A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin Versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Stage II Colon Cancer at High Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular Markers
Phase: PHASE3
Conditions: Colon Adenocarcinoma, Stage IIA Colon Cancer AJCC v7, Stage IIB Colon Cancer AJCC v7, Stage IIC Colon Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

1
December 16, 2014
 MS RAC
Quality Assurance Section EPN Room 7000
CTEP, DCT, NCI
6130 Executive Boulevard
Rockville, MD  20852
Dear Ms. 
Enclosed is E5202, Update #6, A Randomized Phase III Study Comparing 5-FU, 
Leucovorin and Oxaliplatin versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in 
Patients with Stage II Colon Cancer at High Risk for Recurrence to Determine 
Prospectively the Prognostic Value of Molecular Markers.
This update contains administrative and editorial changes only.  We are submitting this update 
to the NCI and activating it within ECOG-ACRIN simultaneously.  
The following revisions to the E5202 protocol were made in this update:
Section
Change
1.
Cover Page
Updated NCI Update Date
2.
Global
Updated names, addresses, numbers, and forms relating to the move from 
ECOG-ACRIN PCO to ECOG-ACRIN CBPF. 
The following revisions to the E5202 Informed Consent were made in this update:
Section
Change
3.
Cover Page
Updated NCI Update Date
If you have any questions regarding this update, please contact 
 at 
 or (617) 632-3610.
Thank you.
Sincerely,
Enclosure
cc:
MD 
 MD
, MD
 MD 
DSc 
 MD
 MD 
MD
 R.N.
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3
A Randomized Phase III Study Comparing 5-FU, 
Leucovorin and Oxaliplatin versus 5-FU, Leucovorin, 
Oxaliplatin and Bevacizumab in Patients with Stage II 
Colon Cancer at High Risk for Recurrence to Determine 
Prospectively the Prognostic Value of Molecular Markers
STUDY CHAIR:
 III, MD
STUDY CO-CHAIRS:
 MD
 MD
PATHOLOGY & LABORATORY CO-CHAIR:
 MD
STUDY STATISTICIAN:
DSc
COMMUNITY CO-CHAIR:
, MD
Rev. 9/11
ECOG-ACRIN SURGERY CHAIR:
 MD
GI COMMITTEE CHAIR:
III, MD
Rev. 11/06
ACOSOG CO-CHAIR:
 MD
Rev. 11/06
SWOG CO-CHAIR:
 MD
Rev. 11/06, 8/09
NCIC-CTG CO-CHAIR:
 MD
Rev. 11/06
CALGB CO-CHAIR:
 MD
Rev. 12/08
DEVELOPMENTAL THERAPEUTICS CO-
CHAIRS:
PhD, PharmD
PhD, PharmD
Rev. 12/08, 8/09
PHARMACOGENETIC SUBCOMMITTEE CHAIR:
 MD
Version Date:  April 30, 2014
NCI Update Date:  December 16
Bevacizumab (NSC 704865, 
) and oxaliplatin (NSC 266046) 
will be supplied by the NCI for this study.
The text of this protocol incorporates Addenda 1-8 and Update #1.
STUDY PARTICIPANTS
ACTIVATION DATE
ALLIANCE / Alliance for Clinical Trials in Oncology*
August 4, 2005
SWOG / SWOG*
Addenda #1-4 Prior to Activation
NCIC-CTG / NCIC Clinical Trials Group *
Addendum #5, January 11, 2006
NRG / NRG Oncology Foundation, Inc
Addendum #6, April 20, 2006
Addendum #7, 11/06
* This study is supported by the NCI Cancer Trials 
Support Unit (CTSU). Institutions not aligned with 
ECOG-ACRIN will participate through the CTSU 
mechanism. (Please see the Table of Contents 
and Appendix V for details.)
Update #1, 3/07
Addendum #8, 7/07 ENTIRE DOCUMENT REVISED
Update #2, 4/08
Update #3, 5/08
Addendum #9, 12/08
Update #4, 12/08
Addendum #10, 8/09
Addendum #11, 8/10
Addendum #12, 9/10
Update #5 – 9/11
Addendum #13, 7/14
Update #6 – 12/14
Rev. 
11/06
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
4
Table of Contents
Schema
7
1.
Introduction
8
1.1
Background
8
1.2
Molecular Analysis for Risk Assessment/Treatment Assignment
13
1.3
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome:
14
1.4
Gastrointestinal Perforation/Fistula:
14
1.5
On Study Guidelines
14
1.6
NSABP C-08 and the AVANT B017920 Trial
15
2.
Objectives
16
2.1
Primary Objective
16
2.2
Secondary Objectives
16
3.
Selection of Patients
17
3.1
Step 1: Initial Registration
17
3.2
Step 2: Randomization (High Risk Patients – Arms A and B only)
19
3.3
Step 2: Registration (Low-Risk Patients – Arm C)
22
4.
Registration/Randomization Procedures
23
4.1
Step 1 Registration
24
4.2
Step 2: Randomization/Registration
25
5.
Treatment Plan
28
5.1
Administration Schedule
28
5.2
Adverse Event Reporting Requirements
29
5.3
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Bevacizumab (rhuMAb VEGF, NSC 704865)
39
5.4
Dose Modifications
48
5.5
Supportive Care
55
5.6
Duration of Therapy
56
5.7
Duration of Follow-up
57
6.
Measurement of Effect
58
6.1
Diagnosis of Colon Cancer Recurrence
58
6.2
Second primary cancer
60
6.3
Disease-Free Survival
60
6.4
Survival
60
7.
Study Parameters
61
7.1
Biological Sample Submissions
61
7.2
Therapeutic Parameters
62
8.
Drug Formulation and Procurement
65
8.1
Bevacizumab
65
8.2
Oxaliplatin
69
8.3
Fluorouracil
71
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
5
8.4
Leucovorin
73
9.
Statistical Considerations
75
9.1
Gender and Ethnicity
78
9.2
Study Monitoring
78
10. Pathology Review
79
10.1 Tumor and Normal Mucosa Block Submission
79
10.2 Required Materials
79
10.3 ECOG-ACRIN Sample Tracking System
81
11. Molecular Analysis for Risk Assessment/Treatment Assignment
82
11.1 Analysis of Tumor Markers:
82
11.2 Institutional Reimbursements
84
11.3 [Section 11.3 deleted in Addendum #10]
84
11.4 Sample Inventory Submission Guidelines
84
11.5 Lab Data Transfer Guidelines
85
12. Records to Be Kept
86
13. Patient Consent and Peer Judgment
86
14. References
86
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #13]
89
Appendix II  Pathology Submission Guidelines
90
Appendix III  Patient Thank You Letter
95
Appendix IV  Staging Criteria – Colon & Rectum
96
Appendix V  Cancer Trials Support Unit (CTSU) Participation Procedures
101
Appendix VI  Collaborative Agreement
105
Appendix VII  Shipment Notification Form
107
Appendix VIII  Procedure for Obtaining a Urine Protein/Creatinine Ratio
108
Appendix IX Patient’s Aspirin Use Diary
109
Appendix X  Diarrhea Management Instructions
110
Appendix XI  Comparison of Symptoms and Treatment Pharyngo-
Laryngodysesthesias  and Platinum Hypersensitivity Reactions
112
Appendix XII  Ancillary For Pharmacogenetic and Genomic Studies:  Correlation of 
Pharmacogenetic Studies with Response and Toxicity of Oxaliplatin
113
Appendix XIII  E5202 Pharmacogenetic Collection and Shipping Kit Order Form 122
Rev. 
Rev. 
Rev. 
Rev. 
Rev. 1/06, 4/06
Rev. 
Rev. 
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
7
Rev. 11/06
ACOSOG CO-CHAIR
Rev. 11/06
SWOG CO-CHAIR
 MD
St. Michael Hospital
30 Bond Street, Suite 16 CCS-046
Toronto, ON, Canada M5B-1W8
Tel: 
Fax:
Email: 
 Gold, MD
Swedish Cancer Institute
221 Madison Street
Seattle, WA 98104
Tel: 
Fax:
Email:
Rev. 11/06, 8/09
NCIC-CTG CO-CHAIR
Rev. 11/06
CALGB CO-CHAIR
 
 MD
Cross Cancer Institute
11560 University Avenue
Edmonton, AB Canada
T6G 1Z2
Tel:
Fax:
Email: 
, MD
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
Tel: 
Fax:
Email: 
Rev. 11/06, 12/14
PATHOLOGY COORDINATING CENTER CONTACT
ECOG-ACRIN Central Biorepository and Pathology Facility
MD Anderson Cancer Center
Department of Pathology, Unit 085
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586
1515 Holcombe Blvd
Houston, TX 77030
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites)
Fax: 713-563-6506
Email: eacbpf@mdanderson.org
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
8
Rev. 3/07
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
Institutions not aligned with ECOG-ACRIN will participate through the CTSU mechanism as outlined 
below and detailed in the CTSU logistical appendix.
x
The study protocol and all related forms and documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://members.ctsu.org
x
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
logistical appendix for specific instructions and documents to be submitted. 
x
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for 
specific instructions and forms to be submitted.
x
Rev.
Data management will be performed by the ECOG-ACRIN. Case report forms (with the exception 
of patient enrollment forms) and clinical reports must be sent to ECOG-ACRIN unless otherwise 
directed by the protocol. Do not send study data or case report forms to the CTSU Data 
Operations. 
x
Data clarification forms and delinquency reports will be sent directly to the enrolling site by 
ECOG-ACRIN.  Please send data clarification form responses and delinquent data to ECOG-
ACRIN and do not copy CTSU Data Operations.  Please mail data clarification form responses 
and delinquent data directly to ECOG-ACRIN unless otherwise directed.  Each site should have a 
designated CTSU Administrator and Data Administrator and must keep their CTEP AMS account 
contact information current. This will ensure timely communication between the clinical site and 
the ECOG-ACRIN data center.
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
Rev. 3/07
To submit site 
registration documents:
For patient enrollments:
Submit study data directly to the 
Lead Cooperative Group unless 
otherwise specified in the protocol:
CTSU Regulatory Office
1818 Market Street, 
Suite 1100
Philadelphia, PA 19103
Phone – 1-888-823-5923
Fax – 215-569-0206
CTSU Patient Registration
Voice Mail – 1-888-462-3009
Fax – 1-888-691-8039 
Hours: 8:00 AM – 8:00 PM 
Eastern Time, Monday – Friday 
(excluding holidays)
[For CTSU patient enrollments 
that must be completed within 
approximately one hour, or other 
extenuating circumstances, call 
301-704-2376.  Please use the 1-
888-462-3009 number for ALL 
other CTSU patient enrollments.]
ECOG-ACRIN Operations Office – 
Boston, FSTRF
900 Commonwealth Avenue
Boston, MA 02215 
(ATTN: DATA).
Phone # 617-632-3610
Fax # 617-632-2990
Data should be sent via postal mail 
(preferred), however fax is accepted.
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.  
For patient eligibility or treatment-related questions:  Contact the Study PI of the Coordinating 
Group. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by 
phone or e-mail: CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Public Web site is located at: www.ctsu.org 
The CTSU Registered Member Web site is located at https://members.ctsu.org
CTSU logistical information is located in Appendix V.
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
10
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
11
1.
Introduction
1.1
Background
It is estimated that 130,000 new cases of colon cancer are diagnosed in the 
United States yearly. Of these, patients with Stage II colon cancer (tumor that 
has penetrated through the muscularis propria with negative lymph nodes, T3-4, 
N0, M0) carry a 20-25% risk of recurrence.  The Intergroup experience 
demonstrates minimal, if any, benefit of adjuvant therapy for stage II colon 
cancer patients perhaps in part because insufficient numbers of patients have 
been evaluated in past studies.  Observation remains an appropriate option for 
these patients and is consistent with the 1990 consensus meeting held at the 
National Institutes of Health.  There is a need to identify the subset of patients 
with stage II colon cancer who are at greatest risk to develop disease recurrence. 
ECOG and other data suggest that two groups of patients can be defined, high-
risk vs. low-risk, based on 18q loss of heterozygosity (LOH) and microsatellite 
instability status (1). If these retrospective molecular observations hold true for 
patients with stage II colon cancer, it will be possible to more clearly define a low-
risk group that would not require postoperative therapy.  The focus for drug 
development would include the high-risk patients (18q LOH in microsatellite 
stable tumors and absence of the mutation of the gene for type II receptor for 
TGF-E1 in tumors with high levels of microsatellite instability).
Although the cure rates for patients with stage III colon cancer are clearly 
improved with 5-FU and leucovorin-based chemotherapy, patients with stage II 
colon cancer have received little, if any, benefit from adjuvant chemotherapy 
(2,3).  In the recent Intergroup adjuvant trial, INT 0089, high-risk stage II patients 
(perforation or obstruction) achieved a 78% survival with adjuvant chemotherapy 
(4-6).  It is unclear whether these patients, whose survival is comparable to the 
entire group of stage II patients, benefited from the adjuvant therapy or whether 
the stated risk factors were truly sufficient to alter survival.  Since 20-25% of 
stage II patients will relapse, there is an expectation that these patients would 
potentially benefit from adjuvant therapy if they could be identified.  
The ECOG retrospective data evaluating 18q where the DCC and other genes 
reside, MSI and integrity of the TGF E1-type II receptor suggest that it may be 
possible to identify a high-risk population who may not benefit from 5-FU-based 
therapy (1). Although the ideal trial for the high-risk stage II patients would 
include a no treatment observation arm, multiple focus groups, including patient 
representatives, have made it clear that a no treatment arm is unacceptable.  
Since the ECOG retrospective molecular data included a majority of patients who 
received a 5-FU-based regimen (e.g., 5-FU and leucovorin, the standard 
adjuvant regimen for stage III patients), a 5-FU –containing regimen would be an 
acceptable control arm for this trial.
Vascular endothelial growth factor (VEGF) has been identified as a crucial 
regulator of both normal and pathologic angiogenesis. Increased levels of VEGF 
expression have been found in most human tumors examined including tumors 
of the gastrointestinal tract. Inhibition of VEGF using an anti-VEGF monoclonal 
antibody blocks the growth of a number of human cancer cell lines in nude mice 
including the colorectal cancer cell lines, LS174T, HM-7, and LSLiM6. In addition, 
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
12
the combination of anti-VEGF antibody and chemotherapy in nude mice injected 
with human cancer xenografts results in an increased antitumor effect compared 
with antibody or chemotherapy alone. Bevacizumab, a recombinant humanized 
version of a murine anti-human VEGF monoclonal antibody (rhuMAB VEGF), has 
been advanced into clinical development by Genentech, Inc.
Clinical development of bevacizumab began with two Phase I studies. Study 
AVF0737g, an open-label, dose-escalation study, evaluated the initial safety and 
pharmacokinetics of single-agent bevacizumab in subjects with advanced 
malignancies. In this study, 3 subjects experienced tumor-related hemorrhagic 
events; in two cases, the event was classified as serious. The pharmacokinetics 
of bevacizumab appeared to be linear for doses of t 1 mg/kg, with a half-life of ~ 
15 days. Study AVF0761g evaluated multiple does of bevacizumab in 
combination with one of three cytotoxic chemotherapy regimens (5-
FU/leucovorin, carboplatin/paclitaxel, or doxorubicin) in subjects with advanced 
solid malignancies.  No subjects in this study experienced serious bleeding.  Co-
administration of bevacizumab with cytotoxic chemotherapy did not appear to 
result in a change in the systemic concentrations of the cytotoxic agents. No 
antibodies to bevacizumab were detected in either study.
Study AVF0780g was a Phase II, multi-dose, randomized, multi-center clinical 
trial to evaluate the efficacy, safety and pharmacokinetics of bevacizumab 
combined with 5-FU/leucovorin in subjects with metastatic colorectal cancer (7).  
Subjects were randomized to three treatment arms: control (5-FU/leucovorin 
alone) 5 mg/kg bevacizumab plus 5-FU/leucovorin, or 10 mg/kg bevacizumab 
plus 5-FU/leucovorin.  Bevacizumab was administered IV every 2 weeks until 
disease progression or for a maximum of 1 year. The primary efficacy endpoints 
were time to disease progression and best confirmed response (complete or 
partial response) rate as determined by an independent review group that was 
blinded to treatment assignment:
Control (n=36)
5 mg/kg (n=35)
10 mg/kg (n=33)
Best Confirmed RR
6 (17%)
14 (40%, p=0.029)
8 (24%)
Median Time to Prog
5.2  mos.
9.0 mos. (p=0.005)
7.2 mos.
Median Survival
13.8 mos.
21.5 mos.
16.1 mos.
Subjects in the control arm who developed progressive disease had the option to 
cross over and receive single-agent bevacizumab. In all, 21 patients crossed-
over and two achieved a partial response on single agent anti-VEGF in the cross-
over phase.
During ASCO 2003, initial results from a randomized Phase III first-line trial of 
bevacizumab in combination with bolus IFL (irinotecan, 5-FU and leucovorin) 
were reported and then published in June 2004 (8, 13). A total of 925 patients 
were accrued with 813 patients randomized to IFL + placebo vs. IFL + 
bevacizumab given at a dose of 5 mg/kg every two weeks. A third group of 
patients (n=110) received 5-FU and leucovorin + bevacizumab. The following 
table summarizes the results.
IFL/Placebo
IFL/BV
p-value
Randomized
411
402
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ECOG-ACRIN
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Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
13
Median survival (mos)
15.6
20.3
< 0.001
PFS (mos)
6.24
10.6
< 0.001
ORR (CR+PR)
34.8%
44.8%
0.004
Duration of response (mos)
7.1
10.4
0.001
Grade ¾ bleeding*
2.5%
3.1%
Any thromboembolism*
16.2%
19.4%
Grade 3 proteinuria*
0.8%
0.8%
Grade 3 hypertension*
2.3%
11%
2.
Uncorrected for differential time on therapy 
Data for the 110 patients who received 5-FU, leucovorin and bevacizumab 
demonstrated an overall survival of 18.3 months, response rate of 40% and 
progression-free survival (PFS) of 8.5 months. Crossover to bevacizumab was 
disallowed for the placebo arm and 110 of 393 patients continued bevacizumab 
after progression on IFL. Fifty-three percent of patients received any second-line 
therapy in the control arm and 62% in the bevacizumab arm. Of these, 25% 
received oxaliplatin. Overall, the addition of bevacizumab to IFL was well 
tolerated. Only grade III hypertension, which was easily controlled with oral 
medications, was increased in the Phase III trial. Compared to the control arm, 
22.4% vs. 8.3% experienced some increase in blood pressure. There was no 
difference in bleeding. Thrombotic events were noted in 19.4% vs. 16.2%.  Sixty-
day mortality was 4.9% vs. 3% in the control arm. There were six cases of bowel 
perforation noted in patients receiving bevacizumab, compared to none on the 
placebo arm.
Additional bevacizumab safety data were presented at ASCO 2003 by ECOG 
investigators (9). E3200 is a randomized Phase III trial evaluating the addition of 
bevacizumab to FOLFOX 4 compared to a bevacizumab alone arm. The dose of 
bevacizumab was 10 mg/kg and a total of 835 patients were randomized. 
Bevacizumab added to FOLFOX 4 did not substantially alter the regimen’s 
toxicity profile, as presented in the table below.
FOLFOX4+BEV
N=75
FOLFOX4
N=73
BEV
N=75
G3
G4
G3
G4
G3
G4
Hemorrhage
3%
0
0
0
3%
0
Thrombosis/embolism
4%
0
1%
0
1%
0
Hypertension
8%
1%
1%
0
7%
0
Neutropenia
n/a
8%
n/a
21%
0
0
Febrile neutropenia
1%
0
3%
0
0
0
Infection 
w/G3-4 neutropenia
0
1%
6%
1%
0
0
Diarrhea
11%
0
11%
0
1%
0
Vomiting
5%
0
1%
0
1%
0
Neuropathy (sensory)
4%
0
3%
0
0
0
Fatigue
8%
0
14%
1%
4%
1%
Worst grade
37%
11%
25%
23%
20%
9%
In the AVF2107 study, there was a 1% incidence of arterial thromboembolic 
events (ATE) (which include myocardial infarction, transient ischemia attack, 
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
14
cerebrovascular accident/stroke and angina/unstable angina) in the IFL + 
placebo arm versus 3% in the IFL + bevacizumab arm. A pooled analysis of the 
rate of ATE from 5 randomized studies showed that treatment with bevacizumab 
increased the risk of these events two- or three-fold (up to 5%). Furthermore, 
certain baseline characteristics, specifically age > 65 years and prior ATE 
conferred additional risk.
At ASCO 2002 and 2003, the safety data and initial outcome data from the 
MOSAIC trial were presented and then published in June 2004 (10, 11, 14). This 
international, multicenter, randomized, Phase III study evaluated the effect of 
disease-free survival (DFS) of oxaliplatin and fluorouracil (5-FU)/leucovorin (LV) 
(FOLFOX4) compared with 5-FU/LV alone (LV5FU2) in the adjuvant setting in 
2,246 stage II/III colon cancer patients. These patients, aged 18 to 75 years with 
completely resected colon cancer, were enrolled from October 1998 to January 
2001 (1,123 in each arm). Additional entry criteria included treatment within 7 
weeks of surgery; no prior radio-, chemo- or immunotherapy and an ECOG 
performance status (PS) ≤ 2 or a Karnofsky performance status (KPS) 60%. 
Patients were stratified according to study center, disease stage and bowel 
obstruction or tumor perforation.  Patients were randomly scheduled to receive 
12 cycles of therapy of either FOLFOX4 or LV5FU2 for 6 months of therapy. 
Patient characteristics were balanced in each arm with respect to gender, age, 
primary site, disease stage (40% stage II, 60% stage III), and performance status 
(KPS of 60%-100%). (11)
Single-agent dose modifications were as follows: Oxaliplatin was dose reduced 
for painful paresthesias or paresthesias with functional impairment; dose 
modifications of 5-FU were stipulated for grade 3/4 skin toxicity. Oxaliplatin and 
5-FU doses were both reduced for grade 3/4 neutropenia, thrombocytopenia, 
diarrhea, stomatitis or other grade 3 drug-related toxicity. Treatment was 
discontinued in the event of cardiac toxicity, allergy or cerebellar toxicity. (10) 
Dose intensities were greater than 80% for both arms. Patients received a 
median of 12 cycles. 
The primary end point, 3-year DFS, was 78.2% for FOLFOX4 vs. 72.9% for 
LV5FU2 (P =.002), with a 23% risk reduction in recurrence in patients treated 
with FOLFOX4 regardless of subset.
General toxicity results are presented in the first table and peripheral sensory 
neuropathy associated with FOLFOX4 is presented in the second table below. 
Toxicity was graded according to NCI Common Toxicity Criteria, version 1.
Toxicity by Percent of Patients, NCI Grade ≥ 3
NCI Grade ≥ 3
FOLFOX4
(n = 1,108)
LV5FU2
(n = 1,111)
Thrombocytopenia
1.7
0.4
Neutropenia
41.1*
4.7
Febrile neutropenia
1.8
0.2
Diarrhea
10.8
6.6
Stomatitis
2.7
2.2
Vomiting
5.8
1.4
Allergy
2.9
0.2
All-cause mortality
0.5
0.5
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NCI Update Date: December 16
15
*Grade 4; 12.3%
Peripheral Sensory Neuropathy in FOLFOX4 Arm
 By Percent of Patients and Cycles
Paresthesias (NCI grade)
FOLFOX4
Patients (%)
(n = 1,106)
18 month follow-up (%)
(n = 967)
Grade 1
48.2
19.8
Grade 2
31.6
3.4
Grade 3
12.4
0.5
Grade 3 sensory neuropathy was observed in 137 patients (12.4%) on the 
FOLFOX4 arm. One month after discontinuing treatment, > 60% of these patients 
had a partial or total recovery from grade 3 neuropathy. By 6 months, < 10% of 
these patients had grade 3 neuropathy and at 1-year follow-up, patients with 
grade 3 neuropathy decreased to 1.1% (11, 14).
Various modifications of the combination of oxaliplatin with 5-FU + LV regimens 
(FOLFOX1-FOLFOX7) have been evaluated18-21. The more recent modifications 
have simplified the schedule of administration and improved patient convenience 
without apparently compromising the efficacy of the regimen. Maindrault-Goebel 
et al reported on a phase II study of oxaliplatin (100 mg/m2) and LV (400 mg/m2) 
as a 2-hour infusion on Day 1 followed by bolus (400 mg/m2) and a 46-hour 
infusion (2.4-3.0 g/m2) of 5-FU every 2 weeks (FOLFOX6) as second-line 
treatment for metastatic colorectal cancer19. Sixteen of 60 patients treated had a 
partial response (27%) and an additional 45% had stable disease. Median PFS 
was 5.3 months and median survival was 10.8 months. Ryan et al evaluated 
biweekly oxaliplatin in combination with a modified FOLFOX6 regimen 
(oxaliplatin 85 mg/m2 as a 2-hour infusion on Day 1 of each 2-week cycle, 
immediately followed by LV, 500 mg/m2 as a 2-hour infusion followed by bolus 5-
FU, 400 mg/m2 and a 46-hour infusion of 5-FU, (total dose 2.4 g/m2) in heavily 
pretreated patients with advanced colorectal cancer. Preliminary data showed a 
response rate of 7%20. Updated information reveals a response rate of 11% (5%-
22%), all in patients who had received prior irinotecan. When only second-line 
patients were considered, the response rate was 25% (8-43%). Andre and 
coworkers reported preliminary results of the Optimox trial comparing first-line 
therapy of FOLFOX4 to FOLFOX7 at ASCO 200321. FOLFOX7 uses an every 2-
week schedule of LV 400 mg/m2 and oxaliplatin 130 mg/m2 followed by a 46-hour 
infusion of 5-FU 2400 mg/m2. With 524 patients randomized, the ORR and PFS 
on the two arms were identical (ORR=59.8 and 63.1% and PFS=8.9 and 9.2 
months). Toxicities with both regimens were similar with the exception that 
FOLFOX7 had significantly less grade 3/4 neutropenia and grade 3 neuropathy, 
but more grade 3/4 alopecia, thrombocytopenia and hand-foot syndrome, when 
compared with FOLFOX4. Finally, FOLFOX6 was compared directly with 5-FU + 
LV + irinotecan (FOLFIRI) in a randomized study conducted by Tournigand and 
coworkers22. These investigators found that the ORR and PFS associated with 
the first-line use of either regimen was nearly identical with response rate of 54 
and 56% and PFS of 8 and 8.5 months, respectively. Taken together, these data 
suggest that the various modifications of the FOLFOX regimen result in similar 
clinical outcomes in patients with advanced colorectal cancer, although data 
concerning direct comparisons between the regimens is limited.
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
16
In E5202, we propose that beginning bevacizumab administration in combination 
with 5-FU, leucovorin and oxaliplatin will maximize its effects for the high-risk 
stage II patients.
1.2
Molecular Analysis for Risk Assessment/Treatment Assignment
The rationale for the molecular analysis is similarly compelling. The data 
generated in previous ECOG trials show that the specific abnormalities of 
individual tumors are an independent determinant of outcome. This important 
retrospective observation needs prospective validation, especially since the 
literature is conflicting at present with small studies purporting to show the 
relevance of several molecular markers, often asserting opposing prognostic 
influences.
The relationship between microsatellite instability and response to adjuvant 
chemotherapy is controversial. The studies of Elsaleh et al showed that patients 
with stage III colorectal cancer, whose tumor demonstrated MSI, derived greater 
benefit from adjuvant chemotherapy than microsatellite-stable cancers; whereas 
Ribic et al found that patients with microsatellite instability in their tumors did not 
benefit from adjuvant chemotherapy and showed a trend toward poor survival. A 
third study by the National Surgical Adjuvant Breast and Bowel Project in stage II 
and III patients showed that patients whose colon cancer had microsatellite 
instability and patients with microsatellite-stable cancers benefited equally from 
adjuvant chemotherapy (15, 16, 17).
This uncertainty was emphasized at a recent CTEP workshop to review the field: 
the ECOG results were discussed in detail at this workshop and the need for 
prospective validation agreed. The major markers to be studied are 18q, MSI and 
integrity of the TGF-E1 type II receptor. Clearly, provision will be made for 
analysis of additional markers in the future and, based on the use of the VEGF 
inhibitor, a retrospective analysis of outcome based on receptor expression and 
additional prognostic markers including those associated with 5-FU 
sensitivity/resistance. Validation of these markers would potentially provide the 
groundwork with which to investigate a role for individualized postoperative 
therapy and to tailor treatment to the specific tumor.
Forty percent of stage II patients will fall into the high-risk patient group, defined 
by a microsatellite-stable tumor with 18q LOH and 60% will fall into the low-risk 
group, defined by a tumor with high levels of microsatellite instability (MSI-H) or 
microsatellite stability with retention of 18q alleles. The molecular markers 
selected to distinguish high-risk vs. low-risk patient groups with stage II colon 
cancer were not selected based on any association to bevacizumab therapy. The 
molecular markers were selected based on clinical trial data of 5-FU-based 
chemotherapy in the adjuvant setting, and did not include bevacizumab as a 
component of therapy.
The low-risk group of stage II patients will have a 5-year survival of 
approximately 90% whereas the high-risk stage II patients will have a 60% 5-year 
survival.
The addition of the anti-VEGF monoclonal antibody, bevacizumab, will improve 
survival in patients with high-risk stage II disease in combination with 5-FU, 
leucovorin and oxaliplatin compared to those high-risk patients randomized to 
receive 5-FU, leucovorin and oxaliplatin.
Rev. 8/09
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
17
1.3
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome: 
RPLS or clinical syndromes related to vasogenic edema of the white matter have 
been rarely reported in association with bevacizumab therapy (< 1%). Clinical 
presentations are variable and may include altered mental status, seizure and 
cortical visual deficit. HTN is a common risk factor and was present in most 
(though not all) patients on bevacizumab who developed RPLS. MRI scans are 
key to diagnosis and typically demonstrate vasogenic edema (hyperintensity in 
T2 and FLAIR images and hypointensity in T1 images) predominantly in the 
white matter of the posterior parietal and occipital lobes; less frequently, the 
anterior distributions and the gray matter may also be involved. RPLS should be 
noted in the differential diagnosis in patients presenting with unexplained mental 
status change, visual disturbance, seizure or other CNS findings. RPLS is 
potentially reversible, but timely correction of the underlying causes, including 
control of BP and interruption of the offending drug, is important in order to 
prevent progression to irreversible tissue damage.
1.4
Gastrointestinal Perforation/Fistula: 
GI perforations/fistula have been rarely reported but occurred at an increased 
rate in bevacizumab-containing therapies. The majority of such events required 
surgical intervention and some were associated with a fatal outcome. In the 
pivotal phase 3 trial in CRC (AVF2107), the incidence of bowel perforation was 
2% in patients receiving IFL/bevacizumab and 4% in patients receiving 5-
FU/bevacizumab compared to 0.3% in patients receiving IFL alone. GI 
perforation has also been reported in patients with gastric/esophageal cancer, 
pancreatic cancer, or comorbid GI conditions such as diverticulitis and gastric 
ulcer. GI perforation should be included in the differential diagnosis of patients on 
bevacizumab therapy presenting with abdominal pain or rectal/abdominal 
abscess.
1.5
On Study Guidelines
This clinical trial can fulfill its objectives only if patients appropriate for this trial 
are enrolled. All relevant medical and other considerations should be taken into 
account when deciding whether this protocol is appropriate for a particular 
patient. It is important that at the time of Informed Consent, the patient 
understands both components of the trial and must be willing to accept the 
treatment assigned based on risk as determined by the microsatellite stability 
and 18q status.
1.6
NSABP C-08 and the AVANT B017920 Trial
Two recent reports discussing the safety and efficacy from analyses of “NSABP 
C-08: A randomized phase III study of modified FOLFOX6 with or without 
bevacizumab for the adjuvant treatment of patients with stage II or III colon 
cancer” have been presented23, 24. Patients were randomized to receive either 
modified FOLFOX6 (oxaliplatin 85 mg/m2, IV d1, leucovorin 400 mg/m2 IV d1, 5-
FU 400 mg/m2 IV bolus d1, and 5-FU 2400 mg/m2 CI over 46 hrs (d1+2) q14 d x 
12 cycles) or mFOLFOX6 + bevacizumab (same mFOLFOX6 regimen + 
bevacizumab 5 mg/kg IV q 2 weeks x 1 year). The initial safety report of NSABP 
C-08 included 2,710 randomized patients demonstrating rates of grade 4 or 5 
Rev.
Rev.
Rev. 7/07
Rev. 8/09
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
18
toxicities which were similar between the two arms, mFOLFOX 6 and 
mFOLFOX6 + bevacizumab (15.2% and 15%, respectively)23. The 6 month 
mortality rates were 0.96% and 0.9% respectively. The grade 3+ toxicities that 
were noted more frequently in the mFOLFOX + bevacizumab included 
hypertension (12% v 1.8%, respectively), wound complications (abdominal 
incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, 
respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, 
respectively). In addition, grade 2+ neuropathy was seen more frequently with 
mFOLFOX + bevacizumab (grade 2, 33% v 29%, respectively; grade 3, 16% v 
14%, respectively; grade 4, < 1% each). There was, however, less 
thrombocytopenia in the mFOLFOX + bevacizumab arm (1.4% v 3.4%, 
respectively) and fewer allergic reactions (3.1% v 4.7%, respectively).  Older 
patients experienced greater grade 4 and 5 toxicities regardless of treatment. 
Overall, it was felt that bevacizumab with modified FOLFOX6 was well tolerated 
in the adjuvant setting.
Efficacy results were reported at ASCO 2009 on 2,672 patients with stage II 
(24.9%) or stage III colon carcinoma24. Median follow up was 36 months. The 
results indicate that the addition of bevacizumab to mFOLFOX6 do not result in a 
statistically significant prolongation in the DFS (3 year DFS 75.5% v 77.4%, 
respectively, HR=0.89, p=0.15). The presentation also included an estimate of 
the DFS HR over time  indicating that becazuimab reduced the risk of a DFS 
event during the interval from 0.5 to 1.0 year (year 1 HR = 0.6, p=0.0004; year 
1.5 HR= 0.74, p=0.004;year 2 HR =0.81, p=0.02).
N
Ev
3yDFS
P
Yr
1
1.5
2
2.5
3
mFF6
1338
312
75.5
HR
0.60
0.74
0.81
0.85
0.87
mFF6 + b
1334
291
77.4
0.15
P
0.0004
0.004
0.02
0.05
0.08
Data from the AVANT BO17920 trial are pending. There were 3,450 patients with 
stage II and III colon cancer accrued through this study between December 2004 
and May 2007. The randomization is a comparison of FOLFOX4 v FOLFOX4 + 
bevacizumab v xelox + bevacizumab. The results of this study are expected 
within 1 year.
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
19
2.
Objectives
2.1
Primary Objective
To demonstrate an improvement in 3-year disease-free survival for high-risk 
stage II colon cancer patients randomly assigned to 5-FU, leucovorin, oxaliplatin 
versus 5-FU, leucovorin, oxaliplatin and bevacizumab.
2.2
Secondary Objectives
2.2.1
To compare overall survival between the regimens.
2.2.2
To further define the toxicity profiles of the regimens.
2.2.3
To prospectively determine the impact of tumor biological 
characteristics on the survival of patients with stage II colon cancer.
2.2.4
Pharmacogenetic Ancillary Objective: To assess the association 
between oxaliplatin exposure, allelic variants in candidate genes, and 
neurotoxicity
R
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
20
3.
Selection of Patients
Applicable criteria in the following section must be met in order for a patient to be 
considered eligible for this study. Please carefully follow the instructions below and use 
the spaces provided to confirm a patient’s eligibility. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
NOTE:
Because assignment to treatment Arms A/B and observation Arm C is 
based upon results of the risk assessment evaluating microsatellite 
instability and loss of heterozygosity at 18q, submission of tumor tissue 
and normal mucosa is pivotal to the completion of study. Your careful 
attention to submission time-points is crucial.
ECOG-ACRIN Patient No. ____________________________
Patient’s Initials (L, F, M) _______________________
Physician Signature and Date __________________________________________
NOTE:
All questions regarding eligibility should be directed to the ECOG-ACRIN 
Operations Office – Boston at (617) 632-3610.
NOTE:
Institutions may use the eligibility checklist below as source documentation if 
it has been reviewed, signed and dated prior to registration/randomization by 
the treating physician.
3.1
Step 1: Initial Registration
NOTE:
During Step 1 initial registration, it is necessary to review 
requirements of Step 2 (3.2) to ensure that medical history and 
available post-operative laboratory values do not result in 
exclusion.
3.1.1
The distal extent of the tumor must be ≥ 12 cm from the anal verge on 
endoscopy. If this distance was not confirmed on endoscopy pre-
operatively, then the distal extent of the tumor must be ≥ 12 cm from 
the anal verge as determined by surgical examination. Colonoscopy 
should be performed postoperatively for those unable to have a 
preoperative colonoscopy to guarantee there are no synchronous 
lesions.
Distal extent of the tumor measures: ______
(If tumor is located beyond sigmoid colon and centimeter distance 
unavailable, include anatomic region of colon, e.g. right colon, 
transverse colon, hepatic flexure descending colon, cecum etc.)
3.1.2
Patients must have paraffin-embedded tumor specimen available for 
evaluation of microsatellite instability and loss of heterozygosity at 
18q, to determine high risk versus low risk. Tumor samples and 
normal mucosa will be shipped as specified in Section 10.2.
3.1.2.1
High-risk patients will be randomized to treatment Arms A 
or B.
Rev. 8/10
Rev. 7/07
Rev. 8/10
Rev. 8/10
Rev. 
12/08
Rev. 7/07
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
21
3.1.2.2
Low-risk patients will be registered to Arm C for 
observation. (Criteria noted in Sections 3.2.1 through 
3.2.18 need not be met.)
NOTE:
Every effort should be made to submit blocks (tumor and 
normal mucosa) to the PCO immediately. Blocks CANNOT 
be accepted after day 50 (post surgery) in order to allow 
for molecular assessment.
Date of surgery: ______ Date blocks sent to PCO: ______
NOTE:
Specific laboratory requirements for Step 2 must be 
obtained within 2 weeks prior to Step 2 randomization.
3.1.3
Patients must not have synchronous tumors.
3.1.4
Patients must not have appendiceal tumors.
3.1.5
Patients must not have a history of inflammatory bowel disease (IBD).
3.1.6
Patients with hereditary non-polyposis colorectal cancer (HNPCC) are 
eligible.
3.1.7
Patients must have no history of isolated, distant, or non-contiguous 
intra-abdominal metastases, even if restricted.
3.1.8
Patients must have histologically confirmed adenocarcinoma of the 
colon that meets the criteria below:
Stage II adenocarcinoma (pT3/pT4a/pT4b pN0 M0 according to the 
definitions of the American Joint Committee on Cancer, 7th Edition, 
2010): The tumor invades through the muscularis propria into pericolic 
tissues (pT3), penetrates to the surface of the visceral peritoneum 
(pT4a), or directly invades other organs or structures (pT4b). Patients 
with mesenteric tumor deposits or satellites without identifiable 
residual lymph node in the absence of lymph node involvement are 
now designated pN1c, rather than pT3. Patients with such tumor 
deposits are not eligible for E5202.
Appendix IV provides the AJCC 7th Edition (2010) TNM nomenclature 
and staging for colon cancer.
Stage: _______
Patients must have had a complete resection (R0 resection).
R0 resection?
Yes_____ No_____
3.1.9
Patients must have ≥ 8 lymph nodes evaluated and reported.
Number of lymph nodes evaluated and reported: ______
3.1.10
Patients must not have presented with clinical complete obstruction or 
perforation of the bowel.
3.1.11
Patients must not have had any systemic or radiation therapy initiated 
for this malignancy.
Rev.
Rev 7/07
Rev. 8/10
Rev 7/07
Rev 7/07
Rev. 7/07, 12/08
Rev 7/07
Rev. 
12/08
Rev. 8/10
Rev. 8/10
Rev. 
12/08
Rev. 
11/06,
12/08
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
22
3.1.12
Patients must not have a previous or concurrent malignancy. 
Exceptions are made for patients who meet any of the following 
conditions:
x
Non-melanoma skin cancer, in situ cervical cancer, or breast 
cancer in situ.
x
Prior malignancy completely excised or removed and patient has 
been continuously disease free for > 5 years.
Date of last evidence of disease: _______
x
Patients with completely excised or removed breast cancer and 
disease free > 5 years, regardless of the continuation of hormonal 
therapy.
Date of last evidence of disease: _______
x
Patients with previous RT to the pelvic region will be ineligible.
3.1.13
Patients must be ≥ 18 years old.
3.1.14
Patients must have ECOG performance status of 0-2.
3.2
Step 2: Randomization (High Risk Patients – Arms A and B only)
NOTE:
Each of the criteria below must be met within 2 weeks prior to 
RANDOMIZATION for eligibility purposes. Please refer to Section 7 
for criteria that must be met within 2 weeks prior to TREATMENT. 
Plan accordingly to avoid repeating tests/assessments.
3.2.1
Within 2 weeks prior to randomization, postoperative absolute 
granulocyte count (AGC) must be ≥ 1500/mm3 (or < 1500/mm3, if in 
the opinion of the investigator, this represents an ethnic or racial 
variation of normal).
AGC count: ______
Date of test: ______
3.2.2
Within 2 weeks prior to randomization, the postoperative platelet 
count must be ≥ 100,000/mm3.
Platelet count: ______
Date of test: ______
3.2.3
Within 2 weeks prior to randomization, there must be postoperative 
evidence of adequate hepatic function.
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.
ULN: ______
Bilirubin: ______
Date of test: ______
Alkaline phosphatase must be < 2.5 x ULN.
ULN: _____
Alk Phos: ______
Date of test: ______
AST must be < 1.5 x ULN.
ULN: ______
AST: ______ Date of test: ______
[Deleted in Addendum #9]
Rev. 
12/08,
8/10
Rev. 8/10
Rev. 8/10
Rev. 11/06, 7/07, 12/08
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NCI Update Date: December 16
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3.2.4
Within 2 weeks prior to randomization, there must be postoperative 
evidence of adequate renal function.
Serum creatinine ≤ 1.5 x ULN.
ULN: ______
Creatinine: ______
Date of test: ______
Urine protein/creatinine (UPC) ratio of < 1.0. Patients with a UPC ratio 
≥ 1.0 must undergo a 24-hour urine collection, which must be an 
adequate collection and must demonstrate < 1 gm of protein in order 
to participate. (See Appendix VIII).
UPC rates: ______
Date of test: ______
3.2.5
Patients with any significant bleeding that is not related to the primary 
colon tumor within 6 months prior to study entry are not eligible.
Date of bleeding episode: ______
3.2.6
Patients with gastroduodenal ulcer(s) determined to be active by 
endoscopy are not eligible.
3.2.7
Patients with a history of hypertension must measure < 150/90 mmHg 
and be on a stable regimen of anti-hypertensive therapy.
BP measurement: ______
Anti-hypertensive therapy: ______
3.2.8
Patients must not have a serious or non-healing wound, skin ulcers or 
bone fracture. 
3.2.9
[Deleted in Addendum #8]
3.2.10
Patients experiencing clinically significant peripheral neuropathy at the 
time of step 2 randomization (defined in the NCI Common 
Terminology Criteria for Adverse Events version 4.0 [CTCAE 4.0] as 
grade 2 or greater neurosensory or neuromotor toxicity) are not 
eligible.
3.2.11
Patients must not have had invasive procedures, defined as follows:
Major surgical procedure, open biopsy or significant traumatic injury 
within 28 days prior to randomization
Yes: ______
No: ______
Date of procedure: ______
Core biopsy or other minor procedure, excluding placement of a 
vascular access device, within 7 days prior to randomization 
Yes: ______
No: ______
Date of procedure:______
or anticipate the need for major surgical procedure(s) during the 
course of the study.
3.2.12
Patients must begin adjuvant treatment no less than 28 days and no 
more than 60 days from surgery.
Date of surgery: _______
[NOTE deleted in Addendum #8]
Rev. 1/06
Rev. 7/07
Rev. 9/11
Rev. 11/06, 7/07
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
24
3.2.13
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 3 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 2 weeks prior to 
step 2 randomization.
Female of childbearing potential?: _____(Yes or No) 
Date of serum pregnancy test: ________
3.2.14
Patients with PT (INR) > 1.5 are not eligible, unless the patient is on 
full-dose anticoagulants. If so, the following criteria must be met for 
enrollment:
The subject must have an in-range INR (usually between 2 and 3) on 
a stable dose of warfarin or on a stable dose of low molecular weight 
heparin.
The subject must not have active bleeding or a pathological condition 
that is associated with a high risk of bleeding.
PT (INR) Measurement: _______
Stable dose warfarin/low molecular weight heparin: 
Yes:______ No: _______
Active bleeding : Yes: ______
No: ______
3.2.15
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:
NYHA Class III or IV congestive heart failure
Yes: ______
No: ______
Current symptomatic arrhythmia
Yes: ______
No: ______
Any non-malignant systemic disease
Yes: ______
No: ______
3.2.16
Patients with a history of transient ischemic attack (TIA) or 
cerebrovascular accident (CVA) are not eligible.
x
TIA? Yes: ______
No:______
x
CVA? Yes: ______
No:______
3.2.17
Patients with a history of the following within twelve months of study 
entry are not eligible. 
x
Arterial thromboembolic events:
Yes:______ Date: ______ No: _______
Rev. 1/06
Rev. 11/06
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
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x
Unstable angina: 
Yes: ______ Date: ______ No: _______
x
Myocardial Infarction: 
Yes: ______ Date: ______ No: _______
3.2.18
Patients with symptomatic peripheral vascular disease are not eligible.
Yes: ______ No: _______
3.2.19
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.
3.2.20
Patients must not have a known allergy to platinum compounds.
Known allergy to platinum compounds? Yes______ No______ 
3.3
Step 2: Registration (Low-Risk Patients – Arm C)
NOTE:
Patients determined as low risk must be registered to Step 2.
3.3.1
Patients determined to be low risk are eligible.
Rev. 7/07
Rev. 7/07
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
26
4.
Registration/Randomization Procedures
Submitting Regulatory Documents
Before an ECOG-ACRIN Institution may enter patients, protocol specific regulatory 
documents must be submitted to the CTSU Regulatory Office at the following address:
CTSU Regulatory Office
Coalition of National Cancer Cooperative Groups
1818 Market Street, Suite 1100
Philadelphia, PA 19103
FAX: (215) 569-0206
Required Protocol Specific Regulatory Documents
1.
CTSU Regulatory Transmittal Form.
2.
Copy of IRB Informed Consent Document.
NOTE:
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB.
1.
A. CTSU IRB Certification Form.
Or
HHS 310 Form.
Or
IRB Approval Letter
NOTE:
The above submissions must include the following details:
x
Indicate all sites approved for the protocol under an assurance 
number.
x
OHRP assurance number of reviewing IRB
x
Full protocol title and number
x
Version Date
x
Type of review (full board vs. expedited)
x
Date of review.
x
Signature of IRB official
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed 
http://www.ctsu.org/rss2_page.asp. If you have questions regarding regulatory document 
submission, please telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com. 
Patients must not start protocol treatment prior to Step 2 randomization.
Treatment must start within 7 days after randomization and no later than Day 60 
post-operatively.
Observation for Arm C patients begins at Step 2 registration.
NOTE:
Please refer to Appendix V for CTSU registration guidelines.
Rev
Rev. 7/07
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
27
Institutions may register eligible patients to this study via the ECOG webpage 24 hours a 
day, 7 days a week, using the Web-based Patient Registration Program 
(https://webreg.ecog.org). If you need assistance or have questions, please telephone 
the Central Randomization Desk at the ECOG-ACRIN Operations Office – Boston 617-
632-2022 Monday through Friday 9:00am-5:00pm (Eastern Time).  Please note that a 
password is required to use this program.  The following information will be requested:
4.1
Step 1 Registration
4.1.1
Protocol Number 
4.1.2
Investigator Identification 
4.1.2.1
Institution and affiliate name
4.1.2.2
Investigator’s name
4.1.3
Patient Identification 
4.1.3.1
Patient’s initials and chart number
4.1.3.2
Patient’s Social Security number
4.1.3.3
Patient demographics
4.1.3.3.1
Sex
4.1.3.3.2
Birth date (mm/yyyy)
4.1.3.3.3
Race
4.1.3.3.4
Ethnicity
4.1.3.3.5
Nine-digit ZIP code
4.1.3.3.6
Method of payment
4.1.4
Eligibility Verification 
Patients must meet all of the applicable eligibility requirements listed 
in Section 3. An eligibility worksheet is posted on the ECOG webpage. 
A confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office – Boston.
4.1.5
Study Requirements 
4.1.5.1
All patients must provide a signed and dated, written 
informed consent form.
4.1.5.2
Two separate tissue blocks, one with normal mucosa and 
one from the resection tumor are to be submitted to the 
PCO no later than Day 50 post-operatively and within 5 
working days of Step 1 registration, as outlined in Section 
10. If only one block is available, it must contain both 
normal AND tumor tissue.
4.1.5.3
For patients participating in the “Pharmacogenetic 
Laboratory Studies”, samples are to be submitted as 
outlined in Appendix XII. Submission of samples after 
registration/randomization to Step 2 is preferred.
Rev. 8/10
Rev 11/06 7/07 12/08
Rev. 4/06
Rev. 
12/08
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4.1.5.4
Pathology samples of recurrent tumor should be submitted 
for banking for future research studies as outlined in 
Section 10.3.
NOTE:
ECOG-ACRIN requires that biological samples 
submitted from patients participating in E5202 
be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). Any 
case reimbursements associated with sample 
submissions may not be captured if samples 
are not logged into STS. See Section 10.3
4.1.6
Instructions for Patients Who Do Not Register to Step 2 
Registration/Randomization 
If a patient does not proceed to Step 2 registration/randomization, the 
baseline forms must still be collected (including source documents) 
and must be submitted according to the instructions in the E5202 
Forms Packet. Document the reason the patient did not 
register/randomize to Step 2 on the E5202 Pre-Registration Form. 
Please note that follow-up data must be submitted according to the 
instructions in the E5202 Forms Packet for patients who had marker 
testing on their tumor (i.e., received a pathological risk status) and did 
not proceed to Step 2.
4.1.7
Information for Medicare Patients
On 1/28/05, the Centers for Medicare and Medicaid Services (CMS – 
formerly HCFA) made a special decision to cover Medicare patients 
enrolled in E5202 and 8 other Cooperative Group cancer studies.  
ECOG-ACRIN wants to let you know about this (Coverage Decision 
No. CAG-00179N), so Medicare beneficiaries considering E5202, and 
their families, will know that most study-related costs will be covered 
by Medicare.
In the event sites encounter any problem obtaining Medicare 
reimbursement for services to a patient enrolled in E5202, your 
institution’s Finance personnel may wish to refer the Medicare 
contractor to Coverage Decision No.CAG-00179N issued January 28, 
2005, which approves coverage for E5202, among other cooperative 
group trials. The Decision Memo from CMS, the Center for Medicare 
and Medicaid Services of DHHS (formerly HCFA), can be found at 
www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=90.
4.2
Step 2: Randomization/Registration
MD Anderson will notify (by fax) the submitting institution’s CRA and the 
ECOG-ACRIN Randomization Desk at the ECOG-ACRIN Operations Office – 
Boston of the results of the risk assessment evaluated for microsatellite 
instability and loss of heterozygosity at 18q within 4 working days of 
receipt of the paraffin-embedded tumor specimens from the ECOG-ACRIN 
PCO.
NOTE:
Due to the complexity of MSI testing, some tumor specimens could 
require laser capture microdissection (LCM). This additional 
Rev. 8/09
Rev. 7/07, 8/10
Rev 5/08
Rev. 1/06
Rev. 
Rev. 7/07
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procedure will delay the turnaround time for reporting results to the 
institution about one week or longer. The CRA will be notified of this 
delay.
Please do not call MD Anderson or the Pathology Coordinating Office for results, 
as testing data cannot be provided over the telephone. To request FAXed copies 
of the result reports, contact MD Anderson or the ECOG-ACRIN Operations 
Office – Boston. 
x
Patients with high risk will be randomized to Arms A or B.
Randomization is accomplished via ECOG-ACRIN’s standard permuted 
blocks within strata algorithm, stratifying on the stratification factors listed in 
4.2.6 and balancing randomizations within main institutions. The strata are 
defined by the cross-classification of factor levels listed in 4.2.6.1 and 4.2.6.2 
(four total strata).
x
Patients with low risk will be registered to Arm C.
Patients must not start protocol treatment prior to step 2 
randomization/registration.
Treatment for patients assigned to Arm A or Arm B must begin by Day 60.
Institutions may register eligible patients to this study via the ECOG webpage 24 
hours a day, 7 days a week, using the Web-based Patient Registration Program 
(https://webreg.ecog.org). If you need assistance or have questions, please 
telephone the Central Randomization Desk at the ECOG-ACRIN Operations 
Office – Boston at (617) 632-2022. Please note that a password is required to 
use this program.  The following information will be requested:
4.2.1
Protocol Number 
4.2.2
Investigator Identification 
4.2.2.1
Institution and affiliate name
4.2.2.2
Investigator’s name
4.2.3
Patient Identification 
4.2.3.1
Patient’s initials and chart number
4.2.3.2
Patient’s Social Security number
4.2.3.3
Patient demographics
4.2.3.3.1
Sex
4.2.3.3.2
Birth date (mm/yyyy)
4.2.3.3.3
Race
4.2.3.3.4
Ethnicity
4.2.3.3.5
Nine-digit ZIP code
4.2.3.3.6
Method of payment
4.2.4
Eligibility Verification 
Rev. 
Rev. 7/07
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Patients must meet all of the eligibility requirements listed in Section 
3. An eligibility worksheet has been posted on the ECOG webpage. A 
confirmation of randomization/registration will be forwarded by the 
ECOG-ACRIN Operations Office – Boston.
4.2.5
Classification Factors
4.2.5.1
High risk for microsatellite instability and loss of 
heterozygosity at 18q.
x
MSS with 18q LOH
x
MSI-L with 18q LOH
4.2.5.2
Low risk for microsatellite instability and loss of 
heterozygosity at 18q.
x
MSS with retention of 18q alleles
x
MSI-L with retention of 18q alleles
x
MSI-H with retention of 18q alleles
x
MSI-H without retention of 18q alleles
x
MSI-H with 18q status uninformative
4.2.6
Stratification Factors
4.2.6.1
Stage IIA versus IIB
4.2.6.2
MSS versus MSI-L
4.2.7
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment 
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
according to the instructions in the E5202 Forms Packet. Document 
the reason for not starting protocol treatment after randomization on 
the E5202 Off-Treatment Form. Also report the date and type of the 
first non-protocol treatment that the patient received.
Rev 1/06
Rev.4/06
Rev. 7/07
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5.
Treatment Plan
5.1
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 tables below.
Administration of Cycle 2 may begin ± 2 days to accommodate patients’ and 
clinics’ schedules.
5.1.1
Arm A
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
Repeated every 2 weeks for a total of 12 (2-week) cycles.
NOTE:
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, as described in Section 8.2.7.
5.1.2
Arm B
Agent
Dose
Route
Treatment 
Administration
Bevacizumab1
5 mg/kg
IV infusion over 90 minutes2
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
Repeated every 2 weeks for a total of 12 (2-week) cycles.
1.
Bevacizumab will continue for 12 additional cycles following 
completion of chemotherapy. Patients will receive a total of 24 (2-
week) cycles of bevacizumab. 
Rev 7/07
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2.
Initial dose should be administered over a minimum of 90 minutes. 
If no adverse reactions occur, the second dose should be 
administered over a minimum of 60 minutes. Again, if no adverse 
reactions occur, the third and subsequent doses should be 
administered over a minimum of 30 minutes. 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.
NOTE:
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, as described in 
Section 8.2.7.
5.2
Adverse Event Reporting Requirements
5.2.1
Purpose
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E5202 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting). Additionally, certain adverse events must be reported in an 
expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting.
5.2.2
Determination of reporting requirements
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event.
An investigational agent is a protocol drug administered under an 
Investigational New Drug Application (IND). In some instances, the 
investigational agent may be available commercially, but is actually 
being tested for indications not included in the approved package 
label.
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial.
When a study arm includes both investigational and commercial 
agents, the following rules apply.
Rev 7/14
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x
Concurrent administration: When an investigational agent(s) is 
used in combination with a commercial agent(s), the combination 
is considered to be investigational and expedited reporting of 
adverse events would follow the guidelines for investigational 
agents.
Steps to determine if an adverse event is to be reported in an 
expedited manner:
Step 1:
Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 will be 
utilized until September 30, 2011 for AE reporting. CTCAE 
version 4.0 will be utilized beginning October 1, 2011. All 
appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. A copy of the CTCAE version 4.0 
can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).
Step 2:
Grade the event using the NCI CTCAE version 4.0.
Step 3:
Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite.
Step 4:
Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or 
the severity of the event is NOT listed in:
x
Arm A – the drug package insert or protocol 
x
Arm B – the current NCI Agent-Specific Adverse Event 
List for the investigational agent or package 
insert/protocol for the commercial agents 
NOTE:
The NCI Agent Specific Adverse Events List (ASAEL) is 
included in Section 5.3 of the protocol. The ASAEL is a list 
of events that should be considered ‘expected’ for adverse 
event reporting purposes. The ASAEL is presented in the 
last column of the Comprehensive Adverse Event and 
Potential Risks list (CAEPR) and identified with bold and 
italicized text.
Step 5:
Review the “Additional instructions, requirements, and 
exceptions for protocol E5202” table in Section 5.2.6 and 
footnote b in Section 5.2.7 for protocol and/or ECOG-
ACRIN specific requirements for expedited reporting of 
specific adverse events that require special monitoring.
Rev. 9/11
Rev. 9/10
Rev. 1/06
Rev. 
12/08,
8/10
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NCI Update Date: December 16
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NOTE:
For general questions regarding expedited reporting 
requirements, please contact the AEMD Help Desk at 
aemd@tech-res.com  or 301-897-7497.
5.2.3
Reporting methods
Arm A and B – This study requires that expedited adverse event 
reporting use CTEP’s Adverse Event Reporting System (CTEP-
AERS).  CTEP’s guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov. A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov.
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to the AE Team at ECOG-
ACRIN (617-632-3610), the NCI (301-897-7497) for Arm B and the 
FDA (1-800-FDA-1088) for Arm A.
An electronic report MUST be submitted immediately upon re-
establishment of internet connection.
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (6176322990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to must be faxed to the NCI (301- 230-
0159) for Arm B and the FDA (800-332-0178) for Arm A in the same 
timeframe.
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457.
5.2.4
When to report an event in an expedited manner
Some adverse events require 24-hour notification (refer to Section 
5.2.6). Please complete a 24-Hour Notification Report via the CTEP- 
AERS website (http://ctep.cancer.gov within 24 hours of learning of 
the event. The full CTEP-AERS report must be completed and 
submitted via CTEP-AERS within 5 calendar days.
If the CTEP-AERS system is down, a 24-hour notification call must be 
made to ECOG-ACRIN (617-632-3610) and to NCI (301-897-7497). 
Once the system is restored, a 24-hour Notification Report must be 
entered into the CTEP-AERS system by the original submitter of the 
report at the site.
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Sections 5.2.6 
and 5.2.7.
NOTE:
Adverse events that meet the reporting requirements in 
Sections 5.2.6 or 5.2.7 and occur within 30 days of the last 
dose of protocol treatment must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
Rev 1/06 4/06
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For any adverse events that occur more than 30 days after 
the last dose of treatment, only those that have an 
attribution of possibly, probably, or definitely AND meet the 
reporting requirements in Sections 5.2.6 or 5.2.7 must be 
reported on an expedited adverse event report form (using 
CTEP-AERS).
5.2.5
Other recipients of adverse event reports
DCTD, NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all Aes reported to FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to the NCI and 
ECOG-ACRIN.
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient.
Rev. 4/06, 11/06
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NCI Update Date: December 16
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5.2.6
Expedited reporting for investigational agents
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-AERS Expedited Reporting 
Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of Investigational 
Agent (Bevacizumab) in this Study (Arm B) OR Within 30 Days of the Last Dose of Any Protocol 
Treatment.
Attribution
Grade 1
Grade 2
Grade 2
Grade 3
Grade 3
Grades
4 & 52
Grades
4 & 52
Unexpected
and 
Expected
Unexpected
Expected
Unexpected
Expected
Unexpected
Expected
with
Hospitali-
zation
without 
Hospitali- 
zation
with
Hospitali-
zation
without 
Hospitali-
zation
Unrelated
Unlikely
Not
Required
Not
Required
Not
Required
10 Calendar
Days
Not
Required
10 Calendar
Days
Not
Required
10 Calendar
Days
10 Calendar
Days
Possible
Probable
Definite
Not
Required
10 Calendar
Days
Not
Required
10 Calendar
Days
10 Calendar
Days
10 Calendar
Days
Not
Required
24-Hour;
5 Calendar
Days
10 Calendar
Days
1
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment with an agent 
under a CTEP IND require reporting as follows:
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for:
x
Grade 4 and Grade 5 unexpected events 
CTEP-AERS 10 calendar day report:
x
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
x
Grade 5 expected events
2
Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table.
Please see additional information below under section entitled “Additional instructions, requirements, and exceptions for protocol E5202”
March 2005
NOTE:
All deaths on study require both routine and expedited reporting regardless of causality.  Attribution to treatment or other 
cause should be provided.
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NCI Update Date: December 16
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x
Expedited AE reporting timelines:
¾
24 Hours; 5 calendar days – The investigator must initially report the AE 
via CTEP-AERS within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report.
¾
10 calendar days – A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the 
event.
x
Any medical event equivalent to CTCAE grade 3, 4, or 5 that 
precipitates hospitalization* (or prolongation of existing 
hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event 
reporting exclusions.
x
Any event that results in persistent or significant 
disability/incapacity, congenital anomaly, or birth defect must be 
reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND
x
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports.
*Hospitalizations are defined as lasting 24 hours or longer and these events 
must be reported via CTEP-AERS.
Additional instructions, requirements and exceptions for protocol E5202
1.
Additional Instructions:
¾
With respect to determining the specific day by which the event must be reported, the 
day the reporter learns of the adverse event constitutes “Day 0”
¾
For grade 2 and 3 unexpected events, CTEP-AERS reporting is only required if the 
event is related to the investigational agent(s); it is not required if the event is related 
only to the commercial agent(s) included in the protocol treatment.  
NOTE:
For grade 3 unexpected events with hospitalization lasting t 24 hours (or 
prolonged hospitalization), a CTEP-AERS report is required even if the event 
is unrelated to the investigational agent(s).
¾
For instructions on how to specifically report events that result in persistent or 
significant disability/incapacity, congenital anomaly, or birth defect events via CTEP-
AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-7497. 
This will need to be discussed on a case-by-case basis.
2. ECOG-ACRIN and Protocol Specific expedited reporting requirements:
The adverse events listed below also require expedited reporting for this trial:
ECOG-ACRIN specific expedited reporting requirements:
¾
Hospitalizations: Any grade 1 or 2 adverse event which precipitates a 
hospitalization lasting ≥ 24 hours (or prolongs hospitalization) must be reported via 
CTEP-AERS within 10 calendar days of learning of the event regardless of the 
attribution and designation as expected or unexpected.
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Protocol specific expedited reporting requirements:
¾
Rev
Additional Events: For this study, the adverse events listed below, regardless of 
attribution, require expedited reporting via CTEP-AERS within 10 calendar days of 
learning of the event:
Hypertension ≥ grade 4
Peripheral arterial ischemia ≥ grade 4
Rev. 9/10
All thrombosis/thrombus/embolisms (including 
vascular access-related) ≥ grade 4
Cardiac ischemia ≥ grade 4
Hemorrhage ≥ grade 3
CNS ischemia ≥ grade 4
Perforation, GI ≥ grade 3
Visceral arterial ischemia ≥ grade 4
Proteinuria ≥ grade 3
Fistula, GI ≥ grade 3
Intra-abdominal abscess/infection ≥ grade 3
Leak, GI ≥ grade 3
Wound complication, non-infectious ≥ grade 3
Veno-occlusive disease of the liver ≥ grade 1
Rev.
All occurrences of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or Posterior 
Reversible Encephalopathy Syndrome (PRES) and associated clinical presentations. [Please report 
under Neurology – Other (Leukoencephalopathy Syndrome)]
3. Protocol specific expedited reporting exceptions:
For study arm B, the adverse events listed below which occur during combination 
chemotherapy (oxaliplatin, 5-FU, and leucovorin) and bevacizumab, including 
hospitalizations for these events, do not require expedited reporting via CTEP-AERS. 
Beginning 30 days following the last dose of chemotherapy and when a patient is 
receiving bevacizumab alone, these adverse events should be reported according 
to instructions in the table above:
x
Grade 3 - 4 leukocytes (total WBC) or neutrophils/granulocytes 
x
Grade 3 - 4 fatigue
x
Grade 3 hand-foot reaction 
x
Grade 3 - 4 dehydration
x
Grade 3 - 4 diarrhea (including associated electrolyte imbalances)
x
Grade 3 - 4 dysphagia
x
Grade 3 - 4 esophagitis
x
Grade 3 – 4 mucositis (clinical exam or functional/symptomatic)
x
Grade 3 - 4 nausea
x
Grade 3 - 4 vomiting
x
Grade 3 - 4 febrile neutropenia
x
Grade 3 – 4 pain
5.2.7
Expedited reporting for commercial agents
Commercial reporting requirements are provided below. The 
commercial agents used in arm A of this study are 5-FU, Leucovorin, 
and Oxaliplatin.
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Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents only 
– Arm A
Attribution
Grade 4
Grade 5a
ECOG-ACRIN and 
Protocol-Specific
Requirements
Unexpected
Expected
Unexpected
Expected
See footnote 
(b) for special 
requirements.
Unrelated or 
Unlikely
7 calendar days
7 calendar 
days
Possible, 
Probable, 
Definite
7 calendar days
7 calendar days
7 calendar 
days
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event.
A
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any death 
that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely to 
the treatment must be reported within 7 calendar days of learning of the event.  
B
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial:
Serious Events:
Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-
AERS within 7 calendar days of learning of the event.  For instructions on how to 
specifically report these events via CTEP-AERS, please contact the AEMD Help Desk at 
aemd@tech-res.com  or 301-897-7497.  This will need to be discussed on a case-by-case 
basis.
Additional Events: For this study, the adverse events listed below, regardless of attribution, require expedited 
reporting via CTEP-AERS within 7 calendar days of learning of the event: Protocol-specific 
expedited reporting requirements: The adverse events listed below, regardless of 
attribution, also require expedited monitoring for this trial:
x Hypertension ≥ grade 4
x Peripheral arterial ischemia ≥ grade 4
x Thrombosis/thrombus/embolism ≥ grade 4
x Cardiac ischemia ≥ grade 4
x Hemorrhage ≥ grade 3
x CNS ischemia ≥ grade 4
x Perforation, GI ≥ grade 3
x Visceral arterial ischemia ≥ grade 4
x Proteinuria ≥ grade 3
x Fistula, GI ≥ grade 3
x Intra-abdominal abscess/infection ≥ grade 3
x Leak, GI ≥ grade 3
x Wound complication, non-infectious ≥ grade 3
x Veno-occlusive disease of the liver ≥ grade 1
x
Rev.
All grade 4 unexpected events, with attribution of 
unrelated or unlikely
x All occurrences of Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) or Posterior 
Reversible Encephalopathy Syndrome (PRES) and 
associated clinical presentations. [Please report under 
Neurology – Other (Leukoencephalopathy Syndrome)]
5.2.8
Reporting second primary cancers
All cases of second primary cancers, including, acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN:
x
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows:
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1.
Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at
ECOG-ACRIN Operations Office – Boston
FSTRF
900 Commonwealth Avenue
Boston, MA 02215
2.
Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis.
3.
If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN
x
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol).  
Secondary malignancies require both routine and expedited 
reporting as follows:
1.
Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at
ECOG-ACRIN Operations Office – Boston
FSTRF
900 Commonwealth Avenue
Boston, MA 02215
2.
Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy
3.
Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis.
4.
If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN and NCI/CTEP.
NOTE:
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease.
NOTE:
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial.
NOTE:
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form.
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5.3
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Bevacizumab (rhuMAb VEGF, NSC 704865)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Below is the CAEPR for bevacizumab (rhuMAb 
VEGF).
Version 2.1, May 4, 20101
Adverse Events with Possible
Relationship to Bevacizumab (rhuMAb VEGF)
(CTCAE 4.0 Term)
EXPECTED AEs FOR CTEP-
AERS REPORTING
Agent Specific Adverse 
Event List
(ASAEL)
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
Expected
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia
Blood and lymphatic system 
disorders - Other (renal 
thrombotic microangiopathy)
CARDIAC DISORDERS
Acute coronary syndrome
Heart failure
Left ventricular systolic 
dysfunction
Myocardial infarction
Myocardial infarction
Supraventricular tachycardia
Supraventricular tachycardia
Ventricular arrhythmia
Ventricular fibrillation
EAR AND LABYRINTH DISORDERS
Vertigo
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain
Colitis
Constipation
Constipation
Diarrhea
Diarrhea
Dyspepsia
Dyspepsia
Gastrointestinal fistula2
Gastrointestinal hemorrhage3
Gastrointestinal 
hemorrhage3 
Gastrointestinal perforation4 
Gastrointestinal ulcer5
Ileus
Mucositis oral
Mucositis oral
Nausea
Nausea
Vomiting
Vomiting
Rev. 1/06, 
11/06, 2/08, 
9/10, 7/14
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
Fatigue
Infusion related reaction
Infusion related reaction
Non-cardiac chest pain
Non-cardiac chest pain
Pain
Pain
IMMUNE SYSTEM DISORDERS
Allergic reaction
Allergic reaction
Anaphylaxis
INFECTIONS AND INFESTATIONS 
Infection6
Infection6
Infections and infestations - Other 
(peri-rectal abscess)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Gastrointestinal anastomotic 
leak
Wound dehiscence
Wound dehiscence
INVESTIGATIONS
Alanine aminotransferase 
increased
Alanine aminotransferase 
increased
Alkaline phosphatase increased
Alkaline phosphatase 
increased
Aspartate aminotransferase 
increased
Aspartate aminotransferase 
increased
Blood bilirubin increased
Blood bilirubin increased
Cardiac troponin I increased
Neutrophil count decreased
Neutrophil count decreased
Weight loss
Weight loss
White blood cell decreased
White blood cell decreased
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia
Arthralgia
Musculoskeletal and connective 
tissue disorder - Other (bone 
metaphyseal dysplasia)7
Myalgia
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness
Headache
Headache
Intracranial hemorrhage
Intracranial hemorrhage
Ischemia cerebrovascular
Ischemia cerebrovascular
Reversible posterior 
leukoencephalopathy syndrome 
 Syncope
RENAL AND URINARY DISORDERS
Acute kidney injury
Hematuria
Hematuria
Proteinuria
Proteinuria
Renal and urinary disorders - 
Other (Nephrotic Syndrome)
Renal and urinary disorders - 
Other (renal failure)
Urinary fistula
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
Vaginal fistula
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Vaginal hemorrhage
Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Bronchopleural fistula
Bronchopulmonary hemorrhage
Cough
Cough
Dyspnea
Dyspnea
Epistaxis
Epistaxis
Hoarseness
Hoarseness
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation)
Respiratory, thoracic, and 
mediastinal disorders - Other 
(rhinitis)
Respiratory, thoracic, and 
mediastinal disorders - 
Other (rhinitis)
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Pruritus
Pruritus
Skin and subcutaneous tissue 
disorders - Other (rash)
Skin and subcutaneous 
tissue disorders - Other 
(rash)
Urticaria
Urticaria
VASCULAR DISORDERS
Hypertension
Hypertension
Thromboembolic event
Thromboembolic event
Vascular disorders - Other 
(arterial thromboembolic event)8
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.
2 Gastrointestinal fistula includes: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC.
3 Gastrointestinal hemorrhage includes: Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC.
4 Gastrointestinal perforation includes: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and 
other sites under the GASTROINTESTINAL DISORDERS SOC.
5 Gastrointestinal ulcer includes: Duodenal ulcer, Esophageal ulcer, Gastric ulcer and other sites under 
the GASTROINTESTINAL DISORDERS SOC.
6 Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC.
7 Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth 
plates.
8 Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack, and stroke.
Also reported on Bevacizumab (rhuMAb VEGF) trials but with the relationship to Bevacizumab 
(rhuMAb VEGF) still undetermined:
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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (idiopathic thrombocytopenia purpura); Disseminated intravascular coagulation
CARDIAC DISORDERS - Pericardial effusion
GASTROINTESTINAL DISORDERS - Small intestinal obstruction
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait disturbance; 
Sudden death NOS
HEPATOBILIARY DISORDERS - Hepatic failure
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis)
METABOLISM AND NUTRITION DISORDERS - Hyponatremia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Musculoskeletal and 
connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and connective 
tissue disorder - Other (myasthenia gravis); Osteonecrosis of jaw
NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral motor neuropathy; Peripheral 
sensory neuropathy; Seizure
PSYCHIATRIC DISORDERS - Confusion
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Pneumonitis; Pneumothorax; Pulmonary hypertension
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Skin ulceration
NOTE:
Bevacizumab (rhuMAb VEGF) 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.
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Comprehensive Adverse Events and Potential Risks List (CAEPR) for Oxaliplatin 
(NSC 266046)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. They are 
developed and continuously monitored by the CTEP Investigational Drug Branch 
(IDB). The information listed in the CAEPR(s) below, as well as the other 
resources described in the 'Determination of reporting requirements' part of the 
Adverse Event Reporting section in this protocol, can be used to determine 
expectedness of an event when evaluating if the event is reportable via CTEP-
AERS. Frequency is provided based on 1141 patients. Below is the CAEPR for 
oxaliplatin.
Version 2.2, March 11, 20101
Adverse Events with Possible
Relationship to Oxaliplatin
(CTCAE 4.0 Term)
[n= 1141]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Disseminated intravascular coagulation
Febrile neutropenia
  Hemolysis
Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS
Atrial fibrillation
Atrial flutter
Paroxysmal atrial tachycardia
Sinus bradycardia
Sinus tachycardia
Supraventricular tachycardia
Ventricular arrhythmia
Ventricular fibrillation
Ventricular tachycardia
EAR AND LABYRINTH DISORDERS
Hearing impaired
Middle ear inflammation
EYE DISORDERS
Conjunctivitis
Dry eye
Eye disorders - Other (amaurosis fugax)
Eye disorders - Other (cold-induced 
transient visual abnormalities)
Eyelid function disorder
Papilledema
GASTROINTESTINAL DISORDERS
Abdominal pain
Ascites
Rev. 12/08, 8/10,
9/10
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Colitis
Constipation
Diarrhea
Dry mouth
Dyspepsia
Dysphagia
Enterocolitis
Esophagitis
Flatulence
Gastritis
 Gastrointestinal disorders – 
 Other (pneumatosis intestinalis)
Gastrointestinal hemorrhage2
Gastrointestinal necrosis3
 Gastrointestinal ulcer4
Ileus
Mucositis oral
Nausea
Pancreatitis
Small intestinal obstruction
Vomiting
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Chills
Edema face
Edema limbs
Fatigue
Fever
Gait disturbance
General disorders and administration site 
conditions - Other (Hepato-renal syndrome)
Injection site reaction
Non-cardiac chest pain
HEPATOBILIARY DISORDERS
Cholecystitis
Hepatic failure
Hepatobiliary disorders - Other (hepatic 
enlargement)
Hepatobiliary disorders - Other (veno-
occlusive liver disease)
IMMUNE SYSTEM DISORDERS
Allergic reaction
INFECTIONS AND INFESTATIONS
Infection5
INVESTIGATIONS
Activated partial thromboplastin time 
prolonged
Alanine aminotransferase 
increased
Alkaline phosphatase increased
Aspartate aminotransferase 
increased
Blood bilirubin increased
Creatinine increased
GGT increased
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INR increased
Lymphocyte count decreased
Neutrophil count decreased
Platelet count decreased
Weight gain
Weight loss
White blood cell decreased
METABOLISM AND NUTRITION DISORDERS
Acidosis
Anorexia
Dehydration
Hyperglycemia
Hyperuricemia
Hypoalbuminemia
Hypocalcemia
Hypoglycemia
Hypokalemia
Hypomagnesemia
Hyponatremia
Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia
Back pain
Bone pain
Myalgia
Trismus
NERVOUS SYSTEM DISORDERS
Ataxia
Depressed level of consciousness
Dizziness
Dysgeusia
Dysphasia
Extrapyramidal disorder
Headache
Intracranial hemorrhage
Ischemia cerebrovascular
Nerve disorder6
Nervous system disorders - Other (multiple 
cranial nerve palsies)
Peripheral motor neuropathy
Peripheral sensory neuropathy
Seizure
PSYCHIATRIC DISORDERS
Anxiety
Confusion
Depression
Insomnia
RENAL AND URINARY DISORDERS
Acute kidney injury
Hematuria
Renal hemorrhage
Urinary frequency
Urinary retention
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REPRODUCTIVE SYSTEM AND BREAST DISORDERS
Hematosalpinx
Ovarian hemorrhage
Prostatic hemorrhage
Spermatic cord hemorrhage
Testicular hemorrhage
Uterine hemorrhage
Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Adult respiratory distress syndrome
Allergic rhinitis
Bronchopulmonary hemorrhage
Bronchospasm
Cough
Dyspnea
Hiccups
Pneumonitis
Pulmonary fibrosis
Sinus disorder
Voice alteration
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Dry skin
Hyperhidrosis
Palmar-plantar erythrodysesthesia 
syndrome
Pruritus
Rash maculo-papular
Urticaria
VASCULAR DISORDERS
Flushing
Hot flashes
Hypertension
Hypotension
Phlebitis
Thromboembolic event
Vascular disorders - Other (hemorrhage 
with thrombocytopenia)
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.
2 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Doudenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC.
3 Gastrointestinal necrosis includes Anal necrosis, Esophageal necrosis, Gastric necrosis, Pancreatic 
necrosis, Peritoneal necrosis, and Rectal necrosis under the GASTROINTESTINAL DISORDERS SOC.
4 Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, Esophageal ulcer, Gastric 
ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under the GASTROINTESTINAL 
DISORDERS SOC.
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5 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.
6 Nerve disorder includes Abducens nerve disorder, Accessory nerve disorder, Acoustic nerve disorder 
NOS, Facial nerve disorder, Glossopharyngeal nerve disorder, Hypoglossal nerve disorder, IVth nerve 
disorder, Oculomotor nerve disorder, Olfactory nerve disorder, Trigeminal nerve disorder, and Vagus 
nerve disorder under the NERVOUS SYSTEM DISORDERS SOC.
7 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC.
Also reported on oxaliplatin trials but with the relationship to oxaliplatin still 
undetermined:
CARDIAC DISORDERS - Heart failure; Left ventricular systolic dysfunction; Myocardial 
infarction; Pericardial effusion
EYE DISORDERS - Eye pain
GASTROINTESTINAL DISORDERS – Gastrointestinal perforation7
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury to superior vena cava; 
Vascular access complication
INVESTIGATIONS - Cardiac troponin I increased; Lipase increased; Serum amylase increased
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Tumor lysis syndrome
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness
NERVOUS SYSTEM DISORDERS - Syncope
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia
VASCULAR DISORDERS - Visceral arterial ischemia
NOTE:
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.
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5.4
Dose Modifications 
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.
The CTCAE version 4.0 is identified and located on the CTEP website at 
http://ctep.cancer.gov. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.
If dose-modifying toxicities last more than 3 weeks, contact Study Chair 
regarding continuation of treatment. According to the following tables, the final 
dose modification should be based upon the worst grade of toxicity experienced. 
If patients require dose reductions lower than level – 2, therapy with that 
particular agent will be discontinued. Any dose reduction is continued for all 
subsequent cycles. 
NOTE:
There are no dose reductions for leucovorin; the dose remains 
fixed at 400 mg/m2 and without modification. In addition, there are no 
dose reductions for bevacizumab; the dose remains at 5 mg/kg and 
without dose modification.
5.4.1
Dose Modifications for Oxaliplatin and 5-FU Toxicity (Arms A and B)
NOTE:
There are no dose reductions for leucovorin. The dose 
remains fixed at 400 mg/m2. Leucovorin is discontinued 
only when 5-FU is discontinued.
NOTE:
Patients on Arm A who require discontinuation of both 5-
FU and oxaliplatin for toxicity will discontinue protocol 
therapy but will continue to be followed as indicated in 
Section 7.
NOTE:
Patients on Arms A and B who require discontinuation of 
oxaliplatin may continue to receive 5-FU/leucovorin.
NOTE: 
Patients on Arm B who discontinue both 5-FU and 
oxaliplatin may continue to receive bevacizumab, provided 
patient experiences no bevacizumab-related toxicities.
Rev. 7/07
Dose Levels of Oxaliplatin, Leucovorin and 5-FU
Starting Dose*
Dose Level – 1
Dose Level – 2
Oxaliplatin
85 mg/m²
65 mg/m²
50 mg/m²
Leucovorin
400 mg/m2
400 mg/m2
400 mg/m2
5-FU Bolus
400 mg/m²
320 mg/m²
200 mg/m²
5-FU Infusion
2.4g/m²
2 g/m²
1.6 g/m² **
2
All patients will start cycle 1 with doses listed in “Starting Dose” column
**
In the case of hand foot syndrome, the dose of infusional 5-FU may be 
further reduced by 20% as needed.
5.4.1.1
Non-Neurologic Toxicity (Oxaliplatin and 5-FU Toxicity)
The following table describes the recommended dose 
modifications at the start of each subsequent course of 
therapy. All dose modifications should be based on the 
worst preceding toxicity.
Rev. 9/11
Rev. 12/08
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Rev 9/11
Toxicity NCI CTCAE v4.0 Grade 
(Value)
NOTE:
 Dose modifications must be based on Aes observed during the cycle (column 2) and 
on the scheduled cycle day 1 (column 3). Dose modifications must be based on the 
AE requiring the greatest modification.
COLUMN 2
Worst Interval Toxicity
(Modifications for Aes that occurred during a 
cycle but DID NOT REQUIRE DELAY IN 
TREATMENT.)
COLUMN 3
Day of Treatment
(Modifications for Aes that require a DELAY 
IN 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
Reduce oxaliplatin one dose level
Omit bolus 5-FU and reduce infusional 
5-FU and oxaliplatin one dose level 
If ANC < 1200 at start of cycle, hold and check 
weekly then treat based on worst interval toxicity.  
If ANC < 1200 after 4 weeks, discontinue 
therapy.
Thrombocytopenia1
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 bolus 5-FU and oxaliplatin by one dose 
level
Omit bolus 5-FU; reduce infusional 5-FU one dose 
level; reduce oxaliplatin by two dose levels
If PLT < 75,000 at start of cycle, hold and check 
weekly then treat based on worst interval toxicity. 
If PLT < 75,000 after 4 weeks, discontinue 
therapy.
Other hematologic toxicities do not 
require dose modification; however 
red blood cell transfusion should be 
strongly considered for hemoglobin 
< 8 g/dl.
Diarrhea
Grade 1
Grade 2
Maintain dose level
Maintain dose level
Reduce both bolus 5-FU and infusional
Hold if any grade of diarrhea above baseline is 
present with the patient not taking anti-diarrheal 
agents within 24 hours of treatment. Reduce 
Rev. 7/07
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Grade 3
Grade 4
5-FU one dose level
Reduce both bolus and infusional 5-FU and 
oxaliplatin by one dose level
drugs per worst interval toxicity (column 2) upon 
resolution of diarrhea. If Grade ≥ 2 after 4 weeks, 
discontinue therapy.
Stomatitis
Grade 1
Grade 2
Grade 3
Grade 4
Maintain dose
Maintain dose
Reduce both bolus and infusional 5-FU one dose 
level
Reduce both bolus and infusional 5-FU and 
oxaliplatin by one dose level
Hold until resolved then dose as follows:
Maintain Dose
Maintain Dose
Reduce both bolus and infusional 5-FU one dose 
level
Reduce both bolus and infusional 5-FU and 
oxaliplatin one dose level
Vomiting (despite antiemetics)
Grade 1
Grade 2
Grade 3
Grade 4
Maintain dose
Maintain dose
Reduce oxaliplatin one dose level
Reduce both bolus and infusional 5-FU and 
oxaliplatin one dose level
Hold until resolved then doses as follows:
Maintain Dose
Maintain Dose
Reduce both bolus and infusional 5-FU one dose 
level
Reduce both bolus and infusional 5-FU and 
oxaliplatin one dose level
R
12/08 Other nonhematologic toxicities2,3 
(except neurologic)*
Dose modifications for other nonhematologic adverse events at the start of subsequent courses of 
therapy, and at time of retreatment are the same as recommended for vomiting (above), with the 
following exception:  Reduce 5-FU bolus and infusion by one dose level for other Grade ≥ 3 non-
hematologic events. 
* Exceptions: alopecia, anorexia, fatigue, nausea/vomiting if can be controlled by antiemetics.
1 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), Anti-thrombin III (ATIII), von Wildebrand Factor (VWF), anti-nuclear antibodies (ANA), rheumatoid factor (RhF), 
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C3, C4, CH50, anti-platelet antibodies, platelet associated IgG, circulating immune complexes. Oxaliplatin should be discontinued for any 
suspected occurrence of HUS or TTP.
2 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.
3 Dose modifications should only be applied for those untoward events (including but not limited to metabolic or vascular toxicities) that 
might bear some relationship to study treatment. 
R
12/08
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5.4.1.2
Dose Modifications of Oxaliplatin for Neurologic and 
Pulmonary Toxicity
Neurologic Toxicitya
Paresthesias/Dysesthesias
1-7 day duration
> 7 day durationb
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 is ruled out.
x
If non-infectious interstitial lung disease is confirmed, 
oxaliplatin must be discontinued.
x
If non-infectious interstitial disease is ruled out and infection (if 
any) has resolved, patients with persistent Grade 2 dyspnea or 
hypoxia can resume treatment at the physician’s discretion.
Rev. 
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. If > 
grade 1 toxicity persists after 4 weeks’ hold, discontinue oxaliplatin.  Continue 5-FU + LV (all patients) and 
bevacizumab (Arm B) while oxaliplatin is held.
5.4.2
Dose Modifications for Bevacizumab (Arm B only)
NOTE:
There are no reductions in the bevacizumab dose (Arm B 
only). If Aes occur that require holding the bevacizumab 
dose, the dose will remain 5 mg/kg when treatment 
resumes. Bevacizumab will end 12 months after 
administration of the first dose regardless of the number of 
missed doses due to toxicity or for any other reason.
NOTE:
If 5-FU/LV and/or oxaliplatin are held due to 
chemotherapy-related Aes, bevacizumab COULD be 
continued if it is preferred to keep the schedule on two-
Rev. 7/07
Rev. 12/08
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week interval with all drugs together unless the patient’s 
medical condition precludes this.
NOTE:
Patients assigned to receive bevacizumab who discontinue 
oxaliplatin prior to completion of the scheduled 12 cycles of 
therapy may continue bevacizumab in conjunction with 5-
FU/LV for the remainder of the 12-cycle course, while 
patients who discontinue all components of FOLFOX 
chemotherapy (5-FU, LV, and oxaliplatin) prior to 
completion of the scheduled 12 cycles may continue 
bevacizumab for the remainder of the treatment course.
NOTE:
If bevacizumab is held or must be discontinued before 
completion of chemotherapy, 5-FU/LV and oxaliplatin 
should be continued.
Table 5.4.2
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/hyper-
sensitivity (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 re-instituted 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.
x
If the planned duration of full-dose anticoagulation is  2 
weeks, hold bevacizumab until anticoagulation is complete.
x
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 and:
 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.
4
Permanently discontinue bevacizumab.
Visceral or peripheral 
arterial ischemia
2b, c, 3 or 4
Permanently discontinue bevacizumab.
Adverse Event
Grade
Action to be Taken
Rev. 9/11
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CTCAE v4.0
Cardiac 
ischemia/infarction
2b, 3 or 4
Permanently discontinue bevacizumab.
CNS ischemia
2b, 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.
Rev. 
1/06, 
7/07, 8/10
Proteinuria
Grade 2 
(only if ! 
2g/24 hrs)
Hold bevacizumab until proteinuria improves to  2g of protein in a 24-
hour urine collection. Re-check 24-hour urine protein every 2-4 weeks.  
If proteinuria does not improve to  2g/24 hrs within 3 months, 
permanently discontinue bevacizumab.
For 2+ dipstick: may administer bevacizumab; obtain 24 hour urine prior 
to next bevacizumab dose.
For 3+ dipstick: Obtain 24 hour urine prior to bevacizumab 
administration.
Chemotherapy (without bevacizumab) may be continued at the 
physician’s discretion while awaiting results of the 24-hour urine 
collection.
Grade 3
Hold bevacizumab. Resume when proteinuria is < 2 grams/24 hours, as 
determined by 24-hour collection < 2.0g
Chemotherapy (without bevacizumab may be continued at the 
physician’s discretion while awaiting results of the 24-hour urine 
collection.
Grade 4
Permanently discontinue bevacizumab.
Rev. 
11/06, 
7/07
Reversible Posterior 
Leukoencephalopathy 
Syndrome (RPLS)
Bevacizumab should be held in patients with symptoms/signs 
suggestive of RPLS, pending work-up and management, including 
control of blood pressure. MRI should be performed.  Bevacizumab 
should be discontinued upon diagnosis of RPLS. If RPLS is not 
diagnosed, bevacizumab may be resumed when presenting symptoms 
are < grade 1 and blood pressure is < 150/90.
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 
Rev. 9/11
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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 Dermatology/Skin 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. 
5.5
Supportive Care 
All supportive measures consistent with optimal patient care will be given 
throughout treatment.
Loperamide (Imodium): Patients will be instructed to begin taking loperamide at 
the earliest signs of a poorly formed or loose stool.  Loperamide should be taken 
in the following manner:  4 mg at the first onset of diarrhea, then 2 mg every two 
hours around the clock until the patient is diarrhea-free for at least 12 hours.  
Patients may take loperamide 4 mg (2 capsules) every four hours during the 
night. (Refer to Appendix IX, Diarrhea Management Instructions.)
Atropine: Diarrhea or abdominal cramping that occurs can be treated with 
atropine (0.25 to 1 mg IV as indicated).  Patients having recurrent problems with 
cholinergic symptoms may receive atropine prophylactically (sc or IV).  Additional 
antidiarrheal measures may be used at the discretion of the treating physician.
Antibiotics (for patients with persistent diarrhea): Begin oral fluoroquinolone and 
continue for 7 days. If diarrhea persists for greater than 48 hours, parenteral 
hydration is recommended (including hospitalization for such). Oral 
fluroquinolone treatment also should be initiated for patients who develop an 
ANC ≤ 500 /mm³ (even in the absence of fever or diarrhea) or a fever that occurs 
with diarrhea (even without neutropenia). Antibiotics should continue until 
resolution of diarrhea. (15)
Antiemetics: Oxaliplatin is emetogenic. All patients receiving oxaliplatin (Arm A 
and Arm B) should be pre-medicated with an acceptable anti-emetic regimen. 
Patients may receive dexamethasone 10 mg IV as pre-treatment antiemetic 
unless there is a relative or absolute contraindication to corticosteroids. Other 
antiemetics may be used in addition to the suggested regimen, if clinically 
indicated. As the majority of patients on previous trials have not experienced 
significant nausea, antiemetics other than decadron are recommended only for 
those patients who demonstrate nausea and/or vomiting despite treatment with 
decadron.
Routine use of antiemetics prior to treatment with standard dose 5-FU is rarely 
indicated. It is recommended that patients not be given routine antiemetics for 
the standard arms of the study and that antiemetics be prescribed by the treating 
physician as clinically indicated if a patient develops nausea and/or vomiting.
Anticoagulants: Patients who are taking warfarin may participate in this study; 
however, it is recommended the prothrombin time be monitored carefully (at least 
weekly). Subcutaneous heparin is permitted.
Hypersensitivity: Platinum hypersensitivity can cause dyspnea, bronchospasm, 
itching and hypoxia. Appropriate treatment includes supplemental oxygen, 
steroids, antihistamines, and epinephrine; bronchodilators and vasopressors may 
be required. Platinum hypersensitivity is an extremely rare event and should be 
treated promptly.
Rev. 7/07
Rev. 
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Oxaliplatin hypersensitivity occurs in approximately 0.5% of patients receiving 
this investigational agent. See Appendix VI for the “Comparison of the Symptoms 
and Treatment of Pharyngo-Laryngodysesthesias and Platinum Hypersensitivity 
Reactions. 
Delayed hypersensitivity reactions have been noted with oxaliplatin. If a subject 
experiences an oxaliplatin-infusion reaction, stop the infusion, administer 
standard allergic hypersensitivity reaction medications including hydrocortisone 
50 – 100 mg IV and diphenhydramine 25 mg IV. Observe patient for one hour. It 
is recommended for all subsequent doses that the patient be premedicated with 
an antihistamine of choice in addition to diphenhydramine 25 mg IV. All 
subsequent doses should be given over 4 hours. 
If the patient has a Grade 3 infusion reaction, for all subsequent infusions 
recommended premedications include:
x
Hydrocortisone 100 mg
x
Diphenhydramine 25 mg IV
x
H2 blocker (Pepcid, etc)
x
H1 blocker: antihistamine of choice
x
Prolong infusion to 6 hours
For a Grade 4 infusion reaction, permanently discontinue oxaliplatin.
Pharyngo-laryngodysesthesias: Oxaliplatin may cause discomfort in the larynx or 
pharynx associated with dyspnea, anxiety, swallowing difficulty and is 
exacerbated by cold.  Appropriate therapy includes use of anxiolytics, cold 
avoidance and monitoring. See Appendix XI for the “Comparison of the 
Symptoms and Treatment of Pharyngo-Laryngodysesthesias and Platinum 
Hypersensitivity Reactions.”
Growth Factors
Prophylactic use of G-CSF or GM-CSF is not permitted on this trial. Therapeutic 
G-CSF use in patients with serious neutropenic complications may be given at 
the investigator’s discretion and should follow ASCO Guidelines for G-CSF use. 
(Refer to latest ASCO guidelines.)
5.6
Duration of Therapy 
Patients will receive protocol therapy unless:
5.6.1
Extraordinary Medical Circumstances: If, at any time, the constraints 
of this therapy are detrimental to the patient’s health, protocol 
treatment should be discontinued. In this event, submit forms 
according to the instructions in the E5202 Forms Packet.
5.6.2
Patient recurs while on therapy.
5.6.3
Patient experiences unacceptable toxicity.
5.6.4
Patient withdraws consent.
5.7
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy 
early or were registered to Arm C, will be followed for recurrence and for survival 
Rev
Rev
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for ten years from the date of registration. All patients must also be followed 
through completion of all protocol therapy.
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6.
Measurement of Effect
6.1
Diagnosis of Colon Cancer Recurrence
The diagnosis of a first colon cancer recurrence can be made only when the 
clinical and laboratory findings meet the criteria of “acceptable” as defined below.  
Anything not listed as acceptable should be considered unacceptable for 
evidence of colon cancer recurrence and should not be an indication to alter 
protocol therapy. Any recurrence of malignant disease should be proven by 
biopsy whenever possible. At the time of colon cancer recurrence, the 
investigator should clearly indicate the site of tumor recurrence and whether 
multiple sites are involved.
Supporting documentation must be submitted following diagnosis of colon cancer 
recurrence or second primary cancer. Refer to the E5202 forms packet for data 
to be collected.
6.1.1
Abdominal and/or pelvic sites
6.1.1.1
Anastomotic
Acceptable: positive cytology or biopsy
6.1.1.2
Abdominal, pelvic and retro-peritoneal nodes
Acceptable: (i) positive cytology or biopsy, (ii) progressively 
enlarging node(s) as evidenced by two CT or MRI scans 
separated by at least a 4 week interval, (iii) ureteral 
obstruction in the presence of a mass as documented on 
CT or MRI scan, or (iv) a single CT or MRI scan showing a 
definite mass which is confirmed to be malignant by a 
positive PET scan at that site.
6.1.1.3
Peritoneum (including visceral and parietal peritoneum or 
omentum)
Acceptable: (i) positive cytology or biopsy or (ii) 
progressively enlarging intraperitoneal solid mass as 
evidenced by two CT or MRI scans separated by at least a 
4 week interval, or a single scan confirmed to be malignant 
by a positive PET scan at that site.
6.1.1.4
Ascites
Acceptable: positive cytology
6.1.1.5
Liver
Acceptable:  (i) positive cytology or biopsy or (ii) three of 
the following which are not associated with benign 
disease:
x
recent or progressive hepatomegaly, abnormal liver 
contour;
x
positive radionucleotide liver scan, or sonogram;
x
positive CT scan or MRI scan;
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x
positive PET scan which confirms abnormal CT scan or 
MRI scan and is associated with a rising CEA;
x
abnormal liver function studies; OR
x
elevated CEA, i.e. a persistent rise in CEA titer of 10 X 
the upper normal value, confirmed on two 
determinations separated by a 4-week interval, in 
patients who had a normal postoperative CEA value 
(the determination should be performed by the same 
laboratory, using the same method).
NOTE:
An elevated CEA level will, as a solitary 
finding, not be considered acceptable 
evidence of colon cancer recurrence. Non-
protocol therapy will not be instituted on the 
basis of an abnormal CEA level. It is 
suggested that when CEA elevations occur 
without other corroborative evidence of 
colon cancer recurrence (hepatomegaly, 
elevated liver function studies, positive 
radionucleotide scans, etc.), the following 
investigation should be considered: 1) 
contrast and/or endoscopic exam; 2) 
abdominal and pelvic CT scan, sonogram, 
MRI scan, PET scan, or anti CEA scan; 
and/or 3) celiac and mesenteric 
arteriography.
6.1.1.6
Pelvic mass not otherwise specified (NOS)
Acceptable: (i) positive cytology or biopsy or (ii) 
progressively enlarging intrapelvic solid mass as 
evidenced by two CT or MRI scans separated by at least a 
4-week interval or (iii) a solid mass on a single CT scan 
confirmed by a positive PET scan at that site.
6.1.1.7
Abdominal wall, perineum, and scar
Acceptable: positive cytology or biopsy
6.1.2
Non-abdominal and non-pelvic sites
6.1.2.1
Skeletal
Acceptable: For all suspected bone-only recurrences, a 
biopsy is required to demonstrate recurrence.
6.1.2.2
Lung
Acceptable: (i) positive cytology, aspirate, or biopsy or (ii) 
radiologic evidence of multiple pulmonary nodules that are 
felt to be consistent with pulmonary metastases.
NOTE:
If a solitary lung lesion is found and no other 
lesions are present on lung tomograms, CT, 
PET or MRI scan, further investigations such as 
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biopsy, needle aspiration, or resection should 
be performed. Proof of neoplastic pleural 
effusion should be established by cytology or 
pleural biopsy.
6.1.2.3
Bone marrow
Acceptable: positive cytology, aspirate, biopsy, or MRI 
scan
6.1.2.4
Central nervous system
Acceptable: (i) positive CT or MRI scan, usually in a patient 
with neurologic symptoms; or (ii) biopsy or cytology (for a 
diagnosis of meningeal involvement).
6.2
Second primary cancer
The diagnosis of a second primary cancer must be confirmed histologically 
whenever possible.
6.3
Disease-Free Survival
Date of Step 2 randomization of Arms A & B to the date of recurrence or death 
before recurrence.
Date of Step 2 registration to the date of recurrence or death before recurrence 
for Arm C.
6.4
Survival
Date of Step 2 randomization of Arms A & B to date of death.
Date of Step 2 registration to date of death for Arm C.
7.
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8.
Study Parameters
8.1
Biological Sample Submissions
Samples submitted after November 3, 2014 are to be submitted to the ECOG-
ACRIN Central Biorepository and Pathology Facility (CBPF)
The tumor risk assessment, performed by the MD Anderson Cancer Center, is 
mandatory for participation in this study and tissue samples must be received by 
the PCO NO LATER than 50 days post-surgery (see Section 10).
Blood samples for the Pharmacogenetic Ancillary are submitted only from 
patients who answer “yes” to “I agree to participate in the protein and DNA 
studies that are being done as part of this treatment trial.
Recurrent tumor block for banking should be submitted from patients who answer 
“yes” to “I agree to allow for additional specimens for research.”
Rev. 8/09
Baseline
Recurrence
Rev. 7/07
Normal Mucosa Tissue Block1
X
Rev. 7/07
Resection Tumor Tissue Block1
X
Rev. 12/08
Peripheral Blood, PAXgene DNA
X2
Rev. 8/09
Tumor Block3
X
1.
MANDATORY SUBMISSION: Tissue samples MUST be submitted within 5 
working days of step 1 registration. Submission requirements are outlined in 
Section 10.
2.
Pharmacogenetic ancillary submissions outlined in Appendix XII. Sample 
may be drawn any time while participating in the protocol, although baseline 
(prior to treatment) preferred. An ACD or EDTA tube may be submitted.
3.
Recurrent tumor blocks should be submitted as outlined in Section 10 from 
patients consenting to banking for future research studies. 
NOTE:
ECOG-ACRIN requires that all samples submitted from patients 
participating in E5202 be entered and tracked via the online ECOG-
ACRIN Sample Tracking System for purposes of monitoring 
compliance and determination of reimbursement levels. See Section 
10.3.
NOTE:
An informed consent MUST be signed prior to the submission of the 
pathology material.
8.2
Rev. 
Rev.
Rev.
Rev 8/09
Rev 8/10
Rev. 8/09
Rev. 7/07
Rev
7/07
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8.3
Therapeutic Parameters
8.3.1
Arms A and B
All required prestudy chemistries and CBC, (with differential and platelet count) as outlined in Section 3, 
should be performed ≤ 2 weeks before Step 2 RANDOMIZATION for eligibility purposes. Please see the 
table below for criteria that must be met within 2 weeks prior to TREATMENT for safety reasons. Plan 
accordingly to avoid repeating tests/assessments.
NOTE:
When recording prestudy results on the Baseline Data Form, please make sure that ALL 
relevant dates are provided. Do NOT indicate results under the date for Day 1 of protocol 
treatment unless tests were performed that day; record the actual dates.
Test/Assessment
Within 2 Weeks Prior 
to Start of Treatment
Day 1 of Each 
Treatment Cycle
6 Weeks after Final Treatment 
(Chemotherapy Arm A or 
Chemotherapy + Bevacizumab Arm B)
Follow-Up4
Rev. 1/06, 
7/07
History and Physical Exam11
X
 X8
X
X
Height/Body Surface
X
Weight
X
X
X
X
ECOG Performance Status
X
X
X
X
Drug Toxicity Assessment
     X1,11
X
X
Rev. 7/07, 
8/10, 9/10
CBC, differential, platelets
  X15
        X1,12,13
X
Rev. 7/07, 
8/10
Serum creatinine
X
        X2,12,13
Rev. 7/07, 
8/10
SGOT (AST), Total bilirubin
X
         X2,12,13
X
Rev. 11/06
Alkaline phosphatase
X
Rev. 11/06, 
7/07, 12/08
Rev. 8/10
CEA
  X14
X
X
Prothrombin time (PT) or INR, PTT6
X
Rev. 7/07, 
5/08
Colonoscopy OR Barium Enema
 X5
 X5
Serum pregnancy test (premenopausal women)
X
Biopsy
 X3
Rev. 7/07
Urine protein/creatinine (UPC) ratio
X
     X7, 12
Blood pressure
X
X
1.
Prior to each cycle of treatment.
Rev. 4/06
Rev. 8/10
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2.
To be obtained as clinically indicated, at the discretion of the principal investigator.
3.
First recurrence should be confirmed by biopsy when possible.
4.
Follow-up assessments performed every 3 months for patients within 2 years of step 2 randomization, every 6 months for patients 
3--5 years from step 2 randomization and every 12 months for patients 10 years from step 2 randomization.
NOTE: Follow-up begins after completion of chemotherapy (Arm A) or twelve (12) additional cycles of bevacizumab alone (Arm B).
5.
Performed prior to surgery or Step 1 Registration (if colonoscopy incomplete due to presence of tumor); must be done to comply with 
eligibility section 3.1.3; can usually be done safely 4 weeks after surgery. Recommended at one year post-surgery and then every 5 years 
thereafter, provided colon is polyp –and cancer – free. 
6.
For patients on full-dose warfarin, the PT (INR) should be monitored throughout the study treatment period weekly or per the physician’s 
usual practice.
7.
UPC should be done at baseline, then day 1 of every treatment for patients on Arm B only. UPC must be < 1.0. If this criterion is not met, the 
patient must have a 24-hour urine collection that demonstrates < 2 gm protein over 24 hours. UPC should be performed prior to every 3rd cycle for 
Arm B patients receiving bevacizumab. If the 24-hour urine collection is required, the bevacizumab should be held and subsequent dosing based 
on the guidelines in Section 5.4.2. Chemotherapy (without Bevacizumab) may be continued at the physician’s discretion while awaiting results of 
the 24-hour urine collection.
8.
Document aspirin use, dose and schedule. Please see forms packet for aspirin use summary form and patient submission schedule.  Administer 
aspirin diary (see Appendix IX) to patient for data collection during each treatment cycle.
9.
[Deleted in Addendum #8]
10.
[Deleted in Addendum #9]
11.
The baseline H and P should be a complete history and physical, including past medical history performed by a physician or a mid-level provider. 
An H&P should be done every 2 cycles (28 days). A focused treatment-related assessment should be done by the MD or other health 
professional during treatment to obtain toxicity information and performance status.
12.
Pretreatment labwork may be performed ≤ 72 hours prior to treatment.
13.
For Arm B patients receiving bevacizumab alone (cycles 13-24), to be obtained as clinically indicated at the discretion of the principal 
investigator.
14.
CEA may be taken within 2 weeks prior to randomization. 
15.
When Arm B patients on Bevacizumab only, CBC may be done every 2 cycles (28 days).
Rev. 8/10
Rev. 7/07, 
9/10 7/14
Rev. 1/06, 
4/06,  7/07,
12/08, 8/10, 
9/10
Rev. 11/06, 
7/07
Rev 4/06
Rev. 7/07,
Rev. 7/07, 
8/10, 9/10
Rev. 7/07, 
12/08
Rev. 8/10
Rev. 8/10
Rev. 9/10
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8.3.2
Arm C
Test/Assessment
After Surgery, before 
registration to Step 1
Follow-Up1
History and Physical Exam
X
X
Weight
X
X
ECOG Performance Status
X
X
CEA
X
colonoscopy OR Barium 
Enema
 X3
 X3
Biopsy
 X2
1.
Follow-up assessments are to be performed every 3 months for patients 
within 2 years of step 2 registration, every 6 months for patients 3--5 
years from step 2 registration and every 12 months for patients 6-10 
years from step 2 registration.
2.
First recurrence should be confirmed by biopsy when possible. To be 
obtained as clinically indicated.
3.
Performed prior to surgery or step 1 registration and is recommended at 
one year post-surgery and then every 5 years thereafter, provided colon 
is polyp- and cancer-free.
9.
Rev 8/10
Rev. 7/07
Rev. 8/10
Rev
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10.
Drug Formulation and Procurement
Information for Medicare Patients
On 1/28/05, the Centers for Medicare and Medicaid Services (CMS – formerly HCFA) 
made a special decision to cover Medicare patients enrolled in E5202 and 8 other 
Cooperative Group cancer studies. ECOG-ACRIN wants to let you know about this 
(Coverage Decision No. CAG-00179N), so Medicare beneficiaries considering E5202, 
and their families, will know that most study-related costs will be covered by Medicare.
In the event sites encounter any problem obtaining Medicare reimbursement for services 
to a patient enrolled in E5202, your institution's Finance personnel may wish to refer the 
Medicare contractor to Coverage Decision No.CAG-00179N issued January 28, 2005, 
which approves coverage for E5202, among other cooperative group trials. The Decision 
Memo from CMS, the Center for Medicare and Medicaid Services of DHHS (formerly 
HCFA), can be found at www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=90.
10.1
Bevacizumab 
10.1.1
Generic Name
Bevacizumab.  
10.1.2
Other Names
NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal 
Anti-VEGF Antibody
10.1.3
Molecular Formula
M.W. = 149 kilodaltons 
10.1.4
Trade Name
AvastinTM (Genentech, Inc)
10.1.5
Classification
Antiangiogenesis agent
10.1.6
Action
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.
10.1.7
Dose Form
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid 
ready for parenteral administration in two vial sizes:
x
Each 100 mg (25 mg/mL - 4 mL fill) glass vial contains 
bevacizumab with phosphate, trehalose, polysorbate 20 and 
Sterile Water for Injection, USP.
x
Each 400 mg (25 mg/mL - 16 mL fill) glass vial contains 
bevacizumab with phosphate, trehalose, polysorbate 20 and 
Sterile Water for Injection, USP.
Rev. 1/06
R
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10.1.8
Drug Procurement
Bevacizumab (NSC# 704865) may be requested by the Principal 
Investigator (or their authorized designees) at each participating 
institution.  Pharmaceutical Management Branch (PMB) policy 
requires that drug be shipped directly to the institution where the 
patient is to be treated.  PMB does not permit the transfer of agents 
between institutions (unless prior approval form PMB is obtained).  
Completed Clinical Drug Requests (NIH-986) should be submitted to 
the PMB by FAX (240) 276-7893 or mailed to:
Pharmaceutical Management Branch
CTEP, DCTD, NCI 
EPN, Rm. 7149 MSC 7422
9000 Rockville Pike
Bethesda, MD, 20892.
See Collaborative Agreement, Appendix VI.
10.1.9
Storage and Stability
Upon receipt, bevacizumab should be refrigerated (2° to 8°C). Do not 
freeze. Vials should not be shaken. Protect from light. Sterile, single-
use vials contain no antibacterial preservatives. Therefore, vials 
should be discarded 8 hours after initial opening.
10.1.10
Drug Preparation
Vials contain no preservatives and are intended for single use only.  
Place the calculated dose in 100 mL of 0.9% sodium chloride for 
injection. 
Bevacizumab should NOT be administered or mixed with dextrose 
solutions.
10.1.11
Dose/Administration
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 60 minutes. 
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. Infusions should be run in via 
a volumetric infusion device. Do NOT administer as an IV push of 
bolus.
10.1.12
Kinetics
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.
10.1.13
Drug Interactions
Rev
R
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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.
10.1.14
Adverse Effects
Allergy/Immunology:
Allergic reaction/hypersensitivity. Infusion-
related reactions. 
Blood/Bone Marrow:
Leukopenia, neutropenia, thrombocytopenia
Cardiac:
Hypertension/hypertensive crisis, cardiac 
ischemia/infarction, supraventricular 
arrhythmia, left ventricular dysfunction 
(congestive heart failure), hypotension, 
syncope
Constitutional symptoms: Asthenia, fever, rigors/chills, weight loss
Dermatology/skin:
Exfoliative dermatitis, complications with 
wound healing, rash, skin ulceration, 
urticaria
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
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
Infection:
Infection with normal ANC
Metabolic/Laboratory:
Increased: alkaline phosphatase, ALT 
(SGPT), AST (SGOT), Bilirubin, serum 
creatinine.  Hyponatremia and hypokalemia.
Neurology:
Cerebrovascular ischemia, dizziness, 
abnormal gait, confusion
Ocular:
Excessive lacrimation
Pain:
Abdominal pain, chest/thoracic pain, 
headache, arthralgias, myalgias, 
generalized. 
Pulmonary/
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Upper Respiratory:
Dyspnea, cough, bronchospasm/wheezing, 
voice changes (hoarseness)
Renal/Genitourinary:
Proteinuria, nephrotic syndrome
Vascular:
Life-threatening and potentially fatal arterial 
thromboembolic events: cerebral infarction, 
transient ischemic attacks, myocardial 
infarction, angina. Venous thromboembolic 
events: deep vein thrombosis, intra-
abdominal thrombosis.
NOTE:
Reversible Posterior leukoencephalopathy Syndrome 
(RPLS) or similar leukoencephalopathy syndrome RPLS or 
clinical syndromes related to vasogenic edema of the white 
matter have been rarely reported in association with 
bevacizumab therapy (< 1%). Clinical presentations are 
variable and may include altered mental status, seizure 
and cortical visual deficit.  HTN is a common risk factor 
and was present in most (though not all) patients on 
bevacizumab who developed RPLS. MRI scans are key to 
diagnosis and typically demonstrate predominantly 
vasogenic edema (hyperintensity in T2 and FLAIR images 
and hypointensity in T1 images) predominantly in the white 
matter of the posterior parietal and occipital lobes; less 
frequently, the anterior distributions and the gray matter 
may also be involved. plo RPLS is potentially reversible, 
but timely correction of the underlying causes, including 
control of BP and interruption of the offending drug, is 
important in order to prevent progression to irreversible 
tissue damage.
10.1.15
Patient Care Information
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.
2.
Monitor patient closely during infusion, for infusion related events 
and for bleeding. 
3.
Monitor blood pressure prior to each dose to assess for 
development of hypertension.
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) 
5.
Baseline urine protein must be performed and repeated with each 
treatment. If elevated, 24-hour urine collection must be 
performed, prior to every 3rd cycle.
Rev. 11/06
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6.
Therapy should be suspended several weeks before elective 
surgery and should not restart until surgical incision is fully 
healed.
7.
Treat pain, arthralgias, etc. with acetaminophen, or other pain 
relief strategies that do not interfere with the clotting cascade.
10.1.16
References
Bevacizumab (AvastinTM) Full Prescribing Information.  Genentech, 
Inc. December 2004.
Bevacizumab Investigators Brochure, Genentech, December 2003.
10.1.17
Date/Reviewer
Updated February, 2005/ Helen McFarland, PharmD (410)-502-1036
10.2
Oxaliplatin
Please refer to the FDA-approved package insert for comprehensive mixing 
instructions and adverse drug reaction information.
10.2.1
Other Names
Eloxatin®, trans-l-diaminocyclohexane oxalatoplatinum, cis-
[oxalato(trans-l-1,2-diaminocyclohexane)platinum(II)]
10.2.2
Classification
Alkylating agent
10.2.3
Mode of Action
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.
10.2.4
Storage and Stability
Oxaliplatin vials are stored at room temperature between 20oC and 
25oC excursions are permissible between 15oC and 30oC).  The 
reconstituted solution in sterile water or 5% dextrose may be stored 
for up to 24 hours at 2oC to 8oC.  After further dilution in 5% dextrose, 
the solution is stable for 6 hours at room temperature (20oC and 25oC) 
or up to 24 hours under refrigeration (2oC to8oC).
10.2.5
Dose Specifics
85 mg/m² in 250 mL to 500 mL D5W.
10.2.6
Preparation
Further dilution is needed in 250 to 500 mL of 5% dextrose prior to 
administration.
10.2.7
Route of Administration
The diluted solution of oxaliplatin in 250 mL 5% dextrose is 
administered by an infusion pump over 2 hours.
10.2.8
Incompatibilities
Rev. 7/07
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Oxaliplatin may degrade in the presence of aluminum-containing 
needles or IV infusion sets or alkaline medications (such as 
fluorouracil).  Oxaliplatin is incompatible with sodium chloride 
solutions.
10.2.9
How Supplied 
Oxaliplatin is available in two distinct dosage forms: 
x
Oxaliplatin for injection (lyophilized sterile powder) is a 
preservative-free, lyophilized powder as a white to off-white cake 
or powder contained in clear vials, sealed with an elastomeric 
stopper and a flip-off cover. It is available in 50 mg and 100 mg 
vials containing 450 mg and 900 mg of lactose monohydrate, 
respectively.  
x
Oxaliplatin injection (sterile solution) is a preservative-free, 
aqueous solution containing oxaliplatin 5 mg/mL. It is available in 
50 mg and 100 mg vials. The primary package is a clear glass 
(Type I) vial sealed with an elastomeric stopper and flip-off cover.
Oxaliplatin will be provided free-of-charge by Sanofi-Synthelabo, Inc 
and distributed by the Pharmaceutical Management Branch (PMB), 
Cancer Therapy Evaluation Program (CTEP), the Division of Cancer 
Treatment and Diagnosis (DCTD) and the National Cancer Institute 
(NCI). 
Oxaliplatin (NSC # 266046) 50 mg or 100 mg vials may be requested 
by the Principal Investigator (or their authorized designees) at each 
participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that drug be shipped directly to the institution where 
the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval form PMB is 
obtained). Completed Clinical Drug Requests (NIH-986) should be 
submitted to the PMB by FAX (240) 276-7893 or mailed to: 
Pharmaceutical Management Branch 
CTEP, DCTD, NCI 
EPN, Rm. 7149 MSC 7422 
9000 Rockville Pike 
Bethesda, MD, 20892 
See Collaborative Agreement, Appendix VI. 
10.2.10
Drug Accountability 
The Investigator, or a responsible party designated by the 
investigator, must maintain careful record of the receipt, disposition 
and return of all drugs received from the PMB, using the NCI 
Investigational Agent Accountability Record Form, available on the 
NCI home page (http://ctep.cancer.gov) or by calling the PMB at 240-
276-6575. (See the NCI Investigators Handbook for procedures on 
drug accountability and storage.)
10.2.11
Side Effects
Rev. 4/08
Rev. 12/08
Rev. 7/14
Rev. 4/08
Rev. 7/14
Rev. 
4/08,
12/08
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Refer to Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 5.3.
10.2.12
Nursing/Patient Implications
x
Do not use needles or intravenous infusion sets containing 
aluminum for the administration of oxaliplatin.
x
Monitor for neurologic symptoms.
x
Administer antiemetics as indicated by the investigator.
x
Monitor complete blood cell and platelet count prior to each 
administration.
10.2.13
References
Investigator's Brochure: Oxaliplatin.  Sanofi Winthrop, Nov. 1996.
Eloxatin® (oxaliplatin injection) Prescribing Information.  Sanofi-
Aventis, May 2006.
10.3
Fluorouracil
For complete prescribing information, please refer to the approved package 
insert.
10.3.1
Other Names
5-Fluorouracil, 5-FU, Adrucil, Efudex.
10.3.2
Classification
Antimetabolite.
10.3.3
Mode of Action
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.
10.3.4
Storage and Stability
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 140 F in a water bath. Do not allow to 
freeze.
10.3.5
Dose Specifics
400 mg/m², then 2.4 g/m².
10.3.6
Administration
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.
10.3.7
Incompatibilities
Incompatible with doxorubicin and other anthracyclines.  When giving 
doxorubicin IV push or through a running IV, flush line before giving 
Rev. 4/08
Rev. 4/08
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fluorouracil.  May form precipitate with fluorouracil in some 
concentrations.
10.3.8
Availability
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.
10.3.9
Side Effects
Hematologic:  Leukopenia, thrombocytopenia, anemia; can be dose 
limiting; less common with continuous infusion.
Dermatologic:  Dermatitis, nail changes, hyperpigmentation, Hand-
Foot Syndrome with protracted infusions, alopecia.
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.
Neurologic:  Cerebellar Syndrome (headache and cerebellar ataxia).
Cardiac:  Angina, noted with continuous infusion.
Ophthalmic:  Eye irritation, nasal discharge, watering of eyes, blurred 
vision.
Hepatic:  Hepatitis with hepatic infusion
10.3.10
Nursing/Patient Implications
Monitor CBC, platelet counts.
Administer antiemetics as indicated.
Monitor for diarrhea.  Encourage fluids and treat symptomatically - 
may be dose limiting.
Assess for stomatitis - oral care recommendations as indicated.
Monitor for neurologic symptoms (headache, ataxia).
Patients on continuous infusions may need instruction regarding 
central IV catheters and portable IV or IA infusion devices.
Inform patient of potential alopecia.
10.3.11
References
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.
10.4
Leucovorin
For complete prescribing information, please refer to the approved package 
insert.
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10.4.1
Other Names
Leucovorin Calcium, Wellcovorin‚ citrovorum factor, folinic acid, 5-
formyl tetrahydrofolate, LV, LCV.
10.4.2
Classification
Tetrahydrofolic acid derivative.
10.4.3
Mode of Action
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.
10.4.4
Storage and Stability
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 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.
10.4.5
Dose Specifics
400 mg/m2
10.4.6
Preparation
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.  
10.4.7
Administration
Intravenous infusion over 2 hours, concurrent with oxaliplatin.
10.4.8
Compatibilities
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.
10.4.9
Availability
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Commercially available in parenteral formulations (50 mg, 100 mg and 
350 mg vial).
10.4.10
Side Effects
Hematologic:  Thrombocytosis.
Dermatologic:  Skin rash.
Gastrointestinal:  Nausea, upset stomach, diarrhea.
Allergic:  Skin rash, hives, pruritus.
Pulmonary:  Wheezing (possibly allergic in origin).
Other:  Headache; may potentiate the toxic effects of fluoropyrimidine 
therapy, resulting in increased hematologic and gastrointestinal 
(diarrhea, stomatitis) adverse effects.
10.4.11
Nursing/Patient Implications
Observe for sensitization reactions.
When given with fluoropyrimidines, monitor closely for diarrhea and 
stomatitis.
10.4.12
References
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.
11.
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12.
Statistical Considerations
Based on previous molecular analysis from adjuvant studies (INT 0035 and INT 0089), it 
is assumed that 40% of all stage II patients will fall into the high risk patient group, 
defined by the combination of microsatellite stability and 18q LOH.  In the months prior 
to closing, CALGB study C89803 accrued roughly 100 stage III patients per month. 
Assuming similar success with study E5202, we expect that the GI Intergroup can enroll 
625 stage II patients per year, with 40% or 250 eligible patients per year to be 
randomized from the high risk group to either oxaliplatin + 5-FU/LV (control arm) or 
oxaliplatin + 5-FU/LV + bevacizumab (experimental arm) in a 1:1 ratio and the remaining 
60% (low risk patients) will be followed under observation.  
Given the results of the MOSAIC trial in stage II disease, it is expected that the overall 
(high risk and low risk) 3-year disease-free survival (DFS) in the control arm will be 87% 
(Andre et al., 2004, NEJM).  From recent results of an extensive analysis by Sargent and 
colleagues on the association between 3-year DFS and 5-year overall survival (OS) 
presented at ASCO 2004, we expect that the combined (high risk and low risk) 5-year 
OS will be roughly 87%.  From ECOG-ACRIN's previous experience with and analysis of 
MSI/18q markers, it is expected that the high risk control group will have 3-year DFS of 
80% and that the low risk group undergoing observation (Arm C) may exhibit 3-year DFS 
of about 90%, but that rate is not exactly known.
With 250 eligible patients per year accrued for 5.5 years (1,375 eligible high risk patients 
randomized; 3,438 eligible patients total) and three years of follow-up, there is at least 
88% power to detect a 37% difference in median disease-free survival (absolute 
difference of 5%, from 80% to 85%, at three years) using a stratified log-rank test, with 
stratification on stage (IIA versus IIB) and MSI status (MSS versus MSI-L).
Power calculations assume one-sided 0.025 level stratified log-rank tests and a 
truncated O'Brien-Fleming group sequential design (truncated at nominal significance 
level 0.0005) with 9 interim analyses of DFS starting at roughly 29% information (120 
events) and continuing every six months corresponding to scheduled ECOG-ACRIN 
Data Monitoring Committee meetings (at roughly 7-8% increments in information).  If 
accrual proceeds according to expectation, three interim analyses will be performed 
before accrual is completed.  A final analysis is expected to be conducted in year 8.5 for 
disease-free survival. Full information for the main endpoint of disease-free survival will 
occur at 420 events.
The truncated O'Brien-Fleming group sequential boundary will be used to adjust for the 
sequential testing and the use function methodology of Lan and DeMets will be 
employed to adjust the boundaries if the actual interim analyses do not correspond with 
the projected information times given here.  Simulation studies conducted by the ECOG-
ACRIN Statistical Center and others (Friedlin, Korn and George, 1999) suggest that 
overall test size is inflated by a negligible factor from the truncation, but there may be a 
small gain in terms of expected stopping time.
This study will also be monitored for early stopping in favor of the null hypothesis using 
repeated confidence interval methodology similar to that described by Jennison and 
Turnbull (1989). At each interim analysis nominal one-sided (1-alpha) confidence 
intervals on the overall survival hazard ratio comparing the experimental arm to control 
will be computed, where alpha is the nominal one-sided significance level of the use 
function boundary at the information fraction at the particular analysis time. If the 
Rev.
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NCI Update Date: December 16
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Rev. 
confidence interval does not contain the target alternative of 1.37, the ECOG-ACRIN 
DSMC may consider stopping the trial early for overall lack of a treatment difference. 
Conversely, if the experimental arm is found to be statistically superior to the control arm 
at a particular interim analysis before accrual is completed, the ECOG-ACRIN DSMC 
may consider closing the trial with early reporting of results.
For the overall survival endpoint, there is approximately 84% power to detect a 37% 
difference in median overall survival (absolute difference of 5% at 5 years, from 80% to 
85%) with the analysis conducted 5 years from the end of accrual using a one-sided 
0.025 level stratified log-rank test.
There is also interest in comparing overall survival among the non-randomized 
populations of low risk patients (60% of 3,438 total eligible patients) to high risk patients 
randomized to control (oxaliplatin + 5-FU/LV) (20% of 3,438 total eligible patients). It is 
anticipated that the low risk group will have three-year disease-free survival in excess of 
90%, but the rate is not exactly known. An unadjusted two-sided 0.05 level log-rank test 
comparing the two groups will have over 95% power to detect differences in disease-free 
survival if the low risk patients have three-year disease survival of at least 85%. 
Adjustment for other risk factors using proportional hazards regression will be used in 
the final analysis and power is expected to be reduced slightly in those analyses.
Calculations are based on the accrual and follow-up assumptions given above. The 
ECOG-ACRIN DSMC will closely monitor the accrual rate and the accrual patterns for 
both the low- and high-risk patient populations at each of its semi-annual meetings and 
advise the study team regarding progress of the trial. The consideration driving the 
accrual goal is to randomize 1,375 eligible patients. Accrual of both low- and high-risk 
patients will be stopped once that objective is reached and the overall accrual goal will 
be adjusted accordingly, based on the proportion of high-risk patients being accrued.  If 
the proportion of high-risk patients were to be much lower than assumed, then the 
DSMC will evaluate the feasibility of continuing with this study. Also, the DSMC will 
formally evaluate accrual rates 18 months after activation. At that time, if the rate of high 
risk patients being randomized has not reached at least 15 patients per month (72% of 
the anticipated rate of 250 per year), then the DSMC will re-evaluate the feasibility of 
continuing accrual.
 In addition to the usual continuous adverse event monitoring via ECOG-ACRIN's real 
time ADR mechanism, toxicity reporting through CRFs and semi-annual interim toxicity 
reporting that occurs on all ECOG-ACRIN studies, this trial will include a detailed toxicity 
review after 50 patients have accrued to each treatment arm to evaluate the rates of all 
toxicities and in particular those events that may be elevated due to the addition of 
bevacizumab (perforation, thrombosis, delays in wound healing). With 50 patients per 
arm, the 90% confidence interval around any given toxicity rate will be no wider than 
25%. To formally evaluate treatment related mortality, we will conduct a one-sample 
one-sided binomial test of CTCAE v4.0 grade 5 toxicities separately in each treatment 
arm to evaluate the hypothesis of a null treatment related mortality rate of 1.5% versus 
an unacceptably high treatment related mortality rate in excess of 3.0%. With 400 
patients in each treatment arm followed for 6 months, we will determine that the 
treatment related mortality is unacceptable if there are 10 or more patients experiencing 
grade 5 toxicity in any arm. Using the exact binomial this test has a type I error rate of 
8.2% and power of 76.2% against an alternative true toxicity rate of 3%. If the true rate is 
3.5%, the power is 89.5%. Throughout the trial we will also monitor arterial thrombotic 
events in patients 65 years and older in both arms and report findings to the ECOG-
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ACRIN DSMC. Specific events to be reported include cardiac ischemia/infarction, 
myocardial infarction, CVA, CNS cerebrovascular ischemia and other related events that 
occur.
After 50 patients per arm have been accrued, the study team will also review and 
evaluate the timing and data flow of molecular analysis results for determination of risk 
categorization to ensure that risk classification is being conducted as expeditiously as 
possible. If more than 5% of the cases have problems in the molecular analyses 
(markers unable to be evaluated), in the timing of results determination (results not 
processed within the specified time window) or in the data flow within the system (results 
not being relayed to the submitting institution and ECOG-ACRIN central office 
expeditiously) the study team will halt recruitment to the trial to evaluate the problem(s) 
and determine the appropriate solution.
The statistical design assumes the Intergroup can enroll at least 625 patients per year.  
At the time of activation this will be the only Intergroup stage II trial and the expectation 
is that the entire Intergroup will participate. Focus groups with investigators and patients 
have indicated a high degree of enthusiasm for this trial, particularly since it will 
determine which patients will receive adjuvant therapy based on a suggested degree of 
risk (molecular profile).
The total sample size for this trial, allowing for 5% ineligibility, is expected to be 3,610 
patients. Patient follow-up will be completed per protocol Section 7. All patients will be 
followed at least yearly for survival for a period of 10 years post registration. 
As described in Section 2.2, secondary endpoints include overall survival, toxicity and 
impact of tumor biological characteristics on survival. Overall survival (OS) will be 
analyzed as described above. No interim monitoring or sequential testing will be done on 
the OS secondary endpoint. In addition to the toxicity analyses described above, we will 
also tabulate and report adverse events by treatment arm and note those events that 
differ statistically between arms. No formal type I error adjustment will be done for the 
toxicity analyses. Analysis of tumor biological characteristics and their relationship to 
overall survival will be conducted between high and low risk populations as described 
above. In addition we will investigate the prognostic value of MSI within the high risk 
randomized group via the logrank test and proportional hazards regression model. We 
will also investigate the prognostic significance of MSI within the low risk subgroup but 
power is expected to be low in that population due to the expected lower event rate. 
Other correlative biological parameters will be analyzed with respect to relevant time-to-
event endpoints once the parameters have been identified and measured from the tumor 
blocks that will be banked on this protocol.
12.1
Gender and Ethnicity 
Based on previous data from INT 0035 and INT 0089, the anticipated accrual in 
subgroups defined by gender and race/ethnicity is:
Ethnic Category
Gender
Females
Males
Total
Hispanic or Latino
28
60
88
Not Hispanic or Latino
1610
1912
3522
Ethnic Category: Total of all subjects
1638
1972
3610
Rev.
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Version Date: April 30, 2014
NCI Update Date: December 16
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Racial Category
American Indian or Alaskan Native
3
0
3
Asian
13
13
26
Black or African American
165
150
315
Native Hawaiian or other Pacific Islander
0
0
0
White
1457
1809
3266
Racial Category: Total of all subjects
1638
1972
3610
We are aware of no gender or racial/ethnic group by treatment interactions using 
the adjuvant regimens being studied in this protocol and the sample size does 
not provide sufficient power to target such interactions. The analysis plan will, 
however, involve tests for gender by treatment and racial/ethnic group by 
treatment interactions.
12.2
Study Monitoring
This study will be monitored by the ECOG-ACRIN Data and Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston.
13.
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14.
Pathology Review
NOTE:
An informed consent MUST be signed prior to the submission of the 
pathology material. Samples for banking should be submitted only from 
patients who have given written consent for the use of their samples for these 
purposes.
14.1
Tumor and Normal Mucosa Block Submission
Tumor and normal mucosa blocks must be submitted for determination of 
disease recurrence risk based on 18q loss of heterozygosity (LOH) and 
microsatellite instability status as outlined in Section 11. Every effort should be 
made to submit blocks to the CBPF immediately. Blocks CANNOT be 
accepted after day 50 (post-surgery) in order to allow for molecular 
assessment.
As of November 3, 2014, recurrent tumor blocks are to be submitted to the CBPF 
for banking for future research studies.
The clinical investigator and the submitting pathologist are responsible for 
submitting representative diagnostic material for review and classification. When 
a patient is registered to the study, the submitting pathologist and clinical 
research associate should refer to Appendix II (Pathology Submission 
Guidelines) which provides the following:
x
Instruction Sheet from ECOG-ACRIN Central Biorepository and Pathology 
Facility providing details for the Submission of Pathology Materials
x
Memorandum to the submitting pathologist from 
, M.D., 
chair, ECOG-ACRIN Laboratory Science and Pathology Committee, 
providing details for the Submission of Pathology Materials
x
List of required materials
x
 Generic Specimen Submission Form (#2981)
14.2
Required Materials
14.2.1
STS-generated shipping manifest
14.2.2
Copy of the surgical pathology report. Please refer to the forms 
schedule for instruction.
In addition to the surgical pathology report, if immunologic studies 
have been performed at the home institution, it is necessary that 
these be forwarded as well.  Please submit pathology reports to the 
ECOG-ACRIN Operations Office – Boston, Attention DATA, as well as 
to the receiving laboratory. (Refer to the forms submission schedule.)
14.2.3
Mandatory Tumor and Mucosa Block Submissions from Resection 
Specimens Submissions to the ECOG-ACRIN PCO at Northwestern
Two separate formalin-fixed, paraffin embedded tissue blocks must be 
submitted: one block with normal mucosa and one block with 
resection tumor. (One block with both normal mucosa and tumor is 
acceptable if 2 blocks cannot be obtained.) 
Rev. 
Rev.
7/07,
Rev 11/06 7/07
Rev. 4/06
Rev. 4/06, 8/09
Rev.
7/07,
Rev. 8/09
Rev. 1/06
Rev. 1/06
Rev.
Rev. 7/07
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NCI Update Date: December 16
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NOTE:
If blocks cannot be submitted, 1 H&E stained slide and 10 
unstained slides of a 4 micron section mounted on 
positively-charged glass slides from each type of block 
(mucosa and tumor) are acceptable.
14.2.4
Tumor Block Submission from Recurrence Specimen – Submission to 
the ECOG-ACRIN CBPF at MD Anderson
One formalin-fixed, paraffin-embedded tumor block from resection, 
biopsy, or fine needle aspiration cell block of recurrence should be 
submitted.
NOTE:
If blocks cannot be submitted, 1 H&E stained slide and 10 
unstained slides with a 4 micron section from tumor block 
mounted on positively-charged glass slides, or a 
representative smear or filter slide from fine needle 
aspiration specimen if there is not cell block, is acceptable.
If you have any questions regarding the submission of the tumor 
blocks, please contact the ECOG-ACRIN CBPF at 844-744-2420.
14.2.5
Shipping Procedures
NOTE:
ECOG-ACRIN requires that all samples submitted from 
patients participating in E5202 be entered and tracked via 
the online ECOG-ACRIN Sample Tracking System (STS). 
See Section 10.3. An STS shipping manifest form must be 
generated and shipped with the sample submissions.
14.2.5.1
Submission Schedule 
The required tissue blocks must be submitted within five 
working days of the patient’s step 1 registration.
The tumor block from recurrence should be submitted 
within one month of collection via standard shipping.
Samples may be shipped at ambient temperature. Use a 
cool pack in warm weather.
14.2.5.2
Required samples must be shipped Federal Express 
OVERNIGHT EXPRESS for next morning delivery.
14.2.5.3
As of November 3, 2014 submit materials to:
ECOG-ACRIN Central Biorepository and Pathology 
Facility
MD Anderson Cancer Center
Department of Pathology, Unit 085
Tissue Qualification Laboratory for ECOG-ACRIN, Room 
G1.3586
1515 Holcombe Blvd
Houston, TX 77030
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local 
or International Sites)
Fax: 713-563-6506
Email: eacbpf@mdanderson.org
Rev. 8/09
Rev 7/07
Rev. 8/09
Rev. 8/09
Rev. 7/07
Rev. 8/09
Rev. 8/09
Rev. 1/06
Rev. 4/06
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Include the shipping manifest generated by the Sample 
Tracking System If STS cannot be accessed at the time 
of shipment, submit samples with Generic Specimen 
Submission Form (#2981) and log submission after 
shipping.
14.2.5.3.1
Include the shipping manifest generated by 
the Sample Tracking System AND a 
completed ECOG-ACRIN Pathology 
Material Submission Form (#638 v04.2) with 
the samples. If STS cannot be accessed at 
the time of shipment, submit samples with 
Form #638 v04.2 and log submission after 
shipping.
14.2.6
Central Sample Processing and Routing
The appropriate materials will be distributed to Dr. 
 for 
analysis. 
Blocks from recurrence will be banked for future research studies.
14.3
ECOG-ACRIN Sample Tracking System
It is required (barring special considerations) that all samples submitted on this 
trial be entered and tracked using the ECOG-ACRIN Sample Tracking System 
(STS). The software will allow the use of either 1) an ECOG-ACRIN user-name 
and password previously assigned (for those already using STS), or 2) a CTSU 
user-name and password.  
When you are ready to log the collection and/or shipment of the any samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.
Please note that the STS software creates pop-up windows, so you will need to 
enable pop-ups within your web browser while using the software. A user manual 
and interactive demos are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to get familiar 
with the software prior to using the new system.
Direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu.
14.3.1
Study Specific Notes
Generic Specimen Submission Form (#2981) (faxed to the receiving 
laboratory) will be required only if STS is unavailable at the time of 
sample submission. Indicate the appropriate Lab on the submission 
form:
x
ECOG-ACRIN CBPF
To obtain the overnight courier number, contact theCBPF (844-744-
2420). Retroactively enter all specimen collection and shipping 
information when STS is available.
15.
Rev. 1/06
Rev. 7/07
Rev. 8/09
Rev. 
11/06
Rev. 4/06, 8/09
Rev. 4/06, 7/07
Rev. 
12/08
Rev. 
12/08
Rev. 
12/08
Rev 8/09
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Version Date: April 30, 2014
NCI Update Date: December 16
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16.
Molecular Analysis for Risk Assessment/Treatment Assignment
NOTE:
Samples for the “Pharmacogenetic Laboratory Studies” are submitted as 
outlined in Appendix XII from patients who answer “yes” to “I agree to 
participate in the protein and DNA studies that are being done as part of this 
treatment trial.”
NOTE:
Pathology materials required for this assessment are outlined in Section 10.
16.1
Analysis of Tumor Markers:
PolymoIphic Dinucleotide Markers D18S69, D18S64, D18S55, D18S61, 
D18S1147 and D18S58 and Mononucleotide Markers BAT25, BAT26 and 
Transforming Growth Factors Beta Type II Receptor.
Polymorphic dinucleotide markers on 18q (D18S69, D18S64, D18S55, D18S61, 
D18S1147 and D18S58 from centromere to telomere) and three mononucleotide 
markers (BAT25, BAT26 and transforming growth factors beta type II receptor) 
are to be amplified with multiplex PCR and sequenced with the ABI 3700 
instrument in the Molecular Diagnostics Laboratory by the protocol-assigned 
technologist. Peak sizes will be quantified and the data reviewed by Drs. 
 and/or 
.
16.1.1
Tumor Marker Reporting
Microsatellite instability (MSI) status will be interpreted on the basis of 
shifts in allele size with the criterion of > 30% increase in tumor DNA 
as compared to the corresponding peak in mucosal DNA. The 5 
dinucleotide and 3 mononucleotide markers will be assessed. Tumors 
are then classified using criteria from the National Cancer Institute-
sponsored workshop on MSI in colorectal cancer (8). Results for each 
marker are recorded in the project database. 
Classification of the tumor is based on the following criteria: 
microsatellite-stable cancers have shift in none of 8 markers; cancers 
with low levels of microsatellite instability (MSI-L) have shift in 1 or 2 
of 8 alleles (< 30%); cancers with high levels of microsatellite 
instability (MSI-H) have shift in 3 or more of 8 markers (> 30%). In 
microsatellite-stable cancers, loss of an 18q allele will be determined 
by a > 50% reduction in the area under the curve in tumor for 1 of the 
2 polymorphic bands in at least 1 marker as compared to non-
neoplastic tissue. A standardized report form has been prepared and 
includes the list of each marker’s result and the interpretation of the 
case as follows:
High Risk
x
Microsatellite-stable with 18q allelic loss (fraction of markers and 
percent) 
x
Low levels of microsatellite instability (MSI-L) with 18q allelic loss 
(fraction of markers and percent)
Low Risk
x
Microsatellite-stable with retention of 18q
x
Low levels of microsatellite instability (MSI-L) with retention of 18q
Rev. 
Rev. 7/07, 12/08
Rev. 7/07
Rev. 12/08
Rev.
Rev. 
12/08
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x
High levels of microsatellite instability (MSI-H) with TGFE1RII 
mutation and retention of 18q alleles (fraction of markers and 
percent)
x
High levels of microsatellite instability (MSI-H) without TGFE1RII 
mutation and with retention of 18q alleles (fraction of markers and 
percent) 
x
High levels of microsatellite instability (MSI-H) with TGFE1RII 
mutation and 18q allelic loss (fraction of markers and percent) 
x
High levels of microsatellite instability (MSI-H) without TGFE1RII 
mutation and with 18q allelic loss (fraction of markers and percent)
x
MSI-H with 18q status uninformative
16.1.2
Notice to the Submitting Institution
The MD Anderson Laboratory will notify (via fax) the submitting 
institution and the ECOG-ACRIN Randomization Desk at the 
ECOG-ACRIN Operations Office – Boston of the results of the 
risk assessment within 4 working days of receipt of the samples 
from the ECOG-ACRIN CBPF.
The institution’s clinical research associate (CRA) will be notified of 
the disease recurrence risk status via fax from the M.D. Anderson 
Laboratory. Do not call the M.D. Anderson laboratory for results, as 
testing data cannot be provided over the telephone. As soon as M.D. 
Anderson has notified the institution’s CRA and the ECOG-ACRIN 
Operations Office – Boston, the CRA may initiate step 2 
randomization/registration (via the ECOG webpage).
If you have any questions pertaining to the test results, please 
telephone Raja Luthra at the Molecular Diagnostic Laboratory at MD 
Anderson Cancer Center at 713-794-4780 and ask for John 
Galbincea or Abdul Khitamy.
NOTE:
Due to the complexity of MSI testing, some tumor 
specimens submitted could require Laser Capture 
Microdissection (LCM). This additional procedure will delay 
the turnaround time for reporting results to the institution to 
about one week or longer. The CRA will be notified of this 
delay.
16.1.3
Sample Preparation Guidelines 
The tumor tissue and mucosa are processed to DNA separately by 
the project-assigned technologist using standard methods in the 
Molecular Diagnostic Laboratory (MDL). An aliquot of DNA for marker 
analysis, an aliquot for collaborator analysis and an aliquot for backup 
storage are prepared.
16.1.4
[Deleted in Addendum #8]
16.1.5
The duration of the pre-analytic, analytic and post-analytic phases of 
the marker analysis will be recorded in the database at the ECOG-
ACRIN Operations Office – Boston and monitored in the semi-monthly 
conference call of the GI Committee and in the meetings of the Data 
Rev. 1/06
Rev. 7/07
Rev. 7/07
Rev. 7/07
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ECOG-ACRIN
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NCI Update Date: December 16
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Monitoring Committee. Loss of more than 5% of eligible cases due to 
unsatisfactory dataflow will lead to specific corrective action of the 
systematic problems that are identified. If accrual problems related to 
molecular analysis persist uncorrected for more than 3 months, 
accrual will be suspended until satisfactory correction of the data 
generation is completed.
16.2
Institutional Reimbursements
Pathology Reimbursements
To offset material and resource costs associated with the collection and 
submission of the required tissue samples, institutions will receive 
reimbursement in the amount of $85 per case submitted. Reimbursements will be 
paid from the ECOG-ACRIN Operations Office – Boston to the submitting 
institution and mailed to the attention of the PI/SI. Payments are made annually. 
These pathology reimbursements are to be distributed to the pathologist 
responsible for collecting samples for those institutions and should not be 
used for any other purpose. Funds to support these pathology reimbursements 
are provided by a grant from Genentech.
Distribution of the pathology reimbursements require:
x
Submission of the required tissue samples - formalin-fixed, paraffin-
embedded tissue blocks of normal mucosa and resection tumor. 
x
Receipt of samples by the CBPF
x
Completion and submission of the Generic Specimen Submission Form 
(#2981) to the CBPF 
The ECOG-ACRIN CBPF is responsible for submitting an electronic file of 
samples received on a quarterly basis to the ECOG-ACRIN TST. The ECOG-
ACRIN TST will instruct the CBPF of the format and data that should be included 
in the electronic file in order to process the reimbursements.
NOTE:
Patients or their insurance companies are not to be billed for the 
collection or submission of these samples.
16.3
[Section 11.3 deleted in Addendum #10]
16.4
Sample Inventory Submission Guidelines 
Inventories of all samples collected, aliquoted and used on the above-mentioned 
laboratory study will be submitted to the ECOG-ACRIN Operations Office – 
Boston on a monthly basis.  Inventories will be transmitted electronically or by 
diskette by any laboratory holding and/or using any specimens associated with 
this study.  Electronic submissions should be transmitted to 
ecog.labdata@jimmy.harvard.edu. All other correspondence should be 
addressed to the attention of the Translational Science Team.
16.5
Lab Data Transfer Guidelines 
The data collected on the above-mentioned correlative studies will be submitted 
to the ECOG-ACRIN Operations Office – Boston by the central laboratory on a 
quarterly basis. The quarterly cut-off dates are March 31, June 30, September 30 
and December 31. Data is due at the ECOG-ACRIN Operations Office – Boston 
Rev. 1/06
Rev.
Rev. 8/09
Rev 8/09
Rev. 1/06
Rev. 
7/07,
8/09
Rev. 7/07
Rev. 7/07
Rev. 7/07, 12/08, 
8/09
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ECOG-ACRIN
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NCI Update Date: December 16
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1 week after these cut-off dates. Electronic submissions should be transmitted to 
ecog.labdata@jimmy.harvard.edu. All other correspondence should be 
addressed to the attention of the Translational Science Team.
17.
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
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18.
Records to Be Kept
Please refer to the E5202 Forms Packet for the forms submission schedule and copies 
of all forms. The E5202 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office – Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA).
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP electronically.
19.
Patient Consent and Peer Judgment
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed.
20.
References
1.
Watanbe T, Wu T-T, Catalano PJ, Ueki T, Satriano R, Haller DG, Benson III AB, 
Hamilton SR.  Molecular predictors of survival after adjuvant chemotherapy for colon 
cancer (E 2284/ E 2288). New Engl J of Med 344(16): 1196-206, 2001.
2.
International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) 
Investigators.  Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer.  J 
Clin Oncol 17(5): 1356-1363, 1999.
3.
Figueredo A, Germond C, Maroun J, Browman G, Walker-Dilks C, Wong S and the 
Gastroinestinal Cancer Disease Site Group.  Adjuvant therapy for stage II colon 
cancer following complete resection. Cancer Prevention and Control 1(5): 379-92, 
1997.
4.
Haller DG, Catalano PJ, Macdonald JS, Mayer RJ. Fluorouracil (FU), leucovorin (LV) 
and levamisole (LEV) adjuvant therapy for colon cancer: preliminary results of INT-
0089. Proc ASCO 15(486): 211, 1996.
5.
Haller DG, Catalano PJ, Macdonald JS, Mayer RJ. Fluorouracil (FU), leucovorin (LV) 
and levamisole (LEV) adjuvant therapy for colon cancer: four-year results of INT-
0089.  Proc ASCO 16(940): 265a, 1997.
6.
Haller DG, Catalano PJ, Macdonald JS, Mayer RJ.  Fluorouracil (FU), leucovorin 
(LV) and levamisole (LEV) adjuvant therapy for colon cancer: five-year final report of 
INT-0089.  Proc ASCO 17(982): 256a, 1998.
7.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, 
Griffing S, Bergsland E. Phase II, Randomized Trial Comparing Bevacizumab Plus 
Fluorour (FU)/Leucovorin (LV) with FU/LV Alone in Patients with Metastatic 
Colorectal Cancer.  J Clin Oncol 21(1): 60-65, 2003.
8.
Novotny W, Hurwitz H, Fehrenbacher L, Cartwright T, Hainsworth J, Griffing S, 
Holmgren E, Kabbinavar F. Bevacizumab (Avastin, a Monoclonal Antibody to 
Vascular Endothelial Growth Factor) Prolongs Survival in First-Line Colorectal 
Cancer (CRC): Results of a Phase III trial of Bevacizumab in Combination with Bolus 
IFL (Irinotecan, 5-Fluorouracil, Leucovorin) as First-Line Therapy in Subjects with 
Metastatic CRC. Proc ASCO, 2003.
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Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
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9.
Benson AB, Catalano PJ, Meropol NJ, O’Dwyer PJ, Giantonio BJ. Bevacizumab 
(anti-VEGF) plus FOLFOX4 in previously treated advanced colorectal cancer 
(advCRC): An interim toxicity analysis of the Eastern Cooperative Oncology Group 
(ECOG) study E3200. Proc ASCO, Abstract; 22(975): 243, 2003.
3.
deGramont A, Boni C, Navarro M, et al. Oxaliplatin/5-FU/LV in adjuvant colon 
cancer; safety results of the international randomized MOSAIC trial. Poster 
presentation: 38th ASCO Annual Meeting; May 18-21, 2002; Orlando, Florida. 
4.
deGramont A, Banzi M, Navarro M, et al. Oxaliplatin/5-FU/LV in adjuvant colon 
cancer:  results of the international randomized phase III MOSAIC trial.  Oral 
presentation:  39th ASCO Annual Meeting; May 31-June 3, 2003; Chicago, Illinois.
5.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, 
Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S.  A National 
Cancer Institute Workshop on microsatellite instability for cancer detection and 
familial predisposition: development of international criteria for the determination of 
microsatellite instability in colorectal cancer.  Cancer Res 58(22): 5248-57, 1998.
6.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin 
J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, 
Kabbinavar F. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for 
Metastatic Colorectal Cancer. New Engl J of Med 350 (23): 2335-2342, 2004.
7.
André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, 
Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A. Oxaliplatin, 
Fluoroucacil, and Leucovorin as Adjuvant Treatment for Colon Cancer. New Engl J 
of Med 350 (23): 2343-2351, 2004.
8.
Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B.  Association of tumour 
site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer.  
Lancet 2000; 355:1745-50.
9.
Ribic CM, Sargent DJ, Moore MJ, et al.  Tumor microsatellite-instability status as a 
predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.  
N Engl J Med 2003; 349:247-57.
10. Allegra CJ, Kim G, Kirsch IR.  Microsatellite instability in colon cancer. N Engl J Med 
2003; 349:1774-1776.
11. Hochster H, Chachoua A, Speyer J, et al. Oxaliplatin with weekly bolus fluorouracil 
and low-dose leucovorin as first-line therapy for patients with colorectal cancer . J 
Clin Oncol 15:2703-2707, 2003.
12. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified 
bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic 
colorectal cancer (FOLFOX6).  GERCOR. Eur J Cancer 35:1338-1342, 1999.
13. Ryan DP, Clark JW, Kulke MH, et al. A phase II study of modified deGramont 5-
fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic 
colorectal cancer.  Cancer Invest 21:505-511, 2003.
14. Andre T, Figer A, Cervantes A, et al. FOLFOX7 compared to FOLFOX4. Preliminary 
results of the randomized optimox study. Proc Am Soc Clin Oncol 22:A1016;253, 
2003.
15. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the 
reverse sequence in advanced colorectal cancer: A randomized GERCOR study.  J 
Clin Oncol 22:229-237, 2004.
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NCI Update Date: December 16
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16. C.J. Allegra, G. Yothers, M.J. O’Connell, S. Sharif, L.H. colangelo, S.H. Lopa, N.J. 
Petrelli, R.M. Goldberg, J.N. Atkins, T.E. Seay, L. Fehrenbacher, S. O’Reilly, L. Chu, 
C.A. Azar, N. Wolmark. Initial safety report of NSABP C-08: A randomized phase III 
study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment 
of patients with stage II or III colon cancer.  JCO 2009 Jul 10; 27(20): 3385-90.
17. N. Wolmark, G. Yothers, M.J. O’Connell, S. Sharif, J.N. Atkins, T.E. Seay, L. 
Feherenbacher, S. O’Reilly, C.J. Allegra. A phase III trial comparing mFOLFOX6 to 
mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon. J Clin Oncol 
2009 Jun 20; 27 (185): LBA4, 793s
18.
Rev 8/09
Rev
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Version Date: April 30, 2014
NCI Update Date: December 16
92
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix I
Informed Consent Template for Cancer Treatment Trials (English Language)
[Deleted in Addendum #13]
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT
Appendix I was removed from the protocol document in Addendum #13 and is posted as 
a separate document on the ECOG website. This was removed from the protocol to 
comply with NCI formatting guidelines.
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
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A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix II
Pathology Submission Guidelines
The following items are included in Appendix II:
1.
Guidelines for Submission of Pathology Materials 
(instructional sheet for Clinical Research Associates [CRAs])
2.
Instructional memo to submitting pathologists
3.
List of Required Materials for E5202
4.
 Generic Specimen Submission Form (#2981)
NOTE:
As of November 3, 2014 all submissions and inquiries pertaining to previous 
submissions are to be directed to the ECOG-ACRIN Central Biorepository 
and Pathology Faciltiy (CBPF) at MD Anderson, telephone 844-744-2420 or 
email: eacbpf@mdanderson.org
Rev. 
Rev. 
1/06
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
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Guidelines for Submission of Pathology Materials
Rev. 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility:
Institutional Surgical Pathology Report
Pathology materials (see attached List of Required Material)
Rev. 
1/06
 Generic Specimen Submission Form (#2981)
Instructions:
1.
Complete blank areas of the pathologist's instructional memo, and forward it, along 
with the List of Required Material and the Submission Form (if used), to the 
appropriate pathologist.
2.
The pathologist should return to you the required pathology samples and surgical 
pathology reports. If any other reports are required, they should be obtained from the 
appropriate department at this time.
3.
 Keep documentation of the submission for your records; the original should be sent 
to the CBPF.
4.
Double-check that ALL required forms, reports, and pathology samples are included 
in the package to send to the Central Biorepository and Pathology Facility (see 
appropriate List of Required Material).
Pathology specimens submitted for a patient WILL NOT be processed by the 
Central Biorepository and Pathology Facility until all necessary items are 
received.
1.
Mail pathology materials to:
ECOG-ACRIN Central Biorepository and Pathology Facility
MD Anderson Cancer Center
Department of Pathology, Unit 085
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586
1515 Holcombe Blvd
Houston, TX 77030
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites)
Fax: 713-563-6506
Email: eacbpf@mdanderson.org
If you have any questions concerning the above instructions or if you anticipate any 
problems meeting the pathology material submission deadline of one month, contact the 
Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility 
at Tel: 844-744-2420 or by email at eacbpf@mdanderson.org.
Rev. 
1/06
Rev. 
1/06
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
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List of Required Material
E5202: A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin 
versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II 
Colon Cancer at High Risk for Recurrence to Determine Prospectively the 
Prognostic Value of Molecular Markers
Pre-Treatment
1.
Generic Specimen Submission Form (#2981)
2.
Institutional surgical pathology report (must be included with EVERY pathology 
submission).
3.
Required pathology materials. (MANDATORY)
Tumor and Mucosa Block Submissions from Resection Specimen
x
Tissue block of formalin-fixed, paraffin-embedded normal mucosa
x
Tissue block of formalin-fixed, paraffin-embedded tumor
NOTE:
Two separate blocks must be submitted: one block with normal mucosa 
and one block with resection tumor. (One block with normal and tumor 
tissue is acceptable if two blocks cannot be obtained.)
NOTE:
If blocks cannot be submitted, 1 H&E stained slide and 10 unstained slides of 
a 4 micron section mounted on positively-charged glass slides from each type 
of block (mucosa and tumor) are acceptable.
Recurrence (Submit within one month of collection)
1.
Generic Specimen Submission Form (#2981)
2.
Institutional surgical pathology report (must be included with EVERY pathology 
submission).
3.
Pathology materials:
x
One formalin-fixed paraffin-embedded tumor block from resection, biopsy, or fine 
needle aspiration cell block of recurrence should be submitted.
NOTE:
If blocks cannot be submitted, 1 H&E stained slide and 10 unstained 
slides with a 4 micron section from tumor block mounted on positively-
charged glass slides, or a representative smear or filter slide from fine 
needle aspiration specimen if there is no cell block, is acceptable.
Rev. 
Rev. 1/06
Rev. 11/06
Rev. 11/06
Rev. 11/06
Rev. 7/07
Rev. 
11/06
Rev. 8/09
Rev. 4/06
Rev. 8/09
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96
MEMORANDUM
TO:
__________________________________________________
(Submitting Pathologist)
FROM:
 M.D., Chair
ECOG-ACRIN Laboratory Science and Pathology Committee
DATE:
____________________________________
SUBJECT:
Submission of Pathology Materials for E5202: A Randomized Phase III 
Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II 
Colon Cancer at High Risk for Recurrence to Determine Prospectively 
the Prognostic Value of Molecular Markers
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for mandatory studies to 
determine treatment assignment and additional pathology for banking for future research 
studies.
Keep a copy for your records and return the completed Submission Form, the surgical 
pathology report(s), the slides and/or blocks and any other required material (see 
attached List of Required Material) to the Clinical Research Associate (CRA). The CRA 
will forward all required pathology material to the ECOG-ACRIN Central Biorepository 
and Pathology Facility.
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for future studies. Blocks will be returned for purposes of patient 
management upon request.
Results of the central review of specimens submitted at trial entry will be distributed to 
the CRA upon completion of the review. There is no review associated with submission 
of the recurrence tissue. 
NOTE:
To offset materials and resource costs associated with the collection and 
submission at trial entry of the required blocks, pathologists will receive 
reimbursement in the amount of $85 per case. Reimbursements will be paid 
from the ECOG-ACRIN Operations Office – Boston to the submitting 
institution and mailed to the attention of the PI. Payments are made annually.
If you have any questions regarding this request, please feel free to contact the Central 
Biorepository and Pathology Facility at TEL:  844-744-2420 or by email at 
eacbpf@mdanderson.org.
The ECOG-ACRIN CRA at your institution is:
Name:
Address:
Phone:
Thank you.
Rev. 
Rev.
Rev
Rev. 1/06
Rev
Rev
Rev
Rev. 11/06, 
8/09
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ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3
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97
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form.
Protocol Number   
Patient ID    
Patient Initials   Last 
 First    
Date Shipped   
Courier    
Courier
Tracking Number   
Shipped To (Laboratory Name)  
Date CRA will log into STS   
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc.
Required fields for all samples
Additional fields for tissue submissions
Completed by 
Receiving Lab
Protocol Specified Timepoint:
Sample Type 
(fluid or fresh tissue,
 include collection tube type)
Quantity
Collection 
Date and Time 24 HR
Surgical or 
Sample ID
Anatomic 
Site
Disease Status 
(e.g., primary, mets, 
normal)
Stain or 
Fixative
Lab ID
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required.
Leukemia/Myelo
ma Studies:
Diagnosis
Intended Treatment Trial
Peripheral WBC Count (x1000)
Study Drug 
Information:
Therapy 
Drug Name
Date Drug Administered
Start Time 24 HR
Caloric Intake:
Date of Last Caloric Intake
Time of Last Caloric Intake 24HR
CRA Name  
CRA Phone  
CRA Email  
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Comments
9/12/14
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
99
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix III
Patient Thank You Letter
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation.
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort.
______________________________________________________________________
[PATIENT NAME]
[DATE]
[PATIENT ADDRESS]
Dear [PATIENT SALUTATION],
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer.
We believe you will receive high quality, complete care. Your physician and research 
staff will maintain very close contact with you. This is important so as to allow your 
physician to provide you with the best care while learning as much as possible to help 
you and other patients.
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you.
Sincerely,
[PHYSICIAN NAME]
Rev. 1/06
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
100
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix IV
Staging Criteria – Colon & Rectum
Rev. 7/07, 12/08, 
8/10
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NCI Update Date: December 16
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E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
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Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
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E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
105
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix V
Cancer Trials Support Unit (CTSU) Participation Procedures
REGISTRATION/RANDOMIZATION
Prior to the recruitment of a patient for this study, investigators must be registered members 
of the CTSU.  Each investigator must have an NCI investigator number and must maintain 
an “active” investigator registration status through the annual submission of a complete 
investigator registration packet (FDA Form 1572 with original signature, current CV, 
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with 
original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These 
forms are available on the CTSU registered member Web site or by calling the PMB at 240-
276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time.
Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval 
for this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of their 
registration packets by querying the Regulatory Support System (RSS) site registration 
status page of the CTSU member web site at http://members.ctsu.org 
All forms and documents associated with this study can be downloaded from the E5202 
Web page on the CTSU registered member Web site (https://members.ctsu.org).  Patients 
can be registered only after pre-treatment evaluation is complete, all eligibility criteria have 
been met, and the study site is listed as ‘approved’ in the CTSU RSS. 
Requirements for E5202 site registration:
x
CTSU IRB Certification
x
CTSU IRB/Regulatory Approval Transmittal Sheet
Prestudy requirements for patient enrollment on E5202: 
x
Patient must meet all inclusion criteria, and no exclusion criteria should apply
x
Patient has signed and dated all applicable consents and authorization forms
x
All baseline laboratory tests and prestudy evaluations performed within the time period 
specified in the protocol. 
CTSU Procedures for Patient Enrollment
Step 1 Initial Registration:
1.
Contact the CTSU Patient Registration Office by calling 1-888-462-3009. Leave a 
voicemail to alert the CTSU Patient Registrar that an enrollment is forthcoming. For 
immediate registration needs, e.g. within one hour, call the registrar cell phone at 1-301-
704-2376.
2.
Complete the following forms:
x
CTSU Patient Enrollment Transmittal Form
Rev. 3/07
Rev. 7/14
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
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x
E5202 Step 1 Eligibility Checklist
4.
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 
8:00 a.m. and 8:00 p.m., Mon-Fri, Eastern Time (excluding holidays).  The CTSU 
registrar will check the investigator and site information to ensure that all regulatory 
requirements have been met. The registrar will also check that forms are complete and 
follow-up with the site to resolve any discrepancies.
5.
Once investigator eligibility is confirmed and enrollment documents are reviewed for 
compliance, the CTSU registrar will contact the ECOG-ACRIN.  The CTSU registrar will 
access the ECOG-ACRIN’s on-line registration system, to obtain and assignment of a 
unique patient ID (to be used on all future forms and correspondence).  The CTSU 
registrar will confirm registration by fax. 
x
Mandatory tissue sample must be submitted for tumor risk assessment within 5 
working days of registration to Step 1 (see Section 10). Results of the risk 
assessment will be reported to the submitting institution’s CRA and the ECOG-
ACRIN Operations Office – Boston via fax from MD Anderson Laboratory within 4 
working days of receipt of the samples.
Step 2: Randomization to Arm A or B / Registration to Arm C:
1.
Contact the CTSU Patient Registration Office by calling 1-888-462-3009. Leave a 
voicemail to alert the CTSU Patient Registrar that an enrollment is forthcoming. For 
immediate registration needs, e.g. within one hour, call the registrar cell phone at 1-301-
704-2376.
2.
Complete the following forms:
x
CTSU Patient Enrollment Transmittal Form (include patient id #)
x
E5202 Step 2 Eligibility Checklist
6.
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 
8:00 a.m. and 8:00 p.m., Mon-Fri, Eastern Time (excluding holidays).  The CTSU 
registrar will check the investigator and site information to ensure that all regulatory 
requirements have been met. The registrar will also check that forms are complete and 
follow-up with the site to resolve any discrepancies.
7.
Once investigator eligibility is confirmed and enrollment documents are reviewed for 
compliance, the CTSU registrar will contact the ECOG-ACRIN.  The CTSU registrar will 
access the ECOG-ACRIN’s on-line registration system and obtain a randomization 
assignment (Arm A or B) for high risk patients or to register low risk patients to Arm C 
observation. The CTSU registrar will confirm registration by fax.
x
High risk patients must not start protocol treatment prior to Step 2 randomization.
x
Protocol treatment on Arms A and B should begin within 5 working days from step 2 
randomization.
x
Observation for Arm C patients begins at Step 2 registration.
DATA SUBMISSION AND RECONCILIATION
1.
All case report forms (CRFs) associated with this study must be downloaded from the 
E5202 Web page located on the CTSU registered member Web site 
(https://members.ctsu.org). Sites must use the current form versions and adhere to the 
instructions and submission schedule outlined in the protocol.
Rev. 
7/07
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NCI Update Date: December 16
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2.
Submit all completed CRFs (with the exception of patient enrollment forms) and clinical 
reports directly to the ECOG-ACRIN [refer to contacts table] unless an alternate location 
is specified in the protocol. Do not send study data to the CTSU.
8.
The ECOG-ACRIN Operations Office – Boston will mail query notices and delinquency 
reports directly to the site for reconciliation. Please send query responses and 
delinquent data to the ECOG-ACRIN Operations Office – Boston and do not copy the 
CTSU Data Operations. Each site should have a designated CTSU Administrator and 
Data Administrator and must keep their CTEP AMS account contact information current. 
This will ensure timely communication between the clinical site and the ECOG-ACRIN 
Operations Office – Boston.
SPECIAL MATERIALS OR SUBSTUDIES
All specimens submitted for this study must be entered and tracked using the ECOG-ACRIN 
Sample Tracking System. You can also access the Tracking System from the CTSU 
Member Web Site. Go to the E5202 protocol page and click on the link provided under the 
Case Report Forms header. Questions may be sent to ecog.tst@jimmy.harvard.edu.
1.
Pathology Submission (Protocol Section 10 and 11)
x
Mandatory biological sample submission for tumor risk assessment at baseline.
x
Pathology samples requested at recurrence for banking for future research.
x
Collect, prepare, and submit specimens as outlined in the protocol.
x
Do not send specimens or supporting clinical reports to the CTSU.
9.
Specimen collection for ancillary study (Protocol Appendix XII)
x
Participation in the ancillary study is optional and requires patient consent.
x
Collect, prepare, and submit specimens as outlined in the protocol.
x
Do not send specimens or supporting clinical reports to the CTSU.
SERIOUS ADVERSE EVENT (AE) REPORTING (Section 5.2)
1.
CTSU sites must comply with the expectations of their local Institutional Review Board 
(IRB) regarding documentation and submission of adverse events.  Local IRBs must be 
informed of all reportable serious adverse reactions. 
10. CTSU sites will assess and report adverse events according to the guidelines and 
timelines specified in the protocol. You may navigate to the CTEP Adverse Event Report 
System (CTEP-AERS) from either the Adverse Events tab of the CTSU member 
homepage (https://members.ctsu.org) or by selecting Adverse Event Reporting Forms 
from the document center drop down list on the E5202 Web page.
11. Do not send adverse event reports to the CTSU.
12. Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, or 
ALL via the CTEP-AERS website (http://ctep.cancer.gov). Submit the completed form 
and supporting documentation as outlined in the protocol.
DRUG PROCUREMENT (Section 8.0)
Investigational IND agents: Bevacizumab (Note that the PMB will ship drug only to the 
shipping address specified by the CTSU investigator on their FDA form 1572.)
Commercial Agents: Oxaliplatin*, Leucovorin, 5-Fluorouracil.
Rev. 12/08
Rev. 7/07
Rev. 7/07
Rev. 
12/08
Rev. 12/08
Rev. 8/09
Rev. 7/07
Rev. 12/08
Rev. 
2 08
Rev. 
7/07
Rev. 
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
108
*Oxaliplatin will be provided free of charge by Sanofi-Synthelabo and distributed by the 
PMB.
1.
Information on drug formulation, procurement, storage and accountability, 
administration, and potential toxicities are outlined in Section 8.0 of the protocol.
2.
You may navigate to the drug forms by selecting Pharmacy Forms from the document 
center drop down list on the E5202 Web page. 
REGULATORY COMPLIANCE AND MONITORING
Study Audit
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 
314 and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation 
Program (CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the conduct of 
clinical trials and study data validity, all protocols approved by NCI/CTEP that have patient 
enrollment through the CTSU are subject to audit.
Responsibility for assignment of the audit will be determined by the site’s primary affiliation 
with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered 
through CTSU will become the responsibility of the Group receiving credit for the enrollment. 
For CTSU Independent Clinical Research Sites (CICRS), the CTSU will coordinate the 
entire audit process.
For patients enrolled through the CTSU, you may request the accrual be credited to any 
Group for which you have an affiliation provided that Group has an active clinical trials 
program for the primary disease type being addressed by the protocol. (e.g., NSABP 
members may only request credit for protocols pertaining to breast or colorectal cancers).  
Registrations to protocols for other disease sites may still take place through CTSU without 
receiving credit for your NSABP activities. Per capita reimbursement will be issued directly 
from CTSU.
Details on audit evaluation components, site selection, patient case selection, materials to 
be reviewed, site preparation, on-site procedures for review and assessment, and results 
reporting and follow-up are available for download from the CTSU Operations Manual 
located on the CTSU Member Web site.
Health Insurance Portability and Accountability Act of 1996 (HIPAA)
The HIPAA Privacy Rule establishes the conditions under which protected health 
information may be used or disclosed by covered entities for research purposes. Research 
is defined in the Privacy Rule referenced in HHS 45 CFR 164.501. Templated language 
addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA Authorization Form 
located on the CTSU website. 
The HIPAA Privacy Rule does not affect participants from outside the United States. 
Authorization to release Protected Health Information is NOT required from patients enrolled 
in clinical trials at non-US sites.
Clinical Data Update System (CDUS) Monitoring
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. The 
sponsoring Group fulfills this reporting obligation by electronically transmitting to CTEP the 
CDUS data collected from the study-specific case report forms.
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
109
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix VI
Collaborative Agreement
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as ACollaborator(s)@) and the NCI Division of 
Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in 
addition to the provisions in the AIntellectual Property Option to Collaborator@ contained 
within the terms of award, apply to the use of the Agent(s) in this study:
1.
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies  utilizing investigational Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement. A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov.
2.
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data.@):
a.
NCI must provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol.
b.
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent.
c.
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent.
13. Clinical Trial Data and Results and Raw Data developed under a collaborative 
agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate. All data made available will comply with HIPAA regulations.
14. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
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Version Date: April 30, 2014
NCI Update Date: December 16
110
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them.
15. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data and Safety Monitoring Committee 
(DSMC), if there is a DSMC for this clinical trial.
16. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication. Collaborator(s) will have 30 days from the date of receipt 
for review. Collaborator shall have the right to request that publication be delayed for 
up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected. Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must 
also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI
Executive Plaza North, Suite 7111
Bethesda, Maryland 20892
FAX 301-402-1584
Email: anshers@ctep.nci.hih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator=s confidential/ proprietary information.
Rev. 
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
111
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix VII
Shipment Notification Form
NOTE:
Generic Specimen Submission Form (#2981) (faxed to the receiving laboratory) will 
be required only if STS is unavailable at the time of sample submission. Indicate the 
appropriate Lab on the submission form:
x
COG-ACRIN CBPF
Retroactively enter all specimen collection and shipping information when STS is available.
Rev. 7/07
Rev. 1/06, 12/14
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
112
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix VIII
Procedure for Obtaining a Urine Protein/Creatinine Ratio
1) Obtain at least 4 ml of a random urine sample (does not have to be a 24 hour urine) 
2) Determine urine protein concentration (mg/dL) 
3) Determine urine creatinine concentration (mg/dL) 
4) Divide #2 by #3 above: urine protein / creatinine ratio = protein concentration (mg /dL) / 
creatinine concentration (mg /dL)
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a 
UPC of 1 should be equivalent to 1g protein in a 24hr urine collection)
Protein and creatinine concentrations should be available on standard reports of urinalyses, not 
dipsticks.  If protein and creatinine concentrations are not routinely reported at an Institution, 
their measurements and reports may need to be requested.
Rev 1/06
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
113
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix IX
Patient’s Aspirin Use Diary
Directions:
1.
Please complete and return this diary to your doctor at the start of each cycle of 
treatment.
2.
Please record the date, amount of aspirin and why you took aspirin (examples: pain, 
heart disease or stroke prevention) on this diary.
3.
If no aspirin was taken since your last cycle of treatment, please check below:
______NO aspirin since last cycle of treatment
Date
Dose
Reason for taking aspirin
NOTE:
Baby aspirin is 81 mg
Rev. 1/06, 4/06
Rev. 11/06
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ECOG-ACRIN
E5202
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Version Date: April 30, 2014
NCI Update Date: December 16
114
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix X
Diarrhea Management Instructions
How to Manage Diarrhea
While you are receiving the chemotherapy drugs, you may experience diarrhea. In some 
individuals, diarrhea has been severe.  Therefore, it is important that you follow the instructions 
noted below if you experience diarrhea while being treated.
What Is Diarrhea?
Diarrhea is when your bowel movements are loose or watery and more frequent than is usual 
for you. In order to help manage the diarrhea that your treatment may cause, you will need to 
keep track of your bowel movements. Keeping a diary may be the easiest way to do this. The 
diary should record how many bowel movements you have during the day, when they occur and 
the consistency of the stool (formed, loose or watery). Having diarrhea for a long period of time 
can result in problems such as dehydration. It is best to treat it early when it first begins. You 
should contact you doctor or nurse if you begin experiencing this side effect.
What Do I Take To Stop the Diarrhea?
The medication used to treat the diarrhea is called loperamide. The most common brand of 
loperamide is Imodium. Loperamide comes in the form of a 2 milligram (mg) caplet and is 
available without a prescription at most pharmacies and grocery stores in the health and beauty 
aids section. 
The loperamide may cause some side effects. These side effects are drowsiness, tiredness and 
dizziness. It is important to avoid driving motorized vehicles or operating machinery if you 
experience any of these side effects.
When Should I Start Taking the Loperamide and For How Long?
At the first sign of diarrhea you will need to begin taking loperamide (Imodium) according to the 
directions below. (These will differ from the usual instructions found on the label.) If you do not 
start taking loperamide right away, severe diarrhea can occur that could require hospitalization. 
It is also important to stop taking any laxatives (medications to treat constipation such as milk of 
magnesia, Colace, Dulcolax, or Senakot).
Please follow these instructions carefully:
x
Take two caplets (4 mg) at the first sign of any change in your normal bowel movement as 
described above.
x
Continue taking one caplet (2 mg) every 2 hours until you have returned to your normal 
pattern of bowel movements for at least 12 hours.  It is important to continue taking the 
loperamide even during the night.  However, during the night you can take two caplets 
(4mg) every four hours instead of one caplet (2 mg) every two hours.
x
Be sure to drink plenty of fluids each day (several glasses of water, fruit juice, soda, soup, 
etc). It is important to try to replace fluid that is being lost because of the diarrhea. This will 
help prevent dehydration and will not cause more diarrhea. You should avoid caffeinated 
beverages (coffee, tea, cola), alcoholic beverages and dairy products.
Rev. 7/07
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NCI Update Date: December 16
115
x
Avoid high roughage foods like high-fiber cereals containing bran or whole grain, broccoli, 
cabbage, beans, fresh vegetables or fruit, fried food, chocolate or doughnuts.
Please call your doctor or nurse if you have any questions about taking loperamide, if your 
diarrhea does not improve, or if you experience new symptoms.
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
116
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix XI
Comparison of Symptoms and Treatment Pharyngo-Laryngodysesthesias 
and Platinum Hypersensitivity Reactions
Clinical Symptoms
Pharyngo-Laryngeal Dysesthesias
Platinum Hypersensitivity
Dyspnea
Present
Present
Bronchospasm
Absent
Present
Laryngospasm
Absent
Present
Anxiety
Present
Present
O2 saturation
Normal
Decreased
Difficulty swallowing
Present (loss of sensation)
Absent
Pruritis
Absent
Present
Urticaria/rash
Absent
Present
Cold-induced Sx
Yes
No
BP
Normal or increased
Normal or decreased
Treatment
Anxiolytics, observation in a 
controlled clinical setting until 
symptoms abate or at the 
physician’s discretion
Oxygen, steroids, 
epinephrine, antihistamines, 
bronchodilators; fluids and 
vascopressors, if 
appropriate.
Rev. 7/07
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ECOG-ACRIN
E5202
Cancer Research Group
Version Date: April 30, 2014
NCI Update Date: December 16
117
A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix XII
Ancillary For Pharmacogenetic and Genomic Studies: 
Correlation of Pharmacogenetic Studies with Response and Toxicity of Oxaliplatin
Study Co-Chairs:
Ph.D., Pharm.D.
Ph.D., Pharm.D.
All patients participating in E5202 and E5204 are eligible to participate in this ancillary study, 
including patients currently receiving protocol treatment.  Submit only from consenting patients 
who answer “yes” to “I agree to participate in the protein and DNA studies that are being done 
as part of this treatment trial.”  
XII.1
Ancillary for Pharmacogenetic and Genomic Studies
The Ancillary for Pharmacogenetic and Genomic Studies is a series of ancillary laboratory 
studies that seek to address questions about treatment response and toxicity that may span 
several studies and/or diseases. Thus, these correlatives may fall within the purview of a single 
disease committee, or span several. Each pharmacogenomic ancillary to be conducted in 
ECOG-ACRIN will be embedded into the parent protocols, with participation in the ancillary 
obtained via responses to questions embedded in the parent consent form. The general 
objectives of the pharmacogenetic ancillary are not specific to any one parent protocol: 
however, specific correlative objectives may be driven by the parent or related parent protocols.
The development of novel targeted agents for the treatment of cancer has altered the process of 
the investigation of new treatments through the various stages of clinical research.  
Simultaneously, advances in biology have brought new questions regarding the mode of action, 
the toxicity, and the efficacy of treatments into the Phase II and III arena, historically the purview 
of the cooperative group.  Some of the questions raised must be addressed in each tumor 
separately; others are independent of the tumor type and are properly asked across studies.  
The major questions may be summarized:
a.
What tumor characteristics are responsible for some patients responding and others 
not? 
b.
What are the characteristics of normal tissues that cause some patients to have side-
effects and others not?
c.
When a treatment is administered at a particular dose, does it achieve the desired effect 
at the level of its target, in tumor and/or in normal tissue?
d.
Can this variation in tumor and normal tissue make-up, and in biological responses to 
treatment be related to the outcome of such treatment in such a way as to refine that 
treatment for future patients?
The answers to these questions are in the tumors and tissues of patients treated on therapeutic 
trials. The analyses that accompany these studies are therefore of major importance to 
understanding both the successes and the failures of the trials.
Rev. 12/08, 12/14
Rev. 
8/09
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The primary focus of the ancillary is in the acquisition of materials to permit pharmacogenetic 
and pharmacogenomic analyses to be performed.  The overall purpose of these analyses is to 
explain and predict variability in drug responses among patients. The central hypothesis of the 
studies under this ancillary is that safe and effective drug use depends on an understanding 
of variability in both normal and tumor cells in individual patients.
XII.2
Correlation of Pharmacogenetic Studies with Response and Toxicity study of 
Oxaliplatin
XII.2.1
Sample Submissions
Submit from patients who answer “yes” to “I agree to participate in the protein 
and DNA studies that are being done as part of this treatment trial.”
Kits for sample collection and shipment are requested by contacting the 
Zemotak-International. Complete the KIT ORDER FORM (Appendix XII) and 
fax to (800)-815-4675.
It is required that all samples submitted from patients participating in E5202 be 
entered and tracked via the online ECOG-ACRIN Sample Tracking System 
(see Section 10.3).
LABELING
All samples are to be labeled with the ECOG-ACRIN protocol number E5202-
PG0207, the ECOG-ACRIN patient sequence number, date and time of 
collection, and type of material (e.g. PAXgene DNA).
A. Tissue
Tumor tissue blocks submitted per Section 10 will be used for these 
studies.
Additional tumor tissue blocks, if available, are requested.  Submit with 
appropriate pathology and surgical reports, and a completed Generic 
Specimen Submission Form (#2981)
B. Peripheral Blood
Peripheral blood (Paxgene DNA, ACD, or EDTA tube) is to be drawn from 
each patient at any time after registration (preference: prior to the start of 
treatment or within the first 60 days after entry to the protocol). Invert tube 
gently 8-10 times to mix contents.
Samples may be shipped overnight at room temperature the day of 
collection or stored at -20˚C and shipped with a frozen kool pack within 2 
weeks of collection.  If several patients are accrued by the site, samples 
may be stored at -70˚C and batch shipped on dry ice on a quarterly basis.
Shipping Guidelines
Timeline and conditions for shipment of PAXgene tube is outlined above. 
Tissue submission guidelines are provided in Section 10. 
A shipping manifest generated from the ECOG-ACRIN STS system must 
accompany the samples.
Ship overnight to:
ECOG-ACRIN Central Biorepository and Pathology Facility
Rev. 8/10
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ECOG-ACRIN
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Version Date: April 30, 2014
NCI Update Date: December 16
119
MD Anderson Cancer Center
Department of Pathology, Unit 085
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586
1515 Holcombe Blvd
Houston, TX 77030
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites)
Fax: 713-563-6506
Email: eacbpf@mdanderson.org
Blood samples are to be shipped overnight SUNDAY THROUGH THURSDAY 
only. Do not ship samples the day before a Holiday.
If the STS is unavailable, an Generic Specimen Submission Form (#2981) 
must be submitted with the blood specimens and the laboratory must be 
notified of overnight shipment by emailing a completed Shipment Notification 
Form (Appendix XIII) to eacbpf@mdanderson.org the day of the shipment. 
Once STS is available, it is requested that samples be retrospectively logged 
into STS, using the actual collection and shipping dates.
XII.2.2
Objectives
To identify SNP profiles corresponding to response and/or toxicity (combination 
studies E5204 and E5202).
XII.2.3.
Polymorphisms in Transporters, detoxifying enzymes, and excisions repair 
genes
Polymorphisms in copper influx transporter CTR1 [SLC31A1], copper influx 
transporters [ATP7A and ATP7B], detoxifying enzymes [GSTP1 and GSTM1], 
excision repair genes [ERCC1, ERCC2, and XRCC1], a renal transporter 
[SLC22A2] and a hepatocellular transporter [SLCO1B3].
NOTE:
Studies on DNA isolated from peripheral blood (PAXgene DNA, 
ACD, or EDTA vacutainer).
Rationale and Preliminary Data:
Peripheral neuropathy is the main and dose-limiting toxicity of oxaliplatin.1-4  
The acute, transient neuropathy occurs in 85% to 95% of patients and is 
associated with distal and perioral parathesias/dythesias.  Resolution occurs 
within hours to days after the infusion.  While, the dose-limiting form is a 
delayed cumulative peripheral neuropathy occurring in 10% to 20% of patients 
at the severity of grade 3. The delayed, cumulative toxicity persists between 
cycles, increases in intensity with cumulative dose, and can resolve to baseline 
after discontinuation of therapy usually after 4-6 months.  The mechanism of 
delayed, cumulative neurotoxicity is unknown and prophylaxis has been 
attempted with little success.  
Factors more likely to correlate with drug disposition and explain much of the 
observed pharmacodynamic variability among individuals are being 
increasingly considered. Genetic polymorphisms in drug-metabolizing 
enzymes, drug transporter proteins, target enzymes, and DNA repair 
mechanisms may represent one key in elucidating the pharmacological 
variability.5 CTR1 (SLC31A1) is a copper transporter that has been linked to 
carboplatin, cisplatin, and oxaliplatin influx transport.6  SLC31A1 has 2 reported 
non-synonymous SNPs. Copper efflux transporters (ATP7A and ATP7B) have 
Rev. 12/08
Rev. 8/10
Rev. 8/09
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also been associated with decreased platinum in resistant cells.7,8 ATP7A and 
ATP7B have 8 and 9 reported non-synonymous SNPs, respectively.  Uptake of 
cisplatin is mediated by SLC22A2 in renal proximal tubules which may be 
linked with the renal toxicity of that platinum analogue.9  SLC22A2 has 8 
reported non-synonymous SNPs.  Unpublished data also demonstrates a 
statistically significant correlation between mRNA expression of the 
hepatocellular transporter SLCO1B3 and cytotoxicity (IC50 values) for platinum 
analogues in the NCI60 panel.10  SLCO1B3 has 3 reported non-synonymous 
SNPs.  There are other genes that have been assessed by other groups 
including excision repair genes (ERCC1, ERCC2, and XRCC1) and detoxifying 
enzymes (GSTM1, GSTP1 and GSTT1) and neuronal voltage-gated sodium 
channels (SCN1A).11-13 ERCC1 (19007T>C;N118N) and ERCC2 (K751Q) 
variants have been linked to response while GSTM1 (DEL) has been linked to 
diarrhea and neutropenia.11,12,14  The GSTP1 variant (I105V) is the only variant 
that has been linked to the onset of neurotoxicity in one study of 299 patients13 
but was negative in another study of 545 patients.11 Most recently, a sodium-
channel alpha 1-subunit (SCN1A) variant (T1067A) has been linked with 
improved response rates, overall survival, and frequency of severe toxicities 
including neuropathy.15
Genotyping:
Genomic DNA will be isolated from whole blood according to the 
manufacturer’s instructions using the QIAamp DNA Blood Midi Kit (Qiagen, 
Valencia, CA).  
The presence of ATP7A, ATP7B, ERCC2, GSTM1, GSTP1, GSTT1, SCN1A, 
SLC22A2, SLC31A1, SLCO1B3, and XRCC1 variants (see table) will be 
assessed using the polymerase chain reaction (PCR) based techniques and a 
DNA amplification protocol established in our laboratory at Johns Hopkins 
University School of Medicine. The primers for PCR will be synthesized by 
Invitrogen Life Technologies (Carlsbad, CA).  For PCR, a 25μl PCR reaction 
will be carried out using HotMaster Mix (Eppendorf, Westbury NY), 0.5μl of 
each forward and reverse primer at a 0.2μM concentration, and 200 ng of 
genomic DNA which will be run for 35 cycles. The existence of the variant will 
be determined by direct nucleotide sequencing in the forward and reverse 
direction and performed using an ABI 3730XL Sequencer in the Genetics 
Resource Core Facility, Johns Hopkins University School of Medicine. 
Genotype will be called as it relates to the Refseq consensus sequence for that 
SNP position. Some SNP’s have an available Taqman probe from ABI (Foster 
City CA). These will be run on a Real Time PCR instrument and the genotype 
will be acquired by use of allelic discrimination software and a control sample of 
each known genotype.
Gene
Potential Variants to Assess
ATP7A
720A > G (I189V) in exon 3
2161T > C (I669T) in exon 9
2263G > A (R703H) in exon 9
2454G > C (V767L) in exon 10
3687T > C (T1178H) in exon 18
4203G > A (E1350K) in exon 21
4356G > C (V1401L) in exon 22
4545A > G (I1464V) in exon 23
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121
ATP7B
1373T > G (S406A) in exon 2
1523G > C (V456L) in exon 3
2186G > A (E667k) in exon 7
2450G > A (D765N) in exon 8
2490 G > T (R778L) in exon 8
2652 A > G (K832R) in exon 10
3012G > A (R952K) in exon 12
3576T > C (V1140A) in exon 16
3777A > G (H1207R) in exon 17
ERCC1
19007T > C (N118N) in exon 4
ERCC2
934 G > A (D312N)in exon 10
2251 T > G (K751Q) in exon 23
GSTM1
GSTM1*0/*0
GSTP1
313A > G (I105V) in exon 5
341C > T (A114V) in exon 6
GSTT1
GSTT1*0/*0
SCN1A
IVS5–91 G > A alternate splicing in exon 5
2623T > C (S875P) in exon 15
3166G > A (A1056T) in exon 16
SLC22A2
160C > T (P54S) in exon 1
390G > T (T(syn)) in exon 1
481T > C (F161L) in exon 2
493A > G (M165V)in exon 2
495G > A (M165I) in exon 2
669C > T (I(syn)) in exon 3
808T > G (S270A) in exon 4
890C > G (A297G) in exon 5
1198C > T (R400C) in exon 7
1203C > T (I(syn)) in exon 7
1294A > C (K432Q) in exon 8
1398C > T (G(syn)) in exon 9
1505G > A (G502E) in exon 10
1506G > A (V(syn)) in exon 10
1587C > T (A(syn)) in exon 10
SLC31A1
199C > G(P25A) in exon 2
491C > G(T122S) in exon 4
SLCO1B3
334T > G (S112A) in exon 3
699G > A (M233I) in exon 6
1557G > A (A519A) in exon 11
XRCC1
26304C > T (R194W) in exon 6
27466G > A (R280H) in exon 9
28152A > G (Q399R) in exon 10
XII.2.4.
Statistical Considerations
The pharmacogenetic/pharmacodynamic studies of oxaliplatin are open to 
patients on the following studies with anticipated enrollment of eligible patients 
as follows: E5204 (2,100 patients), or E5202 (1,375 high-risk patients) for a 
total of 3,475 eligible patients. Throughout, it is assumed that 50% of eligible 
patients will participate and have adequate samples submitted, so that samples 
will be available for analysis for about 1,700 patients. The studies listed above 
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involve combination oxaliplatin and chemotherapy or other biologics in 
colorectal cancer.
For all studies, 85 mg/m2oxaliplatin is administered intravenously over 2 hours 
every 2 weeks, however, cycle number of cycles vary across studies; the type 
of chemotherapy or other biologics differ across the combination studies.
Due to differences in disease stage, oxaliplatin schedule, and treatment 
regimen, the effects of genotypes on outcomes may be different across 
studies.  Analyses will be conducted within individual studies, and by pooling 
across all studies as appropriate. Initial univariate analyses will not adjust for 
disease and treatment regimen differences. Additional analyses correlating 
genotypes associated with oxaliplatin activity with outcome will attempt to 
control for disease and treatment differences and their potential interactions 
with genotype on outcome using stratified analyses or adjusting for these 
factors in multivariate regression models.
Data Analysis Plan
To have a sufficiently high statistical power, we will include only SNPs with 
minor allele frequency of > 1%. However, we may include some polymorphisms 
for which the frequency was not previously known (taking the risk to include 
rare variants) but that had reasonable chances to alter the function of the gene, 
such as missense variants.  Univariate analyses will be conducted to test 
associations within subgroups between each polymorphisms and outcome of 
interest, including toxicity and disease-free survival. The overall type I error rate 
of 0.05 will be controlled within each group and for each outcome by adjusting 
the alpha level within each set of univariate tests of polymorphisms using a 
resampling based approach.
The joint association of combinations of polymorphisms on outcome will be 
explored using logistic regression (toxicity endpoints) and Cox proportional 
hazards regression (survival endpoints). These multivariate analyses will also 
control for other important predictors of outcome and will examine interactions 
between polymorphisms, disease, and treatment. Recursive partitioning and 
other exploratory regression techniques will be used to explore SNP-SNP 
interactions and gene interactions in order to identify combinations of 
polymorphisms that can be used to predict high and low risk groups.
We base power calculations on the ability to detect differences in toxicity and 
disease-free survival (DFS) by individual polymorphisms both within each 
parent protocol and combining the studies. For the former, assuming that the 
overall 3-year DFS for E5202 and E5204 to be 82.5% and 68%, respectively, 
and that 1,050 and 650 patients are participating in E1Y03, respectively, there 
will be 89% [E5204] and 87% [E5202] power to detect a 50% (100%) difference 
in median DFS (66% vs 76% at 3 years in E5204; 80.5% vs 90% at 3 years in 
E5202) if the polymorphism rate is 20% and patients with polymorphism 
sustain a better outcome. Power for these comparisons will be higher if the 
polymorphism rate is higher. Polymorphisms with lower frequency will have 
lower power in the individual studies but differences should be detectable in 
these cases by combining the two parent trials in a pooled analysis. For 
example if the polymorphism rate is 10% and polymorphism correlates to a 
worse outcome, there will be 84% power to detect a combined difference of 
42% in median DFS, combining the two parent studies. The above power 
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calculations assume a two-sided .05 level log rank test; power for detecting 
effects with proportional hazards regression models may be higher or lower 
depending upon the role of adjustment covariates in the modeling.
For toxicity, assuming a two-sided .05 level two group binomial test and an 
overall 80% rate of neurotoxicity due to oxaliplatin, the two parent protocols 
E5204 and E5202 will have 84% and 85% power to detect, respectively, 
absolute differences in toxicity rates of 12% and 15% between patients with 
and without a given polymorphism, assuming a marginal polymorphism rate of 
10% and that polymorphism correlates with higher toxicity. A pooled analysis of 
the two studies will have greater than 90% power to detect an absolute 
difference in toxicity of less than 12%. In some analyses power will still be 
reasonable if the polymorphism rates are lower than 10%. For example, in the 
E5204 analysis if the true polymorphism rate is around 5% there is roughly 
80% power to detect an absolute toxicity rate difference of 15%. For 
polymorphism with very low rates, only the pooled analyses combining studies 
will have adequate power, however. 
For analyses of higher grade neurotoxicity that might have lower rates of 
occurrence (overall 15% expected of grade 3 or higher toxicity), the individual 
protocol (E5204, E5202) analyses will have roughly 90% and 74% power to 
detect an absolute difference of toxicity rates of 12% (polymorphism/no 
polymorphism) wherease the pooled analyses of both studies together will 
have greater than 90% power to detect these differences. For the toxicity 
analyses, power for detecting effects with logistic regression models may be 
higher or lower depending upon the role of adjustment covariates in the 
modeling.
Additional genes and exploratory analyses
Additional genes found to be important to oxaliplatin resistance or sensitivity 
through anti-angiogenesis or apoptosis pathways will be explored in a similar 
manner as above.  Exploratory pathway analysis methods, including multi-
dimensional scaling (Cox and Cox, 2001) will also be used.
A comprehensive analysis will be performed using the Illumina bead to identify 
variant genes involved in oxaliplatin toxicity and outcome.  In addition to the 
genes mentioned, genes  identified in association studies using CEPH and 
non-CEPH lymphoblasoid cell lines derived from large pedigrees1617 by Drs. 
Eileen Dolan at the University of Chicago and Howard McLeod at the University 
of North Carolina may be included in the analysis.
An analysis of indirectly-measured haplotypes and their associations with 
phenotypes, possibly adjusting for other covariates and their interactions, will 
be conducted using haplo.stats software available on-line, and associations will 
be tested based on the family of score tests proposed by Schaid et al (2002), 
which assume ambiguous haplotypes due to unknown linkage phase of the 
genetic markers. The score test handles both continuous and categorical 
phenotypes.
XII.2.5.
References
1.
Mani S., Graham M. A., Bregman D. B., Ivy P., Chaney S. G.: Oxaliplatin: a 
review of evolving concepts. Cancer Invest 20:246-63, 2002
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2.
Extra J. M., Marty M., Brienza S., Misset J. L.: Pharmacokinetics and safety 
profile of oxaliplatin. Semin Oncol 25:13-22, 1998
3.
Misset J. L.: Oxaliplatin in practice. Br J Cancer 77 Suppl 4:4-7, 1998
4.
Cersosimo R. J.: Oxaliplatin-associated neuropathy: a review. Ann 
Pharmacother 39:128-35, 2005
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McLeod H. L., Papageorgio C., Watters J. W.: Using genetic variation to 
optimize cancer chemotherapy. Clin Adv Hematol Oncol 1:107-11, 2003
6.
Song I. S., Savaraj N., Siddik Z. H., Liu P., Wei Y., Wu C. J., Kuo M. T.: 
Role of human copper transporter Ctr1 in the transport of platinum-based 
antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol 
Cancer Ther 3:1543-9, 2004
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Samimi G., Katano K., Holzer A. K., Safaei R., Howell S. B.: Modulation of 
the cellular pharmacology of cisplatin and its analogs by the copper 
exporters ATP7A and ATP7B. Mol Pharmacol 66:25-32, 2004
8.
Samimi G., Safaei R., Katano K., Holzer A. K., Rochdi M., Tomioka M., 
Goodman M., Howell S. B.: Increased expression of the copper efflux 
transporter ATP7A mediates resistance to cisplatin, carboplatin, and 
oxaliplatin in ovarian cancer cells. Clin Cancer Res 10:4661-9, 2004
9.
Ciarimboli G., Ludwig T., Lang D., Pavenstadt H., Koepsell H., Piechota H. 
J., Haier J., Jaehde U., Zisowsky J., Schlatter E.: Cisplatin nephrotoxicity is 
critically mediated via the human organic cation transporter 2. Am J Pathol 
167:1477-84, 2005
10. Personal communication between 
 and, 2006
11. McLeod H. L., Sargent D. J., Marsh S., Fuchs C., Ramanathan R. K., 
Williamson S., Findlay B., Thibodeau S., Petersen G., Goldberg R.: 
Pharmacogenetic analysis of systemic toxicity and response after 5-
fluorouracil (5FU)/CPT-11, 5FU/oxaliplatin (oxal), or CPT-11/oxal therapy 
for advanced colorectal cancer (CRC): Results from an intergroup trial. 
Proc ASCO 22:253 (Abtract 1013), 2003
12. Park D. J., Stoehlmacher J., Zhang W., Tsao-Wei D. D., Groshen S., Lenz 
H. J.: A Xeroderma pigmentosum group D gene polymorphism predicts 
clinical outcome to platinum-based chemotherapy in patients with advanced 
colorectal cancer. Cancer Res 61:8654-8, 2001
13. Grothey A., McLeod H. L., Green E. M., Sargent D. J., Fuchs C., 
Ramanathan R. K., Williamson S. K., Findlay B. P., Goldberg R. M.: 
Glutathione S-transferase P1 I105V (GSTP1 I105V) polymorphism is 
associated with early onset of oxaliplatin-induced neurotoxicity. Proc ASCO 
23:248s (Abstract 3509), 2005
14. Stoehlmacher J., Park D. J., Zhang W., Yang D., Groshen S., Zahedy S., 
Lenz H. J.: A multivariate analysis of genomic polymorphisms: prediction of 
clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory 
colorectal cancer. Br J Cancer 91:344-54, 2004
15. Nagashima F., Zhang W., Yang D., Gordon M., Schultheis A., Fazzone W., 
Azuma M., El-Khoueiry A., Iqbal S., Lenz H. J.: Polymorphism in sodium-
channel alpha 1-subunit (SCN1A) predicts response, TTP, survival, and 
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toxicity in patients with metastatic colorectal cancer treated with 5-
FU/oxaliplatin. Proc ASCO 24: Abstract No. 3533, 2006
16. Shukla S. J., Dolan M. E.: Use of CEPH and non-CEPH lymphoblast cell 
lines in pharmacogenetic studies. Pharmacogenomics 6:303-10, 2005
17. Dolan M. E., Newbold K. G., Nagasubramanian R., Wu X., Ratain M. J., 
Cook E. H., Jr., Badner J. A.: Heritability and linkage analysis of sensitivity 
to cisplatin-induced cytotoxicity. Cancer Res 64:4353-6, 2004
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A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, 
Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High 
Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular 
Markers
Appendix XIII
E5202 Pharmacogenetic Collection and Shipping Kit Order Form
Date
:  
Fa
x:
(800) 815-4675
To obtain the proper kit, provide the following information:
E5202 patient case number:  _______________________
PG0207 Kit Requested:

Pharmacogenomic (PAXgene DNA or ACD tube)
Kit is to be shipped to:
Institution Contact:  ___________________________________
Phone number for contact:  _________________________________
Institution Address:
__________________________________________
__________________________________________
__________________________________________
FAX Completed form to Zemotak-International at (800) 815-4675
NOTE:
Questions are to be directed to the ECOG CBPF, 
Attn
Tel: 
Pager: 
Comments:
Rev. 12/08, 12/14
Rev. 8/10
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