Clinical trial NCT01212822
Conditions: Adenocarcinoma of the Esophagus Adenocarcinoma of the Gastroesophageal Junction Diffuse Adenocarcinoma of the Stomach Intestinal Adenocarcinoma of the Stomach Mixed Adenocarcinoma of the Stomach Squamous Cell Carcinoma of the Esophagus Stage IA Esophageal Cancer Stage IA Gastric Cancer Stage IB Esophageal Cancer Stage IB Gastric Cancer Stage IIA Esophageal Cancer Stage IIA Gastric Cancer Stage IIB Esophageal Cancer Stage IIB Gastric Cancer Stage IIIA Esophageal Cancer Stage IIIA Gastric Cancer Stage IIIB Esophageal Cancer Stage IIIB Gastric Cancer Stage IIIC Esophageal Cancer Stage IIIC Gastric Cancer
Sponsor: Fox Chase Cancer Center
Start date: 2011-04-27; Completion date: 2018-01-03
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial studies how well giving bevacizumab and combination chemotherapy together before surgery works in treating patients with locally advanced esophageal or stomach cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

Detailed description:
PRIMARY OBJECTIVES:

I. To investigate two-year disease-free survival in patients with resectable esophageal and gastroesophageal (GE) junction cancer treated with perioperative bevacizumab and leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX).

SECONDARY OBJECTIVES:

I. To assess, by pathological examination after surgical resection, complete and partial response to neoadjuvant therapy.

II. To characterize overall and progression free survival. III. To compare baseline and post-chemotherapy/bevacizumab tissues for biomarkers predicting response or resistance to this approach.

IV. To investigate safety in this setting.

OUTLINE:

NEOADJUVANT THERAPY: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1. Patients also receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46 hours on days 1-2. Treatment with bevacizumab repeats every 2 weeks for 4 courses and treatment with FOLFOX repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients then undergo planned surgical resection 4-6 weeks after 6 courses of chemotherapy and at least 8 weeks since the last dose of bevacizumab.

ADJUVANT THERAPY: Beginning 8-10 weeks after surgery, patients receive bevacizumab IV, oxaliplatin IV, leucovorin calcium IV, and fluorouracil IV as in neoadjuvant therapy. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Arms: arm 1: NEOADJUVANT THERAPY: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46 hours on days 1-2. Treatment with bevacizumab repeats every 2 weeks for 4 courses and treatment with FOLFOX repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients then undergo planned surgical resection 4-6 weeks after 6 courses of chemotherapy and at least 8 weeks since the last dose of bevacizumab.

ADJUVANT THERAPY: Beginning 8-10 weeks after surgery, patients receive bevacizumab IV, oxaliplatin IV, leucovorin calcium IV, and fluorouracil IV as in neoadjuvant therapy. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: bevacizumab intervention 2: oxaliplatin intervention 3: leucovorin calcium intervention 4: fluorouracil intervention 5: therapeutic conventional surgery intervention 6: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Undergo surgical resection intervention 6: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
FER-GI-029 
 
 
Phase II Trial of Pre-operative Bevacizumab and FOLFOX Chemotherapy in Locally Advanced 
Esophageal Cancer 
 
Principal Investigator: 
Crystal Denlinger, M.D. 
Fox Chase Cancer Center 
333 Cottman Ave 
Philadelphia, PA 19111 
215-214-1676 
fax 215-214-3229 
crystal.denlinger@fccc.edu 
 
Co-Investigators: 
Fox Chase Cancer Center 
 
Walter Scott, MD 
 
 
Michael Hall, MD 
Steven Cohen, MD                    
Jonathan Cheng, MD 
Harry Cooper, MD 
 
Co-Investigators: 
University of Pittsburgh 
 
Weijing Sun, MD 
UPMC Cancer Pavilion 
5115 Centre Avenue, 5th Floor 
Pittsburgh, PA 15232 
412 864-7764 
412 648-6579 (fax) 
sunw@upmc.edu 
 
James Luketich, MD 
 
UPMC Presbyterian  
200 Lothrop Street 
Suite C- 800 
 
Pittsburgh, PA  15213  
luketichjd@upmc.edu  
412 647-7555  
412 647-3007 (Fax)  
 
Vincent Reyes, MD 
UPMC Cancer Center  
Upper St. Clair 
101 Drake Road,  
Suite B 
Pittsburgh, PA  15241 
(412) 831-9748 
(412) 831-1320 (Fax) 
 
 
 
 
 
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Co-Investigators: 
Case Western Comprehensive Cancer Center 
 
Michael Gibson, MD, PhD 
Case Comprehensive Cancer Center 
University Hospitals Seidman Cancer Center 
11100 Euclid Avenue, LKS 3128 
Cleveland, OH 44106 
216-844-5220 
216-844-5234(fax)  
 
 
Statistician: 
 
Brian Egleston, PhD 
Fox Chase Cancer Center 
333 Cottman Ave 
Philadelphia PA 19111 
brian.egleston@fccc.edu 
 
Study Monitor 
 
Beth Adaire-Halenda, CCRP 
Fox Chase Cancer Center 
333 Cottman Avenue 
CRU 2nd Floor 
Philadelphia, PA 19111 
(P) 215-214-3704 
(F) 215-214-1511 
beth.adaire@fccc.edu 
 
 
 
 
 
 
 
 
Version   
 
 
Date May 17, 2010 
Amendment 1  
 
Date September 17, 2010 
Amendment 2  
 
Date February 21, 2011 
Amendment 3  
 
Date October 19, 2011 
Amendment 4  
 
Date August 7, 2013 
Amendment 5  
 
Date February 19, 2014
 
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FER-GI-029 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 4 cycles (each cycle is 2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 2 cycles 
 
 
 
 
 
 
Patients should proceed to surgery 4-6 
weeks after 6 cycles of chemo or the last 
dose of chemotherapy, if chemotherapy was 
discontinued before 6 cycles.  Planned 
surgery must not take place until at least 8 
weeks have elapsed since the last dose of 
bevacizumab. 
 
 
 
 
 
Chemotherapy and bevacizumab will  
 
resume 8-10 weeks after surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 6 cycles  
 
 
Oxaliplatin 85 mg/m2 
5-Fluoruracil 2400mg/m2 
5-Flurouracil 400mg/m2 
Leucovorin 400mg/m2 
Bevacizumab 5mg/kg 
Oxaliplatin 85 mg/m2 
5-Fluorouracil 2400mg/m2 
5-Flurouracil 400mg/m2 
Leucovorin 400mg/m2
Restaging 
Surgery 
Oxaliplatin 85 mg/m2 
5-Flurouracil 2400mg/m2 
5-Flurouracil 400mg/m2 
Leucovorin 400mg/m2 
Bevacizumab 5mg/kg 
 
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TABLE OF CONTENTS 
 
 
 
 
1.0 
Introduction………………………………………………………………. 6 
 
2.0 
Objectives……………………………………………………………….. 
10 
 
3.0 
Investigational Plan……………………………………………………… 11 
3.1 
Summary of Study Design……………………………………….. 11 
3.2. 
Illustration of Study Design……………………………………… 11 
 
4.0 
Safety Plan………………………………………………………………. 
12 
4.1. 
Measures………………………………………………………… 
12 
 
5.0 
Selection Criteria ……………………………………………………… 
13 
5.1. 
Eligibility Criteria……………………………………………... 
13 
5.2. 
Ineligibility Criteria…………………………………………….. 
14 
5.3. 
Discontinuation of patients…………………………………….. 
15 
5.4. 
Inclusion of Women and Minorities…………………………… 
17 
5.5. 
Pregnancy………………………………………………………. 
17 
5.6. 
Baseline Pretreatment Studies………………………………...... 
17 
 
6.0 
Chemotherapy Treatment Plan…………………………………………. 
18 
6.1. 
Registration Procedures………………………………………… 
18 
6.2. 
Administration Schedule………………………………………... 
19 
6.3. 
Initial bevacizumab doses……………………………………….. 
20 
6.4. 
Oxaliplatin and leucovorin ……………………………………… 20 
6.5. 
Dexamethasone/Antiemetic……………………………………. 
21 
6.6. 
Correlative Studies……………………………………………… 
21 
 
7.0. 
Dose Modifications………………………………………………………. 21 
7.1. 
Common Terminology Criteria for Adverse Effects……………... 21 
7.2. 
Dose Modifications for Oxaliplatin and 5FU Toxicity…………… 22 
7.3. 
Non-Neurologic Toxicity ………………………………………… 22 
7.4. 
Dose Modifications of Oxaliplatin Toxicity……..………………..   25 
7.5. 
Dose Modifications for Bevacizumab …………………………….  26 
7.6. 
Supportive Care……………………………………………………  31 
7.7. 
Duration of Therapy……………………………………………… 31 
 
8.0 
Study Parameters………..………………………………………………… 32 
 
9.0. 
Drug Formulation and Procurement………………………………………. 35 
 
9.1. 
Bevacizumab  …………………………………………………….. 35 
 
9.2 
Oxaliplatin 
…………………………………………………..… 45 
 
9.3. 
5-Fluorouracil ..…………………………………………………… 50 
 
9.4. 
Leucovorin………………………………………………………… 52 
 
 
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10.0 
Adverse Event Reporting and Definitions………………………………… 54 
 
 
 
11.0 
Measurement of Effect 
…………………………………………… 64 
 
11.1 Measurement of Pathological Response …………………………… 68 
 
 
12.0 
Data Safety Monitoring Plan  …………………………………………… 69 
 
13.0 
Informed Consent………………………………………………………... 69 
 
14.0  Statistical Considerations………………………………………………… 69 
 
14.1 Primary Outcome/Objective………………………………………... 69 
 
14.2 Secondary Objective………………………………………………... 70 
 
14.3 Secondary Objective………………………………………………... 70 
 
14.4 Secondary Objective………………………………………………… 70 
 
14.5 Early Stopping for Toxicity………………………………………… 71 
 
REFERENCES…………………………………………………………………… 73 
 
 
 
 
 
 
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1. INTRODUCTION 
 
Cancer of the esophagus is uncommon, but lethal.  The mortality rates are roughly 
equivalent to the incidence: 14,550 people with esophageal cancer are diagnosed in the 
United States each year with 13,770 deaths each year.  There exists ample room for 
improvement over current treatment options.  From the National Cancer Institute 
Surveillance, Epidemiology and End Results (SEER) Program, the 5 year survival rate 
for all patients with esophageal cancer is 15 percent from 1995-2001. (1) 
 
Surgery alone had been the standard treatment for early stage esophageal cancer. The 
Radiation Therapy Oncology Group studied chemoradiation verses chemotherapy in a 
phase III prospective randomized trial evaluating the efficacy of 5-fluorouracil and 
cisplatin plus 50Gy of radiation therapy compared to 64 Gy of radiation therapy alone.  
This was done with patients with adenocarcinoma or squamous cell carcinoma of the 
thoracic esophagus.  121 patients were randomized.  The median survival was 8.9 months 
in the radiation treated patient compared to 12.5 months in the patients treated with 
chemotherapy and radiation.  Statistically significant differences were observed in 12 
month (50% vs. 33%) and 24 month (38 vs. 10%) survival ratios (p<.001). Concurrent 
therapy with cisplatin and 5 fluorouracil and radiation is superior to radiation therapy 
alone in patients with localized carcinoma of the esophagus.  This became the standard of 
care for patients with inoperable disease, and the results were not notably different from 
those obtained in series of resectable patients. (2) 
 
The evidence for effective radiosensitization and the ability to use a lower dose of 
radiotherapy raised the question of whether the pre-operative use of chemoradiation 
would downstage cancers to permit higher resection rates, greater success in local control 
with resection, and early treatment of micrometastatic disease. A series of phase II and 
small phase III studies have addressed this question. 
 
A prospective randomized trial with 113 patients in Ireland was undertaken to evaluate 
preoperative concurrent chemoradiotherapy with surgery alone.  Patients assigned to 
multimodality therapy received 2 courses of chemotherapy in weeks 1 & 6 (5-fluorouracil, 
15mg/kg for five days, and cisplatin, 75 mg/m2 on day 7) and a course of radiotherapy 
(40 Gy) over a 3 week period beginning with the first course of chemotherapy.  The 
patient then had surgery.  The other arm consisted of surgery with no preoperative 
therapy.  At time of surgery, 23 out of 55 patients who had preoperative therapy (42%) 
had positive nodes or metastasis versus 45 of 55 (82%) for surgery alone (p<.001).  
Thirteen of 52 (25%) had a CR after chemoradiation.  Median survival was longer for 
combined modality therapy 16 months vs. 11 months (p=.01).  At 3 years, overall 
survival statistically favored the multimodality arm as compared to the surgery alone, 
32% vs. 6% (p=.01) (5). This study has been criticized for the use of inadequate staging 
at baseline, a criticism that is the more to the point as survival in the surgery alone arm 
was markedly inferior to historical controls; however, other trials (6,7) have also 
supported or tended to support an advantage for preoperative chemoradiation for patients 
with Stage II-IVa squamous cell carcinoma or adenocarcinoma of the esophagus.  
 
In CALGB 9781, a prospective randomized Intergroup trial of trimodality therapy versus 
surgery alone for the treatment of stages I-III esophageal cancer. Patients were 
 
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FER-GI-029 
 
randomized to surgery alone or cisplatin (100mg/m2) and 5-FU (1000mg/m2 x 4d) with 
concurrent radiation therapy followed by esophagectomy with lymph node dissection.  
Fifty-six of a planned 475 patients were randomized. The study was terminated because 
of the poor accrual; nonetheless, informative results regarding the primary endpoint of 
overall survival were obtained.  Median survival was 4.5 years after trimodality therapy, 
vs. 1.8 years after surgery alone (p=.02).  This randomized study demonstrated a long 
term survival advantage with the use of chemoradiation therapy followed by surgery in 
the treatment of esophageal cancer.  Since this presentation, trimodality therapy has been 
accepted as a standard of care. 
 
Local failure alone occurs in fewer than 10% of patients treated with trimodality therapy. 
The majority of patients who fail will do so at metastatic sites, and the interval 
development of metastatic disease is also an important cause of failure to achieve 
resection after neoadjuvant chemoradiation (8,9).  One way to address distant metastatic 
recurrence is to add post-operative adjuvant therapy.  A phase II trial evaluated cisplatin 
and 5FU combined with radiotherapy followed by esophagectomy.  The objective of the 
trial was to determine complete pathologic response rate, survival rate, toxicity, pattern of 
failure and feasibility of administering adjuvant chemotherapy in patients with resectable 
cancer of the esophagus treated with preoperative chemoradiation. Eleven out of 29 
patients enrolled on the trial achieved pathologic CR (pCR = 26%). The low pathologic 
CR rate may to some extent have been related to the high pre-therapy stage of patients 
enrolled in this study. Paclitaxel and cisplatin were given as adjuvant therapy. Of the 35 
patients with potentially curative resections who were candidates for adjuvant 
chemotherapy, twenty-six (74%) received at least one course of paclitaxel and cisplatin, 
whereas 6 refused further treatment and 3 had inadequate Karnofsky performance status 
(60%) for further chemotherapy. Sixteen patients (62%) received 100% of the total 
paclitaxel dose, whereas 15 patients (58%) received 100% of the total cisplatin dose. 
Despite the high baseline stage of patients in this trial, and the relatively low pathologic 
CR rate, the 2 year survival was 62% (9). This provides some support that post-operative 
adjuvant therapy with a non cross resistant agent may reduce distant metastasis.  The 
pattern of initial failure after this pre-operative approach in the study cited above and a 
prior study which had not included adjuvant therapy was reported with longer follow-up: 
local/regional alone in 6% (5 of 90), local/regional plus distant in 3% (3 of 90); distant 
metastases without locoregional recurrence were the initial manifestation of relapse in 
47% (42 of 90) (10). The predominance of distant failure after aggressive pre-operative 
therapy indicates that further intensification of local therapy is unlikely to significantly 
improve long-term outcome for these patients, and that advances in the systemic therapy 
of esophagogastric therapy should be brought to bear early in the course in therapy of 
micrometastatic disease. 
 
Radiation may preclude further intensification of systemic therapy.  The use of 
perioperative regimens to surgery without radiation was examined in the MAGIC Trial.   
Cunningham et al assessed whether the addition of perioperative regimen of Epirubicin, 
Cisplatin, 5-FU (ECF) to surgery improves outcomes among patients with potentially 
curable gastric cancer.  503 patients were randomly assigned with resectable 
adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either 
perioperative chemotherapy and surgery or surgery alone.  Chemotherapy consisted of 3 
preoperative and 3 postoperative cycles of epirubicin, cisplatin, and fluorouracil.  Primary 
 
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FER-GI-029 
 
end point was overall survival.  The perioperative–chemotherapy group had a higher 
likelihood of survival (HR .75; 95% CI .6 to .93).  5 year survival favored the 
perioperative chemotherapy verses surgery 36 to 26% p=.09.   It also favored progression 
free survival (HR .66, p<.001).  With operable gastric or lower esophageal 
adenocarcinomas, the perioperative regimen of ECF decreased tumor size and stage and 
improved significantly progression free and overall survival (11). 
 
The introduction of the platinoid oxaliplatin yields an active regimen in esophagogastric 
cancer, with somewhat less toxicity than the ECF combination. In a Phase I study, the 
safety and activity of radiotherapy with 5-fluorouracil, leucovorin, and oxaliplatin were 
assessed in 33 patients with inoperable esophageal cancer. Three cycles of oxaliplatin, 5-
FU, and folinic acid with standard dose level oxaliplatin/5-FU starting on D1, D15, and 
D29 concomitant with 5 week’s radiotherapy.  An additional 3 cycles of standard 
FOLFOX4 were administered every 2 weeks after the end of radiotherapy. The  ORR 
was 61% (3 CR, 14PR), median TTP 5 months (95% CI 3-6 mo) and the overall survival 
9 months (95% CI 5-13 months).This showed that this regimen of oxaliplatin (85mg/m2) 
was well tolerated and active. (3)   
 
Also, Mauer et al ran a phase II trial evaluating the efficacy and tolerability of FOLFOX 
in patients with advanced esophagus cancer.  Thirty-five patients with recurrent or 
metastatic esophageal cancer enrolled.  All were evaluated for toxicity and 34 were 
evaluable for response.  The overall response rate was 40% (95% CI 24-57%).  The 
overall survival was 7.1 months and th one year survival was 31%.  The predominant 
toxicity was neutropenia, with 29% having grade 4 neutropenia.  Cumulative peripheral 
neuropathy, grade 2 or 3, occurred in  26%.  Thus, FOLFOX has favorable toxicity 
profile and anti tumor activity in patients with metastatic carcinoma of the esophagus 
(12). 
 
In the REAL 2 trial Cunningham et al aimed to establish the use of the third generation 
platinum, oxaliplatin in substitution for cisplatin in advanced esophagogastric cancer.  
The trial objective was a non inferiority trial for survival with capecitabine compared to 
fluorouracil and oxaliplatin compared to cisplatin.  1002 patients were randomized in a 
2x2 design.  As seen in Table 1, oxaliplatin based therapy is non inferior to cisplatin 
based therapy (13).    
 
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Table 1: 
OS results for Non-Inferiority (2x2 comparisons) and individual Regimens 
2x2 comparisons Per Protocol 1 year OS (95% CI) Median OS HR (95% CI) 
5FU: ECF + EOF 
39.4% (35.0-43.7) 
9.6 mths 
1 
Capecitabine: ECX + EOX 
44.6% (40.1-49.0) 
10.9 mths 
0.86 (0.75-0.99)* 
Cisplatin: ECF + ECX 
40.1% (35.7-44.4) 
10.1 mths 
1 
Oxaliplatin: EOX + EOF 
43.9% (39.4-48.4) 
10.4 mths 
0.92 (0.80-1.05)* 
Regimens ITT 
 
 
 
ECF n=263 
37.7% (31.8-43.6) 
9.9 mths 
1 
EOF n=245 
40.4% (34.2-46.5) 
9.3 mths 
0.95 (0.79-1.15) 
ECX n=250 
40.8% (34.7-46.9) 
9.9 mths 
0.92 (0.76-1.11) 
EOX n=244 
46.8% (40.4-52.9) 
11.2 mths 
0.80 (0.65-0.97) ‡ 
* The Upper limit of the 95% CI excludes 1.23 we can therefore conclude non-inferiority ‡ p=0.025 comparison with ECF 
There were no significant differences in response rates comparing ECF to, EOF, ECX and EOX (41%, 42%, 46%, and 48% 
respectively); grade 3-4 non haematological toxicity 36%, 42%, 33% and 45%; and grade 3-4 neutropaenia 42%, 30% (p=0.008), 51% 
(p=0.043) and 28% (p=0.001) respectively. 
 
Alterations in neoadjuvant chemoradiation regimens have had only a modest impact on 
survival, but the advent of novel therapies may permit more than incremental 
improvement. Bevacizumab, a monoclonal antibody to VEGF, may be one such agent.  
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.  The following discussion summarizes bevacizumab’s safety 
profile and presents some of the efficacy results pertinent to this particular trial.  Please 
refer to the bevacizumab Investigator Brochure for descriptions of all completed Phase I, 
II, and III trials reported to date. 
In a large phase III study (AVF2107g) in patients with metastatic colorectal cancer, the 
addition of bevacizumab, a monoclonal antibody directed against vascular endothelial 
growth factor (VEGF), to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy 
resulted in a clinically and statistically significant increase in duration of survival, with a 
hazard ratio of death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).  Similar 
increases were seen in progression-free survival (6.2 vs. 10.6 months; p < 0.001), overall 
response rate (35% vs. 45%; p < 0.01) and duration of response (7.1 vs. 10.4 months; 
p < 0.01) for the combination arm versus the chemotherapy only arm (14). 
Bevacizumab improves survival or disease-free survival in several other solid tumor 
malignancies, including lung cancer (15).  In colorectal cancer ECOG 3200, 829 
metastatic colorectal patients previously treated with a fluoropyrimidine and irinotecan 
assigned to one of three treatment groups.  The primary end point was overall survival.  
Median survival treated with FOLFOX4 and bevacizumab was 12.9 months compare to 
10.8 months treated with FOLFOX4 alone (HR =.75; p=.0011) and 10.2 months for 
bevacizumab alone.  The median progression free survival for FOLFOX4 with 
 
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FER-GI-029 
 
bevacizumab was 7.3 months compared to 4.7 months (p<.001).  The overall response 
rates for FOLFOX4 with bevacizumab was 22.7% and 8.6% with FOLFOX4 alone 
(p<.0001) (16).   
 
The addition of bevacizumab to combination irinotecan/cisplatin chemotherapy has been 
evaluated in 47 patients with metastatic or unresectable esophagogastric cancer.  The 
study aimed to demonstrate a 50% improvement in time to progression over historical 
values.  Median time to progression was 8.3 months (95% CI 5.5 to 9.9 months).  The 
overall response rate was 65 % (95% CI 5.5 to 9.9 months).  Median survival was 12.3 
months (95 % CI 11.3 to 17.2 months).  The addition of bevacizumab did not increase the 
rate of hematologic toxicity compared with prior experience.  The most common non-
hematologic toxicities were fatigue and diarrhea.  Thromboembolism was detected in 
28% of the patients and 6% experienced perforation of the gastrointestinal tract, which 
occurred at the primary tumor site.  The study demonstrated a striking 75% improvement 
in time to progression, a longer than expected overall survival, and no increase in 
chemotherapy side effects, although the rates of thrombotic events and bowel perforation 
may have been greater than with chemotherapy alone  (17). 
 
The present study aims to introduce bevacizumab into the peri-operative chemotherapy-
based management of esophagogastric cancer, utilizing FOLFOX to reduce toxicity. 
Radiotherapy will not be included, as it was not in MAGIC, as the principal barrier to 
cure in these patients is distant dissemination. The study will be closely monitored for the 
overall disease-free survival rate. 
 
   
2.0 
OBJECTIVES 
 
2.1 
Primary: To investigate two-year disease-free survival in patients with 
resectable esophageal and GE junction cancer treated with perioperative 
bevacizumab and FOLFOX.  
 
2.2 
Secondary: To assess, by pathological examination after surgical resection, 
complete and partial response to neoadjuvant therapy.  To characterize 
overall and progression free survival. 
 
2.3 
Secondary: To compare baseline and post-chemotherapy/bevacizumab 
tissues for biomarkers predicting response or resistance to this approach. 
 
2.4 
Secondary: To investigate safety in this setting. 
 
 
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3.0 
INVESTIGATIONAL PLAN 
 
3.1 
Summary of Study Design 
 
3.1.1 This is a pilot, open-label, non-randomized, phase II study for 
patients with locally advanced esophageal or proximal gastric cancer.  
Patients must not have received prior surgery or radiation therapy.  
Patients must not have received prior chemotherapy.  The study will 
be open to FCCC and the University of Pittsburgh investigators.   
 
3.1.2 All eligible patients will receive FOLFOX with bevacizumab every 2 
weeks (oxaliplatin 85mg/m2, 5-fluorouracil 2400mg/m2 , 5-
fluorouracil 400mg/m2, leucovorin 400 mg/m2, and bevacizumab 
5mg/kg) x 4 doses, then FOLFOX at the same doses q 2 weeks x 2.  
Patients will then undergo restaging, if there is no interval 
development of metastatic disease, the patient will be taken to 
resection.  Patients will then complete the regimen with 6 cycles of 
FOLFOX plus bevacizumab. 
 
3.2 
Illustration of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 4 cycles (each cycle is 2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 2 cycles 
 
 
 
 
 
 
Patients should proceed to surgery 4-6 
weeks after 6 cycles of chemotherapy or the 
last dose of chemotherapy, if chemotherapy 
was discontinued before 6 cycles.  Planned 
Oxaliplatin 85 mg/m2 
5-Fluoruracil 2400mg/m2 
5-Flurouracil 400mg/m2 
Leucovorin 400mg/m2 
Bevacizumab 5mg/kg 
Oxaliplatin 85 mg/m2 
5-Fluorouracil 2400mg/m2 
5-Flurouracil 400mg/m2 
Leucovorin 400mg/m2
Restaging 
 
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FER-GI-029 
 
surgery must not take place until at least 8 
weeks have elapsed since the last dose of 
bevacizumab. 
 
 
 
 
 
 
 
 
 
 
Chemotherapy and bevacizumab will  
 
resume 8-10 weeks after surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 6 cycles  
 
 
 
 
4.0 
SAFETY PLAN 
 
4.1 
A number of measures will be taken to ensure the safety of patients 
participating in this trial.  These measures will be addressed through 
exclusion criteria and routine monitoring as follows: 
 
4.1.1 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 (as per sections 4.1.2 
and 8.0).  Patients will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit for the duration of 
their participation in the study.  Patients discontinued from the 
treatment phase of the study for any reason will be evaluated 
~30 days (28–42 days) after the decision to discontinue treatment 
(see section 5.3).   
 
4.1.2 Specific monitoring procedures are as follows: 
 
4.1.2.1 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. 
 
Surgery 
Oxaliplatin 85 mg/m2 
5-Flurouracil 2400mg/m2 
5-Flurouracil 400mg/m2 
Leucovorin 400mg/m2 
Bevacizumab 5mg/kg 
 
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4.1.2.2 Proteinuria will be monitored by urine protein:creatinine 
(UPC) ratio or dipstick as per guidelines in Section 8.0. 
 
4.1.2.3 Bevacizumab should be held for 8 weeks prior to elective 
surgery, including the curative intent esophagectomies 
planned in the management of patients enrolled in this trial. 
In the event of emergent surgery it will be at the 
physician’s discretion to determine risk of time since the 
last dose of bevacizumab and benefit of needed surgery.  
Patients undergoing a major surgical procedure should not 
begin/restart bevacizumab until 8-10 weeks after that 
procedure. 
 
 
5.0 
SELECTION CRITERIA 
 
5.1 
Eligibility Criteria 
 
5.1.1 Patients must have biopsy proven adenocarcinoma, squamous cell 
carcinoma or undifferentiated carcinoma of the esophagus, GE 
junction and/or gastric cardia. 
 
5.1.2 Patients must have potentially resectable disease by the thoracic, 
minimally invasive or transhiatal approach. 
 
5.1.2.1 No portion of the lesion may be within 5 cm of the 
cricopharyngeus 
5.1.2.2  Patient must be considered medically fit for surgery with 
average or below average risk.   
5.1.2.3  T1-3 or T4 with local invasion confined to diaphragm, 
pleura or pericardium  
5.1.2.4 –No myocardial infarction within 12 months of enrollment. 
 
5.1.3 Patients must be > 18 years of age. 
 
5.1.4 Patients must have ECOG performance status 0 or 1. 
 
5.1.5 Patients must have WBC > 3,500/mm3, platelet count > 
100,000/mm3. 
 
5.1.6 Patients must have serum creatinine (Cr) < 1.5 mg and/or creatinine 
clearance > 60cc/min. 
 
5.1.7 Bilirubin must be < ULN unless the patient has a chronic grade 1 
bilirubin elevation due to Gilbert's disease or similar syndrome due 
to slow conjugation of bilirubin.  Alkaline phosphatase must be 
<ULN.  AST & ALT must be <ULN.  
 
 
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5.1.8 Urine protein/creatinine (UPC) ratio of < 1.0 or dipstick for protein 
of < 2+, Common Terminology Criteria for Adverse Events version 
4.0 (CTCAE v 4) grade < 2. Patients with a UPC ratio > 1.0 or 
dipstick of 2+ must undergo a 24-hour urine collection and must 
demonstrate < 1 gm of protein in order to participate.  
 
5.1.9 Patients must give written informed consent and HIPAA consent 
 
5.2 
Ineligibility Criteria 
 
5.2.1 Patients with prior chemotherapy for any malignant disorder, 
thoracic radiotherapy or prior surgical resection of an esophageal 
tumor are ineligible. 
 
5.2.2 Patients with biopsy-proven invasion of the tracheobronchial tree or 
tracheo-esophageal fistula are ineligible. 
 
5.2.3 Patients with a history of a curatively treated malignancy must be 
disease-free for at least two years and have a survival prognosis that 
is greater than five years. 
 
5.2.4 Eligible patients of reproductive potential (both sexes) must agree to 
use an accepted and effective method of contraceptive during study 
therapy and for at least 6 months after the completion of 
bevacizumab.  Women must not be pregnant or breast-feeding 
because the study drugs administered may cause harm to an unborn 
fetus or breastfeeding child. All females of childbearing potential 
must have a serum pregnancy test to rule out pregnancy within 7 
days prior to registration. See further details in section 5.5. 
 
5.2.5 Patients with a history of hypertension must measure <150/90 
mmHg and be on a stable regimen of anti-hypertensive therapy. 
Patients with a history of hypertension who have a blood pressure of 
150/90 mmHg, or greater are not eligible. Patients with a history of 
hypertension who have a blood pressure of < 150/90 mmHg but are 
not on a stable regimen of anti-hypertensive therapy, are not eligible. 
 
5.2.6 Any prior history of hypertensive crisis or hypertensive 
encephalopathy. 
 
5.2.7 New York Association (NYHA) Grade II or greater congestive heart 
failure. 
 
5.2.8 Patients must not have a serious or non-healing wound, skin ulcers 
or unhealed bone fracture, or known HIV infection. 
 
5.2.9 Patients with > grade 2 neuropathy are not eligible. 
 
 
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5.2.10 Patients must not have had significant traumatic injury within 28 
days prior to randomization.   
 
5.2.11 Patients with PT (INR) > 1.5 are not eligible. The patient may not be 
receiving full-dose anticoagulation. Prophylactic or full dose 
anticoagulation are permitted post-resection or for treatment of an 
intercurrent thrombotic event.   
 
5.2.12 Patients with non-malignant systemic disease (cardiovascular, renal, 
hepatic, etc.) that would preclude any of the study therapy drugs are 
not eligible. Specifically excluded are the following conditions: 
current symptomatic arrhythmia, symptomatic peripheral vascular 
disease. 
 
5.2.13 Patients with a history of the following within 12 months of study 
entry are not eligible: arterial thromboembolic events, unstable 
angina.  
 
5.2.14 Any history of stroke or transient ischemic attack. 
 
5.2.15 Significant vascular disease (i.e. aortic dissection, aortic aneurysm). 
 
5.2.16 Patients with psychiatric or addictive disorders or other conditions 
that, in the opinion of the investigator, would preclude them from 
meeting the study requirements are not eligible. 
 
5.2.17 Distant metastases. 
 
5.2.18 History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within 6 months prior to study enrollment. 
 
5.2.19 Known hypersensitivity to any component of bevacizumab. 
 
5.3 
Discontinuation of Patients 
 
5.3.1 Treatment will be discontinued for any of the following reasons 
 
5.3.1.1 
Disease progression  
 
5.3.1.2 
Administration of radiotherapy, non-protocol 
chemotherapy, or biological therapy.  
 
5.3.1.3 
In the Neo-adjuvant setting, excessive toxicity that requires 
> 2 dose reductions of all study treatment should not be 
retreated in the pre-op setting. If the investigator desires to 
keep the patient on study for surgery and projected post-
operative therapy, this must be discussed with the PI. 
(Section 7.1) 
 
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5.3.1.3 
Severe co-morbidities that preclude continuation of study 
therapy. 
 
5.3.1.4 
Non-compliance that compromises safety of therapy. 
 
5.3.1.5 
Patient choice. 
 
5.3.1.6 
Investigator discretion (if continued treatment is no longer 
in the best interest of the patient). 
 
5.3.1.7 
Study closure. 
 
5.3.1.8 
Patient lost to follow up.  If the patient does not return for 
scheduled visits, every effort should be made to re-establish 
contact. In any circumstance, every effort should be made 
to document patient outcome.  All efforts to contact the 
patient must be clearly documented. 
 
5.3.1.9 
Clinical or symptomatic deterioration. 
 
5.3.1.10 
Patient becomes pregnant  
 
5.3.1.11 
Inability of subject to comply with study requirements. 
 
5.3.1.12 
Determination by the investigator that it is no longer safe 
for the subject to continue therapy. 
 
Subjects who meet the following criteria should be 
discontinued from study treatment:  
• 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  
• Any grade arterial thromboembolic event 
• Grade 4 congestive heart failure 
• Perforation of the large bowel  
• Tracheoesophageal fistula (any grade) or Grade 4 
fistula 
• 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 
 
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Patients who have an ongoing bevacizumab-related 
Grade 4 or serious adverse event at the time of 
discontinuation from study treatment will be followed 
for toxicity until resolution of the event or until the 
event is considered irreversible 
 
 
5.4 Inclusion of Women and Minorities 
 
 
Both men and women and members of all races and ethnic groups  
 
 
are eligible for this study 
 
5.5 Pregnancy  
Women of childbearing potential (WOCBP) includes any female who has 
experienced menarche and who has not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation, or a bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 
consecutive months, or women on hormone replacement therapy (HRT) with 
documented plasma follicle-stimulating hormone (FSH) level > 35 mIU/ml).  
Even women who are using oral, implanted, or injectable contraceptive 
hormones or mechanical products (diaphragm, condoms, spermicides) to 
prevent pregnancy or practicing abstinence or where partner is sterile (e.g. 
vasectomy), should be considered to be WOCBP. 
 
The effects of this treatment on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason, women of 
child-bearing potential (WOCBP) and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior 
to study entry and for the duration of study participation.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, 
she should inform her treating physician immediately. 
 
Prior to study enrollment, WOBCP must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for 
an unintentional pregnancy.  In additional, men enrolled on this study should 
understand the risks to any sexual partner of childbearing potential. 
 
All WOCBP must have a negative pregnancy test within 7 days of registration 
prior to receiving the first dose of the investigational agent(s).  If the 
pregnancy test is positive, the patient must not receive protocol treatment and 
must not be enrolled in the study. 
 
5.6 Baseline Pretreatment Studies 
 
Within 21 days prior to registration: 
 
 
Endoscopic esophageal ultrasound  
 
CT scan chest 
 
CT scan abdomen/pelvis 
 
PET Scan 
 
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PFTs/DLCO 
Medical oncology evaluation  
Surgical evaluation 
Biopsies 
 
 
 
Within 7 days prior to registration 
 
 
 
CBC, diff, platelets 
 
U/A 
 
PT, PTT, INR 
 
Comprehensive metabolic panel 
 
UPC ratio or dipstick for protein 
 
Serum pregnancy test 
 
 
 
 
6 TREATMENT PLAN 
 
6.1 Registration Procedures 
 
 
Eligible patients will be entered on study centrally by the Fox Chase 
Cancer Center Office Quality Assurance (QA) Coordinator or their designee.  
Following registration, patients must begin protocol treatment within 7 days of 
registration.  Issues that would cause treatment delays must be discussed with the 
Principal Investigator.  If a patient does not receive protocol therapy following 
registration, the patient’s will be considered a screen failure or participant 
withdraw and will be replaced.  The QA Coordinator must be notified of 
cancellations as soon as possible.  
 
Participants may be registered from 9:00 am to 5:00 pm by calling the QA 
Coordinator at 215-728-4770.  The investigator or designee will then fax the 
completed registration form, informed consent and HIPAA signature pages, and 
eligibility checklist to 215-214-1511.  The QA Coordinator will notify the site 
when registration is confirmed and the sequence number has been assigned.  
Participants must be registered and have received a sequence number assigned by 
the QA Coordinator prior to the initiation of treatment.  The following forms must 
be completed at the time of registration: 
 
• Signed and dated informed consent form 
• Signed and dated HIPAA consent form 
• Registration form 
• Signed eligibility checklist 
 
 
Exceptions to the current registration policies will not be permitted as well as: 
• Late registrations (after initiation of treatment) 
• Exceptions to eligibility requirements 
• Participation by an institution/member not identified as eligible 
• Non-Compliance with regulatory paperwork 
 
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6.2 Administration Schedule - Dose calculations are based on actual body weight 
at the beginning of each cycle. One cycle is two treatment days every 2 weeks. 
Drugs are administered in the order listed in the table below. 
Phase I – Neoadjuvant therapy 
*Neoadjuvant Chemotherapy q 2 weeks x 4 Cycles 
Agent  
 
Dose  
Route 
Treatment 
Administration 
Bevacizumab 
5 mg/kg 
IV infusion over 90 
minutes  
Day 1 
Oxaliplatin 
85 mg/m2 
IV infusion over 2 
hours  
Day 1 
Leucovorin 
400 mg/m2 
IV infusion over 2 
hours 
Day 1 
5 –FU 
400 mg/m2 
IV bolus injection 
immediately 
following leucovorin 
Day 1 
5-FU 
2.4 gm/m2 
IV continuous 
infusion over 
46 hours immediately 
following bolus 5-FU 
Days 1 and 2 
 
 
 
 
 
*Neoadjuvant Chemotherapy q 2 weeks x 2 cycles (NOTE: Given after 4 
Cycles of FOLFOX + Bevacizumab) 
Agent  
 
Dose  
Route 
Treatment 
Administration 
Oxaliplatin 
85 mg/m2 
IV infusion over 2 
hours  
Day 1 
Leucovorin 
400 mg/m2 
IV infusion over 2 
hours 
Day 1 
5 –FU 
400 mg/m2 
IV bolus injection 
immediately 
following leucovorin 
Day 1 
5-FU 
2.4 gm/m2 
IV continuous 
infusion over 
46 hours immediately 
following bolus 5-FU 
Days 1 and 2 
 
 
 
Patients should proceed to surgery 4-
6 weeks after 6 cycles of 
chemotherapy or the last dose of 
chemotherapy, if chemotherapy was 
discontinued before 6 cycles.  
Restaging 
 
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Planned surgery must not take place 
until at least 8 weeks have elapsed 
since the last dose of bevacizumab 
 
  
 
 
 
 
 
 
Phase II – Adjuvant therapy 8 to 10 weeks after surgery 
*Adjuvant Chemotherapy q 2 weeks x 6 cycles 
Agent  
 
Dose  
Route 
Treatment 
Administration 
Bevacizumab 
5 mg/kg 
IV infusion over 90 
minutes (see below) 
Day 1 
Oxaliplatin 
85 mg/m2 
IV infusion over 2 
hours  
Day 1 
Leucovorin 
400 mg/m2 
IV infusion over 2 
hours 
Day 1 
5 –FU 
400 mg/m2 
IV bolus injection 
immediately 
following leucovorin 
Day 1 
5-FU 
2.4 gm/m2 
IV continuous 
infusion over 
46 hours immediately 
following bolus 5-FU 
Days 1 and 2 
 
 
6.3 Initial bevacizumab doses must be administered over a minimum of 90 
minutes. If no adverse reactions occur, the second dose should be 
administered over a minimum of 30 minutes. Again, if no adverse reactions 
occur, the third and subsequent doses may be administered according to 
institutional practice. Infusions should be run in via a volumetric infusion 
device. If infusion-related adverse reactions occur, subsequent infusions 
should be administered over the shortest period that is well tolerated. 
 
6.4 Oxaliplatin and leucovorin can be administered simultaneously using Y-line 
tubing provided that the leucovorin has been diluted with 5% dextrose in 
water and NOT 0.9% sodium chloride because of the incompatibility of 
oxaliplatin and saline. 
 
6.4.1 Supportive Care: Magnesium Sulfate 8 milliequivalent (meq) and 
Calcium gluconate 10 meq.  Infuse at a rate and volume of solution 
according to your institution standards pre and post oxaliplatin 
 
Surgery 
 
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6.5 All patients will be premedicated with Dexamethasone 10mg IV and 
antiemetic therapy using for example, Palonosetron .025mg IV prior to each 
infusion 
 
6.6 Correlative Studies 
Tissue will be collected at baseline during baseline UGI/endoscopy prior 
to the start of chemotherapy/Bevacizumab and at surgery.  Post-treatment 
samples for biomarker analysis will be performed on FFPE tissue after 
diagnostic evaluation is completed. The research studies must not deplete 
diagnostic tissue so that future clinical tests would not be possible when 
residual disease is minimal; however, assays would be of low yield when 
only isolated tumor cells remain 
6.6.1  Tissue will be studied for ICAM, VEGFR2 tumoral expression and 
ERCC1 by AQUA (18) technology at the Fox Chase Cancer Center 
Biosample Repository. Additional tissue-based biomarkers may be 
performed in the future as the state of knowledge evolves. 
 
6.6.2  Pathology materials should be sent to: 
 R. Katherine Alpaugh PhD 
 Fox Chase Cancer Center 
 Protocol Support Laboratory 
 333 Cottman Avenue P2011 
 Philadelphia, PA 19111 
 Telephone 215 214-1634 
 FAX 215 214-1635 
 e-mail RK_Alpaugh@fccc.edu 
 
6.6.3  Banking of Tissue 
Remaining tissue will be banked in the Fox Chase Cancer Center 
Biosample Repository for future assessment.   
 
Additional instructions are provided in the “Procedure for Tissue Specimen” 
(located in each patient case report form binder) for collection, processing and 
shipping blood specimens. 
 
 
7 DOSE MODIFICATIONS 
 
7.1 All toxicities must be graded according to the CTCAE v 4.0.  According to the 
following tables, the final dose modification must be based upon the worst 
grade of toxicity experienced. If patients require dose reductions lower than 
level -2, the drug to which the adverse event is attributed will be discontinued.  
The remaining drugs may be continued per the protocol schema. Leucovorin 
and oxaliplatin must not be continued after the discontinuation of 5-
fluorouracil, but 5-fluorouracil may be continued without oxaliplatin or 
bevacizumab and 5-fluorouracil and oxaliplatin may be continued without 
bevacizumab.  Any dose reduction is continued for all subsequent cycles in 
the pre- or post-operative phase; therefore, dose re-escalation in the same 
 
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phase of treatment is not allowed following a dose reduction. Oxaliplatin may 
be reintroduced at full dose post-operatively if neuropathy has resolved. 
Bevacizumab may be reintroduced at full dose post-operatively unless adverse 
event Action to be Taken column of the neo-adjuvant Dose Modification for 
Bevacizumab table requires permanent discontinuation.  (Please see below for 
specific dose modifications).  Missed doses will not be made up. 
 
7.2 Dose Modifications for oxaliplatin and 5-FU Toxicity  
 
7.2.1 There are no dose reductions for leucovorin. The dose remains fixed 
at 400 mg/m2. Leucovorin is discontinued only when 5-FU is 
discontinued. 
 
7.2.2  Patients who require discontinuation of oxaliplatin may continue to 
receive 5-FU/leucovorin and bevacizumab. 
 
7.2.3 Patients who discontinue both 5-FU and oxaliplatin may continue to 
receive bevacizumab, provided patient experiences no bevacizumab-
related toxicities after surgery.  However if patients discontinue both 
5-FU and oxaliplatin during the preoperative period, surgery will be 
scheduled for approximately 8 weeks from the most recent dose of 
bevacizumab. 
 
Dose Levels of Oxaliplatin, 5-FU, Bevacizumab 
 
Starting Dose* 
Dose Level - 1 
Dose Level - 2 
Oxaliplatin 
85 mg/m² 
65 mg/m² 
50 mg/m² 
5-FU Bolus 
400 mg/m² 
320 mg/m² 
200 mg/m² 
5-FU Infusion 
2.4gm/m² 
2 gm/m² 
1.6 gm/m² 
Bevacizumab 
5mg/kg 
- 
- 
* All patients will start cycle 1 with doses listed in “Starting Dose” column. 
 
7.3 Non-Neurologic Toxicity (Oxaliplatin and 5-FU Toxicity) 
 
The following table describes the recommended dose modifications at the 
start of each subsequent cycle of therapy. All dose modifications must be 
based on the worst preceding toxicity. 
 
 
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*NOTE: Neoadjuvant & Adjuvant Dose Modifications 
Toxicity NCI Grade 
(Value) 
Worst interval toxicity  
 
Day of treatment 
No toxicity  
 
Maintain dose level  
Maintain dose level 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 
1500/mm³) 
 
 
Grade 2 (ANC <1499 - 
1000/mm³) 
 
Grade 3 (ANC <999 - 
500/mm³) 
 
Grade 4 (ANC < 500/mm³) 
 
 
Maintain dose level 
 
 
 
Maintain dose level 
 
 
Maintain dose level 
 
 
Reduce 5-FU and oxaliplatin 
1 dose level 
 
If ANC < 1000 on day of 
treatment, hold and check 
weekly until > 1000mm3. 
Filgrastim may be utilized. 
PEG-filgrastim may be 
utilized in subsequent cycles. 
Then treat based on interval 
toxicity. If ANC < 1000 after 
2 weeks, discontinue. 
Thrombocytopenia 
Grade 1 (PLT < LLN - 
75,000/mm3) 
 
Grade 2 (PLT 74,999 – 
50,000/mm3) 
 
Grade 3 (PLT 49,999 – 
25,000/mm3) 
 
Grade 4 (PLT< 25,000/mm3) 
 
 
Maintain dose level 
 
 
Maintain dose level 
 
 
Reduce 5-FU and oxaliplatin 
1 dose level 
 
Reduce 5-FU and oxaliplatin 
2 dose levels 
If PLT < 75,000 on day of 
treatment, hold and check 
weekly until > 75,000 
mm3. Then treat based on 
interval toxicity.  If PLT < 
75,000 after 2 
weeks, discontinue. 
 
Other hematologic toxicities 
do not require dose 
modification; however red 
blood cell transfusion should 
be strongly considered 
for hemoglobin <8 g/dl. 
 
 
 
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Toxicity NCI Grade 
(Value) 
Worst interval toxicity  
 
Day of treatment 
Other nonhematologic 
toxicities (except 
neurologic)*,  
 
Grade 1 
 
Grade 2 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
 
 
Maintain dose level 
 
Maintain dose level 
 
 
Reduce 5-FU and/or 
oxaliplatin 1 dose level** 
 
 
Reduce 5-FU and/or 
oxaliplatin 1 dose level** 
 
 
 
 
 
Maintain dose level 
 
Hold until resolved to grade 
<1.  Maintain dose level 
 
Hold until resolved to grade 
<1.  Reduce 5-FU or 
oxaliplatin 1 dose level 
 
Hold until resolved to grade 
<1.  Reduce 5-FU or 
oxaliplatin 1 dose level 
 
*Exceptions: alopecia, anorexia, nausea/vomiting if can be controlled by antiemetics 
**Reduce only the drug associated with the toxicity.  May dose reduce both drugs if 
toxicity may be related to both drugs. 
 
Hemolytic Uremic Syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP): The 
hemolytic uremic syndrome should be suspected in individuals who experience 
unexplained severe hemolysis, hemoglobinemia and renal failure as demonstrated by an 
increase in serum creatinine. 
 
Patients suspected of experiencing HUS or demonstrating symptoms of TTP should have 
the following laboratory analyses conducted: creatinine, BUN, urinalysis with 
microscopic evaluation, CBC with differential and platelets, PT/PTT, Fibrinogen, 
Fibrinogen Degradation Products (FDP), Antithrombin III (ATIII), von Wildebrand 
Factor (VWF), anti-nuclear antibodies (ANA), rheumatoid factor (RhF), C3, C4, CH50, 
anti-platelet antibodies, platelet associated IgG, circulating immune complexes.  
 
Oxaliplatin and 5-fluorouracil should be discontinued for HUS or TTP. 
With any suspicion of veno-occlusive disease (VOD) of the liver (hyperbilirubinemia, 
ascites, unexplained weight gain, hepatomegaly, splenomegaly, esophageal varices or 
other sign of portal hypertension), chemotherapy must be held. If VOD is diagnosed 
clinically, chemotherapy must be discontinued. 
 
 
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7.4 Dose Modifications of Oxaliplatin for Toxicity 
 
*NOTE: Neoadjuvant & Adjuvant Dose Modifications 
Neurologic Toxicitya 
Paresthesias/Dysesthesias 
1-7 day duration 
> 7 day duration 
Grade 1 – 
Paresthesias/dysesthesias 
that resolve and 
do not interfere with 
function  
 
Maintain dose 
Maintain dose 
Grade 2 – 
Paresthesias/dysesthesias 
interfering with 
function, but not activities 
of daily living 
Maintain doseb 
Decrease oxaliplatin one 
dose levelb 
 
Grade 3 – 
Paresthesias/dysesthesias 
with pain or with functional 
impairment that also 
interfere with activities of 
daily living 
First episode: Decrease only 
oxaliplatin one dose levelb 
Second episode: Stop 
oxaliplatin only 
 
Stop oxaliplatin only 
 
+Grade 4 - Persistent 
paresthesias/dysesthesias 
that are disabling or life-
threatening 
Stop oxaliplatin only 
Stop oxaliplatin only 
 
Laryngeal Dysesthesias (Grading at physician’s discretion)  
Grade 1 – Mild 
Grade 2 – Moderate 
Maintain dose and consider 
increasing duration of 
oxaliplatin infusion to 6 
hours 
Maintain dose and consider 
increasing duration of 
oxaliplatin infusion to 6 
hours 
Grade 3 - Severe 
 
At physician’s discretion, 
either stop oxaliplatin or 
increase duration of 
infusion to 6 hours 
Stop oxaliplatin only 
 
Pulmonary Toxicity 
Dyspnea ≥ grade 2  
Hypoxia ≥ grade 2 
Pneumonitis/pulmonary 
infiltrates ≥ grade 2 
Pulmonary fibrosis ≥ grade 
2 
Cough ≥ grade 3 
Hold all therapy until interstitial lung disease and 
pulmonary embolism are ruled out. 
• If non-infectious interstitial lung disease is confirmed, 
oxaliplatin must be discontinued. 
• If non-infectious interstitial disease is ruled out and 
infection (if any) has resolved, patients with persistent 
Grade 2 dyspnea/hypoxia or grade 3 cough can resume 
treatment at the physician’s discretion. All others do not 
resume treatment with oxaliplatin. 
a These toxicity descriptions should be used to determine dose modifications and delays. Use the CTCAE 
v4.0 to assess neurologic toxicity for adverse event reporting. 
b Hold oxaliplatin for ≥ grade 2 neurotoxicity. When ≤ grade 1, resume treatment with dose modifications. 
 
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If > grade 1 toxicity persists after 4 weeks’ hold, discontinue oxaliplatin. Continue 5-FU 
+ LV and bevacizumab) while oxaliplatin is held. 
 
7.5 Dose Modifications for Bevacizumab  
 
7.5.1 If AEs occur that require holding the bevacizumab dose, the dose 
will remain 5mg/kg when treatment resumes. 
 
7.5.2 If 5-FU/LV and/or oxaliplatin are held due to chemotherapy-related 
AEs, bevacizumab should be continued unless the patient’s medical 
condition precludes this, adjuvantly.  If the 5-FU/LV and oxaliplatin 
is held prior to surgery, bevacizumab will not be continued and the 
patient will proceed to resection at 8 weeks following the most 
recent dose of bevacizumab. 
 
 If bevacizumab is held or must be discontinued before completion of chemotherapy, 5-
FU/LV and oxaliplatin should be continued.   
 
*NOTE: Neo-Adjuvant Dose Modifications for Bevacizumab 
Adverse Event 
Grade 
CTCAE v4.0 
Action to be Taken 
 
Acute infusion reaction 
e.g., fever, chills, headache, 
nausea (see Syndrome-
Cytokine 
reaction) 
or 
Allergic 
reaction/hypersensitivity 
(e.g., fever, rash, 
urticaria, bronchospasm) 
 
1, 2 or 3 
 
If infusion-related or allergic reactions occur, pre-
meds should be given with the next dose, but the 
infusion time may not be reduced for the subsequent 
infusion. If the next dose is well-tolerated with pre-
meds, the subsequent infusion time may be reduced 
by 30 ± 10 min. as long as pre-meds continue to be 
used. If infusion-related AEs occur with the 60-min. 
infusion, all subsequent doses should be given over 
90 ± 15 min. (with pre-meds). If infusion-related AEs 
occur with the 30-min. infusion, all subsequent doses 
should be given over 60 ± 10 min. (with pre-meds). 
 
For patients with grade 3 reactions, the bevacizumab 
infusion must be stopped and not re-started on that 
day. At the physician's discretion, bevacizumab may 
be permanently discontinued or reinstituted 
with pre-medications and at a rate of 90 ± 15 minutes. 
If the reaction occurred at the 90-minute rate, initially 
challenge at a slower infusion rate and gradually 
increase to 90 minutes. When bevacizumab is re-
instituted, the patient should be monitored, per 
physician's usual practice, for a 
duration comparable to duration of reaction 
4 
Permanently discontinue bevacizumab. 
 
 
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FER-GI-029 
 
Adverse Event 
Grade 
CTCAE v4.0 
Action to be Taken 
 
Hemorrhagea 
3  
  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. 
• 
Subjects who experience a repeat Grade 3 
hemorrhagic event will be discontinued from 
receiving bevacizumab. 
 For hemorrhage from tumor site, stop neoadjuvant 
bevacizumab.  Bevacizumab may be resumed in the 
adjuvant phase.  
 
4 
  Discontinue bevacizumab. 
For hemorrhage from tumor site, stop neoadjuvant 
bevacizumab.  Bevacizumab may be resumed in the 
adjuvant phase. 
Thrombosis/thrombus/ 
embolism-venous (including 
vascular access device) 
 
2 or 3 
 
Hold bevacizumab until resolution by clinical 
assessment or Doppler. 
• If the planned duration of full-dose anticoagulation 
is < 2 weeks, hold bevacizumab until anticoagulation 
is complete. 
• If the planned duration of full-dose anticoag is ≥ 2 
weeks, bevacizumab may be resumed during anticoag 
if no grade 3 or 4 hemorrhage event occurred while 
on therapy   
- If unfractionated heparin, PTT must be in 
therapeutic range. 
Discontinue bevacizumab if thromboembolic events 
worsen or recur after resuming therapy 
*Pre-operative setting, low molecular weight 
heparin will be used only, no coumadin 
4  
Permanently discontinue bevacizumab. 
 
Visceral or peripheral 
arterial ischemia 
2 b,c, 3 or 4 
Permanently discontinue bevacizumab. 
 
Cardiac ischemia/infarction 
2 b, 3 or 4 
Permanently discontinue bevacizumab. 
 
CNS ischemia 
2 b, 3 or 4 
Permanently discontinue bevacizumab. 
 
Reversible Posterior 
Leukoencephalopathy   
Any grade 
(confirmed by 
MRI) 
Discontinue bevacizumab. 
 
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FER-GI-029 
 
Adverse Event 
Grade 
CTCAE v4.0 
Action to be Taken 
 
GI perforation including GI 
leak and GI fistula 
≥1 
Permanently discontinue bevacizumab. 
 
Intra-abdominal abscessd 
 
>1 
Hold Neoadjuvant therapy. Resection can be 
undertaken when medically safe, and no sooner than 
4 weeks following the most recent dose of 
bevacizumab. 
Complication, non-infectious 
wound 
dehiscencee 
1 
Hold bevacizumab for at least 1 month. If, in the 
physician's opinion, substantial healing has taken 
place within 1-3 months, bevacizumab may be 
resumed. If wound dehiscence recurs, permanently 
discontinue bevacizumab. 
2, 3, or 4 
Permanently discontinue bevacizumab. 
Proteinuria 
UPC ratio < 
3.5 or dipstick 
1+ 
Continue bevacizumab. 
 
UPC ratio > 
3.5 or dipstick 
> 2+ 
Hold bevacizumab until it UPC recovers to < 3.5 or 
dipstick is ≤ 2+. 
If therapy is held for > 2 months due to proteinuria, 
discontinue bevacizumab. 
Nephrotic 
Syndrome or 
dipstick > 3+ 
Discontinue bevacizumab. 
 
Hypertension 
 
3 
 
Bevacizumab may be continued in conjunction with 
standard anti-hypertensive therapy at physician 
discretion. Bevacizumab mus be held for 
uncontrolled or symptomatic hypertension present on 
the day that the bevacizumab dose is to be given. If 
BP is not controlled with medication within 1 month, 
permanently discontinue bevacizumab. 
4 
Permanently discontinue bevacizumab. 
Other clinically significant 
(AEs)f 
3 
Hold until AE has resolved to ≤ grade 1. 
4 
Permanently discontinue bevacizumab. 
a If coagulation disorders develop, secondary to other medical conditions, hold 
bevacizumab until the PT INR and PTT return to ≤ grade 1. 
b New or worsening grade 2 events. (Therapy may be continued for grade 2 conditions 
present at baseline that have not worsened.) 
c Patients who develop brief, reversible, exercise-induced claudication (grade 2) not 
attributable to arterial thromboembolic events may continue on study. 
d Refer to grading criteria listed for the appropriate adverse event in the Infection section 
of the CTCAE v 4.0. 
e Refer to Injury, Poisoning, Procedural Complications section of the CTCAE v 4.0. 
f Determination of "clinically significant" is at the physician’s discretion and applies to 
those adverse events that can be attributed to bevacizumab and are not related to 
chemotherapy. 
 
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FER-GI-029 
*NOTE: Adjuvant Dose Modifications for Bevacizumab 
Adverse Event 
Grade 
CTCAE 
v4.0 
Action to be Taken 
 
Acute infusion reaction 
e.g., fever, chills, headache, 
nausea (see Syndrome-
Cytokine 
reaction) 
or 
Allergic 
reaction/hypersensitivity 
(e.g., fever, rash, 
urticaria, bronchospasm) 
 
1, 2 or 3 
 
If infusion-related or allergic reactions occur, pre-
meds should be given with the next dose, but the 
infusion time may not be reduced for the subsequent 
infusion. If the next dose is well-tolerated with pre-
meds, the subsequent infusion time may be reduced 
by 30 ± 10 min. as long as pre-meds continue to be 
used. If infusion-related AEs occur with the 60-min. 
infusion, all subsequent doses should be given over 
90 ± 15 min. (with pre-meds). If infusion-related AEs 
occur with the 30-min. infusion, all subsequent doses 
should be given over 60 ± 10 min. (with pre-meds). 
 
For patients with grade 3 reactions, the bevacizumab 
infusion should be stopped and not re-started on that 
day. At the physician's discretion, bevacizumab may 
be permanently discontinued or reinstituted with pre-
medications and at a rate of 90 ± 15 minutes. If the 
reaction occurred at the 90-minute rate, initially 
challenge at a slower infusion rate and gradually 
increase to 90 minutes. When bevacizumab is re-
instituted, the patient should be monitored, per 
physician's usual practice, for a duration comparable 
to duration of reaction 
4 
Permanently discontinue bevacizumab. 
Hemorrhagea 
3 or 4 
Permanently discontinue bevacizumab. 
Thrombosis/thrombus/ 
embolism-venous (including 
vascular access device) 
 
2 or 3 
 
Hold bevacizumab until resolution by clinical 
assessment or Doppler. 
• If the planned duration of full-dose anticoagulation 
is < 2 weeks, hold bevacizumab until anticoagulation 
is complete. 
• If the planned duration of full-dose anticoag is ≥ 2 
weeks, bevacizumab may be resumed during anticoag 
if no grade 3 or 4 hemorrhage event occurred while 
on therapy  
- If stable dose of warfarin (or other anticoagulant), 
INR must be in range (usually between 2 and 3); or 
- If unfractionated heparin, PTT must be in 
therapeutic range. 
Discontinue bevacizumab if thromboembolic events 
worsen or recur after resuming therapy 
*Post operatively, physician’s discretion to use low 
molecular weight heparin or coumadin 
4  
Permanently discontinue bevacizumab. 
 
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FER-GI-029 
Adverse Event 
Grade 
CTCAE 
v4.0 
Action to be Taken 
 
Visceral or peripheral 
arterial ischemia 
2 b,c, 3 or 4 
Permanently discontinue bevacizumab. 
 
Cardiac ischemia/infarction 
2 b, 3 or 4 
Permanently discontinue bevacizumab. 
CNS ischemia 
2 b, 3 or 4 
Permanently discontinue bevacizumab. 
GI perforation including GI 
leak and GI fistula 
≥1 
Permanently discontinue bevacizumab. 
 
Intra-abdominal abscessd 
 
3 
Hold bevacizumab until resolved. 
4 
Permanently discontinue bevacizumab. 
Complication, non-infectious 
wound 
dehiscencee 
1 
Hold bevacizumab for at least 1 month. If, in the 
physician's opinion, substantial healing has taken 
place within 1-3 months, bevacizumab may be 
resumed. If wound dehiscence recurs, permanently 
discontinue bevacizumab. 
2, 3, or 4 
Permanently discontinue bevacizumab. 
Proteinuria 
UPC ratio < 
3.5 or 
dipstick 1+  
Continue bevacizumab. 
 
UPC ratio > 
3.5 or 
dipstick  > 
2+ 
Hold bevacizumab until it UPC recovers to < 3.5 or 
dipstick is ≤ 2+  
If therapy is held for > 2 months due to proteinuria, 
discontinue bevacizumab. 
Nephrotic 
syndrome or 
dipstick > 
3+ 
Discontinue bevacizumab. 
 
Hypertension 
 
3 
 
Bevacizumab may be continued in conjunction with 
standard anti-hypertensive therapy at physician 
discretion. Bevacizumab should be held for 
uncontrolled or symptomatic hypertension present on 
the day that the bevacizumab dose is to be given. If 
BP is not controlled with medication within 1 month, 
permanently discontinue bevacizumab. 
4 
Permanently discontinue bevacizumab. 
Other clinically significant 
(AEs)f 
3 
Hold until AE has resolved to ≤ grade 1. 
4 
Permanently discontinue bevacizumab. 
a If coagulation disorders develop, secondary to other medical conditions, hold bevacizumab until the PT 
INR and PTT return to ≤ grade 1. 
b New or worsening grade 2 events. (Therapy may be continued for grade 2 conditions present at baseline 
that have not worsened.) 
c Patients who develop brief, reversible, exercise-induced claudication (grade 2) not attributable to arterial 
thromboembolic events may continue on study. 
d Refer to grading criteria listed for the appropriate adverse event in the Infection section of the CTCAE v 
4.0. 
e Refer to Injury, Poisoning, and Procedural Complication section of the CTCAE v 4.0. 
f Determination of "clinically significant" is at the physician’s discretion and applies to those adverse 
events that can be attributed to bevacizumab and are not related to chemotherapy. 
 
 
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FER-GI-029 
 
7.6 Supportive Care 
 
7.6.1 All supportive measures consistent with optimal patient care will be 
given throughout treatment.  
 
7.7 Duration of Therapy 
 
7.7.1 Patients will receive protocol therapy unless: Extraordinary Medical 
Circumstances: If, at any time, the constraints of this therapy are 
detrimental to the patient's health, protocol treatment should be 
discontinued.  
 
7.7.2 Patients should proceed to surgery 4-6 weeks after 6 cycles of 
chemotherapy or if chemotherapy was stopped secondary to adverse 
reactions.  Surgery must not take place until at least 8 weeks have 
elapsed since the last dose of bevacizumab. 
 
7.7.3 Patients will continue with adjuvant chemotherapy 8-10 weeks after 
surgery.   
 
 
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FER-GI-029 
8 STUDY PARAMETERS 
 
Phase I – Neoadjuvant therapy 
Tests 
Baseline 
Cycle 
1 
Cycle 
28 
Cycle 
3 
Cycle 
48 
Cycle 
5 
Cycle 68 
H&P 
X 
X 
 
X 
 
X 
 
PS 
X 
X 
X 
X 
X 
X 
X 
CBC, plat, diff2 
X2 
X 
X 
X 
X 
X 
X 
Serum Cr + Mg2 
X2 
X 
X 
X 
X 
X 
X 
Comp Metabolic 
Panel2 
X2 
 
 
X 
 
X 
 
U/A 
X2 
 
 
 
 
 
 
CT 
Chest/Abd/Pelvis 
X2 
 
 
 
 
 
 
UGI endoscopy 
with endoscopic US 
X 
 
 
 
 
 
 
PET Scan 
X2 
 
 
 
 
 
 
Surgical Eval 
X 
 
 
 
 
 
 
Correlative Biopsies X 
 
 
 
 
 
 
PT, INR, PTT1 
X2 
 
 
 
 
 
 
LFTs 
X2 
X 
X 
X 
X 
X 
X 
Serum Pregnancy 
Test 
(Premenopausal)2 
X 
 
 
 
 
 
 
Vital signs (T, P, 
BP) 
X 
X 
X 
X 
X 
X 
X 
Ht7, Wt, BSA 
X 
X 
X 
X 
X 
X 
X 
Urine Protein/Cr 
(UPC) Ratio3 or 
dipstick 
X2 
 
X 
 
X 
 
 
PFT/DLCO 
X2 
 
 
 
 
 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
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FER-GI-029 
 
 
Tests 
Prior to 
Surgery2, 5 
Surgery 
H & P, VS, PS 
X 
 
CBC, Plat, diff 
X 
 
Serum Cr + Mg 
X 
 
CT Chest/Abd/Pelvis 
X 
 
 
PET Scan 
X 
 
Surgical Eval 
X 
 
PT, INR, PTT 
X 
 
LFTs 
X 
 
EKG 
X 
 
PFTs/DLCO 
X 
 
Correlative sampling 
 
X 
Pathological assessment 
for response 
 
X 
 
Phase II Adjuvant Therapy 
Tests 
Post Op 
Baseline 4 
Cycle 
7 
Cycle 
88 
Cycle 
9 
Cycle 
108 
Cycle 
11 
Cycle 
128 
6 weeks 
after final 
Treatment 
Follow 
Up6 
H & P 
X 
X 
 
X 
 
X 
 
 
X 
PS 
X 
X 
X 
X 
X 
X 
X 
 
 
CBC, Plat, diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Cr + Mg2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Compr Metabolic 
Panel2 
X 
 
 
X 
 
X 
 
X 
X 
CT Scan 
Chest/Abd/Pelvis 
X 
 
 
 
 
 
 
X 
X 
Surgical Eval 
X 
 
 
 
 
 
 
 
X 
PT, INR, PTT1, 
X 
 
 
 
 
 
 
X 
 
LFTs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs (T, P, 
BP) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Protein/Cr 
(UPC) Ratio or 
dipstick 
X 
 
X 
 
X 
 
X 
X 
 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight, BSA 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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FER-GI-029 
 
1For patients on full-dose warfarin, the PT (INR) should be monitored throughout the 
study treatment period per the physician’s usual practice. 
 
2 All baseline neoadjuvant labs must be complete within 7 days of registration.  All 
baseline neoadjuvant disease assessments must be complete within 21 days of 
registration.  All pre-op labs and disease assessments must be completed within a 
timeframe defined by the surgeon.  All cycle specific labs must be completed within 48 
hours prior to day 1 of that cycle.  
 
3UPC ratio or dipstick for protein is to be performed every other cycle. If UPC ratio is > 
1.0 or urine dipstick for protein is ≥ 2+,  a 24-hour urine collection is required for more 
accurate assessment. Treatment must continue as per dose modification section during the 
24 hr urine collection and can only be held according to dose modification section 
directions. 
 
4 Post-op baseline studies to be performed within 8 days prior to resumption of 
chemotherapy (8-10 weeks post-operatively). 
 
5 Studies Prior to Surgery are performed between the final cycle of pre-operative therapy 
and the operation, at the discretion of the treating physicians, consistent with institutional 
pre-operative testing guidelines, and with the CBC more than 2 weeks after the last dose 
of FOLFOX.  
 
6Follow up: 
If asymptomatic with H&P q 4 mos from the date of the last treatment x 1 yr, then q 6 
mos x 2 yrs, then annually until death  
Chemistry profile + CBC as clinically indicated 
Chest x-ray as indicated 
Radiology and endoscopy, as clinically indicated (i.e. persistent or recurrent dysphagia) 
CT chest/abdomen/pelvis at 12 months and 24 months after the 6 week post final 
treatment timepoint  
Nutritional counseling is recommended 
Dilation for anastomotic stenosis as indicated 
 
7Height cycle 1 day 1 only. 
 
8For cycles where physician visit is not indicated, the study coordinator will collect all 
the assessment data (labs, PS, adverse events) and discuss with treating physician to 
determine treatment orders.  The treating physician or designee must be available for 
triage visit if assessments indicate that exam/assessment by physician is needed.  
 
9Only need to follow toxicities that are possibly, probably and definitely related to study 
treatment.  
 
 
 
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FER-GI-029 
9 DRUG FORMULATION AND PROCUREMENT 
 
9.1 Bevacizumab 
 
9.1.1 Generic Name - Bevacizumab. 
 
9.1.2 Other Names 
 
9.1.2.1 NSC 704865, RhuMAb VEGF, Recombinant Humanized 
Monoclonal Anti-VEGF Antibody 
 
9.1.3 Molecular Formula 
 
9.1.3.1 M.W. = 149 kilodaltons 
 
9.1.4 Trade Name - AvastinTM (Genentech, Inc) 
 
9.1.5 Classification - Antiangiogenesis agent 
 
 
9.1.6 Action 
 
9.1.6.1 Bevacizumab binds Vascular Endothelial Growth Factor 
(VEGF) preventing the binding of VEGF to its receptors 
(Flt-1 and KDR), thus inhibiting endothelial cell 
proliferation and new blood vessel formation. 
 
9.1.7 Dose Form 
 
9.1.7.1 Bevacizumab is supplied as a clear to slightly opalescent, 
sterile liquid ready for parenteral administration in two vial 
sizes: Each 400 mg (25 mg/mL - 16 mL fill) glass vial 
contains bevacizumab with phosphate, trehalose, 
polysorbate 20 and Sterile Water for Injection, USP. 
 
 
9.1.8 Drug Procurement 
 
9.1.8.1 Bevacizumab (NSC# 704865) will be supplied by 
Genentech 
 
9.1.9  Drug Ordering and Accountability 
All study drug required for completion of this study will be provided 
by Genentech. 
   
Following submission and approval of the required regulatory 
documents, the initial order may be placed.  Drug order forms and 
ordering procedure will be presented at the site initiation meeting. 
 
 
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FER-GI-029 
 
It is the responsibility of the Investigator to ensure that a current 
record of investigational product disposition is maintained at each 
study site where investigational product is inventoried and disposed.  
Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 
Amount received and placed in storage area. 
Amount currently in storage area. 
 
Label ID number or batch number. 
Dates and initials of person responsible for each investigational 
product inventory entry/movement. 
Amount dispensed to and returned by each patient, including unique 
patient identifiers. 
Amount transferred to another area for dispensing or storage. 
Non-study disposition (e.g., lost, wasted, broken). 
 
At the time of study closure, the unused, used and expired study drug 
will be destroyed at the site per Institutional SOPs. 
 
9.1.10 Storage and Stability 
 
9.1.10.1 Upon receipt, bevacizumab must be refrigerated (2° to 
8°C). Do not freeze. Do Not Shake. Protect from light. Sterile, 
single-use vials contain no antibacterial preservatives. Therefore, 
vials must be discarded 8 hours after initial opening.  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. 
 
9.1.11 Drug Preparation 
 
9.1.11.1 The calculated dose should be placed in a sterile, empty 
IV bag and diluted with 0.9% sodium chloride for injection to a 
final volume of 100 mL. If the drug volume is greater than 100ml, 
the calculated dose should be placed in a sterile empty IV bag and 
infused undiluted. Bevacizumab should NOT be administered or 
mixed with dextrose solutions. 
 
9.1.12 Dose/Administration 
 
9.1.12.1 5 mg/kg IV infusion once every 14 days. Initial dose 
should be infused over 90 minutes. If no adverse reactions occur, 
the second dose should be administered over 30 minutes minimally. 
Again, if no adverse reactions occur, the third and subsequent 
doses should be administered over 30 minutes. If infusion-related 
adverse reactions occur, subsequent infusions should be 
administered over the shortest period that is well-tolerated. 
 
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FER-GI-029 
 
Infusions should be run in via a volumetric infusion device. Do 
NOT administer as an IV push of bolus. 
 
9.1.13 Kinetics 
 
9.1.13.1 Estimated half-life of bevacizumab is approximately 20 
days (range 11-50 days). The clearance of bevacizumab was higher 
in males and in patients with a higher tumor burden. 
 
9.1.14 Drug Interactions 
 
9.1.14.1 Bevacizumab may increase the concentration of SN38 
(the active metabolite of irinotecan) by as much as 33%. This may 
potentially increase the incidence of irinotecan-induced side effects 
such as diarrhea and leucopenia. 
 
9.1.15Adverse Effects 
9.1.15.1 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. 
 
9.1.15.2 Allergy/Immunology: Allergic reaction/hypersensitivity. 
Infusion-related reactions. 
 
9.1.15.3 Blood/Bone Marrow: Leukopenia, neutropenia, 
thrombocytopenia.  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). 
 
9.1.15.4 Cardiac: Hypertension/hypertensive crisis, cardiac 
ischemia/infarction, supraventricular arrhythmia, left ventricular 
dysfunction (congestive heart failure), hypotension, syncope.  
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 
 
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FER-GI-029 
 
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 must be permanently 
discontinued.  Bevacizumab must be permanently discontinued in 
patients who develop hypertensive crisis or hypertensive 
encephalopathy.  
 
Congestive heart failure:  In clinical trials CHF was observed in 
all cancer indications studied to date, but predominantly in patients 
with metastatic breast cancer.  In the Phase III clinical trial of 
metastatic breast cancer (AVF2119g), 7 (3%) bevacizumab-treated 
patients experienced CHF, compared with two (1%) control arm 
patients.  These events varied in severity from asymptomatic 
declines in left ventricular ejection fraction (LVEF) to 
symptomatic CHF requiring hospitalization and treatment.  All the 
patients treated with bevacizumab were previously treated with 
anthracyclines (doxorubicin cumulative dose of 240360 mg/m2).  
Many of these patients also had prior radiotherapy to the left chest 
wall.  Most of these patients showed improved symptoms and/or 
left ventricular function following appropriate medical therapy 
(Miller et al. 2005). 
In a randomized, Phase III trial of patients with previously 
untreated metastatic breast cancer (E2100), the incidence of LVEF 
decrease (defined as CTCAE v4.0 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 patie
cytarabine, mitoxantrone, and bevacizumab.  All but 1 of these 
 
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FER-GI-029 
 
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.  
Patients receiving concomitant anthracyclines or with prior 
exposure to anthracyclines should have a baseline MUGA scans or 
echocardiograms (ECHOs) with a normal LVEF. 
 
9.1.15.5 Constitutional symptoms: Asthenia, fever, rigors/chills, 
weight loss 
 
9.1.15.6 Dermatology/skin: Exfoliative dermatitis, complications 
with wound healing, rash, skin ulceration, urticaria.  Wound 
healing complications: Wound healing complications such as 
wound dehiscence have been reported in patients receiving 
bevacizumab. In an analysis of pooled data from two trials in 
metastatic colorectal cancer, patients undergoing surgery 28-60 
days before study treatment with 5-FU/LV plus bevacizumab did 
not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone 
(Scappaticci et al., 2005). Surgery in patients currently receiving 
bevacizumab is not recommended. No definitive data are available 
to define a safe interval after bevacizumab exposure with respect to 
wound healing risk in patients receiving elective surgery; however, 
the estimated half life of bevacizumab is 21 days. Bevacizumab 
must 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 must  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). 
 
9.1.15.7 Gastrointestinal: GI perforation and wound dehiscence, 
sometimes complicated by intra-abdominal abscesses. Large bowel 
leakage, GI fistula, intestinal obstruction, intestinal necrosis, 
mesenteric venous occlusion, colitis, mucositis/stomatitis, nausea, 
vomiting, anorexia, constipation, diarrhea, heartburn/dyspepsia, 
dry mouth, taste disturbance.  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 must 
be permanently discontinued in patients who develop 
 
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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. 
 
9.1.15.8 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
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. 
 
9.1.15.9 Hemorrhage/Bleeding: Life-threatening or fatal 
pulmonary hemorrhage (primarily in lung cancer patients), CNS 
bleeding, GI hemorrhage, subarachnoid hemorrhage, hemorrhagic 
stroke, epistaxis (nose bleeds), vaginal bleeding, gum bleeding.  
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 
 
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radiotherapy, bevacizumab therapy, previous medical history of 
atherosclerosis, central tumor location, and cavitation of tumors 
during therapy), the only variables that showed statistically 
significant correlations with bleeding were bevacizumab therapy 
and squamous cell histology.  GI hemorrhages, including rectal 
bleeding and melena have been reported in patients with CRC, and 
have been assessed as tumor associated hemorrhages. 
Tumor-associated hemorrhages were also seen rarely in other 
tumor types and locations, including a case of CNS bleeding in a 
patient with hepatoma with occult CNS metastases and a patient 
who developed continuous oozing of blood from a thigh sarcoma 
with necrosis.  Mucocutaneous Hemorrhage:  Across all 
bevacizumab clinical trials, mucocutaneous hemorrhage has been 
seen in 20%-40% of patients treated with bevacizumab. These 
were most commonly CTCAE v4.0 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. 
 
9.1.15.10 Infection: Infection with normal ANC 
 
9.1.15.11 Metabolic/Laboratory: Increased: alkaline phosphatase, 
ALT (SGPT), AST(SGOT), Bilirubin, serum creatinine. 
Hyponatremia and hypokalemia. 
 
9.1.15.12 Neurology: Cerebrovascular ischemia, dizziness, 
abnormal gait, confusion.  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). 
 
9.1.15.13 Ocular: Excessive lacrimation 
 
9.1.15.14 Pain: Abdominal pain, chest/thoracic pain, headache, 
arthralgias, myalgias, generalized. 
 
 
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9.1.15.15 Pulmonary/Upper Respiratory: Dyspnea, cough, 
bronchospasm/wheezing, voice changes (hoarseness) 
 
9.1.15.16 Renal/Genitourinary: Proteinuria, nephrotic syndrome.  
Proteinuria:  An increased incidence of proteinuria has been 
observed in patients treated with bevacizumab compared with 
control arm patients.  In the bevacizumab containing treatment 
arms of clinical trials (across all indications), the incidence of 
proteinuria (reported as an adverse event) was up to 38% 
(metastatic CRC Study AVF2192g). The severity of proteinuria 
has ranged from asymptomatic and transient events detected on 
routine dipstick urinalysis to nephrotic syndrome; the majority of 
proteinuria events have been grade 1. CTCAE v4.0 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 
must 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 performed every other cycle. If the UPC ratio is not available, 
a dipstick urinalysis may be used to allow treatment to proceed. 
 
9.1.15.17 Vascular: Life-threatening and potentially fatal arterial 
thromboembolic events: cerebral infarction, transient ischemic 
attacks, myocardial infarction, angina.  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.  
 
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The incidence of CTCAE v4.0 Grade 
 3 venous VTE eve
one NSCLC trial (E4599) was higher in the bevacizumab-
containing arm compared to the chemotherapy control arm (5.6% 
vs. 3.2%).  One event (0.2%) was fatal in the bevacizumab-
containing arm; not fatal events were reported in the 
carboplatin/paclitaxel arm (see Bevacizumab Investigator 
Brochure).  In metastatic CRC clinical trials, the incidence of VTE 
events was similar in patients receiving chemotherapy  
bevacizumab and those receiving the control chemotherapy alone.  
In clinical trials across all indications the overall incidence of VTE 
events was 2.8%17.3% in the bevacizumab-containing arms 
compared with 3.2%15.6% in the chemotherapy control arms.  The 
use of bevacizumab with chemotherapy does not substantially 
increase the risk of VTE event compared with chemotherapy alone.  
However, patients with metastatic CRC who receive bevacizumab 
and experienced a VTE event may be at higher risk for recurrence 
of VTE event. 
Arterial Thromboembotic Events:  An increased incidence of 
ATE events was observed in patients treated with bevacizumab 
compared with those receiving control treatment.  ATE events 
include cerebrovascular accidents, myocardial infarction, transient 
ischemic attacks (TIAs), and other ATE events.  In a pooled 
analysis of data from five randomized Phase II and III trials 
(mCRC [AVF2107g, AVF2192g, AVF0780g]; locally advanced or 
metastatic NSCLC [AVF0757g]; metastatic breast cancer 
[AVF2119g]), the incidence rate of ATE events was 3.8% (37 of 
963) in patients who received chemotherapy  bevacizumab 
compared with 1.7% (13 of 782) in patients treated with 
chemotherapy alone.  ATE events led to a fatal outcome in 0.8% (8 
of 963) of patients treated with chemotherapy  bevacizumab and 
0.5% (4 of 782) of patients treated with chemotherapy alone.  
Cerebrovascular accidents (including TIAs) occurred in 2.3% of 
patients treated with chemotherapy  bevacizumab and 0.5% of 
patients treated with chemotherapy alone.  Myocardial infarction 
occurred in 1.4% of patients treated with chemotherapy  
bevacizumab compared with 0.7% of patients treated with 
chemotherapy alone (see the Bevacizumab Investigator Brochure 
for additional details). 
Aspirin is a standard therapy for primary and secondary 
prophylaxis of arterial thromboembolic events in patients at high 
risk of such events, and the use of aspirin ≤ 325 mg daily was 
allowed in the five randomized studies discussed above. Use of 
aspirin was assessed routinely as a baseline or concomitant 
medication in these trials, though safety analyses specifically 
regarding aspirin use were not preplanned. Due to the relatively 
small numbers of aspirin users and arterial thromboembolic events, 
retrospective analyses of the ability of aspirin to affect the risk of 
such events were inconclusive. However, similarly retrospective 
 
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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. 
 
9.1.15.18 Venous thromboembolic events: deep vein thrombosis, 
intra-abdominal thrombosis. 
 
9.1.16 Patient Care Information 
 
9.1.16.1 Monitor CBC and platelets. For patients taking warfarin 
for thrombosis, monitor PT or INR closely (weekly until two stable 
therapeutic levels attained). For patients on warfarin for venous 
access prophylaxis, routine PT monitoring. 
 
9.1.16.2 Monitor patient closely during infusion, for infusion 
related events and for bleeding. 
 
9.1.16.3 Monitor blood pressure prior to each dose to assess for 
development of hypertension. 
 
9.1.16.4 Instruct patient to monitor and report signs/symptoms of : 
bleeding (nose bleeds, blood in sputum), wound healing problems, 
abdominal pain, thromboembolic problems (chest or leg pain, 
dyspnea, vision changes, severe headache, cough, swelling) 
 
9.1.16.5 Baseline urine protein must be performed and repeated 
every other cycle.. If elevated, 24-hour urine collection must be 
performed. 
 
9.1.16.6 Therapy should be suspended several weeks before 
elective surgery and should not restart until surgical incision is 
fully healed. 
 
9.1.16.7 Treat pain, arthralgias, etc. with acetaminophen, or other 
pain relief strategies that do not interfere with the clotting cascade. 
 
 
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9.1.17 References 
 
9.1.17.1 Bevacizumab (AvastinTM) Full Prescribing Information. 
Genentech, Inc. 2007. Bevacizumab Investigators Brochure, 
Genentech, November 2009 
9.2 Oxaliplatin 
 
9.2.1 For complete instruction regarding preparation, handling, dosing and 
storage, please refer to the FDA-approved package insert. 
 
9.2.2 Other Names 
 
9.2.2.1 Eloxatin, trans-l-diaminocyclohexane oxalatoplatinum, cis-
[oxalato(trans-l-1,2-diaminocyclohexane)platinum(II)]. 
 
9.2.3 Classification 
 
9.2.3.1 Platinating agent. 
 
9.2.4 Mode of Action 
 
9.2.4.1 The mechanism of action of oxaliplatin is similar to 
cisplatin. The main site of action is intrastrand cross-linking, 
therefore inhibiting DNA replication and transcription. 
 
9.2.5 Storage and Stability 
 
9.2.5.1 Oxaliplatin vials are stored at room temperature between 
20E and 25EC protected from light. Reconstituted solution in 
sterile water or 5% dextrose may be stored for 24 to 48 hours at 2E 
to 8EC. After further dilution in 5% dextrose, the solution is stable 
for 24 hours at room temperature. 
 
9.2.6 Dose Specifics 
 
9.2.6.1 85 mg/m² IV in 500 ml D5W. 
 
9.2.7 Preparation 
 
9.2.7.1 The freeze-dried powder is reconstituted by adding 10 mL 
(for the 50 mg vials) or 20 mL (for the 100 mg vials of Water for 
Injection or Dextrose 5% in Water to yield a 5 mg/mL solution. 
The reconstituted solution must be further diluted in an infusion 
solution of 250 mL to 500 mL  Dextrose 5% in Water to give an 
oxaliplatin concentration between 0.2 mg/mL and 2.0 mg/mL. The 
reconstitution or final dilution must never be performed with a 
sodium chloride solution. 
 
 
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FER-GI-029 
 
9.2.8 Administration 
 
9.2.8.1 The diluted solution of oxaliplatin is administered 
intravenously over 2 hours concurrent with leucovorin. Separate 
infusion bags and lines must be used with Yline tubing connecting 
the two lines before the single injection site. 
 
9.2.9 Incompatibilities 
 
9.2.9.1 When oxaliplatin is administered with 5-fluorouracil, the 
oxaliplatin infusion should precede that of 5-fluorouracil. Ensure 
the infusion lines are adequately flushed with 5% Dextrose 
between administration of the two drugs. 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 mix with 
alkaline solutions. Oxaliplatin is unstable under alkaline conditions. 
Do not use components containing aluminum for the preparation of 
oxaliplatin administration. There is a risk of drug degradation 
when in contact with aluminum. 
 
9.2.10 Procurement 
 
9.2.10.1 Oxaliplatin (NSC # 266046) is commercially available 
 
9.2.11 Reported Adverse Events and Potential Risks 
 
9.2.11.1 Allergy/Immunology: Rhinitis, Allergic/Hypersensitivity 
reactions (including drug fever). Can be fatal and occur with any 
cycle of therapy. Manifested by: urticaria, pruritus, flushing of the 
face, diarrhea (during infusion), shortness of breath, bronchospasm, 
diaphoresis, chest pains, hypotension, disorientation, and syncope. 
 
9.2.11.2Auditory: Middle ear/hearing (ototoxicity, mild), inner 
ear/hearing (mild hearing loss). 
 
9.2.11.3   Blood/Bone Marrow: decreased hemoglobin, hemolysis 
(e.g. immune hemolytic anemia, drug-related hemolysis), 
decreased leukocytes, decreased platelets, neutropenia. Single-
agent oxaliplatin produces only mild myelosuppression with 
minimal to severe neutropenia, anemia or thrombocytopenia. In 
combination, more grade 3/4 neutropenia or thrombocytopenia 
may be noted. 
 
9.2.11.4 Cardiovascular (Arrhythmia): Sinus tachycardia, 
supraventricular arrhythmias (SVT/atrial fibrillation/flutter), 
ventricular arrhythmias (PVCs/bigeminy/trigeminy/ventricular 
tachycardia). 
 
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9.2.11.5 Cardiovascular (General): Edema, hypertension, 
hypotension 
 
9.2.11.6 Coagulation: DIC (disseminated intravascular 
coagulation), thrombosis/embolism(including pulmonary 
embolism), prolonged prothrombin time, increased INR,thrombotic 
microangiopathy (thrombotic thrombocytopenic purpura, 
hemolytic uremic syndrome). The hemolytic uremic syndrome 
should be suspected in individuals who experience the following: 
unexplained severe hemolysis, hemoglobinemia and renal failure 
as demonstrated by an increase in serum creatinine. Patients 
suspected of experiencing HUS should have the following 
laboratory analyses conducted: 
 
9.2.11.6.1 Creatinine, BUN, Urinalysis with microscopic 
evaluation CBC with differential and platelets, PT/PTT, 
Fibrinogen, Fibrinogen Degradation Products (FDP),Anti-
thrombin III (ATIII),Von Willebrand Factor (VWF), Anti-
nuclear antibodies (ANA), Rheumatoid Factor (RhF), C3, 
C4, CH50, Anti-platelet antibodies, Platelet associated IgG, 
Circulating immune complexes 
 
9.2.11.6.2 Oxaliplatin should be discontinued for any 
suspected occurrence of hemolytic uremic syndrome. 
 
9.2.11.7 Constitutional Symptoms: Fever (in the absence of 
neutropenia, where neutropenia is defined as AGC < 1.0 x l09L), 
fatigue (lethargy. malaise, asthenia), rigors/chills, insomnia, 
sweating, weight gain, weight loss. 
 
9.2.11.8 Dermatology/Skin: Erythema or skin eruptions, alopecia, 
hand-foot skin reaction, injection site reaction, rash/desquamation, 
urticaria, pruritus/itching, dry skin, nail changes, pigmentation 
changes. 
 
9.2.11.9 Endocrine: Hot flashes/flushes. 
 
9.2.11.10 Gastrointestinal: Anorexia, ascites (non-malignant), 
colitis, constipation, dehydration, diarrhea, dysphagia, enteritis, 
esophagitis, flatulence, gastritis, gastrointestinal reflux (heartburn, 
dyspepsia), ileus (or neuroconstipation), intestinal obstruction, 
nausea, odynophagia (painful swallowing), stomatitis /pharyngitis 
(oral/pharyngeal mucositis), taste disturbance (dysgeusia), 
typhilitis, ulcer, vomiting, xerostomia (dry mouth). 
 
9.2.11.11 Hemorrhage: CNS hemorrhage/bleeding, hemoptysis, 
hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, melena, 
 
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GI bleeding, rectal bleeding/hematochezia, pulmonary hemorrhage, 
vaginal hemorrhage, other (hemorrhage NOS). 
 
9.2.11.12 Hepatobiliary/Pancreas: increased alkaline phosphatase, 
increased bilirubin, increased GGT (gamma glutamyl 
transpeptidase), hepatic enlargement, increased SGOT (AST) 
(serum glutamic oxaloacetic transaminase), increased SGPT (ALT) 
(serum glutamic pyruvic transaminase), pancreatitis, hepatic veno-
occlusive disease (manifested by hepatomegaly, ascites, and 
jaundice). 
 
9.2.11.13 Infection/Febrile Neutropenia: Febrile neutropenia (fever 
of unknown origin without clinically or microbiologically 
documented fever (ANC <1.0 x l09L fever >38.5°C), infection 
(documented clinically or microbiologically with grade 3 or 4 
neutropenia (ANC <1.0 x l09L), infection with unknown ANC, 
infection without neutropenia. 
 
9.2.11.14 Metabolic/Laboratory: Acidosis (metabolic or 
respiratory), hypoalbuminemia, hypocalcemia, hyperuricemia, 
hyperglycemia, hypoglycemia, hypokalemia, hypophosphatemia, 
hyponatremia, hypomagnesemia 
 
9.2.11.15 Musculoskeletal: Involuntary muscle contractions, 
trismus. 
 
9.2.11.16 Neurology: Ataxia (incoordination, including abnormal 
gait), cerebrovascular ischemia, confusion, dizziness, 
extrapyramidal movements/restlessness, insomnia, mood alteration 
(depression, anxiety), neuropathy cranial (ptosis), vertigo, acute 
sensory neuropathy induced or exacerbated by cold (including 
acute laryngopharyngeal dysesthesias, Lhermitte's sign, upper 
extremity paresthesia), chronic peripheral neuropathy (paresthesias, 
dysesthesias, hypoesthesias), seizure, somnolence, speech 
impairment, syncope. 
 
9.2.11.17 Ocular/Visual: Conjunctivitis, vision abnormalities 
including blindness, optic neuritis, papilledema, hemianopsia, 
visual field defect, transient blindness. 
 
9.2.11.18 Pain: abdominal pain or cramping, arthralgia (joint pain), 
bone pain, chest pain (noncardiac and non- pleuritic), headache 
(including migraine), myalgia (muscle pain including cramps and 
leg cramps). 
 
9.2.11.19 Pulmonary/Upper Respiratory: Bronchospasm/wheezing, 
pulmonary fibrosis, cough, dyspnea (shortness of breath), 
hiccoughs (hiccups, singultus), pneumonitis/pulmonary infiltrates 
 
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(including eosinophilic pneumonia, interstitial pneumonitis, and 
interstitial lung disease), laryngospasm, nasal cavity/paranasal 
sinus reactions, voice changes (hoarseness, loss or alteration in 
voice, laryngitis). 
 
9.2.11.20 Renal/Genitourinary: Increased creatinine, renal failure, 
urinary retention, urinary urgency, dysuria. 
 
9.2.11.21 Hemolytic Uremic Syndrome (HUS) – see coagulation. 
 
9.2.11.22 Vascular: Phlebitis, thrombosis 
 
9.2.11.23 Also reported on oxaliplatin trials but with the 
relationship to oxaliplatin still undetermined: tongue paralysis, 
anemia, aphasia, abnormal hepatic function, hyporeflexia, anxiety, 
depression, dysarthria, insomnia, increased sweating, rhinitis, 
epistaxis, gout, pancreatitis, idiopathic thrombocytopenia (5 cases), 
thrombocytopenia associated with hemolytic anemia (2 cases). 
 
9.2.11.24 Oxaliplatin in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused 
by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
9.2.13 Nursing/Patient Implications 
 
9.2.13.1 Premedicate with antiemetics (5 HT3 antagonist and 
steroid) to prevent severe nausea and vomiting.  
 
9.2.13.2 Monitor for diarrhea and treat symptomatically. 
 
9.2.13.3 Monitor for neuropathies (paresthesias of hands, feet and 
toes, pharynx; occasionally cramps). If they occur, tend to be brief 
(less than one week) during the first course but longer with 
subsequent courses. Advise patients to avoid cold exposure and 
against touching cold objects. Sensory neuropathies develop with 
continued treatment. Ask patient if changes in ambulation, 
swallowing, breathing or fine motor activity have been noted. 
 
9.2.13.4 Prolonging the oxaliplatin infusion time to 6 hours may 
alleviate acute neurologic toxicities. Monitor for respiratory 
changes, such as shortness of breath. 
 
9.2.13.5 The hemolytic uremic syndrome should be suspected in 
individuals who experience the following: unexplained severe 
hemolysis, hemoglobinemia, and renal failure as demonstrated by 
an increase in serum creatinine. 
 
 
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9.2.14 References 
 
Investigator’s Brochure: Oxaliplatin. Sanofi Winthrop 1996 
Prescribing Information: Oxaliplatin (Eloxatin) Sanofi-Sythelabo 
Inc., November 2004, Physician’s Desk Reference 2010 
 
9.3 5-Fluorouracil 
 
9.3.1 For complete prescribing information, please refer to the approved 
package insert. 
 
9.3.2 Other Names 
 
9.3.2.1 Fluorouracil, 5-FU, Adrucil, Efudex. 
 
9.3.3 Classification 
 
9.3.3.1 Antimetabolite. 
 
9.3.4 Mode of Action 
 
9.3.4.1  Fluorouracil is a pyrimidine antagonist that interferes with 
nucleic acid biosynthesis. The deoxyribonucleotide of the drug 
inhibits thymidylate synthetase, thus inhibiting the formation of 
thymidylic acid from deoxyuridylic acid, thus interfering in the 
synthesis of DNA. It also interferes with RNA synthesis. 
 
9.3.5 Storage and Stability 
 
9.3.5.1 Stable for prolonged periods of time at room temperature if 
protected from light.  Inspect for precipitate; if apparent, agitate 
vial vigorously or gently heat to not greater than 140EF in a water 
bath. Do not allow to freeze. 
 
9.3.6 Dose Specifics 
 
9.3.6.1 400 mg/m², then 2.4 g/m². 
 
9.3.7 Administration 
 
9.3.7.1 5-FU will be administered at 400 mg/m² IV bolus, followed 
by 2.4 g/m² continuous infusion over 46 hours on day 1 and day 2. 
 
9.3.8 Incompatibilities 
 
9.3.8.1 Incompatible with doxorubicin and other anthracyclines. 
When giving doxorubicin IV push or through a running IV, flush 
 
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line before giving fluorouracil. May form precipitate with 
fluorouracil in some concentrations. 
 
9.3.9 Availability 
 
9.3.9.1 Commercially available in 500 mg/10 ml ampules and vials, 
and 1 g/20 mL, 2.5 g/50 mL, and 5 gm/100 mL vials. 
 
9.3.10 Side Effects 
 
9.3.10.1 Hematologic: Leukopenia, thrombocytopenia, anemia; can 
be dose limiting; less common with continuous infusion.  
 
9.3.10.2 Dermatologic: Dermatitis, nail changes, 
hyperpigmentation, Hand-Foot Syndrome with protracted infusions, 
alopecia. 
 
9.3.10.3 Gastrointestinal: Nausea, vomiting, anorexia; diarrhea, 
can be dose limiting; mucositis, more common with 5-day infusion, 
occasionally dose limiting; severe, cholera-like diarrhea which can 
be fatal when given with leucovorin. 
 
9.3.10.4 Neurologic: Cerebellar Syndrome (headache and 
cerebellar ataxia). 
 
9.3.10.5 Cardiac: Angina, noted with continuous infusion. 
 
9.3.10.6 Ophthalmic: Eye irritation, nasal discharge, watering of 
eyes, blurred vision. 
 
9.3.10.7 Hepatic: Hepatitis with hepatic infusion. 
 
9.3.11 Nursing/Patient Implications 
 
9.3.11.1 Monitor CBC, platelet counts. 
 
9.3.11.2 Administer antiemetics as indicated. 
 
9.3.11.3 Monitor for diarrhea. Encourage fluids and treat 
symptomatically - may be dose limiting. 
 
9.3.11.4 Assess for stomatitis - oral care recommendations as 
indicated. 
 
9.3.11.5 Monitor for neurologic symptoms (headache, ataxia). 
 
 
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9.3.11.6 Patients on continuous infusions may need instruction 
regarding central IV catheters and portable IV or IA infusion 
devices. 
 
9.3.11.7 Inform patient of potential alopecia. 
 
9.3.12 References 
 
9.3.12.1 Hansen R, Quebbeman E, Ausman R, et al. Continuous 
systemic 5-fluorouracil in advanced colorectal cancer: Results in 
91 patients. J Surg Oncol 1989; 40:177- 181. Freeman NJ, 
Costanza ME. 5-Fluorouracil-associated cardiotoxicity. Cancer 
1988; 61:36-45. 
 
9.4 Leucovorin 
 
9.4.1 For complete prescribing information, please refer to the approved 
package insert. 
 
9.4.2 Other Names  
 
9.4.2.1 Leucovorin Calcium, Wellcovorin‚ citrovorum factor, 
folinic acid, 5-formyl tetrahydrofolate, LV, LCV. 
 
9.4.3 Classification  
 
9.4.3.1 Tetrahydrofolic acid derivative. 
 
9.4.4 Mode of Action 
 
9.4.4.1 Leucovorin acts as a biochemical cofactor for 1-carbon 
transfer reactions in the synthesis of purines and pyrimidines. 
Leucovorin does not require the enzyme dihydrofolate reductase 
(DHFR) for conversion to tetrahydrofolic acid. The effects of 
methotrexate and other DHFR-antagonists are inhibited by 
leucovorin. Leucovorin can potentiate the cytotoxic effects of 
fluorinated pyrimidines (i.e., fluorouracil and floxuridine). After 5-
FU is activated within the cell, it is accompanied by a folate 
cofactor, and inhibits the enzyme thymidylate synthetase, thus 
inhibiting pyrimidine synthesis. Leucovorin increases the folate 
pool, thereby increasing the binding of folate cofactor and active 5-
FU with thymidylate synthetase. 
 
9.4.5 Storage and Stability 
 
9.4.5.1 All dosage forms are stored at room temperature. The 
reconstituted parenteral solution, 10 mg/ml, is stable for at least 7 
days at room temperature. At concentrations of 0.5-0.9 mg/ml the 
 
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drug is chemically stable for at least 24 hours at room temperature 
under normal laboratory light. The oral solution, 1 mg/ml, is stable 
for 14 days refrigerated and 7 days at room temperature. 
 
9.4.6 Dose Specifics 
 
9.4.6.1 400 mg/m² 
 
9.4.7 Preparation 
 
9.4.7.1 The 50 and 100 mg vials for injection are reconstituted with 
5 and 10 mL of sterile water or bacteriostatic water, respectively, 
resulting in a 10 mg/mL solution. The 350 mg vial is reconstituted 
with 17 mL of sterile water resulting in a 20 mg/mL solution. 
 
9.4.8 Administration 
 
9.4.8.1 Intravenous infusion over 2 hours, concurrent with 
oxaliplatin. 
 
 
9.4.9 Compatibilities 
 
9.4.9.1 Leucovorin (0.5-0.9 mg/mL) is chemically stable for at 
least 24 hours in normal saline, 5% dextrose, 10% dextrose, 
Ringer's injection or lactated Ringer's injection. Leucovorin (0.03, 
0.24 and 0.96 mg/mL) is stable for 48 hours at room and 
refrigeration temperatures when admixed with floxuridine (FUDR, 
1, 2 and 4 mg/mL) in normal saline. Leucovorin is compatible with 
fluorouracil and oxaliplatin. 
 
9.4.10 Availability 
 
9.4.10.1 Commercially available in parenteral formulations (50 mg, 
100 mg and 350 mg vial). 
 
9.4.11 Side Effects 
 
9.4.11.1 Hematologic: Thrombocytosis. 
 
9.4.11.2 Dermatologic: Skin rash. 
 
9.4.11.3 Gastrointestinal: Nausea, upset stomach, diarrhea. 
 
9.4.11.4 Allergic: Skin rash, hives, pruritus. 
 
9.4.11.5 Pulmonary: Wheezing (possibly allergic in origin). 
 
 
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9.4.11.6 Other: Headache; may potentiate the toxic, effects of 
fluoropyrimidine therapy, resulting in increased hematologic and 
gastrointestinal (diarrhea, stomatitis) adverse effects. 
 
9.4.12 Nursing/Patient Implications 
 
9.4.12.1 Observe for sensitization reactions. 
 
9.4.12.2 When given with fluoropyrimidines, monitor closely for 
diarrhea and stomatitis. 
 
9.4.13 References 
 
9.4.13.1 Arbuck SG. Overview of clinical trials using 5-
fluorouracil and leucovorin for the treatment of colorectal cancer. 
Cancer 1989; 63: 1036-1044. Bleyer WA. New vistas for 
leucovorin in cancer chemotherapy. Cancer 1989; 63: 995-1007. 
Grem JL. 5-Fluorouracil plus leucovorin in cancer therapy. In: 
Cancer: Practices and Principles of Oncology Updates. Devita VT, 
Hellman S, Rosenberg SA, editors. 1988; 2(7): 1-12 
 
 
 
10.0 
ADVERSE EVENT REPORTING AND DEFINTIONS 
 
 
10.1 Definitions 
 
10.1.1 Adverse Events  
 
An Adverse Event (AE) is the unfavorable and unintended sign 
symptom or disease temporally associated with the use of a medicinal 
(investigational) device or procedure regardless of whether it is 
considered related to the medical treatment or procedure (NCI CTEP 
Guidelines March 28, 2011). 
 
For purposes of this clinical trial, only AEs associated (Possibly, 
Probably or Definitely Related) with the process of collecting breath  
or blood samples required by this clinical trial will be captured. The 
sample collections required in this clinical trial involve both blood and 
breath collections. Adverse Event recordability begins with the first 
protocol related procedure; specifically the first breath collection or 
Plasma, Serum and PBMC collection for banking; whichever occurs 
first.  
 
10.1.2 Serious Adverse Events  
 
 
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A Serious Adverse Event (SAE) is an AE that is fatal or life 
threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization (for >24 hours), persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life 
functions or is a congenital anomaly/birth defect, or results in any 
important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE 
when, based upon appropriate medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent 
any of the above outcomes.  A “life-threatening” adverse event places 
the patient at immediate risk of death in the judgment of the 
investigator or sponsor. 
 
10.1.3 Severity Rating  
 
The investigator will evaluate the severity of each adverse event using the NCI 
Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0) or 
study specific toxicity tables provided in the protocol define severity.  If not 
included in CTCAE v.4.0, severity is expressed in numerical grade using the 
following definitions: 
 
• 
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• 
Grade 2: Moderate-minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADL. 
• 
Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care ADL. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5: Death related to AE 
 
10.1.4 Attribution to Study Procedure – Sample Collection 
  
• 
Definite – clearly related 
• 
Probable - likely related 
• 
Possible – may be related 
• 
Unlikely – doubtfully related 
• 
Unrelated – clearly not related 
 
10.1.5 Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent 
with the current information available from the resources.  Expected Adverse 
Events may include: 
• 
Anxiety 
• 
Dizziness 
 
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• 
Cough 
• 
Fainting 
An Unexpected Adverse Event is one where the nature, severity, or 
frequency related to participation in the research is not consistent with 
either: 
 
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the 
protocol-related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package 
inserts: or 
 
2. The expected natural progression of any underlying disease, 
disorder, or condition of the subject (s) experiencing the adverse 
event and the subjects(s) predisposing risk factor profile for the 
adverse event. (see OHRP Guidance on reviewing unanticipated 
problems 2007) 
 
For purposes of this clinical trial, only SAEs associated (Possibly, Probably or 
Definitely Related) with the process of collecting samples required by this clinical 
trial will be reported. Serious Adverse Event reportability begins with the first 
protocol related procedure; specifically the first breath collection or Plasma, 
Serum and PBMC collection for banking; whichever occurs first.  
 
10.2 Recording and Reporting Responsibilities 
 
10.2.1 Investigative Site Recording Responsibilities 
 
The following set of instructions applies to the study team / 
participating site. 
 
1. Upon identification of a recordable AE or reportable SAE, the site 
investigator will utilize the above definitions to properly classify 
the event.  Each category listed above must be recorded for each 
event. 
2. All AEs and SAEs that are possibly, probably or definitely related 
to the clinical trial sample collection procedures must be recorded 
on the “AE case report forms” (CRF) and in progress reports with 
details about the grade and attribution of each episode.  The action 
taken with respect to the study device, and the patient’s outcome 
must be recorded in the CRF. All recorded events must be 
followed  for the duration of the study, until they resolve. 
3. All SAEs will be recorded on the FDA Med Watch form unless 
otherwise directed.  After submitting the initial report it may be 
 
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necessary to submit follow up reports to the study monitor and/or 
manufacturer by the investigator should the event require further 
investigation. 
 
 
 
10.2.2 Investigative Site Reporting Responsibilities 
 
1. The investigator/ site is responsible to report all SAEs to the study 
monitor within 24 hours of becoming aware of the event.    
2. Institutional Review Board (IRB):  Each investigator is responsible 
to report all AEs/SAEs to the IRB following guidelines set by that 
IRB.  Fox Chase Cancer Center Quality Assurance (QA) reserves 
the right to request an event be reported to the IRB at their 
discretion.  Copies of events reviewed by the IRB must be sent to 
the Regulatory Coordinator. 
 
3. Any investigator who is in doubt of whether a particular AE needs 
to be reported is directed to call the study monitor who will 
confirm reportability of the event with the principal investigator. 
4. If the results of an investigator review or investigation show an 
adverse event not initially determined to be reportable is so 
reportable, the investigator will report the event following the 
above guidelines based on the date the determination is made. 
 
The participating site should report events to: 
 
 
 
 
 
Quality Assurance Specialist/ Study Monitor 
 
 
Fox Chase Cancer Center 
 
 
333 Cottman Avenue 
 
 
Philadelphia PA 19111 
 
 
Phone: 215-214-3704 
 
 
Fax: 215-214-1511 
 
 
beth.adaire@fccc.edu 
 
 
10.2.3 Sponsor  Reporting Responsibilities 
 
 
This section applies to the Sponsor ONLY. 
 
 
10.2.3.1 
The sponsor will report adverse events which are 
serious (refer to above definitions), have a causal relation to the research, 
and are unexpected, to all participating institutions within 48 hours of 
becoming aware of the event. 
 
 
10.2.3.2 
If the adverse event requires modification of the 
study protocol and informed consent, then these changes will be provided 
to all participating institutions in the form of an amendment from OER for 
each site’s IRB of record along with the report of the adverse event. 
 
 
10.2.3.3 
SAEs that occur with commercially available agents 
are reportable through the Food and Drug Administration (FDA) 
 
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MedWatch program.  The timing of submissions are as directed by FDA 
guidelines. (http://www.fda.gov/medwatch/index.html) 
 
 
10.2.3.4 
OER will report events to the Study Principal 
Investigator, Genentech Inc. and the FDA on behalf of the reporting site as 
information becomes available or upon request. 
 
Genentech, Inc. 
Attn:  Tarceva Clinical Trial Manager 
1 DNA Way, Mailstop #443B 
South San Francisco, CA 94080-4990 
Tel: (650) 467-7603 
Fax:  650-467-3130 
 
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-800-FDA-0178 
Internet http://www.fda.gov/medwatch/report.htm 
 
Voluntary Drug Reporting: 
MedWatch 
The FDA Safety Information and Adverse Event Reporting Program 
Food and Drug Administration 
5600 Fishers Lane 
 
 
Rockville, MD 20857-9787 
 
 
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10.1 
OER Reporting Responsibilities:  
 
 
 
10.3  Special Warning for Bevacizumab 
 
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 
nephrotic syndrome; the majority of proteinuria events have been grade 1. NCI-
CTCAE v4.0 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) 
 
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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 6 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 CTCAE v4.0 Grade ≥ 3 venous VTE events in one NSCLC trial 
(E4599) was higher in the bevacizumab-containing arm compared to the 
chemotherapy control arm (5.6% vs. 3.2%).  One event (0.2%) was fatal in the 
bevacizumab-containing arm; not fatal events were reported in the 
carboplatin/paclitaxel arm (see Bevacizumab Investigator Brochure).  
In metastatic 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 
 
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compared with 1.7% (13 of 782) in patients treated with chemotherapy alone.  
ATE events led to a fatal outcome in 0.8% (8 of 963) of patients treated with 
chemotherapy + bevacizumab and 0.5% (4 of 782) of patients treated with 
chemotherapy alone.  Cerebrovascular accidents (including TIAs) occurred in 
2.3% of patients treated with chemotherapy + bevacizumab and 0.5% of patients 
treated with chemotherapy alone.  Myocardial infarction occurred in 1.4% of 
patients treated with chemotherapy + bevacizumab compared with 0.7% of 
patients treated with chemotherapy alone (see the Bevacizumab Investigator 
Brochure for additional details). 
 
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of 
aspirin ≤ 325 mg daily was allowed in the five randomized studies discussed 
above. Use of aspirin was assessed routinely as a baseline or concomitant 
medication in these trials, though safety analyses specifically regarding aspirin 
use were not preplanned. Due to the relatively small numbers of aspirin users and 
arterial thromboembolic events, retrospective analyses of the ability of aspirin to 
affect the risk of such events were inconclusive. However, similarly retrospective 
analyses suggested that the use of up to 325 mg of aspirin daily does not increase 
the risk of grade 1-2 or grade 3-4 bleeding events, and similar data with respect to 
metastatic colorectal cancer patients were presented at ASCO 2005 (Hambleton et 
al., 2005). Further analyses of the effects of concomitant use of bevacizumab and 
aspirin in colorectal and other tumor types are ongoing. 
 
Gastrointestinal perforation Patients with metastatic carcinoma may be at 
increased risk for the development of gastrointestinal perforation and fistula when 
treated with bevacizumab and chemotherapy. Bevacizumab should be 
permanently discontinued in patients who develop gastrointestinal perforation. A 
causal 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. 
 
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Permanently discontinue bevacizumab in patients with tracheoesophageal fistulae 
or any Grade 4 fistula.  Limited information is available on the continued use of 
bevacizumab in patients with other fistulae.  In cases of internal fistula not arising 
in the GI tract, discontinuation of bevacizumab should be considered. 
 
Wound healing complications: Wound healing complications such as wound 
dehiscence have been reported in patients receiving bevacizumab. In an analysis 
of pooled data from two trials in metastatic colorectal cancer, patients undergoing 
surgery 28-60 days before study treatment with 5-FU/LV plus bevacizumab did 
not appear to have an increased risk of wound healing complications compared to 
those treated with chemotherapy alone (Scappaticci et al., 2005). Surgery in 
patients currently receiving bevacizumab is not recommended. No definitive data 
are available to define a safe interval after bevacizumab exposure with respect to 
wound healing risk in patients receiving elective surgery; however, the estimated 
half life of bevacizumab is 21 days. Bevacizumab should be discontinued in 
patients with severe wound healing complications. 
 
If patients receiving treatment with bevacizumab require elective major surgery, it 
is recommended that bevacizumab be held for 4–8 weeks prior to the surgical 
procedure.  Patients undergoing a major surgical procedure should not begin or 
restart bevacizumab until 4 weeks after that procedure (in the case of high-risk 
procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that chemotherapy be restarted no earlier than 6 weeks and 
bevacizumab no earlier than 8 weeks after surgery). 
 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% of 
1132 patients treated with bevacizumab in a pooled database from eight phase I, 
II, and III clinical trials in multiple tumor types (bevacizumab Investigator 
Brochure, October 2005). The hemorrhagic events that have been observed in 
bevacizumab clinical studies were predominantly tumor-associated hemorrhage 
(see below) and minor mucocutaneous hemorrhage.  
 
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC.  
Life-threatening and fatal hemoptysis was identified as a bevacizumab-related 
adverse event in NSCLC trials.  These events occurred suddenly and presented as 
major or massive hemoptysis.  Among the possible risk factors evaluated 
(including squamous cell histology, treatment with 
anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, 
central tumor location, and cavitation of tumors during therapy), the only 
variables that showed statistically significant correlations with bleeding were 
bevacizumab therapy and squamous cell histology. 
 
GI hemorrhages, including rectal bleeding and melena have been reported in 
patients with CRC, and have been assessed as tumor-associated hemorrhages. 
Tumor-associated hemorrhages were also seen rarely in other tumor types and 
locations, including a case of CNS bleeding in a patient with hepatoma with 
 
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occult CNS metastases and a patient who developed continuous oozing of blood 
from a thigh sarcoma with necrosis. This is potentially relevant because patients 
in this study will initially have untreated tumor present in the esophagus or GE 
junction, which may be at risk for bleeding. 
 
Mucocutaneous Hemorrhage:  Across all bevacizumab clinical trials, 
mucocutaneous hemorrhage has been seen in 20%-40% of patients treated with 
bevacizumab. These were most commonly CTCAE v4.0Grade 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 
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 CTCAE v4.0 
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. 
 
 
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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).  
 
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. 
 
10.4  Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Bevacizumab (NSC #704865) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) was 
developed to provide a single, complete list of reported and/or potential adverse 
events associated with an agent using a uniform presentation of events by body 
system. The subset of AEs that is used to guide expedited reporting requirements 
[i.e., the Agent Specific Adverse Event List (ASAEL)], as presented in the right 
hand column, is identified with bold and italic text. This subset contains events 
that are considered expected and may not need to be reported via expedited AE 
reporting. Refer to the “CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements” for further clarification.  
 
 
11.0  MEASURMENT OF EFFECT 
 
Response Evaluation Criteria in Solid Tumors (RECIST) 
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used for 
objective tumor response assessment.  Assessments will be performed after neoadjuvant 
therapy, after surgery and about 6 weeks after final adjuvant treatment.  
Definitions 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.  
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions 
are used in the RECIST criteria.  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. 
 
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Definitions of Measurable and Non-Measurable Disease 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
Guidelines for Evaluation of Measurable Disease 
Measurement Methods: All measurements should be recorded in metric notation (i.e., 
decimal fractions of centimeters) using a ruler or calipers. 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 at the same 
evaluation to assess the antitumor effect of a treatment. 
 
Acceptable imaging modalities for measurable disease: CT scan (conventional and spiral), 
MRI, chest x-ray, and physical examination. 
 
 
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Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Measurement of Effect 
 
 
Response Criteria 
 
All identified sites of disease must be followed on re-evaluation. Specifically, a change in 
objective status to either a PR or CR cannot be done without rechecking all identified 
sites (i.e., target and non-target lesions) of pre-existing disease. 
 
 
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Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameter of target 
lesions, taking as reference the baseline sum. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters since the 
treatment started 
Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis) 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical 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.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase.     
 
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 PI. 
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. 
 
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For Patients with Measurable Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD/not evaluated 
No 
PR 
PR 
Non-PD/not evaluated 
No 
PR 
SD 
Non-PD/not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that 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 progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1 Measurement of Pathologic Response 
Pathologic response will be based on ypTNM staging as described. Fibrosis in the 
treatment sample is not expected as patients are treated with chemotherapy and a biologic 
rather than chemoradiation. 
 
An additional measure of treatment effect based on histologic evaluation will be: 
• Complete response: no residual cancer cells seen on H&E or with keratin stain 
• Major treatment effect: estimated <20% tumor cells 
• Partial treatment effect: estimated 20-50 % tumor cells 
• Minor treatment effect: > 50% tumor cells seen 
 
 
 
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12   DATA SAFETY MONITORING PLAN 
 
The Study PI, biostatistician and study team will monitor toxicity and outcome on a 
continual basis.  Early stopping rules are described in section 14.5.  Interim analysis of 
toxicity, outcome and ongoing scientific investigations may be performed every 6 months 
by the Extramural Data Safety Monitoring Committee (EDSMC).  In this capacity the 
EDSMC will serve as an advisory committee to OER.  The EDSMC will review those 
aspects of this trial that are outlined in the responsibilities section of the OER Data and 
Safety Monitoring Plan (DSMP).  If the committee decides that changes should be made 
to this trial, it will make recommendations in writing to the study Principal Investigator, 
the Extramural Research Committee and Division Medical Director, which, in turn, have 
the authority to approve or disapprove these recommendations.  These changes will be 
discussed with the Study Principal Investigator before they are implemented.  These 
changes may include early termination of accrual, altering the accrual goals or changing 
the eligibility criteria for the trial. 
 
13 
INFORMED CONSENT 
 
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study.  
The case history for each patient shall document that informed consent was obtained 
prior to participation in the study.  A copy of the informed consent documents must be 
provided to the patient or the patient’s legally authorized representative.  If applicable, 
they will be provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in the site study binder or in each patient’s 
study file. 
 
14 
STATISTICAL CONSIDERATIONS 
 
14.1 Primary outcome / objective:  
We expect to accrue 39 patients at the rate of 18 per year, for an accrual 
period of approximately 26 months.  Because the primary endpoint is 2-year 
disease-free survival, we will have finished accrual before we have enough 
2-year data to implement a meaningful early stopping rule for futility.  A 2-
year disease-free survival rate of 30% for the experimental treatment would 
be discouraging, and not warrant further investigation because the 
experimental therapy would not provide a benefit over standard therapy.  A 
2 year disease-free survival rate of 50% for the experimental treatment 
would be promising, and justify further investigation into the agent.  Our 
decision rule will be to declare the study a success if 16 or more participants 
survive to 2 years.  Under the discouraging rate of 30%, we would have a 
9.4% chance of declaring the study a success.  Under the promising rate of 
50%, we would have a 90.0% chance of declaring the study a success.   
 
 
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14.2. Secondary objective (from section 2.2): To assess, by pathological 
examination after surgical resection, complete and partial response to 
neoadjuvant therapy.  To characterize overall and progression free survival.  
 
Pathologic response will be based on ypTNM staging as described. Fibrosis 
in the treatment sample is not expected as patients are treated with 
chemotherapy and a biologic rather than chemoradiation. 
 
An additional measure of treatment effect based on histologic evaluation will 
be: 
• complete response: no residual cancer cells seen on H&E or with 
keratin stain 
• major treatment effect: estimated <20% tumor cells 
• partial treatment effect: estimated 20-50 % tumor cells 
• Minor treatment effect: > 50% tumor cells seen 
 
The analysis of response and survival outcomes will be descriptive and 
intended to provide information to guide future trials.  We do not propose any 
hypothesis testing for these outcomes. 
 
We will characterize complete and partial response to neoadjuvant therapy 
using proportions and 95% confidence intervals.  We will use Kaplan-Meier 
curves to characterize overall and progression free survival. 
 
14.3 Secondary objective (from section 2.3): To compare baseline and post-
chemotherapy/bevacizumab tissues for biomarkers predicting response or 
resistance to this approach. 
 
For continuous biomarkers, we will investigate the association of baseline 
biomarker levels and change in biomarker levels (baseline to post- 
chemotherapy/bevacizumab) with the binary response/resistance outcomes 
using Wilcoxon rank-sum tests.  We will report means, medians, and standard 
deviations of the biomarker levels and change in biomarker levels within 
groups defined by response/resistance outcomes. 
 
For binary biomarkers (patient either has biomarker or does not have it), we 
will use Fisher's exact tests to investigate the association of cross-sectional 
presence of biomarker with response/resistance outcomes.  We will report 
proportions of patients with biomarkers within groups defined by 
response/resistance outcomes. 
 
This objective is exploratory and hypothesis generating only.  We do not 
expect to have sufficient power to detect associations of interest. 
 
14.4 Secondary objective (from section 2.4): To investigate safety in this setting. 
 
 
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This objective is descriptive only.  To investigate safety in this setting, we will 
characterize toxicities experienced using means, standard deviations, 
proportions, and 95% confidence intervals.  
 
14.5 Early stopping for toxicity 
 
We have incorporated stopping rules to stop the study in the presence of the 
adverse events of unexpectedly high rates of 30-day post-surgical treatment 
mortality or 1-year local recurrence.   If 3 or more of the first 18 patients die 
of any cause within 30 days of surgery the study will also be stopped.  Since 
the 30 day post-operative mortality outcome for a patient will not be observed 
for several months after entry into the study (chemotherapy will be given for 
12 weeks prior to surgery), we may not have 30-day post-surgery data on 18 
patients by the time the 19th person enters the study.  The following rules to 
pause accrual to ensure safety after the 19th patient is accrued will be applied.  
 
1) When the 19th patient is accrued, and complete 30-day post-surgical 
mortality data are available on 16 of the first 18 patients, if zero of the 16 died 
from any cause within 30-days of surgery, we will not pause accrual as it will 
not be possible to have three 30-day post-surgical deaths among the first 18 
patients. 
 
2) When the 19th patient is accrued, if we only have complete 30-day post-
surgical mortality data on 16 patients and one or two patients out of 16 died 
from any cause within 30 days of surgery, we will pause accrual until we have 
complete 30-day post-surgery data on the first 18 patients.   
 
3) When the 19th patient is accrued, with complete 30-day surgery-related 
mortality data on 17 of the first 18 patients, we will not pause accrual if one or 
zero patients died from any cause within 30 days of surgery as it will not be 
possible to have three 30-day post-surgery deaths among the first 18 patients. 
 
4) When the 19th patient is accrued, if we only have complete 30-day post-
surgery mortality data on 17 patients and two out of 17 patients have died 
from any cause within 30 days of surgery, we will pause accrual until we have 
complete 30-day post-surgery data on the first 18 patients.  
 
5) When the 19th patient is accrued, if we have complete 30-day post surgery 
data on all 18 of the first 18 patients accrued, we will halt the study 
immediately if 3 of the 18 died within 30 days of surgery. 
 
Some characteristics of our stopping rule are described in the table below. 
 
Characteristics of early stopping rule for 30-day treatment related mortality. 
True 30-day treatment 
related death rate 
5% 
10% 
15% 
20% 
25% 
 
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Probability of stopping 
the study before the 19th 
patient is enrolled 
6% 
27% 
52% 
73% 
86% 
 
We will examine the 12-month local recurrence rate after we have data on 9 
individuals (approximately month 18 of the study).  If 3 or more individuals 
have local recurrences, we will close the study.  Some characteristics of our 
stopping rule for local recurrence are described in the table below. 
 
Characteristics of early stopping rule for recurrence. 
True local 12-month 
local recurrence rate 
10% 
20% 
30% 
40% 
50% 
Probability of stopping 
the study before the 10th 
patient is enrolled 
5% 
26% 
54% 
77% 
91% 
 
The early stopping rules are designed to protect patients; this is necessary for 
2 reasons: first, the safety and efficacy of a systemic therapy-only approach, 
as tested in MAGIC, may not be confirmed and second, the addition of 
bevacizumab in patients with an intact primary cancer of the esophagus or 
proximal stomach may be associated with unacceptably high rates of on-
treatment toxicity or post-operative mortality. 
 
If a patient goes off study and does not undergo surgical resection after the 
first 6 cycles of chemotherapy, the reason for not having surgery could be due 
to the inefficacy of the approach.  This patient will therefore not be replaced. 
 
 
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