse events due to 
bevacizumab see table 4.  For dose modifications due to capecitabine and 
oxaliplatin see tables 5 and 6.   
 
7.4.1 Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events occur that 
require holding bevacizumab, the dose will remain the same once treatment 
resumes. 
Any toxicities associated or possibly associated with bevacizumab treatment 
should be managed according to standard medical practice. Discontinuation of 
bevacizumab will have no immediate therapeutic effect. Bevacizumab has a 
terminal half-life of 21 days; therefore, its discontinuation results in slow 
elimination over several months. There is no available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion. If unmanageable toxicity occurs because of bevacizumab at any time 
during the study, treatment with bevacizumab should be discontinued.  
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects 
who develop dyspnea or clinically significant hypotension. Subjects who 
experience a NCI CTCAE v. 4.0 Grade 3 or 4 allergic reaction / hypersensitivity, 
adult respiratory distress syndrome, or bronchospasm (regardless of grade) will 
be discontinued from bevacizumab treatment. 
The infusion should be slowed to 50% or less or interrupted for subjects who 
experience any infusion-associated symptoms not specified above. When the 
subject’s symptoms have completely resolved, the infusion may be continued at 
no more than 50% of the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. Infusions may be restarted at the 
full rate during the next cycle.  
Adverse events requiring delays or permanent discontinuation of bevacizumab 
are listed in Table 4. 


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


2009-0626 
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Page 38 
 
Table 4 
Bevacizumab Dose Management due to Adverse Events (continued) 
 
Grade 3 or 4 
Hold study drug treatment.  If the planned duration of full-dose 
anticoagulation is <2 weeks, bevacizumab should be held until the 
full-dose anticoagulation period is over.  If the planned duration of 
full-dose anticoagulation is >2 weeks, bevacizumab may be resumed 
during the period of full-dose anticoagulation if all of the following 
criteria  are met: 
 
The subject must have an in-range INR (usually between 
2 and 3) if on warfarin; LMWH, warfarin, or other 
anticoagulant dosing must be stable prior to restarting 
bevacizumab treatment. 
 
The subject must not have had a Grade 3 or 4 
hemorrhagic event while on anticoagulation. 
Arterial Thromboembolic event 
(New onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event) 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1-2 events 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria 
No dose modifications for grade 1-2 events 
Grade 3 
(UPC> 3.5, urine 
collection > 3.5 g/24 
hr)   
 
Hold bevacizumab treatment until  Grade 2, as determined by either 
UPC ratio ≤ 3.5 or 24 hr collection ≤ 3.5 g 
 
Grade 4 (nephritic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
 
Discontinue bevacizumab. 
Fistula  
 
Any grade (TE fistula) 
Discontinue bevacizumab. 
Grade 4 fistula 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring medical 
intervention. 
Table 4 
Bevacizumab Dose Management due to Adverse Events (continued) 
 


2009-0626 
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Page 39 
 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention.  
Patient may restart upon complete resolution. 
Grade 3-4 
Hold bevacizumab for complete obstruction.  If surgery is necessary, 
patient may restart bevacizumab after full recovery from surgery, and 
at investigator’s discretion. 
Wound dehiscence 
Any grade (requiring 
medical or surgical 
therapy) 
Discontinue bevacizumab. 
Reversible Posterior Leukoencephalopathy   
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab. 
 


2009-0626 
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Page 40 
 
7.4.2 Oxaliplatin and Capecitabine Dose Modification and Toxicity Management 
Table 5: Dose Modifications 
 
During a Cycle 
Start of New Cycle 
 
Dose Adjustments 
During a Cycle of 
Therapy 
Dose Adjustments at the Start of Subsequent Cycles of 
Therapy (Change from previous cycle’s starting dose 
based upon maximum toxicity encountered in the 
previous cycle) 
NCI CTCAE 
Toxicity Grade 
Capecitabine 
Capecitabine 
Oxaliplatin 
Hematological Toxicity (except anemia)* 
 
1 or 2 
Maintain dose 
Maintain dose 
Maintain dose 
3 or 4 
Interrupt until grade 0-1, 
then continue with 
unchanged dose 
Maintain dose 
Reduce one dose level 
Febrile neutropenia 
 (grade 3 or 4) 
Interrupt until clinical 
resolution, in the 
investigator’s opinion, 
then dose reduce by 
one dose level. 
Reduce one dose level 
Reduce one dose level 
Grade 2 thrombocytopenia 
not recovered to ≤grade 1 
by Day 28 
 
Maintain dose 
Upon recovery, treat at one dose 
level reduction 
Non-Hematological Toxicity except for Acute Hyersensitivity Reaction, Hand-Foot Syndrome, Grade 2 
Nausea/Vomiting, and Nail/Skin toxicities.  For neurological toxicities, see Table 6.  
1 
Maintain dose 
Maintain dose 
Maintain dose 
2 
Interrupt until resolved to 
grade 0-1 (grade 
0/baseline for 
diarrhea/cramps), then 
continue at 100% of 
dose. If grade 2 toxicity 
recurs, continue at same 
dose, or at the discretion 
of the investigator, one 
dose level reduction. 
Treat at 100% of dose, 
or at the discretion of 
the investigator, reduce 
one dose level 
Maintain dose 
3 
Interrupt until resolved to 
grade 0- 1 (grade 
0/baseline for 
diarrhea/cramps), then 
continue one dose level 
reduction 
Reduce one dose level 
Reduce one dose level 
4 
Interrupt until resolved to 
grade 0- 1 (grade 
0/baseline for 
diarrhea/cramps), then 
continue at one dose 
level reduction. If it 
recurs, discontinue 
treatment 
Reduce one dose level 
Reduce one dose level  
Not recovered to baseline 
or Grade 1 by Day 28 
 
Upon recovery, treat at 
one dose level 
reduction 
Upon recovery, treat at one dose 
level reduction 
 
 
 


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Grade 2 nausea and/or 
vomiting 
Maintain dose # 
Maintain dose# 
Maintain dose#  
Acute Hypersensitivity 
Reaction 
Grade 3 or 4 
 
Discontinue treatment** 
Hand-Foot Syndrome: 
Grade 1 
 
Grade 2 
 
 
 
Grade 3 
 
 
(Grade 4 NA) 
 
 
Maintain dose 
 
Interrupt until grade 0-1, 
then continue at one dose 
level reduction 
 
Interrupt until grade 0-1, 
then continue at one dose 
level reduction 
 
 
Maintain dose 
 
Treat at one dose level 
reduction 
 
 
Treat at one dose level 
reduction 
 
 
Maintain dose 
For all grades 
 
 
Two dose reductions are allowed for oxaliplatin and capecitabine.  Any patient 
requiring a third dose reduction will be removed from the study.  
* 
No dose reductions or interruptions will be required for anemia as it can be 
satisfactorily managed with transfusions and/or erythropoietin. 
#  While providing standard medical supportive care for nausea/vomiting 
**For grade 3 toxicity treatment may be continued if it is felt to be in the patient’s 
best interest and the treating physician feels the use of additional 
premedications are likely to eliminate or reduce the severity of the reaction. 


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Table 6:  Neurological Toxicity Scale and Oxaliplatin Dose Adjustments 
Toxicity (Grade) 
Duration of Toxicity 
Persistent 
between 
Cyclesa 
1-7 days       
>7 days 
Grade 1 
Paresthesias/dysesthesiasb 
that do not interfere with 
function 
No change 
No change 
No change 
Grade 2 
Paresthesias/dysesthesiasb 
interfering with function but 
not activities of daily living 
(ADL)d 
No change 
No change 
Decrease by 
one dose level 
Grade 3 
Paresthesias/dysesthesiasb 
with pain or with functional 
impairment that also 
interfere with ADL 
No change 
Decrease by 
one dose level 
Stop oxaliplatin 
Grade 4 
Persistent  
paresthesias/dysesthesiasb 
that are disabling or life-
threatening 
Stop oxaliplatin 
Stop oxaliplatin Stop oxaliplatin 
Acute laryngopharyngeal 
dysesthesiasb (during or 
after the 2 hour infusion) 
Increase duration of next infusion to 6 hoursc 
a Not resolved at the beginning of the next cycle 
b May be cold-induced 
c May also be pre-treated with benzodiazepines 
d If patient had baseline grade 2 paresthesias/dysesthesias then maintain dose 
for grade 2 toxicity 
 
Table 7: Dose Levels 
 
Capecitabine 
Oxaliplatin 
Bevacizumab 
Dose Level 0 
1500 mg/m2 
130 mg/m2 
7.5 mg/kg 
Dose Level -1 
1125 mg/m2 
97.5 mg/m2 
7.5 mg/kg 
Dose Level -2 
843 mg/m2 
73 mg/m2 
7.5 mg/kg 
 
 
 


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7.4.3  Special Instructions Regarding Treatment of Chemotherapy-related 
Toxicity 
Diarrhea 
Capecitabine should be stopped at diarrhea ≥ grade 2, and treated 
symptomatically. The recommended dosage regimen for loperamide: 4 mg at the 
first onset of late diarrhea and then 2 mg every 2 hours until the patient is 
diarrhea-free for at least 12 hours. During the night, the patient may take 4 mg of 
loperamide every 4 hours. Note: This dosage regimen exceeds the usual dosage 
recommendations for loperamide.  Pre-medication with loperamide is not 
recommended.   If control takes longer than 2 days, medical evaluation including 
relevant diagnostic procedures, alternative treatment and possible investigation 
of DPD deficiency should be considered.  The use of drugs with laxative 
properties should be avoided because of the potential for exacerbation of 
diarrhea. Patients should be advised to contact their physician to discuss any 
laxative use.  Capecitabine can not be re-started until diarrhea has resolved to 
grade 0 or baseline. 
 
Nausea/Vomiting >1 Grade 
For nausea and vomiting, patients must be supplied with antiemetics (compazine 
is recommended, 5-HT3 antagonist administration is at the discretion of the 
investigator). Adequate secondary prophylactic treatment should be initiated 
once nausea or vomiting has occurred.  
 
 Neutropenic Infection 
Capecitabine should be stopped immediately. Appropriate anti-infective therapy 
should be initiated. When the ANC has recovered to ≥1,500/mm3 and the fever 
or infection has resolved, the patient may restart treatment. 
 
Grade 2/3 Hand-Foot Skin Reaction 
Treat symptomatically (emollients are recommended).  
 
Laryngopharyngeal dysesthesias 
A loss of sensation of breathing (acute respiratory distress) without any objective 
evidence of respiratory distress (hypoxia, laryngospasm, or bronchospasm), also 
has been observed.  This neurotoxicity may be induced or exacerbated upon 
exposure to cold. Should a patient develop laryngopharyngeal dysesthesia, the 


2009-0626 
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patient's oxygen saturation will be evaluated via a pulse oximeter and, if normal, 
an anxiolytic agent or benzodiazepine should be given and the patient should be 
observed in the clinic until the episode has resolved.  The oxaliplatin infusion 
may then be continued at 1/3 the rate.  Because this syndrome may be 
associated with the rapidity of oxaliplatin infusion, subsequent doses of 
oxaliplatin should be administered as 6-hour infusions (instead of the normal 2-
hour infusion).  Patients will be counseled to avoid cold drinks and exposure to 
cold water or air, especially for 3-5 days following oxaliplatin administration. 
 
 Oral cryotherapy 
Patients on oxaliplatin should not receive oral cryotherapy (such as ice chips) on 
Day 1 of each cycle as this may exacerbate oral or throat dysesthesias, and 
laryngopharyngeal dysesthesia. 
 
Allergic reactions 
For Grade 1 or 2 acute hypersensitivity reactions, no dose modification is 
required.  Administration of anti-histamine agents and/or steroids should be done 
according to the institutional policy and the treating physician’s judgment.  For 
Grade 3* or 4 acute hypersensitivity reactions, treatment should be 
discontinued.; *for a grade 3 Oxaliplatin hypersensitivity reaction, treatment may 
be continued if it is felt to be in the patient’s best interest and the treating 
physician feels the use of additional premedications are likely to eliminate or 
reduce the severity of the reaction. 
 
Treatment of Oxaliplatin allergic reaction 
For Grade 1 or 2 or 3 [after discussion with treating physician for grade3] 
hypersensitivity reactions the infusions should be stopped until resolution and the 
administration of an anti-histamine agent and/or steroid is recommended.  Upon 
resolution of symptoms, treatment may resume and a 50% reduction in the rate 
of infusion should be considered.   
 
Following a Grade 1 or 2 or 3 [after discussion with treating physician for grade 3] 
hypersensitivity reaction subsequent treatment cycles with oxaliplatin should 
have additional premedications.  Suggested premedications included 
dexamethasone 20 mg IV, diphenhydramine 50 mg IV, and one of the following:  
cimetidine 300 mg IV, ranitidine 50 mg IV, or famotidine 20 mg IV 30 minutes 


2009-0626 
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prior to study drug administration.  If a Grade 1 or 2 or 3 hypersensitivity reaction 
persists into the next cycle and it is felt, in the Investigators opinion, it is in the 
patient’s best interest to continue than pre-medication with 50 mg 
dexamethasone PO 12 hours and 6 hours prior to administration of oxaliplatin 
can be considered. 
 
Treatment of Bevacizumab allergic reaction 
Hypersensitivity reactions to bevacizumab are rare, with severe allergic reactions 
occuring in 1% of patients.  Infusion of bevacizumab should be interrupted for 
subjects who develop dyspnea or clinically significant hypotension. Subjects who 
experience a Grade 3 or 4 allergic reaction / hypersensitivity, adult respiratory 
distress syndrome, or bronchospasm (regardless of grade) will be discontinued 
from bevacizumab treatment. 
The infusion should be slowed to 50% or less or interrupted for subjects who 
experience any infusion-associated symptoms not specified above. When the 
subject’s symptoms have completely resolved, the infusion may be continued at 
no more than 50% of the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. Infusions may be restarted at the 
full rate during the next cycle.  
 
Pulmonary Fibrosis 
In the case of unexplained respiratory symptoms such as nonproductive cough, 
dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be 
discontinued until further investigations exclude interstitial pulmonary fibrosis.  
 
7.5 
BEVACIZUMAB PLUS CAPOX  
 
7.5.1   Capecitabine 
Capecitabine will be administered orally as twice-daily intermittent therapy on 
Days 1-14, followed by 7 days without treatment. The morning and evening dose 
should be taken approximately 12 hours apart.  On Day 1 of any cycle, the first 
dose of capecitabine may be administered in the evening.  If this occurs, the last 
dose of capecitabine for the cycle would be taken on the morning of Day 15.  
Capecitabine should be taken with approximately 200 ml of water (not fruit 


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juices), within 30 minutes after the ingestion of food to improve bioavailability. If 
the two daily doses are unequivalent, the larger dose should be taken in the 
evening.  Higher levels of thymidine phosphorylase are noted to occur at night 
and this may improve cytotoxicity.  Refer to Appendix 3 for the rounded total daily 
dose of capecitabine in mg each patient should receive.    
7.5.2Oxaliplatin 
Oxaliplatin will be administered before bevacizumab at 130mg/m2 given as a 2-
hour intravenous infusion by central venous catheter on Day 1 of a three-week 
cycle.   
7.5.3 Bevacizumab 
Bevacizumab will be administered after oxaliplatin at 7.5 mg/kg.  The initial dose 
will be delivered over 9015 minutes.  If the first infusion is tolerated without 
infusion-associated adverse events (fever and/or chills), the second infusion may 
be delivered over 6010 minutes.  If the 60-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 3010 minutes.   
If a subject experiences an infusion–associated adverse event, he or she may be 
premedicated for the next study drug infusion; however, the infusion time may 
not be decreased for the subsequent infusion.  If the next infusion is well 
tolerated with premedication, the subsequent infusion time may then be 
decreased by 3010 minutes as long as the subject continues to be 
premedicated.  If a subject experiences an infusion-associated adverse event 
with the 60-minute infusion, all subsequent doses should be given over 
9015 minutes.  Similarly, if a subject experiences an infusion-associated 
adverse event with the 30-minute infusion, all subsequent doses should be given 
over 6010 minutes. 
 
7.6  CONCOMITANT MEDICATIONS 
Patients are allowed to continue other medications as directed. Any new 
medications prescribed by other providers or non-prescription medications 
obtained by the patient shall be reported to the Principal Investigator and noted in 
the patient's medical record.  
Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for 
arterial thromboembolic disease. Subjects developing signs of arterial ischemia 


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or bleeding on study should be evaluated for possible bevacizumab 
discontinuation per Table 4, Bevacizumab Dose Management Due To Adverse 
Events. 
Not Permitted 
 Any other chemotherapy. 
 Prevention of alopecia with cold cap or stomatitis with iced mouth rinses is not 
permitted (risk of triggering cold-related dysesthesias). 
 Concomitant radiotherapy, unless local for control of bone pain, the irradiated 
area should be as small as possible and lesions within the irradiated field 
cannot be used for response assessment. 
 Capecitabine should not be administered together with sorivudine (antiviral).  
A clinically significant drug-drug interaction between sorivudine and 5-FU, 
resulting from the inhibition of dihydropyrimidine dehydrogenase (DPD) by 
sorivudine, has been described in the literature.  This interaction, which leads 
to increased fluoropyrimidine toxicity, is potentially fatal. 
 Any "herbal" medications or dietary supplements at the discretion of the 
Investigator.  
 Therapeutic anticoagulant dosing of coumarin anticoagulants is not allowed.  
Altered coagulation parameters and/or bleeding have been reported in 
patients 
taking 
capecitabine 
concomitantly 
with 
coumarin-derivative 
anticoagulants such as warfarin and phenprocoumon.  Low-dose Coumadin 
(e.g. 1 mg PO per day) in patients with in-dwelling venous access devices is 
allowed but frequent INR monitoring is recommended. 
Permitted 
 Palliative and supportive care for disease-related symptoms will be offered as 
needed to all patients in this study. 
 Colony-stimulating factors (i.e., G- or GM-CSF) may be used at the discretion 
of the Investigator.. 
 Patients taking therapeutic dose-levels of coumarin-derivate anticoagulants 
concomitantly with capecitabine should be switched to low molecular weight 
heparin. Low-dose coumadin (e.g. 1 mg po per day) in patients with in-


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dwelling venous access devices is allowed but frequent INR monitoring is 
recommended. 
 Increased phenytoin plasma concentrations have been reported during 
concomitant use of capecitabine with phenytoin, suggesting a potential 
interaction.  Patients taking phenytoin concomitantly with capecitabine should 
be regularly monitored (e.g. weekly phenytoin and albumin levels) for 
increased 
phenytoin 
plasma 
concentrations 
and 
associated 
clinical 
symptoms.


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8.0 CLINICAL AND LABORATORY EVALUATIONS 
Table 8 
Evaluation or Procedure 
Screening1 
Study Treatment  
End of 
Treatment 
Evaluation12 
30-day Post-
Treatment 
Evaluation13/Long 
Term Follow-up 
 
 
On or before Day 
1 of each cycle 
 
 
Informed consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Examination 
X 
X3,4 
X 
 
Neurosensory assessment 15 
X 
X 
X 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
X3,4 
X 
 
Vital Signs (Blood Pressure) 
X 
X3,4 
X 
 
ECOG Performance Status 
X 
X 3,4 
X 
 
Hematology
11 
X 
X
3,4 
X 
 
Biochemistry10,11  
X 
X
3,4 
X 
 
Urine protein:creatinine ratio or urine  
dipstick for protein11 
X 
Every 3 cycles14 
 
 
Serum or urine pregnancy test (for females 
of child-bearing potential)  
X 
 
 
 
Optional Collection of Archival Tumor 
Tissue for Future Research 
X
2 
 
 
 
Toxicity assessment 
X 
X3.4 
X 
X
8 
Diagnostic Imaging for Tumor Assessment7 
X 
Restaging 3 
cycles
5 
X  
X6 
Survival  
 
 
 
X
9 
 
1. Informed consent must be obtained before any evaluations are initiated.  Diagnostic imaging 
studies must be completed within 28 days prior to first day of study treatment. All other 
baseline evaluations must be completed within 7 days prior to first doses of study drugs. 
2. In consenting patients, archival tissue will be collected and stored in a locked cabinet in a 
locked secure office (FC10.2052) under the direction of the PI for banking for use in future 
research.  The receipt of the archival tissue may take place at any time during the study. 
3. For Cycle 1, baseline evaluations will suffice as they are performed within 7 days prior to first 
dose of study drug (except for imaging studies which are performed within 28 days prior). 
4. Within 72 hours prior to start of the cycle (except for Cycle 1 as noted above). 
5.  Imaging should be obtained every 3 cycles (+/- 1week allowance is made for scheduling).  
After a tumor demonstrates a tumor response (partial or complete), confirmation of the 
response will be obtained by a second evaluation to be performed 2 cycles later (+/- 1week).   
6. For patients discontinued from the study for reasons other than progression, perform every 
12 weeks (+/- 1 week) after the End of Treatment Evaluation visit until documentation of 
progression or for 12 months after their first dose of study drug, whichever comes first, if no 
other anti-cancer treatment is given.   
7. CT of the chest, abdomen, and pelvis. MRI may be used in cases where it is felt to be unsafe to 
perform CT secondary to patient's history of dye allergy, or if the tumor is not adequately 
seen on CT for the purposes of this study. 


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8. Treatment-related adverse events occurring during study treatment or within 30 days (window 
of 28-35 days allowed) after the last administration of study drug(s) will be followed until 
resolution or stabilization.  If the patient is unable or unwilling to return to M. D. Anderson for 
this assessment, the patient will be contacted by phone for this assessment.   
9. Every 3 months (+/- 2 weeks) from Post-Treatment Evaluation. 
10. Increased phenytoin plasma concentrations have been reported during concomitant use of 
capecitabine, suggesting a potential interaction.  Patients taking phenytoin concomitantly with 
capecitabine should be regularly monitored (e.g. weekly phenytoin and albumin levels) for 
increased phenytoin plasma concentrations and associated clinical symptoms.  Elevations in 
INR have been correlated with capecitabine and concomitant use of coumadin.  Patients 
taking low dose 1 mg/day of coumadin should receive frequent INR monitoring.  The 
recommended testing frequency is once a week for the first cycle and then on Day 1 of all 
subsequent cycles. 
11. Hematology: hemoglobin, platelets, and absolute neutrophil count.  Chemistry:  creatinine, 
total bilirubin, AST, ALT, magnesium, potassium. In patients with known Gilbert’s syndrome 
direct bilirubin will also be performed. Urine protein:creatinine ratio or urine dipstick for 
protein.  Patients discovered to have either a (1) urine protein:creatinine (UPC) ratio of ≥ 1.0 
or (2) ≥2+ proteinuria on dipstick urinalysis must undergo a 24 hour urine 
collection).Creatinine clearance using the Cockcroft and Gault formula should be calculated 
at baseline and then repeated during the study when deemed necessary by the treating 
physician. 
12.  Within 10 days of decision to discontinue study treatment.  
13. At 28-45 days from last dose of study medication. 
14.  +/- 1week allowance  
 
15.  As oxaliplatin chemotherapy is neurotoxic a neurosensory assessment should be conducted 
and grading of this toxicity should be based upon the “Neurologic Toxicity Scale for 
Oxaliplatin” (table 6) 
 
  
 
8.1 
PRE-TREATMENT EVALUATIONS 
Diagnostic imaging studies (CT scan or MRI of the chest, abdomen, and pelvis) 
 must be completed within 28 days prior to first dose of study drug. 
All other baseline evaluations must be completed within 7 days prior to first dose 
of study drug: 
 
Medical History   
 
Neurosensory assessment 
 
Physical Examination  
 
Height and weight 
 
ECOG Performance Status. 
 
Hematology: hemoglobin, platelets and absolute neutrophil count 


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 
Biochemistry: creatinine (calculate clearance using Cockcroft and Gault 
formula), total bilirubin (in patients with known Gilbert’s syndrome direct 
bilirubin will also be performed) AST, ALT, magnesium, potassium 
 Urine protein:creatinine ratio or urine dipstick for protein.  Patients discovered 
to have either a (1) urine protein:creatinine (UPC) ratio of ≥ 1.0 or (2) ≥2+ 
proteinuria on dipstick urinalysis must undergo a 24 hour urine collection). 
 
Serum Pregnancy test for females of childbearing potential 
 
Toxicity assessment 
 
Vital signs (blood pressure) 
8.1.1 Optional Collection of Tumor Tissue for Future Research:   
All patients who sign consent for this study will also be asked to consider 
participation in this optional part of the study.  This collected tissue will be used 
for future research, at such time as funds are available, to try and further 
understand the biology of adenocarcinoma of the small bowel and ampulla of 
Vater. This research will not be undertaken until a laboratory protocol appropriate 
to the aims of the research has been submitted and received full IRB approval. 
In consenting patients, five unstained slides of 5 to 10 microns thick will be 
requested from the outside institution or prepared from the patient’s tumor block, 
if applicable.  The tissue will be stored at MD Anderson Cancer Center in a 
locked cabinet in a locked, secure office (FC10.2052) under the direction of the 
PI.  
Any residual tumor tissue above what is specified here will be returned to the 
sending institution. 


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8.2 
EVALUATIONS DURING TREATMENT 
Before each cycle (Up to 72 hours prior except for Cycle 1 as noted on 
Table 8)  
 Physical examination  
 Neurosensory assessment 
 Weight  
 ECOG Performance Status 
 Hematology: hemoglobin, platelets and absolute neutrophil count 
 Vital signs (blood pressure) 
 Biochemistry: creatinine (if indicated, calculate clearance using Cockcroft and 
Gault formula), total bilirubin (in patients with known Gilbert’s syndrome direct 
bilirubin will also be performed), AST, ALT, magnesium, potassium 
 Toxicity assessment.   
Every 3 cycles (+/- 1 week) 
1. Urine protein:creatinine ratio or urine dipstick and 24 hour urine collection if 
indicated. Patients discovered to have either a (1) urine protein:creatinine 
(UPC) ratio of ≥ 1.0 or (2) ≥2+ proteinuria on dipstick urinalysis should 
undergo a 24 hour urine collection. 
 CT scan or MRI of the chest, abdomen, and pelvis  
 Tumor evaluations will be performed to assess disease response.  The same 
measuring instrument should be used throughout treatment to maintain 
consistency.  After a tumor evaluation is performed which demonstrates a 
tumor response (partial or complete), confirmation of the response will be 
obtained by a second evaluation to be performed 2 cycles later.   
8.3 
END OF TREATMENT EVALUATIONS  
Within 10 days of decision to discontinue treatment 


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 
The investigator will evaluate the results of the following clinical and 
laboratory assessments to be conducted at the time the patient 
discontinues study treatment: 
 
Physical examination  
 
Neurosensory assessment 
 
ECOG Performance Status 
 
Weight 
 
Vital signs (blood pressure) 
 
Hematology:  hemoglobin, platelets and absolute neutrophil count 
 
Biochemistry:  creatinine (if indicated, calculate clearance using Cockcroft 
and Gault formula), total bilirubin (in patients with known Gilbert’s 
syndrome direct bilirubin will also be performed), ALT, AST, magnesium, 
potassium. 
 
Toxicity (adverse events) assessment (including neurologic toxicities) 
 
Tumor evaluations including CT scan or MRI of the chest, abdomen, and 
pelvis  
8.4 
FOLLOW-UP (OFF-TREATMENT)   
Follow-up/observation for all treatment related adverse events will be through 
Day 30 (Day 28 to Day 45 allowed) following the last dose of study drug or until 
resolution or stabilization of the toxicity or start of another treatment regimen. If it 
is not feasible for the patient to return to M. D. Anderson for the Day 30 toxicity 
assessment, the patient will be contacted by phone for this assessment.  
Patients with documented (radiological) disease progression at any point during 
the study will discontinue treatment with study drugs under this protocol. 
Objective evidence of progressive disease will be recorded at the time of 
progression.  Patients without evidence of progression while on study, regardless 
of the number of treatment cycles received, will be followed for progression until 
it is documented.  If a patient is off treatment with no documented disease 
progression and no subsequent anti-cancer treatment is received, he/she should 


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be followed every 12 weeks (+/- 1 week) after the End of Treatment Evaluation 
visit with tumor evaluations until disease progression is documented or for 12 
months after their first dose of study drug, whichever comes first. 
All patients will be followed for survival status every 3 months from End of 
Treatment evaluation.  Survival status may be obtained by checking the  
electronic medical record or by telephone call.   
9.0 
SUBJECT DISCONTINUATION  
Subjects who meet the following criteria should be discontinued from study 
treatment:  
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s)  
 Treatment delay more than 4 weeks due to toxic effects of study treatment 
 Patient decides to withdraw from the study  
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Grade 4 hypertension or Grade 3 hypertension not controlled with medication 
 Nephrotic syndrome 
 Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
 Symptomatic Grade 4 venous thromboembolic event (for lung protocols: any 
venous thromboembolic event requiring full dose warfarin or equivalent (i.e., 
unfractionated or low molecular weight heparin)  
 Any grade arterial thromboembolic event 
 Grade 4 congestive heart failure 
 Gastrointestinal perforation  
 Tracheoesophageal fistula (any grade) or Grade 4 fistula 
 Grade ≥ 2 bowel obstruction that has not fully recovered despite medical or 
surgical intervention 
 Wound dehiscence requiring medical or surgical intervention 


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 Unwillingness or inability of subject to comply with study requirements 
 Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 All Grade 4 events thought to be related to bevacizumab by the investigator 
Patients who have an ongoing study drug-related Grade 4 or serious adverse 
event at the time of discontinuation from study treatment will continue to be 
followed until resolution of the event or until the event is considered irreversible.   
10.0 RESPONSE EVALUATION 
10.1 MEASUREMENT OF EFFECT  
 Response and progression will be evaluated in this study using the new 
international RECIST criteria (version 1.1, 2009) proposed by the RECIST 
committee. [35]  All patients who have measurable disease according to the 
RECIST criteria and who have their disease re-evaluated will be evaluable for 
response.  For the purposes of this study, patients should be reevaluated for 
response approximately every 3 cycles.  Note:  Lesions are either measurable or 
non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional 
meaning or accuracy. 
10.2 DEFINITIONS 
All sites of disease should be followed as either target or nontarget lesions, as 
categorized at baseline.  All measurable lesions up to a maximum of 2 lesions 
per organ or 5 lesions in total, representative of all involved organs should be 
identified as target lesions, while all other lesions (either additional measurable 
lesions or nonmeasurable lesions) should be classified as nontarget lesions. In 
cases where a target lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned. To ensure 
comparability, the baseline radiology/scans and subsequent radiology/scans to 
assess response should be performed using identical techniques (eg, scans 
performed immediately following bolus contrast administration should be made 
with a standard volume of contrast, the identical contrast agent, and preferably 
the same scanner). The same method, radiological or physical, should be 


2009-0626 
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employed and assessed by the same individual on each occasion, when 
possible.  
10.3 MEASURABLE DISEASE 
Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >10 mm with CT scan 
(with minimum slice thickness no greater than 5mm, or 10mm caliper 
measurement by clinical exam, or 20mm by chest X-ray.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Pathological lymph nodes may also be considered as target or nontarget lesions.  
To be considered pathologically enlarged and measurable (target lesion), 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). Lymph nodes with a 
short axis ≥ 10 mm but < 15 mm should be considered nontarget lesions. Lymph 
nodes that have a short axis < 10 mm are considered nonpathologic and should 
not be recorded. The short axis measurement of any lymph node that is 
considered a target lesion should continue to be recorded regardless if the node 
progresses to below 10 mm. This may prevent the sum of lesions from being 
zero even if complete response criteria are met, since a normal lymph node is 
defined as having a short axis of < 10 mm.  In rare circumstances, when a target 
lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned.  
10.4 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) as well as 
truly non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI).  For bone and cystic lesions please refer to the RECIST criteria 
(version 1.1, 2009). 
10.5 TARGET LESIONS 


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All measurable lesions up to a maximum of five lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions and recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  A sum of the diameters for all target lesions (longest for non-nodal 
lesions, short axis for nodal lesions) will be calculated and reported as the 
baseline sum diameters (LD).  The baseline sum diameters will be used as 
reference by which to characterize the objective tumor response. 
10.6 NON-TARGET LESIONS 
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline.  Non-target lesions include measurable 
lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions. It is possible to record multiple non-
target lesions involving the same organ as a single item on the case record form 
(e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).   
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
10.7 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers.  All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor 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).  In 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 Magnetic Resonance Imaging.  Conventional CT and MRI 
should be performed to obtain images of 5 mm or less slice thickness. 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
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. 
10.8 RESPONSE CRITERIA 
10.8.1 Evaluation of target lesions 
 Complete Response (CR): 
 Disappearance of all target and nontarget 
lesions including normalization of elevated tumor marker level. Any 
pathological lymph nodes (whether target or nontarget) must have reduction 
in short axis to < 10 mm. All nontarget lymph nodes must be nonpathological 
in size (< 10 mm short axis). Complete response must be confirmed at a 
second tumor assessment not less than 4 weeks apart from the assessment 
at which CR was observed. 
 Partial Response (PR):  At least a 30% decrease in the sum of LD of target 
lesions taking as reference the baseline sum LD. Partial response must be 
confirmed at a second tumor assessment not less than 4 weeks apart from 
the assessment at which PR was observed. 


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 Progressive Disease (PD): At least a 20% increase (and an absolute increase 
of at least 5 mm) in the sum of LD of measured lesions taking as references 
the smallest sum LD recorded since the treatment started. Appearance of 
new lesions will also constitute PD. In exceptional circumstances, 
unequivocal progression of nontarget lesions may be accepted as evidence of 
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 LD 
since the treatment started 
 Non-CR/Non-PD:  Persistence of 1 or more nontarget lesions and/or 
maintenance of tumor marker level above the normal limits. 
10.8.2 Evaluation of non-target lesions 
 Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level 
 Incomplete Response/ Stable Disease (SD): 
Persistence 
of 
one 
or 
more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits 
 Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
 Although a clear progression of “non-target” lesions only is exceptional, in 
such circumstances the opinion of the treating physician should prevail, 
and the progression status should be confirmed at a later time by the 
study chair. 
 Note:  If tumor markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete clinical 
response. 
10.9 TIME POINT EVALUATION 
At each protocol specified time point, a response assessment occurs.   Table 9 
provides a summary of this for patients who have measurable disease at 


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baseline.  Table 10 provides a summary of this for patients with non-measurable 
(therefore non-target) disease. 
 
 


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Table 9: Response for measurable disease 
Target 
Lesions 
Nontarget 
Lesions  
New 
Lesions  
Overall 
Respons
e  
Best Response for this 
Category also Requires  
CR  
CR  
No  
CR  
≥ 4 weeks Confirmation  
CR  
Non-CR/Non-
PD  
No  
PR  
≥ 4 weeks Confirmation 
CR  
Not evaluated  
No  
PR  
PR  
Non-PD or not 
all evaluated  
No  
PR  
SD  
Non-PD or not 
all evaluated  
No  
SD  
Documented at least 
once ≥ 6 weeks from 
baseline  
Not All 
Evaluate
d  
Non-PD  
No  
NE  
NE  
PD  
Any  
Yes or No  
PD  
No prior SD, PR or CR 
Any  
PD*  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
* In exceptional circumstances, unequivocal progression in nontarget lesions 
may be accepted as disease progression. NE = inevaluable Note: Patients with 
a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
 
 
Table 10: Response for non-measurable disease 
Nontarget Lesions  
New Lesions  
Overall Response  
CR  
No  
CR  
Non-CR/Non-PD  
No  
Non-CR/Non-PD  
Not all evaluated  
No  
NE  
Unequivocal PD  
Yes or No  
PD  
Any  
Yes  
PD  
NE = inevaluable a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-
target disease since SD is increasingly used as 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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10.10 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 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Table 11: Response Assignment 
Overall Response First 
Time Point  
Overall Response 
Subsequent Time Point  
BEST Overall 
Response  
CR  
CR  
CR  
CR  
PR  
SD, PD, or PRa  
CR  
SD  
SD provided minimum 
criteria for SD duration 
met, otherwise, PD  
CR  
PD  
SD provided minimum 
criteria for SD duration 
met, otherwise, PD  
CR  
NE  
SD provided minimum 
criteria for SD duration 
met, otherwise, NE  
PR  
CR  
PR  
PR  
PR  
PR  
PR  
SD  
SD  
PR  
PD  
SD provided minimum 
criteria for SD duration 
met, otherwise, PD  
PR  
NE  
SD provided minimum 
criteria for SD duration 
met, otherwise, NE  
NE  
NE  
NE  
NE = inevaluable a If a CR is truly met at first time point, then any disease seen 
at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum 
duration for SD was met. However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the 
patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR.  
 


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Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having “symptomatic deterioration.”  Every effort should be made 
to document the objective progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
10.11 
CONFIRMATION 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessment at a minimum follow-up interval of 6 weeks after 
the criteria for response are first met.  In the case of SD, follow-up 
measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 6 weeks. 
10.12 
DURATION OF OVERALL RESPONSE 
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
10.13 
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.  
 
 
11.0 STUDY DISCONTINUATION  


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This study may be discontinued at any time.  Reasons for discontinuing the study 
include but are not limited to the incidence or severity of adverse events 
observed in this study indicate a potential health hazard to subjects.   
 
12.0 STATISTICAL METHODS 
12.1 STUDY DESIGN AND SAMPLE SIZE  
This study is a phase II single treatment arm study.  Thirty patients will be 
accrued in this study in total. This sample size will ensure that, if the trial is not 
terminated early, a posterior 90% credible interval (CI) of PFS at six months will 
be (0.52, 0.79), assuming that the PFS at 6 months is 0.67 (20/30) with the new 
treatment.    
12.2 PLANNED EFFICACY EVALUATIONS 
Endpoint: 
The primary endpoint of this phase II, single arm study is progression-free 
survival (PFS) at 6 months for patients treated with CAPOX plus bevacizumab. 
PFS is defined as from date of treatment start to date of first documentation of 
progression or symptomatic deterioration or death due to any cause. Patients last 
known to be alive and progression free are censored at date of last contact. 
Interim Analysis:  
A Bayesian sequential monitoring design (Thall et al. 1995) will be used to 
monitor the trial. Let p1 be the PFS at 6 months of the new treatment and p0 the 
PFS from the historical data. A previous study with 25 patients with CAPOX 
alone has shown that PFS at six months is 52%. The prior distributions of p1 and 
p0 are assumed to be beta(1, 1) and beta(13, 12), respectively. We will stop the 
trial if  Prob{p1  > p0 + 0.15 | data} < 0.025.  Following this rule, the trial will be 
terminated if [# Progression-free]/[# patients evaluated] =<  3/10 and 7/20. In 
particular, 10 patients will be accrued in the first stage. If 3 or less patients have 
a PFS over 6 months to the combination treatment, stop the trial and the 
treatment will be declared as ineffective. If 4 or more patients have a PFS over 6 
months, additional 10 patients will be entered in the study with a net total 20 
patients in the second stage. If 7 or fewer patients of those 20 patients have PFS 
over 6 months to the combination treatment stop the trial. If there are 8 or more 


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patients with PFS over 6 months, additional 10 patients will be entered in the 
study to reach a total of 30 patients.  Accrual will not be suspended for this 
monitoring; data are analyzed as they accrue. 
The operating characteristics based on 1000 simulations are shown in the 
following table. 
 Table 12 
Stop if Prob{p1  > p0 + 0.15 | data} < 0.025 
True response rate  
Pr(stop early) 
mean number of patients (median) 
0.35 
0.69 
18 (10) 
0.40 
0.52 
21 (20) 
0.50 
0.23 
26 (30) 
0.55 
0.13 
28 (30) 
0.60 
0.06 
29 (30) 
0.65 
0.03 
30 (30) 
0.70 
0.01 
30 (30) 
 
The probability of treatment related toxicity (grade 3 or 4) will be monitored based 
on the Bayesian model (beta-binomial) by assuming a priori probability of toxicity 
following Beta(1,1). The trial will be terminated if Prob(toxicity > 0.25 | data) > 
0.8. Following this rule, the trial will be terminated if [# toxicities]/[# patients 
evaluated] >=  4/10, 5/15, 7/20, and 8/25. 
12.3 STATISTICAL ANALYSIS:  
Descriptive statistical analysis will be calculated, including histograms or box-
plots, proportions, range, means and standard deviations. Fisher’s exact test and 
Wilcoxon rank test will be used in univariate analyses of categorical and 
continuous variables, respectively. Survival or times to progression functions will 
be estimated using the Kaplan-Meier method. The two-sided log-rank test will be 
used to assess the differences of time to events between groups. 
Patients who drop out of the study will be included in the time to event data 
analysis (survival analysis and progression-free survival) as “censored data”. For 


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progression-free survival as a binary endpoint, the intent-to-treat analysis will be 
performed using all available patients. 
13. 
DATA AND PROTOCOL MANAGEMENT 
Data Collection for Enrolled patients 
Designated research personnel must enter the information required by the 
protocol onto electronic Case Report Forms (CRFs). The University of Texas M 
D Anderson Cancer Center’s Clinical oncology Research (CORE) system, and 
the University of Texas MD Anderson Cancer Center’s Protocol Data 
Management System(PDMS) CRF system will be used for this study.  PDMS is 
a clinical research information management system. The PDMS CRF is an 
electronic document designed to record all the protocol-required information to 
be reported on each trial subject. 
PDMS provides data entry templates as defined in the protocol. Laboratory 
results are automatically transferred from M. D. Anderson Cancer Center 
Laboratory Medicine’s server to PDMS each morning. Users must have 
clearance through the M. D. Anderson Cancer Center Information Services 
Security Department in order to access PDMS. PDMS login is password 
protected.  
Only adverse events that are grade 1, 2,3,4,5 possible, probable or definite will 
be recorded.The Investigator is responsible for verifying and providing source 
documentation for all adverse events and assigning attribution for each event for 
all subjects enrolled on the trial.     
 
 


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14. 
OPTIONAL TISSUE COLLECTION FOR FUTURE RESEARCH  
At the time of initial enrollment, patients will be asked to consider consenting to 
collection of samples of their archival tumor tissue.   This optional part of the 
study will store 5 unstained tumor slides on each consenting patient at MD 
Anderson Cancer Center for future research purposes.  This collected tissue will 
be used for future research, at such time as funds are available. This research 
will not be undertaken until a laboratory protocol appropriate to the aims of the 
research has been submitted and received full IRB approval 
All unstained tumor will be stored in a locked cabinet in a locked secure office 
(FC10.2052) under the direction of the PI. Slides will be de-identified from any 
personal information and will be labeled by protocol number and patient 
enrollment number. 
 
15.0 SAFETY REPORTING OF ADVERSE EVENTS 
15.1 Adverse Event Reporting and Definitions  
In the event of an adverse event the first concern will be for the safety of the 
subject.   
 
Investigators are required to report to Genentech Drug Safety ANY serious 
treatment emergent adverse event (STEAE) as soon as possible.   
 
A STEAE is any sign, symptom or medical condition that emerges during 
Bevacizumab treatment or during a post-treatment follow-up period that (1) was 
not present at the start of Bevacizumab treatment and it is not a chronic condition 
that is part of the patient’s medical history, OR (2) was present at the start of 
Bevacizumab treatment or as part of the patient’s medical history but worsened 
in severity and/or frequency during therapy, AND that meets any of the following 
regulatory serious criteria: 
 
 Results in death  
 Is life-threatening  
 Requires or prolongs inpatient hospitalization  
 Is disabling  
 Is a congenital anomaly/birth defect  


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 Is medically significant or requires medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
15.2 REPORTING OF SERIOUS TREATMENT EMERGENT ADVERSE 
EVENTS  
 
All STEAEs should be recorded on a MedWatch 3500a Form and faxed to: 
 
Genentech Drug Safety  
Fax: (650) 225-4682 or (650) 225-5288 
 
(Please use the safety reporting fax cover sheet attached to this document for fax 
transmission) 
 
STEAES will also be reported to the M. D. Anderson Cancer Center Institutional 
Review Board as per their requirements.   
 
MedWatch 3500a Reporting Guidelines: 
 
In addition to completing appropriate patient demographic and suspect 
medication information, the report should include the following information within 
the Event Description (section 5) of the MedWatch 3500a form: 
 
 Treatment regimen (dosing frequency, combination therapy) 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of 
the following methods: 
 
 Adding to the original MedWatch 3500a report and submitting it as follow-
up 
 Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500a form  
 Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e. D.O.B. initial, subject number), protocol description 
and number, if assigned, suspect drug, brief adverse event description, 
and notation that additional or follow-up information is being submitted  


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(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.  
 
Assessing Causality: 
 
Investigators are required to assess whether there is a reasonable possibility that 
bevacizumab caused or contributed to an adverse event.  The following general 
guidance may be used. 
Yes: if the temporal relationship of the clinical event to bevacizumab 
administration makes a causal relationship possible, and other drugs, therapeutic 
interventions or underlying conditions do not provide a sufficient explanation for 
the observed event. 
 
No: 
if the temporal relationship of the clinical event to bevacizumab 
administration makes a causal relationship unlikely, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
 
15.3 
Safety Reporting Requirements for IND Exempt Studies 
For Investigator Sponsored IND Exempt Studies, there are some reporting 
requirements for the FDA in accordance with the guidance set forth in 21 CFR 
314.80. 
 
Postmarketing 15-Day “Alert Report”: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of Bevacizumab. An 
unexpected adverse event is one that is not already described in the Investigator 
Brochure. Such reports are to be submitted to the FDA (2 copies) at the following 
address: Central Document Room, 12229 Wilkins Avenue, Rockville, MD 20852. 
 
All Postmarketing 15-Day “Alert Reports” submitted to the FDA by the Sponsor-
Investigator must also be faxed to: Genentech Drug Safety  
 
Fax: (650) 225-4682 or (650) 225-5288 (Please use the safety reporting fax 
cover sheet attached to this document for your fax transmission) 
 
For questions related to safety reporting, contact: 
 
Genentech Drug Safety 


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Tel: 
1-888-835-2555 
         or 
Fax: (650) 225-4682 or (650) 225-5288 
(Please use the safety reporting fax cover sheet attached to this document for fax 
transmission) 
 
16.0 RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study, including CRFs, 
consent forms, laboratory test results, documentation of adverse events, records 
of study drug receipt and dispensation, and all IRB correspondence will be 
retained by the Principal Investigator for at least 2 years after the investigation is 
completed.  


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Twelves, C.J., et al., Capecitabine/oxaliplatin, a safe and active first-line 
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Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings 
Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4028. 
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Haller D, C.J., Clarke S et al., Tolerability of fluoropyrimidines appears to 
differ by region. . 2006 ASCO Annual Meeting abstract #3514. 
34. 
Hochset H, H.L., Ramanathan et al., Safety and efficacy of 
oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-
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Appendix 1 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all self care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self care. Totally confined to 
bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 


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Appendix 2 
Calculated creatinine clearance (CrCl) calculated using the Cockcroft and 
Gault formula 
 
 
Cockcroft-Gault Formula for Females 
 
Creatinine clearance (mL/min) = 
[(140 - age) x weight (in kg) x 0.85] / [72 x serum creatinine (in mg/dL)] 
 
or 
 
[(140 - age) x weight (in kg) x 0.85] / [0.81 x serum creatinine (in 
µmol/L)] 
 
 
 
Cockcroft-Gault Formula for Males 
 
Creatinine clearance (mL/min) = 
[(140 - age) x weight (in kg)] / [72 x serum creatinine (in mg/dL)] 
 
or 
 
[(140 - age) x weight (in kg)] / [0.81 x serum creatinine (in µmol/L)] 


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Appendix 3 
Capecitabine Dosing 
 
Doses of capecitabine will be calculated on the basis of milligrams per square 
meter of body surface area (BSA) (mg/m2).  BSA will be recalculated prior to 
each cycle.  The total daily dose will be administered in 2 divided doses (AM 
and PM).  Doses will be rounded as outlined below. Please refer to section 6.0 of 
the protocol to determine the appropriate mg/m2 dose of capecitabine for each 
patient.   
 
Calculated 
TOTAL Daily Dose in mg 
 
 
Actual Rounded 
Total Daily Dose 
(this dose is 
divided into 2 for a 
morning and evening 
dose) 
 
Number of 500 mg 
tablets to be taken in 
the 
Morning 
 
Number of 500 mg 
tablets to be taken in 
the 
Evening 
751-1250 mg 
1000 mg 
1 
1 
1251-1750 mg 
1500 mg 
1 
2 
1751-2250 mg 
2000 mg 
2 
2 
2251-2750 mg 
2500 mg 
2 
3 
2751-3250 mg 
3000 mg 
3 
3 
3251-3750 mg 
3500 mg 
3 
4 
3751-4250 mg 
4000 mg 
4 
4 
4251-4750 mg 
4500 mg 
4 
5 
4751-5250 mg 
5000 mg 
5 
5 
 
Example:   
1.   Planned dose of capecitabine to be administered is 
1500 mg/m2/day 
2.    Patient's BSA is 1.67. 
3.   Therefore, the total daily dose to be administered is 
2505 mg.   
4.   Per the above table, total daily dose is rounded to 
2500 mg/day. This will be divided in to a morning and 
evening dose. 
5.   The patient will receive two 500 mg tablet in the 
morning and three 500 mg tablets in the evening. 


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APPENDIX 4:  FDA MEDWATCH 3500a FORM 
 
 


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APPENDIX 5:  NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES 
 
Class I 
People whose physical activity is not limited. Ordinary physical 
activity does not cause undue fatigue, heart palpitations, 
trouble breathing, or chest pain. 
Class II 
People who have some limitation on physical activity. They are 
comfortable at rest, but ordinary physical activity causes 
fatigue, heart palpitations, trouble breathing, or chest pain. 
Class III 
People who have a marked limitation on physical activity. They 
are comfortable at rest, but less-than-ordinary physical activity 
causes fatigue, heart palpitations, trouble breathing, or chest 
pain. 
Class IV 
People who are unable to carry on any physical activity without 
discomfort.  Symptoms may be present even at rest. If any 
physical activity is undertaken, discomfort is increased. 


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APPENDIX 6 
 
Procedure for Obtaining a Urine Protein / Creatinine Ratio  
 
1)  Obtain at least 4 ml of a random urine sample (does not have to be a 24 
hour urine)  
2)  Determine protein concentration (mg/dL)  
3)  Determine creatinine concentration (mg/dL)  
4)  Divide #2 by #3 above:  urine protein / creatinine ratio = protein 
concentration (mg /dL) / creatinine concentration (mg /dL) 
 
The UPC directly correlates with the amount of protein excreted in the urine per 
24 hrs (i.e. a UPC of 1 should be equivalent to 1g protein in a 24hr urine 
collection) 
                                            
Protein and creatinine concentrations should be available on standard reports 
of urinalyses, not dipsticks. If protein and creatinine concentrations are not 
routinely reported at an Institution, their measurements and reports may need 
to be requested. 
 


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Appendix 7  
SAFETY REPORTING FAX COVER SHEET 
Investigator Sponsored Trials 
 
SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
Study Number 
(Genentech study number) 
AVF4762 
Principal Investigator 
Michael Overman, MD 
Site Name 
 
M. D. Anderson Cancer Center 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
(DD/MON/YYYY) 
____ / _____ /_____ 
Follow-up Report Date 
(DD/MON/YYYY) 
____ / _____ /_____ 
 
 
Subject Initials 
(Please enter a dash if the patient has no 
middle name) 
____ - ____ -____ 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS 
COVER SHEET 
 
Please contact Genentech Safety for any questions 
regarding SAE or Safety reporting at (888) 835-
2555 
 
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