Phase II/III Study of Circulating Tumor DNA as a Predictive Biomarker in Adjuvant Chemotherapy in Patients With Stage IIA Colon Cancer (COBRA)
Phase: PHASE2
Conditions: Colon Adenocarcinoma, Stage IIA Colon Cancer AJCC v8
Sponsor: NRG Oncology

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NRG ONCOLOGY 
NRG-GI005 
(ClinicalTrials.gov NCT-04068103) 
 
Phase II/III Study of Circulating tumOr DNA as a Predictive BiomaRker in Adjuvant 
Chemotherapy in Patients with Stage IIA Colon Cancer (COBRA) 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI).  The trial will be led by NRG Oncology with the participation of the 
network of NCTN organizations:  ALLIANCE/Alliance for Clinical Trials in Oncology,  
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group, NRG/NRG Oncology, SWOG/SWOG, and 
CCTG/Canadian Cancer Trials Group. 
STUDY TEAM 
NRG Oncology 
Four Penn Center, 1600 JFK Blvd., Suite 1020 
Philadelphia, PA 19103 
Coordinating Center 
NRG Oncology 
Nova Tower 2 
Two Allegheny Center – Suite 1200 
Pittsburgh, PA 15212-5402 
Principal Investigator/ 
Medical Oncology Chair 
 MD 
University of Texas-MD Anderson Cancer 
Center 
1400 Holcombe Boulevard, Unit 426 
Houston, TX 77030 
  
For eligibility and clinical questions: 
Phone: 1-800-477-7227 
E-mail: ccdPGH@nrgoncology.org 
NRG Oncology Colorectal Committee Chair 
 MD, FACP 
University of Florida 
PO Box 100278, 1600 SW Archer Rd 
Gainesville, FL 32610-0278 
  
 
For eligibility and clinical questions: 
Phone: 1-800-477-7227 
E-mail: ccdPGH@nrgoncology.org 
 
Pathology Co-Chair 
 MD, PhD 
NRG Oncology Biospecimen Bank – Pittsburgh 
1307 Federal Street, Suite 303 
Pittsburgh, PA 15212 
 
 
 
Protocol Statistician 
 PhD 
NRG Oncology  
Statistics and Data Management Center  
One Sterling Plaza 
201 North Craig Street, Suite 500 
Pittsburgh, PA 15213 
  
  
Medical Oncology Protocol Officer 
 MD 
NRG Oncology, Nova Tower 2 
 
 
CCTG Co-Chair 
 MD 
BCCA-Vancouver Cancer Centre 
600 West 10th Avenue 
Vancouver, BC V5Z 4E6 
 
 
 
 

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NRG Surgical Oncology Colorectal Committee 
Co-Chair 
 MD 
Baylor College of Medicine 
7200 Cambridge St., 7th Floor 
Houston, TX 77030 
 
Translational Science Co-Chair 
 MD, PhD 
University of Texas-MD Anderson Cancer Center 
1400 Holcombe Boulevard, Unit 426 
Houston, TX 77030 
 
The following NCTN Group Study Champions have been added to this trial: 
ALLIANCE 
 
 MD 
Roswell Park Comprehensive Cancer Center 
ECOG-ACRIN 
 
 
 MD 
The University of Wisconsin 
 
SWOG 
 
 
 MD 
The University of Arizona Cancer Center 
 
CCTG 
 MD, PhD 
BC Cancer Centre 
 
STUDY MANAGEMENT PERSONNEL 
Clinical Coordinating Department (CCD) 
For questions concerning eligibility and clinical 
aspects of the trial. 
NRG Oncology 
Nova Tower 2 
Two Allegheny Center – Suite 1200 
Pittsburgh, PA 15212 
Phone: 1-800-477-7227 
E-mail: ccdPGH@nrgoncology.org 
Protocol Coordinator 
For questions concerning IRB review and informed 
consent 
Department of Regulatory Affairs 
Nova Tower 2 
NRG Oncology 
Two Allegheny Center – Suite 1200 
Pittsburgh, PA 15212 
Phone: 412-339-5300 
E-mail: NRG-Pitt-Regulatory@nrgoncology.org 
Data Manager 
For questions concerning data submission 
NRG Statistics and Data Management Center 
One Sterling Plaza 
201 North Craig Street, Suite 500 
Pittsburgh, PA 15213 
Phone: 412-624-2666 
 
 
 

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NRG ONCOLOGY 
NRG-GI005 
Phase II/III Study of Circulating tumOr DNA as a Predictive BiomaRker in Adjuvant 
Chemotherapy in Patients with Stage IIA Colon Cancer (COBRA) 
 
Protocol Agents 
Agent 
Supply 
NSC # 
IND* 
IDE # 
IDE Sponsor 
Oxaliplatin
Commercial
266046 
N/A 
G190082 
Guardant 
Health 
5-Fluorouracil 
Commercial
19893 
Leucovorin 
Commercial
3590
Capecitabine 
Commercial
712807 
Levoleucovorin 
Commercial
807037 
*This study is exempt from IND Requirements per 21 CFR 312.2(b). 
 
Participating Sites 
☒ U.S. 
☒ Canada 
☐ Approved International Member Sites 
Document History 
 
Version Date 
Amendment #1
April 7, 2021 
Pre-activation Revision 2
September 16, 2019
Pre-activation Revision 
March 14, 2019
Initial 
December 5, 2018
 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be used only in 
conjunction with institution-specific IRB approval for study entry.  No other use or reproduction 
is authorized by NRG Oncology nor does NRG Oncology assume any responsibility for 
unauthorized use of this protocol. 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal: 
Regulatory Submission Portal (Sign in at 
www.ctsu.org, and select the Regulatory 
Submission sub-tab under the Regulatory 
tab.) 
Institutions with patients waiting that are 
unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 
1-866-651-2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory Help Desk 
at 1-866-651-2878 for regulatory 
assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions 
on using the Oncology 
Patient Enrollment 
Network (OPEN), which 
can be accessed at 
https://www.ctsu.org/ 
OPEN_SYSTEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave®.  
Please see the data 
submission section of the 
protocol for further 
instructions 
Do NOT submit study data or 
forms to CTSU Data 
Operations.  Do NOT copy 
the CTSU on data 
submission. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member website located at https://www.ctsu.org.  
Access to the CTSU members' website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e., patient eligibility or treatment-related), contact the Clinical 
Coordinating Department at NRG Oncology at 1-800-477-7227 or by e-mail at 
ccdPGH@nrgoncology.org 
For non-clinical questions (i.e., unrelated to patient eligibility or treatment), contact the CTSU 
Help Desk by phone or email: 
CTSU General Information Line – 1-888-823-5923 or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For clinical data submission questions, contact the GI005 Data Manager at the NRG Oncology 
Statistics and Data Management Center by calling 412-624-2666. 
The CTSU website is located at https://www.ctsu.org. 
 
 

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TABLE OF CONTENTS 
Cancer Trials Support Unit (CTSU) Address And Contact Information ......................................... 4 
 
1.0 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objectives ............................................................................................................. 8 
1.2 
Secondary Objectives ......................................................................................................... 8 
1.3 
Exploratory Objectives ....................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................. 9 
2.1 
Introduction ......................................................................................................................... 9 
2.2 
Guardant Health LUNAR Assay ...................................................................................... 10 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ............................ 11 
3.1 
Eligibility Criteria ............................................................................................................. 11 
3.2 
Ineligibility Criteria .......................................................................................................... 12 
4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP....................... 14 
5.0 
TREATMENT REGIMENS .......................................................................................................... 18 
5.1 
Regimen for Arm 1 (Active Surveillance) and Arm 2 patients with "ctDNA  
not detected" ..................................................................................................................... 18 
5.2 
Treatment regimen for Arm 2 patients with "ctDNA detected" ....................................... 18 
5.3 
Dose determinations ......................................................................................................... 19 
5.4 
Supportive care guidelines for Arm 2 patients with "ctDNA detected" ........................... 19 
5.5 
Duration of Therapy .......................................................................................................... 21 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT ................................................................. 23 
6.1 
General instructions .......................................................................................................... 23 
6.2 
Treatment management for Arm 2 patients with "ctDNA detected" receiving 
mFOLFOX6 ...................................................................................................................... 23 
6.3 
Treatment management for Arm 2 patients with "ctDNA detected" receiving  
CAPOX ............................................................................................................................. 26 
6.4 
Management for all Arm 1 patients and Arm 2 patients with "ctDNA not detected" ....... 28 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS .............................................................. 29 
7.1 
Study Agents ..................................................................................................................... 29 
7.2 
Adverse Events and Serious Adverse Events ................................................................... 29 
7.3 
Adverse Events for the Study Agents ............................................................................... 30 
7.4 
Expedited Reporting of Adverse Events ........................................................................... 30 
7.5 
Routine Reporting of Adverse Events .............................................................................. 32 
7.6 
Reporting Colon Cancer Recurrence and Second Primary Cancer ................................... 33 
8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES .......................... 34 
8.1 
Cancer Therapy Evaluation Program registration procedures .......................................... 34 
8.2 
Cancer Trials Support Unit Registration Procedures ........................................................ 35 
8.3 
Patient Enrollment ............................................................................................................ 37 
8.4 
Reimbursement ................................................................................................................. 38 
8.5 
Investigator-Initiated Discontinuation of chemotherapy .................................................. 38 
8.6 
Patient-Initiated Discontinuation of Chemotherapy ......................................................... 38 
8.7 
Patient-Initiated Consent Withdrawal from the Study ...................................................... 38 
8.8 
ctDNA Testing Outside of the Conduct of the GI005 Study ............................................ 38 
9.0 
DRUG INFORMATION ............................................................................................................... 39 
9.1 
Commercial Agents .......................................................................................................... 39 

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10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..................................................... 40 
10.1 
Specimen Submissions ..................................................................................................... 40 
10.2 
Integrated Correlative Studies ........................................................................................... 42 
10.3 
Exploratory Correlative Studies ........................................................................................ 42 
11.0 
SPECIAL STUDIES (NON-TISSUE) ........................................................................................... 43 
12.0 
DIAGNOSIS OF COLON CANCER RECURRENCE ................................................................. 44 
12.1 
Abdominal and/or pelvic sites .......................................................................................... 44 
12.2 
Non-abdominal and non-pelvic sites ................................................................................ 45 
12.3 
Secondary malignancy ...................................................................................................... 45 
12.4 
Second primary cancer ...................................................................................................... 45 
12.5 
Documentation requested following death ....................................................................... 45 
13.0 
DATA AND RECORDS ............................................................................................................... 46 
13.1 
Data Reporting .................................................................................................................. 46 
13.2 
Summary of Data Submission .......................................................................................... 48 
13.3 
Global Reporting /Monitoring .......................................................................................... 48 
14.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 49 
14.1 
Abstract ............................................................................................................................. 49 
14.2 
Endpoint(s)........................................................................................................................ 49 
14.3 
Stratification and randomization ....................................................................................... 49 
14.4 
Patient Cohorts .................................................................................................................. 50 
14.5 
Patient Accrual .................................................................................................................. 50 
14.6 
Sample Size Determination............................................................................................... 50 
14.7 
Study Monitoring .............................................................................................................. 50 
14.8 
Analysis ............................................................................................................................ 52 
14.9 
Gender/Ethnicity/Race Distribution .................................................................................. 53 
15.0 
REFERENCES .............................................................................................................................. 55 
Appendix A 
Assessment of Performance Status and Activities of Daily Living .................................. 56 
Appendix B 
Clinical Management of Diarrhea ..................................................................................... 57 
Appendix C 
Levoleucovorin Drug Dose and Administration Instructions ........................................... 57 
Appendix D 
Patient Diary ..................................................................................................................... 59 
 
Figure 1.  NRG-GI005 Schema .................................................................................................................... 7 
Table 1. 
Tests, exams, and other requirements prior to randomization .......................................... 14 
Table 2. 
Tests, exams, and other requirements for all patients through Year 3 .............................. 15 
Table 3. 
Treatment regimen for Arm 2 patients with "ctDNA detected"- (mFOLFOX6) .............. 18 
Table 4. 
Treatment regimen for Arm 2 patients with "ctDNA detected"-(CAPOX) ...................... 19 
Table 5. 
mFOLFOX6 dose levels ................................................................................................... 23 
Table 6. 
Treatment management for mFOLFOX6 -(See Table 7 for oxaliplatin-specific  
toxicities.) ......................................................................................................................... 24 
Table 7. 
Treatment management for oxaliplatin-specific toxicities ................................................ 26 
Table 8. 
CAPOX dose levels .......................................................................................................... 27 
Table 9. 
Treatment management for capecitabine (Arm 2 patients with "ctDNA detected") ......... 27 
Table 10. 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Study Therapy1,2 ................. 31 
Table 11. 
Mandatory and optional sample requirements .................................................................. 40 
Table 12. 
Gender/Ethnicity/Race Distribution .................................................................................. 54 
 
 

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Figure 1.  NRG-GI005 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Acceptable regimens for Arm 2 patients with "ctDNA detected" are: 
 
mFOLFOX6: oxaliplatin 85 mg/m2 IV Day 1 + leucovorin 400 mg/m2 IV Day 1 + 5-fluorouracil 
(5-FU) 400 mg/m2 IV bolus Day 1 followed by 5-FU 2400 mg/m2 continuous infusion over  
46 hours every 2 weeks for twelve cycles 
or 
 
CAPOX: Oxaliplatin 130 mg/m2 IV over 2 hours on day 1 + capecitabine 1000 mg/m2 PO BID 
on days 1-14 every 3 weeks for eight cycles  
 
Arm 1 
 Standard of Care (Active surveillance) 
 
Arm 2 
Assay-directed Therapy 
 
ctDNA Detected 
* mFOLFOX6 
or 
*CAPOX 
Resected stable stage IIA colon cancer for which physician decides no adjuvant 
chemotherapy ("suitable for active surveillance") 
ctDNA Not Detected 
Active surveillance 
Randomize 
 
Samples analyzed prospectively for the detection of 
ctDNA to guide adjuvant chemotherapy decision 
 
 
Samples batched and analyzed 
retrospectively for ctDNA status 
 

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1.0 
OBJECTIVES 
1.1 
Primary Objectives 
1.1.1 
Primary Objective Phase II 
To compare the rate of ctDNA clearance in "ctDNA detected" patients treated with or without 
adjuvant chemotherapy following resection of stage IIA colon cancer. 
1.1.2 
Primary Objective Phase III 
To compare recurrence-free survival (RFS) in "ctDNA detected" patients treated with or without 
adjuvant chemotherapy following resection of stage IIA colon cancer. 
1.2 
Secondary Objectives  
1.2.1 
To describe the prevalence of detectable ctDNA in patients with stage IIA colon cancer following 
surgical resection. 
1.2.2 
To estimate time-to-event outcomes (overall survival [OS], recurrence-free survival [RFS], and 
time to recurrence [TTR] by ctDNA marker status and treatment for patients with resected stage 
IIA colon cancer. 
1.2.3 
To estimate the rate of compliance with adjuvant chemotherapy and/or active surveillance  
for patients with resected stage IIA colon cancer. 
1.3 
Exploratory Objectives 
1.3.1 
To describe the association of quantitative ctDNA levels with time to event outcomes (RFS, OS, 
and TTR). 
1.3.2 
To characterize genomic profiles associated with recurrence using a ctDNA assay in patients with 
resected stage IIA colon cancer. 
1.3.3 
To model the cost effectiveness of the use of ctDNA versus standard of care in this setting. 
1.3.4 
To evaluate performance of a ctDNA assay after incorporation of patient tumor and peripheral 
blood mononuclear cells. 
 

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2.0 
BACKGROUND  
2.1 
Introduction 
Multiple series, from SEER databases, academic centers, and community oncology practices, 
have reported rates of adjuvant chemotherapy treatment in 25-30% of patients with stage II colon 
(non-rectal) cancer in the United States (O'Connor 2011; Schrag 2002; Kumar 2015).  NCCN 
Guidelines for patients with stage II colon cancer recommend several acceptable management 
approaches following resection (i.e., observation, adjuvant chemotherapy, or clinical trial) based 
upon assessment by the medical oncologist of prognostic tumor characteristics (NCCN 
Guidelines [Colon Cancer]).  Nonetheless, the decision of whether or not to recommend adjuvant 
chemotherapy for patients with stage II colon cancer deemed low-risk for recurrence remains 
highly variable among providers.  This lack of consistency in (1) the decision whether or not to 
give chemotherapy and (2) if given, what regimen to administer (e.g., 5-fluorouracil with or 
without oxaliplatin) is driven by patient factors, pathologic characteristics of the tumor, and 
physician preference.  Current guidelines recommend that a personalized risk stratification 
approach is taken, generating subjectivity in the treating physician’s interpretation of when to 
offer adjuvant chemotherapy in patients with stage II colon cancer at “low risk” for recurrence.  
Validated, objective parameters for deciding whom to recommend adjuvant chemotherapy for 
stage II colon cancer are lacking. 
Arising from tumor cell secretion and apoptosis, circulating tumor DNA (ctDNA) from release of 
tumor DNA into the bloodstream is considered a surrogate for minimal residual disease.  These 
somatically mutated tumor DNA fragments can be detected with high specificity and high 
sensitivity.  Detection of ctDNA following resection across all stages of colon cancer has been 
demonstrated as a strong prognostic biomarker for tumor recurrence. 
An Australian study analyzed 230 patients with stage II colon cancer who had identifiable 
mutations using a ctDNA next-generation sequencing (NGS) panel on blood collected 4-10 weeks 
after surgical resection (Tie 2016).  Among the 178 of these patients that did not receive adjuvant 
chemotherapy, 164 patients had no detectable ctDNA at baseline, while 14 (8.5%) had detectable 
ctDNA.  Three -year recurrence-free survival was 90% in the ctDNA-negative group and 0% in 
the ctDNA-detectable group (all relapsed).  Detectable ctDNA following resection had a positive 
predictive value of 100% and negative predictive value of 92%.  Multivariate analysis of various 
clinicopathologic risk factors for recurrence showed that the detection of ctDNA was associated 
with the highest risk for recurrence (HR 28, P<.001), and the only traditionally utilized factor 
with a significant risk for recurrence was a T4 tumor (HR 8.1, P<.001).  Other commonly utilized 
patient and tumor characteristics (i.e., < 12 lymph nodes examined, presence of lymphovascular 
invasion, microsatellite status) did not meet statistical significance in this analysis.  These data 
suggest that detection of postoperative ctDNA can serve as both a specific and sensitive tool in 
quantifying minimal residual disease following resection as a prognostic biomarker, independent 
of traditional clinical risk factors. 
These findings were validated in another dataset of patients with resected stages II and III colon 
cancers.  Here, employing another NGS plasma assay (Roche Avenio) corroborated the use of 
ctDNA technology as a method to identify patients with colon cancer at high risk for recurrence 
Diehn 2017).  Here, 145 patients with R0 resections for colorectal cancer (86 stage II patients and 
59 stage III patients) underwent interrogation using this 197-gene panel for the presence of 
ctDNA in the blood at a median of 10 days postoperatively.  A median of 4 (range, 1-24) somatic 
variants were detected in 144 of 145 tumors.  Detectable ctDNA (N=12, 8.3%) was associated 
with an inferior RFS (17% vs. 88%, HR 10.3, P < .00001), inferior time to recurrence (HR 20.6, 
P < .00001), and a shorter overall survival (HR 3.4, P < .00001).  The time to recurrence was 

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shorter in the ctDNA (+) patients relative to the ctDNA (-) patients alike for both the stages II and 
III cohorts (P < .00001).  These data validate the previously described Australian findings of 
detectable ctDNA as a poor prognostic biomarker. 
As the prognostic implications of remnant ctDNA may surpass those typically considered to 
classify a patient as having a “high risk” stage II colon cancer, these data suggest that "ctDNA 
detected" is associated with a high probability for recurrence, warranting consideration of 
adjuvant chemotherapy for “high risk” stage II colon cancer.  If detectable ctDNA is considered a 
surrogate for micrometastatic disease, it remains unclear whether or not early intervention may 
improve survival outcomes or hasten toxicity relative to standard radiographic detection of 
(recurrent) macrometastatic colon cancer. 
2.2 
Guardant Health LUNAR Assay 
The Guardant LUNAR assay is a next generation sequencing-based diagnostic test developed by 
Guardant Health for the qualitative detection of cancer-derived circulating tumor DNA in EDTA-
anticoagulated peripheral whole blood. Briefly, plasma is isolated from whole blood collected in 
Streck cell-free DNA blood collection tubes, ctDNA is isolated, processed, and sequenced on an 
Illumina platform.  Sequencing data are then analyzed using proprietary bioinformatics 
algorithms trained to detect the presence of ctDNA based on multiple analytical features, 
including somatic variation and epigenetic signals, and exclude common sources of interference 
such as inflammation and clonal hematopoiesis.  Based on this analysis, the Guardant LUNAR 
test returns a result of ctDNA detected or not detected.  No somatic or germline genotyping 
results are reported. 
Thus, for patients with colorectal cancer undergoing definitive resection, regardless of the stage 
of disease, this ctDNA biomarker may potentially identify patients who would benefit the most 
from systemic adjuvant treatment, even in the absence of other clinical features traditionally 
considered high-risk.  However, use of ctDNA technology is limited by the absence of 
prospective data for demonstrating benefit as a predictive biomarker for adjuvant chemotherapy. 
With the rapid evolution of ctDNA use in the clinical management of solid tumors, it is possible 
that Guardant Health may develop different methodologies for subsequent generations of ctDNA 
assays in the coming years.  Nonetheless, for the duration of the study, the assay proposed here 
will be fixed/not permitted to be changed for analyses of all study objectives.  Collection of 
additional blood samples at each time point will allow for availability of specimens to be 
examined in the future by alternative assays outside the context of this study.  In addition, with 
the prognostic implications of detectable ctDNA as a surrogate for minimal residual disease, this 
technology has the potential to provide clinicians with an objective assay to identify patients at 
high risk for recurrence following resection.  We hypothesize that the detection of ctDNA may 
provide an objective endpoint for identifying patients with stage IIA colon cancer at high-risk for 
recurrence following resection that have the most potential to benefit from adjuvant 
chemotherapy. 
 

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3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
Per NCI guidelines, exceptions to inclusion and exclusion criteria are not permitted.  For 
questions concerning eligibility, please contact the Clinical Coordinating Department (CCD). 
Investigators also should consider all other relevant factors (medical and non-medical), as well as 
the risks and benefits of mFOLFOX6 or CAPOX, when deciding if a patient is an appropriate 
candidate for this trial. 
Submission of blood samples for ctDNA analysis, archived resected primary tumor tissue (FFPE), 
and uninvolved margin of resection (normal tissue) is required for all patients.  In addition, all 
patients will be asked to consent to the submission of optional blood and tumor tissue samples for 
future research. 
Investigators should check with their site Pathology department regarding release of tissue before 
approaching patients about participation in the trial. 
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following conditions 
are met. 
3.1.1 
The patient must have signed and dated an IRB-approved consent form that conforms to federal 
and institutional guidelines. 
3.1.2 
Age  18 years at diagnosis. 
3.1.3 
ECOG Performance Status of 0 or 1 (see Appendix A). 
3.1.4 
Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0, M0) 
with at least 12 lymph nodes examined at the time of surgical resection. 
3.1.5 
Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion of and as 
documented by the evaluating oncologist based on current practice patterns. 
3.1.6 
The distal extent of the tumor must be ≥12 cm from the anal verge on pre-surgical endoscopy 
(i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation).  If the patient 
did not undergo a pre-surgical endoscopy, then the distal extent of the tumor must be ≥12 cm 
from the anal verge as determined by surgical examination or pre-operative imaging. 
3.1.7 
The patient must have had an en bloc complete gross resection of tumor (curative resection) as 
definitive surgical cancer treatment within 14 to 60 days of study randomization.  Patients who 
have had a two-stage surgical procedure to first provide a decompressive colostomy and then, in a 
later procedure, to have the definitive surgical resection, are eligible. 
3.1.8 
Availability and provision of adequate surgical tumor tissue for molecular diagnostics and 
confirmatory profiling. 
3.1.9 
Adequate hematologic function within 28 days before randomization defined as follows: 
 Absolute neutrophil count (ANC) must be  1200/mm3; 
 Platelet count must be  100,000/mm3; and 
 Hemoglobin must be  9 g/dL. 
3.1.10 Adequate hepatic function within 28 days before randomization defined as follows: 
 
total bilirubin must be  ULN (upper limit of normal) for the lab unless the patient has a 
chronic grade 1 bilirubin elevation due to Gilbert’s disease or similar syndrome involving 
slow conjugation of bilirubin; and 
 
alkaline phosphatase must be < 2.5 x ULN for the lab; and 
 
AST and ALT must be < 1.5 x ULN for the lab. 

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3.1.11 Adequate renal function within 28 days before randomization defined as serum creatinine  1.5 x 
ULN for the lab or measured or calculated creatinine clearance  50 mL/min using the Cockroft-
Gault formula for patients with creatinine levels  1.5 x ULN for the lab. 
For Women 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) x 0.85 
72 x serum creatinine (mg/dL) 
For Men 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) 
72 x serum creatinine (mg/dL) 
3.1.12 Pregnancy test (urine or serum according to institutional standard) done within 14 days before 
randomization must be negative (for women of childbearing potential only). 
3.1.13 Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of INR 
if they are randomized to Arm 2 and receive capecitabine. 
3.2 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this study. 
3.2.1 
Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, 
lymphoma, squamous cell carcinoma, etc.). 
3.2.2 
Pathologic, clinical, or radiologic evidence of overt metastatic disease.  This includes isolated, 
distant, or non-contiguous intra-abdominal metastases, even if resected (including the presence of 
satellite nodules constituting N1c disease in the absence of lymph node involvement). 
3.2.3 
Tumor-related bowel perforation. 
3.2.4 
History of prior invasive colon malignancy, regardless of disease-free interval. 
3.2.5 
History of organ transplantation. 
3.2.6 
Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy 
administered as treatment for colorectal cancer (e.g., primary rectal adenocarcinomas for which 
treatment with neoadjuvant chemoradiation is warranted are not permitted). 
3.2.7 
Other invasive malignancy within 5 years before randomization.  Exceptions are colonic polyps, 
non-melanoma skin cancer or carcinoma-in-situ including those of the cervix and breast (DCIS). 
3.2.8 
Synchronous primary rectal and/ or colon cancers. 
3.2.9 
Antineoplastic therapy (e.g., chemotherapy, targeted therapy, or immunotherapy) within 5 years 
before randomization.  (For the purposes of this study, hormonal therapy is not considered 
chemotherapy.) 
3.2.10 Uncontrolled cardiac disease, in the opinion of the treating medical oncologist, that would 
preclude the use of any of the drugs included in the GI005 treatment regimen.  This includes but 
is not limited to: 
 Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic 
bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling 
temporary pacemaker. 
 Ventricular tachycardia or supraventricular tachycardia that requires treatment with Class Ia 
antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide) or Class III 
antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide).  Use of other antiarrhythmic drugs 
is permitted. 

NRG-GI005 
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 Second- or third-degree atrioventricular (AV) block unless treated with a permanent 
pacemaker. 
 Complete left bundle branch block (LBBB) unless treated with a permanent pacemaker 
3.2.11 Sensory or motor neuropathy ≥ grade 2, according to CTCAE v5.0. 
3.2.12 Active seizure disorder uncontrolled by medication. 
3.2.13 Active or chronic infection requiring systemic therapy. 
3.2.14 Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency. 
3.2.15 Pregnancy or lactation at the time of randomization. 
3.2.16 Co-morbid illnesses or other concurrent disease that, in the judgement of the clinician obtaining 
informed consent, would make the patient inappropriate for entry into this study (i.e., unable to 
tolerate 6 months of combination chemotherapy or interfere significantly with the proper 
assessment of safety and toxicity of the prescribed regimens or prevent required follow-up). 
3.2.17 Prior testing with any available ctDNA test as part of the management of colon cancer is not 
permitted. 
 

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4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
Tests, exams and other studies required before randomization are listed on Table 1.  
Requirements following randomization are outlined on Table 2. 
Table 1. Tests, exams, and other requirements prior to randomization 
Required Assessments 
Before randomization 
(see footnote a)
Consent form signed by the patient
X 
History & physical examb
X 
Within 28 days 
 
Assessment of concomitant medicationsc
X 
Performance status (Appendix A) 
X 
Height & weight
X
CEA
X
CBC/differential/platelet count 
X 
Total bilirubin/AST/ALT/Alkaline phosphatase 
X 
Serum chemistries: glucose, BUN, sodium, potassium, chloride, 
bicarbonate or carbon dioxide, calcium, serum creatinine 
X 
Distant disease stagingd
X 
Pregnancy test e 
X 
Within 14 days 
Mandatory collection of whole blood for ctDNAf 
X 
Before or after 
randomization 
Optional collection of whole blood specimensf 
X 
Mandatory submission of archived resected primary tumor tissue 
and uninvolved margin of resection (normal tissue)f
 X 
Within 60 days after 
randomization 
a Informed consent must be obtained before performance of any screening assessments; however, 
results of screening tests or examinations performed as standard of care before obtaining informed 
consent but within the timeframes outlined in Table 1 may be used rather than repeating required 
tests. 
b Documentation of complete history and physical by a physician or other healthcare professional. 
c Include all prescribed and over-the-counter medications, supplements, herbal therapies. 
d For distant (metastatic) staging  It is recommended that the same imaging tests performed before 
randomization be used at follow-up time points.  CT with IV contrast or MRI imaging is acceptable 
and must include chest, abdomen, and pelvis. 
e For women of childbearing potential only.  Pregnancy testing should be done according to 
institutional standards. 
f See Section 10.0 and the NRG-GI005 Pathology and Correlative Science Instructions.  Mandatory 
and optional blood specimens cannot be collected until informed consent is obtained. 

 
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Table 2. Tests, exams, and other requirements for all patients through Year 3 
Note: Arm 2 patients with "ctDNA detected" ONLY, treated with mFOLFOX6 or CAPOX, have treatment related assessments prior to each cycle 
and approximately 30 days after the last dose of therapy 
Required assessments 
(See footnote a) 
 Arm 1 patients and 
Arm 2 patients with" 
ctDNA not detected" 
ONLY  
Arm 2 patients with "ctDNA detected" ONLY 
All patients 
9 months from 
randomization 
All patients 
12 months from 
randomization 
through Year 3* 
Within 3 days before 
Day 1 of each cycle of 
mFOLFOX6 or 
CAPOX 
(beginning with Cycle 2)
30 days (+/-7 days) 
after the last dose of 
chemotherapy 
History & physical examb 
X
(3 and 6 months from 
randomization) 
X 
X 
 
X 
(every 6 months) 
Adverse event assessmentc
 
X 
X 
 
 
CBC/differential/platelet 
count
 
X 
X 
 
 
Total bilirubin/AST/Alk phos 
Serum chemistries: glucose, 
BUN, creatinine, sodium, 
chloride, bicarbonate or 
carbon dioxide 
 
X 
X 
 
 
Potassium, magnesium, and 
calcium 
 
X 
X 
 
 
INRd 
 
X 
X 
 
 
CEA 
X 
(3 and 6 months from 
randomization) 
X 
(prior to week 13 and 
prior to last cycle of 
chemotherapy) 
 
X 
X
(12, 18, 24, 30, 36 
months from 
randomization 
AND at 
recurrence) 
Disease imaginge 
X
(every 6 months for all patients) 
Submission of unstained 
slides -optionalf
X 
(for all patients at time of recurrence, second primary/secondary malignancy) 
Table continued on next page 
 

 
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Table 2. Tests, exams, and other requirements for all patients through Year 3 
Note: Arm 2 patients with "ctDNA detected" ONLY, treated with mFOLFOX6 or CAPOX, have treatment related assessments prior to each cycle 
and approximately 30 days after the last dose of therapy 
Required assessments 
(See footnote a) 
 Arm 1 patients and 
Arm 2 patients with 
"ctDNA not 
detected" ONLY  
Arm 2 patients with "ctDNA detected" ONLY 
All patients 
9 months from 
randomization 
All patients 
12 months from 
randomization 
through Year 3*  
Within 3 days before 
Day 1 of each cycle of 
mFOLFOX6 or 
CAPOX 
(beginning with Cycle 2)
30 days (+/-7 days) 
after the last dose of 
chemotherapy 
Whole Blood for ctDNA 
(mandatory)g 
Xh 
(6 months from 
randomization) 
Xh 
(prior to last cycle of 
chemotherapy) 
 
 
 
Whole Blood (optional)i  
X 
(3 and 6 months from 
randomization) 
X 
(prior to week 13 and 
prior to last cycle of 
chemotherapy) 
 
 
X 
(12 months from 
randomization ) 
Vital Status Update* 
 
 
 
 
X 
(every 6 months) 
a History and physical, blood tests, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b Updated history and physical with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and 
follow-up. 
c See Section 7.0 for adverse events reporting requirements. 
d Only for patients receiving concomitant capecitabine and a coumarin-derivative anticoagulant.  Monitor INR weekly and for an additional 4 
weeks after the patient's last capecitabine dose (see Section 5.4.8). 
e It is recommended that the same imaging tests performed before randomization be used at follow-up time points.  See Section 12.0 for required 
confirmation of abnormal imaging related to study endpoints. 
f Submission of unstained slides from tumor tissue obtained at the time of recurrence, second primary/secondary malignancy, if available, is 
only required for patients who have agreed to the optional tumor sample submission when signing the consent form (see Section 10.0 and the 
NRG-GI005 Pathology and Correlative Science Instructions). 
Table continued on next page 
 

 
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Table 2. Tests, exams, and other requirements for all patients through Year 3 continued 
g Submission of blood for ctDNA analysis is required for all patients (see Section 10.0 and the NRG-GI005 Pathology and Correlative 
Science Instructions). 
h Patients who recur or have a second primary/second malignancy prior to 6 months or prior to the last cycle of chemotherapy should have a 
whole blood draw for ctDNA at that time to replace the 6 months or prior to the last cycle of chemotherapy timepoint. 
i Requirement for all patients who agreed to optional blood collection and submission in the consent form (see Section 10.0 and the NRG-
GI005 Pathology and Correlative Science Instructions). 
*Note: Following documented disease recurrence or diagnosis of an invasive second primary/secondary malignancy, tests, exams, and 
assessments are not required; however, patients will continue to be followed for vital status until Year 3 from randomization. 
 

 
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5.0 
TREATMENT REGIMENS 
5.1 
Regimen for Arm 1 (Active Surveillance) and Arm 2 patients with "ctDNA not detected" 
 
Patients will enter active surveillance, consistent with standard of care for low-risk patients. 
 
For Arm 1 patients, ctDNA results will be analyzed as a batch at approximately a quarterly 
interval, and results will not be reported back to the patient or the enrolling site. 
5.2 
Treatment regimen for Arm 2 patients with "ctDNA detected" 
 
Results will be reported as, "ctDNA detected," "ctDNA not detected,", or "Failed" for the 
presence of ctDNA, respectively, in the initial postoperative sample.  "ctDNA detected" 
results will direct the patient to be treated with chemotherapy (mFOLFOX6 for 12 cycles (24 
weeks) or CAPOX for 8 cycles (24 weeks); see Table 3 or Table 4).  "ctDNA not detected" 
will assign the patient to active surveillance.  A "failed" assay at baseline will require a blood 
redraw, and testing should be completed within 4 weeks following randomization. 
 
Choice of regimen (mFOLFOX6 or CAPOX) is per the investigator. 
 
Chemotherapy should begin within 4 weeks following randomization and preferably no 
longer than 12 weeks from surgery. 
 
Central venous access is strongly recommended for administration of oxaliplatin and for 5-
fluorouracil. 
 
Results of laboratory safety assessments are to be reviewed prior to administration of each 
cycle of adjuvant chemotherapy. 
 
Administer mFOLFOX6 in the order listed, but infusion times for all chemotherapy in this 
protocol are per institutional guidelines. 
 
Patient treatment setting (inpatient/outpatient) is per institutional guidelines. 
 
If there are no treatment delays, each mFOLFOX6 cycle = 2 weeks or 14 days, or each 
CAPOX cycle=3 weeks or 21 days. 
 
Total suggested duration of treatment is 12 cycles of mFOLFOX6 or 8 cycles of CAPOX. 
 
Dose reductions/modifications and/or discontinuation of one or both chemotherapeutic agents 
is permitted at the clinical judgment of the treating medical oncologist and must be 
documented.  If oxaliplatin is prematurely discontinued, it is strongly recommended that 5-
fluorouracil (or capecitabine) is continued for the remaining duration of the intended 
treatment course. 
Table 3. Treatment regimen for Arm 2 patients with "ctDNA detected"- (mFOLFOX6) 
Drug 
Dose 
Administration 
Dosing 
Interval 
Planned 
Duration 
Oxaliplatin 
85 mg/m2  
IV, given concurrently 
through separate lines 
connected by Y-line tubing, 
over 2 hours. 
(see footnote a)
Day 1 
every 2 weeks 
12 cycles 
(24 weeks) 
Leucovorin 
400 mg/m2 
5-Fluorouracil (5-FU) 
400 mg/m2 
IV bolus recommended 
infusion time of 24 minutes 
immediately following 
oxaliplatin/leucovorin 
infusion 
2400 mg/m2 
IV continuous infusion over 
46-48 hours (total dose)
 
 
Table continued on next page 
 

 
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Table 3. Treatment regimen for Arm 2 patients with "ctDNA detected"- (mFOLFOX6) 
a Oxaliplatin is not compatible with normal saline solution or with 5-FU.  The infusion line must be 
thoroughly flushed with D5W after administration with oxaliplatin.  If oxaliplatin is held, administer 
leucovorin over 2 hours (preferred); however, administration time per institutional practice is 
permitted.  Levoleucovorin can be substituted for leucovorin throughout this protocol, per 
institutional practice or as needed for drug availability, at a dose of 200 mg/m2 (see Appendix C). 
Table 4. Treatment regimen for Arm 2 patients with "ctDNA detected"-(CAPOX) 
Drug 
Dose 
Administration 
Dosing 
Interval 
Planned 
Duration 
Oxaliplatin 
130 mg/m2  
IV given over 2 hours. 
(see footnote a) 
Day 1 
every 3 weeks 
8 cycles 
(24 weeks) 
Capecitabine 
1000 mg/m2 BID 
By mouth 
(see footnotes b, c) 
Days 1-14 
every 3 weeks 
a Oxaliplatin is not compatible with normal saline solution. 
b Capecitabine should be taken in the morning and evening within 30 minutes after a meal (breakfast 
and dinner). 
c Use of a patient pill diary (Appendix D) to record capecitabine compliance is recommended.
5.3 
Dose determinations 
5.3.1 
Calculations of BSA and/or Drug Doses 
 
Recommended chemotherapy doses will be provided at the time of randomization. 
 
Recalculations of BSA and drug doses are required if the patient has a 10% or greater weight 
change (+/-) from baseline or from the last weight used to calculate BSA and drug doses.  At 
the investigator's discretion, the BSA and drug doses may also be recalculated prior to each 
treatment. 
5.3.2 
Rounding Doses 
Follow institutional practice for standard drug rounding. 
5.4 
Supportive care guidelines for Arm 2 patients with "ctDNA detected" 
5.4.1 
G-CSF 
 
Use of growth factor support as primary prophylaxis to prevent neutropenia is discouraged 
but not prohibited however, do not administer G-CSF within 24 hours of chemotherapy.  
See Section 6.0 for treatment modifications/management. 
 
Choice of growth factor is at the investigator’s discretion. 
 
If needed, pegfilgrastim and filgrastim are recommended; however, if required by 
institutional standards, GM-CSF may be administered as an alternative. 
 
Loratadine (10 mg) or similar agents are permitted if pegfilgrastim is used. 
 

 
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5.4.2 
Management of anemia 
Chemotherapy should not proceed with  grade 3 anemia.  Transfusion is acceptable for 
improving the hemoglobin value to allow therapy to continue without delay.  The patient should 
be assessed to rule out other causes of anemia.  Use of erythropoiesis-stimulating agents is 
prohibited. 
5.4.3 
Management of diarrhea 
Diarrhea is a commonly occurring toxicity with the therapies included in GI005/Arm 2 patients 
with "ctDNA detected".  Without appropriate treatment, diarrhea can be prolonged, severe, and 
lead to dehydration and other complications.  (See Appendix B for clinical management of 
diarrhea.) 
 
Inform patients that they may experience diarrhea while on chemotherapy and possibly for 
several weeks after chemotherapy has stopped. 
 
Patients must be instructed to: 
 
have ready access to antidiarrheal agents (e.g., loperamide) starting on Day 1 of 
treatment. 
 
All patients must be instructed to begin taking loperamide at the earliest sign of poorly-
formed or loose stools (≥ grade 1).  Early intervention is important for patient safety.  See 
Section 6.0 for dose modifications and delays. 
 
continue prophylactic therapy as directed 
 
promptly report diarrhea symptoms 
 
report constipation before taking any laxatives or stopping antidiarrheal medication. 
Patients who have multiple loose bowel movements and any worsening of fatigue, nausea, 
vomiting, right upper quadrant abdominal pain or tenderness, fever, rash, or eosinophilia should 
be promptly evaluated for changes in liver function.  (See Appendix B for sample patient 
instructions for diarrhea management.) 
Aggressive supportive care should be provided for patients with grade 4 ANC and ≥ grade 3 
diarrhea until neutropenia and diarrhea resolve.  See Appendix B for clinical management of 
diarrhea.  Hospitalization for evaluation and management of grade 3 or grade 4 complicated 
diarrhea, as defined in Appendix B, is strongly recommended. 
Refer to the ASCO Recommended Guidelines for Treatment of Cancer Treatment-Induced 
Diarrhea for additional recommendations regarding diarrhea (Benson 2004). 
5.4.4 
Management of nausea or vomiting 
Antiemetic therapy should be administered according to National Comprehensive Cancer 
Network (NCCN) (https://www.nccn.org) or American Society of Clinical Oncology (ASCO) 
clinical practice guidelines (Hesketh 2017).  See Section 6.0 for dose modifications and delays. 
5.4.5 
Management of pharyngolaryngeal dysesthesias 
Oxaliplatin may cause discomfort in the larynx or pharynx associated with the sensation of 
dyspnea, anxiety, and swallowing difficulty.  Exposure to cold can exacerbate these symptoms. 
 
Refer to Table 7 for dose modification instructions. 
 
Do NOT use ice chips or other forms of oral cryotherapy to decrease stomatitis in conjunction 
with oxaliplatin. 
 
Anxiolytics may be used at the physician's discretion. 
5.4.6 
Management of anaphylaxis 
Oxaliplatin may cause anaphylactic reactions.  Management of such reactions is per institutional 
guidelines. 
 

 
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5.4.7 
Management of injection site reactions 
Injection site reactions, including redness, swelling, and pain, have been reported with 
oxaliplatin.  Extravasation, in some cases including soft tissue necrosis has occurred.  For this 
reason, administration of oxaliplatin is recommended intravenously through a central venous 
catheter.  Management of injection site reactions is per institutional guidelines. 
5.4.8 
Drug/drug interactions 
 Coumarin: Altered coagulation parameters and/or bleeding, including death, have been 
reported in patients taking capecitabine concomitantly with coumarin-derivative 
anticoagulants such as warfarin and phenprocoumon.  These events occurred within several 
days and up to several months after initiating capecitabine therapy and, in a few cases, within 
1 month after stopping capecitabine.  These events occurred in patients with and without liver 
metastases. 
It is required that the INR be monitored carefully (at least weekly) while the patient is 
receiving treatment with capecitabine and warfarin concurrently and for an additional 4 weeks 
following the patient's last capecitabine dose.  Institutional standards for this drug combination 
should be followed closely.  Subcutaneous heparin or fractionated heparin products are 
permitted. 
 Phenytoin: Increased phenytoin levels have also been reported in patients taking capecitabine 
concurrently with phenytoin and, therefore, need to be monitored. 
5.4.9 
Prohibited Therapies 
The following types of treatment, in addition to any cancer therapy other than the therapy 
specified in this protocol, are prohibited: 
 
Chemotherapy 
Administration of chemotherapy other than the chemotherapy specified in this protocol is 
prohibited. 
 
Targeted therapy 
Administration of targeted therapy for malignancy is prohibited. 
 
Radiation therapy 
Administration of radiation therapy is prohibited. 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from study treatment; however, patients 
should continue to be followed for subsequent cancer events and for survival every 6 months until 
Year 3. 
5.4.10 Participation in Other Trials 
If a GI005 patient is considering participation in another clinical trial (including supportive 
therapy trials), contact the NRG Oncology Clinical Coordinating Department. 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as specified in 
the above treatment modality sections or until one of the following criteria applies: 
 
Disease recurrence 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
Clinical progression 

 
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 
Patient non-compliance 
 
Pregnancy 
 
All women of child bearing potential must be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) 
at any time during study participation. 
 
The investigator must immediately notify CTEP in the event of a confirmed pregnancy in 
a female patient or the partner of a male patient participating in the study. 
 
Termination of the study by sponsor 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 

 
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6.0 
TREATMENT MODIFICATIONS/MANAGEMENT 
6.1 
General instructions 
 
The CTCAE v5.0 must be used to grade the severity of AEs.  Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Deviations from the recommended treatment modifications/management must be documented 
in the patient treatment record. 
 
Treatment schedule changes for non-medical reasons: When rescheduling chemotherapy for 
non-medical adjustments, refer to the memo "Scheduling Protocol Therapy during the 
Holidays."  This memo provides information regarding treatment over holidays/vacations and 
other non-medical delays (e.g. physician or patient schedules).  This memo is updated 
annually and is posted on the CTSU Web site under the specific protocol memoranda.  Any 
treatment schedule changes for non-medical reasons must be documented in the patient 
treatment record. 
 
In the event of disease recurrence or diagnosis of an invasive second primary cancer or 
secondary malignancy, chemotherapy (mFOLFOX6/CAPOX) as part of this clinical trial will 
be discontinued; further therapy is at the investigator's discretion.  However, patients will 
continue to be followed off treatment for survival. 
6.2 
Treatment management for Arm 2 patients with "ctDNA detected" receiving mFOLFOX6 
Chemotherapy dose modifications for Arm 2 patients with "ctDNA detected" are detailed in 
Tables 6 and 7.  Dose modifications are based on the dose level changes outlined in Table 5. 
Additionally, the following mFOLFOX6 dose modification instructions must be followed: 
 
All doses must be based on the AE requiring the greatest modification. 
 
Any chemotherapy doses that have been reduced may not be escalated. 
 
If ≥ grade 2 toxicity occurs during the 46-48 hour infusion of 5-FU, discontinue the infusion 
and refer to Table 6 for dose modifications for the next cycle of mFOLFOX6. 
 
The leucovorin dose remains 400 mg/m2 regardless of changes in the 5-FU and oxaliplatin 
doses.  If 5-FU is held, leucovorin should also be held. 
 
If oxaliplatin is discontinued, treatment should continue with 5-FU and leucovorin. 
 
If treatment with mFOLFOX6 must be discontinued for reasons other than disease recurrence 
or diagnosis of a second primary cancer or secondary malignancy, tests, exams, and 
assessments and specimen submissions will continue (see Table 2 and Table 11). 
 
In the event of disease recurrence or diagnosis of an invasive second primary cancer or 
secondary malignancy during treatment with mFOLFOX6, mFOLFOX6 will be discontinued; 
further therapy is at the investigator's discretion.  However, patients will continue to be 
followed off treatment for survival (see Table 2).  See Table 11 for specimen submission 
requirements. 
Table 5. mFOLFOX6 dose levels 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level 
-1 
(mg/m2) 
Dose Level  
-2 
(mg/m2) 
Dose Level  
-3 
Oxaliplatin 
85
65
50
Discontinue 
Leucovorin* 
400
400
400
Discontinue 
5-FU bolus 
400
320
270
Discontinue 
5-FU infusion 
2400 
1920 
1600
Discontinue 
*Levoleucovorin at 200 mg/m2 can be substituted for leucovorin per institutional practice or as needed 
for drug availability (see Appendix C). 

 
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Table 6. Treatment management for mFOLFOX6 -(See Table 7 for oxaliplatin-specific toxicities.) 
Important table instructions: 
 All dose modifications for mFOLFOX6 are based on the dose level changes on Table 5. 
 Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on 
the scheduled Day 1 of Cycles 2-12 (column 3).  Refer to other applicable instructions in  
Section 6.1 and 6.2. 
 Refer to Section 5.4.2 for management of anemia. 
 Modifications in dose levels apply to 5-fluorouracil and oxaliplatin unless otherwise indicated; leucovorin 
doses remain unchanged. 
Dose modifications must be based on the AE requiring the greatest modification.
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION OF THE 
TREATMENT CYCLE 
(See footnote b)
Neutrophil count decreased: 
Grades 2 (ANC 1000-
1199/mm3) 
 
Maintain dose 
Consider use of growth factors to 
avoid delay with subsequent cycles. 
Hold until   1200/mm3. If recovery 
takes: 1-3 wks – maintain dose 
Grade 3, 4 
Maintain dose or  one dose 
level - at discretion of treating 
oncologist 
Consider use of growth factors to 
avoid delay with subsequent cycles. 
Hold until   1200/mm3. If recovery 
takes: 
1 wk – maintain dose or  one dose 
level at discretion of treating 
oncologist;  
2-3 wks – one dose level
Platelet count decreased: 
Grades 2 
 
Maintain dose 
Hold until   75,000/mm3.   
If recovery takes: 
1-3 wks – maintain dose
Grade 3,4 
Maintain dose or  one dose level 
at discretion of treating oncologist 
Hold until   75,000/mm3.If recovery 
takes: 1-3 wks -  one dose level 
GI: 
Diarrhea (despite optimal 
antidiarrheal management)  
Grade 2 
 
 
 
Maintain dose
 
 
 
↓ only 5-FU one dose level 
Grade 3
↓ only 5-FU one dose level 
↓ only 5-FU one dose level
Grade 4 
↓ 5-FU one dose level and  
↓ oxaliplatin one dose level or 
discontinue
Discontinue
Mucositis oral 
Grade 2
Maintain dose
↓ only 5-FU one dose level
Grade 3  
↓ only 5-FU one dose level 
↓ 5-FU two dose levels and 
↓ oxaliplatin one dose level 
Grade 4 
↓ 5-FU two dose levels and 
oxaliplatin one dose level
Discontinue
Vomiting (despite optimal 
antiemetics) 
Grade 2 
 
 
Maintain dose or  one dose 
level 
 
 
Maintain dose or ↓ one dose level 
Grades 3, 4 
↓ one dose level or discontinue 
Discontinue

 
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Table 6. Treatment management for mFOLFOX6 (continued) 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION OF THE 
TREATMENT CYCLE 
(See footnote b) 
Investigations (hepatic): 
Bilirubin, AST, alk phos 
 
Grade 2 
 
 
 
Maintain dose or ↓ oxaliplatin one 
dose level 
Hold until bilirubin returns to the 
baseline grade and AST and alk 
phos have returned to  
 grade 1, then:  
↓ oxaliplatin one dose level
 
 
 
Grade 3 
 
 
 
↓ 5-FU and oxaliplatin one dose 
level 
Hold until bilirubin returns to the 
baseline grade and AST and alk 
phos have returned to  
 grade 1, then:  
↓ 5-FU and oxaliplatin two dose 
levels or discontinue
Grade 4 
Discontinue 
Discontinue 
Febrile neutropenia: 
Grade 3 
 
Maintain dose or  one dose level 
 
Maintain dose or  one dose level 
Grade 4 
 one dose level or discontinue 
 one dose level or discontinue 
Infection: 
Grade 2 
 
Maintain dose or  one dose level 
 
Maintain dose or  one dose level 
Grade 3 
 one dose level 
 one dose level 
Grade 4 
 one dose level or discontinue 
 one dose level or discontinue 
Other clinically 
significant AEs:c 
Grade 2
 
 
Maintain dose or  one dose level 
 
 
Maintain dose or  one dose level 
Grade 3
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or discontinue
Discontinue 
a Resolved means that all clinically significant AEs are  grade 1 (except neutrophils, which must be 
 1200/mm3 and bilirubin, which must be  the baseline grade) on Day 1 of the next scheduled 
cycle (i.e., treatment can be given without delay). 
b Hold and check weekly.  With exception of neutrophils and bilirubin, resume treatment when 
toxicity is ≤ grade 1.  If toxicity has not resolved after 4 weeks of delay, discontinue mFOLFOX6 
(see Section 6.2 for instructions regarding further study treatment). 
c 
Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
 

 
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Table 7. Treatment management for oxaliplatin-specific toxicities 
Nervous System Disorders
Paresthesias/Dysesthesias/ 
Neuropathy (Peripheral 
motor; Peripheral sensory) 
1-7 day duration 
> 7 day durationa 
Grade 1 
Maintain dose 
Maintain dose
Grade 2  
Maintain dosea
Decrease oxaliplatin one 
dose levela 
Grade 3  
First episode: 
Decrease oxaliplatin one dose level 
a 
Second episode:  
Discontinue oxaliplatin 
Discontinue oxaliplatin  
Respiratory, thoracic and mediastinal disorders 
Laryngopharyngeal 
dysesthesia 
1-7 day duration 
(intermittent or continuous)
> 7 day duration 
(intermittent or continuous) 
Grade 1 
Grade 2 
Maintain dose and consider 
increasing infusion time of 
oxaliplatin to 6 hours 
Maintain dose and consider 
increasing infusion time of 
oxaliplatin to 6 hours
Grade 3 
At the investigator discretion, either 
discontinue oxaliplatin or increase 
duration of infusion to 6 hours
Discontinue oxaliplatin 
Grade 4 
Discontinue oxaliplatin
Discontinue oxaliplatin
Respiratory, thoracic and mediastinal disorders 
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. 
 If non-infectious interstitial lung disease is confirmed, 
oxaliplatin must be discontinued. 
 If non-infectious interstitial disease is ruled out and infection (if 
any) has resolved, patients with persistent Grade 2 dyspnea or 
hypoxia can resume treatment at the discretion of the 
investigator. 
a Hold oxaliplatin for   grade 2 neurotoxicity. When  grade 1, resume treatment with dose 
modifications. If > grade 1 toxicity persists after 4 weeks of delay, discontinue oxaliplatin.  
Continue 5-FU + LV while oxaliplatin is held. 
6.3 
Treatment management for Arm 2 patients with "ctDNA detected" receiving CAPOX 
Capecitabine dose modifications for Arm 2 patients with "ctDNA detected" treated with CAPOX 
are detailed in Table 9. See Table 7 for oxaliplatin-specific toxicities.  Dose modifications are 
based on the dose level changes outlined in Table 8. 
Additionally, the following dose modification instructions must be followed: 
 
All dose modifications should be based on the adverse event requiring the greatest dose 
modification. 
 
If capecitabine is held or discontinued, oxaliplatin continues per protocol unless otherwise 
contraindicated. 
 
Capecitabine and oxaliplatin doses that have been reduced may not be escalated. 

 
NRG-GI005 
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 
If treatment with CAPOX must be discontinued for reasons other than disease recurrence or 
diagnosis of a second primary cancer or secondary malignancy, tests, exams, and assessments 
and specimen collections will continue (see Table 2 and Table 11). 
 
In the event of disease recurrence or diagnosis of an invasive second primary cancer or 
secondary malignancy during treatment with CAPOX, CAPOX will be discontinued; further 
therapy is at the investigator's discretion.  However, patients will continue to be followed off 
treatment for survival (see Table 2).  See Table 11 for specimen submission requirements. 
Table 8. CAPOX dose levels 
(See Table 7 for oxaliplatin-specific toxicities.) 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level 
-1 
(mg/m2) 
Dose Level  
-2 
(mg/m2) 
Dose Level  
-3 
Oxaliplatin 
130 
100 
85 
Discontinue 
Capecitabine 
1000 BID 
750 BID 
500 BID 
Discontinue 
 
Table 9. Treatment management for capecitabine (Arm 2 patients with "ctDNA detected") 
Important table instructions: 
  Dose modifications for capecitabine are based on the dose level changes on Table 8. 
 Hold capecitabine until any AE requiring dose modification returns to  grade 1 unless indicated 
otherwise in the treatment management sections/tables.  If recovery to  grade 1 (or to other level 
specified) has not occurred after 3 weeks of delay, study therapy must be discontinued.
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
Neutrophil count 
decreased: 
Grades 2 (ANC 1000-
1199/mm3), 3, 4
Hold until   1200/mm3.If recovery takes: 
 
1 wk – maintain dose;  
         2-3 wks – one dose level 
Platelet count decreased: 
Grades 2, 3 
Hold until   75,000/mm3  
If recovery takes: 
1 wk – maintain dose;  
2-3 wks –  one dose level
Grade 4 
Hold until   75,000/mm3 
↓ one dose level 
GI: 
Diarrhea (despite optimal 
antidiarrheal management)  
Grade 2, 3 
 
Treatment must be held for grades 2 and 3 diarrhea to avoid severe 
complications. 
1st occurrence  ↓ one dose level 
2nd occurrence ↓ one dose level 
3rd occurrence Discontinue
Grade 4
Discontinue 
Mucositis - oral 
Grade 2
 
Maintain dose or ↓ one dose level
Grade 3 
↓ one dose level 
Grade 4
Discontinue 
Vomiting (despite optimal 
antiemetics) 
Grade 2
 
 
↓ one dose level 
Grades 3, 4 
↓ one dose level or discontinue  
Table continued on next page 
 

 
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Table 9. Treatment management for capecitabine (Arm 2 patients with "ctDNA detected") continued 
CTCAE v5.0 
Adverse Event/Grade
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
Investigations (hepatic): 
Bilirubin, AST, alk phos 
Grade 2 
 
 
 
Hold until bilirubin returns to the baseline grade and AST and alk phos 
have returned to  grade 1; 
↓ one dose level 
Grade 3, 4
Discontinue  
Febrile neutropenia: 
Grade 3 
 
Hold until clinical resolution, then one dose level 
Grade 4 
Discontinue  
Infection: 
Grade 2 
 
Maintain dose or  one dose level 
Grade 3 
 one dose level 
Grade 4 
 one dose level or discontinue 
Skin and subcutaneous 
tissue disorders: 
Palmer-planter 
erythrodysesthesia 
syndrome 
Grades 2, 3 
 
 
 
 
 
 
1st occurrence   one dose level 
2nd occurrence   one additional dose level 
3rd occurrence discontinue  
Other clinically 
significant AEs:* 
Grade 3
 
 
↓ one dose level 
Grade 4 
Discontinue 
* Determination of 
"clinically significant" AEs 
is at the discretion of the 
investigator. 
 
6.4 
Management for all Arm 1 patients and Arm 2 patients with "ctDNA not detected" 
Patients will enter active surveillance, consistent with standard of care for low-risk patients (see 
Table 2). 
 

 
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7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Study Agents 
7.1.1 
Investigational agents 
There are no investigational agents in NRG-GI005. 
7.1.2 
Commercial agents 
The commercial agents in NRG-GI005 are 5-fluorouracil (NSC #19893), leucovorin (NSC 
#3590), levoleucovorin (NSC-#807037), oxaliplatin (NSC #266046), and capecitabine (NSC 
#712807). 
7.2 
Adverse Events and Serious Adverse Events 
7.2.1 
Adverse Event Characteristics 
CTCAE term (Adverse event [AE] description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
7.2.2 
Definition of an adverse event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product (attribution 
of unrelated, unlikely, possible, probable, or definite).  (International Conference on 
Harmonization [ICH] E2A, E6). 
7.2.3 
Definition of a serious adverse event 
Any adverse event (experience) occurring at any dose that results in ANY of the following 
outcomes: 
 
Death 
 
A life-threatening adverse experience 
 
Inpatient hospitalization or prolongation of existing hospitalization (for  24 hours) 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
 
A congenital anomaly/birth defect 
 
Important Medical Events (IME) that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition (FDA, 21 CFR 312.32; 
ICH E2A and ICH E6). 
 

 
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7.3 
Adverse Events for the Study Agents 
7.3.1 
Commercial agents 
Refer to the current FDA-approved package insert for detailed pharmacologic and safety 
information. 
FOLFOX (5-fluorouracil, leucovorin or levoleucovorin, and oxaliplatin): 
Levoleucovorin can be substituted for leucovorin throughout this protocol, per institutional 
practice or as needed for drug availability, at a dose of 200 mg/m2 (see Appendix C). 
CAPOX (capecitabine, oxaliplatin) 
7.4 
Expedited Reporting of Adverse Events 
 
All serious adverse events that meet expedited reporting criteria defined in Table 10 will be 
reported via the CTEP Adverse Event Reporting System (CTEP-AERS), accessed via the 
CTEP web site, https://ctepcore.nci.nih.gov/ctepaers/public/login.  The reporting timelines 
are outlined in Table 10. 
 
Submitting a report via CTEP-AERS serves as notification to the NRG Statistics and Data 
Management Center (SDMC) and satisfies NRG requirements for expedited adverse event 
reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made 
to the NRG Oncology SDMC by phone at 412-383-2557.  An electronic report must be 
submitted into CTEP-AERS immediately upon re-establishment of the Internet connection. 
7.4.1 
Expedited reporting methods 
 
CTEP-AERS 24-hour Notification: Per CTEP NCI Guidelines for Adverse Events 
Reporting, a CTEP-AERS 24-hour notification must be submitted within 24 hours of 
learning of the adverse event.  Each CTEP-AERS 24-hour notification must be followed by a 
CTEP-AERS 5 Calendar Day Report (see Table 10). 
 
CTEP-AERS 10 Calendar Day Report requires that a complete report is electronically 
submitted within 10 calendar days of learning of the AE (see Table 10). 
 
Supporting source documentation is requested for this study by NRG Oncology as needed 
to complete adverse event review.  When submitting supporting source documentation, 
remove all identifiers and include the protocol number, patient ID number, and CTEP-AERS 
ticket number on each page.  Contact NRG Oncology at 1-412-624-2666 for source 
documentation assistance. 
7.4.2 
Expedited reporting requirements (CTEP-AERS-24, CTEP-AERS) 
Expedited reporting requirements begin with the administration of the first mFOLFOX6 or 
CAPOX dose.  Expedited reporting requirements for all patients are provided in Table 10.

 
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Table 10. Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Study Therapy1,2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NRG Oncology) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011
7.4.3 
Additional protocol-specific requirements or exceptions to expedited reporting 
Protocol-specific expedited reporting exceptions:  For this study, the following adverse events, 
including hospitalizations for these events, do not require expedited reporting via CTEP-AERS: 
 
Investigations: Grade <4 decreased neutrophil count, platelet count, and white blood cell 
count. 
7.4.4 
Secondary malignancy 
A secondary malignancy is a cancer that is caused by a treatment for previous malignancy  
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 

 
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All secondary malignancies that occur on NCI-sponsored trials either during or following 
treatment must be reported via CTEP-AERS within 10 days of learning of the secondary 
malignancy.  Three options are available to describe the event: 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the GI005 Follow-up Folder in Medidata Rave.  Supporting documentation should be 
uploaded into the relevant form in the Follow-up folder in Medidata Rave using available upload 
fields within those forms.  Please upload each document into a different upload field, as any later 
uploads into a given field erases the document that exists there. 
7.4.5 
Second malignancy 
A second malignancy is a cancer that is unrelated to the treatment of a prior malignancy and is 
NOT a metastasis from the initial malignancy.  Second malignancies require ONLY routine 
reporting within the GI005 Follow-up folder in Medidata Rave (see Section 7.6). 
7.4.6 
Expedited reporting of pregnancy, pregnancy loss, and death neonatal 
Any pregnancy, pregnancy loss, or death neonatal occurring in a female patient or partner of a 
male patient from the time of consent to 3 months following the last dose of chemotherapy must 
be reported via CTEP-AERS as a medically significant event.  Definitions and reporting 
instruction for these events are provided in the Cancer Therapy Evaluation Program's (CTEP) 
revised NCI Guidelines for Investigators: Adverse Event Reporting Requirements (Section 7.0) 
located at the following CTEP website:  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf). 
Upon learning of a pregnancy, fetal death, or death neonatal that occurs during study or within  
3 months following the last dose of chemotherapy the investigator is required to: 
 
Immediately discontinue mFOLFOX6/CAPOX. 
 
Call the NRG Oncology Clinical Coordinating Department (CCD). 
 
Within 5 working days of learning of the event, and as required by the NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements (Section 7.0): 
 
Create and submit a CTEP-AERS report; 
 
Complete the Pregnancy Information Form (located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm); and  
 
Contact NRG Oncology at 1-412-624-2666 for documentation assistance. 
 
The pregnancy outcome for patients on study should be reported via CTEP-AERS at the 
time the outcome becomes known, accompanied by the same Pregnancy Information 
Form used for the initial report. 
7.5 
Routine Reporting of Adverse Events 
7.5.1 
Reporting routine adverse events through Medidata Rave 
 
Reporting of routine adverse events is done through Medidata Rave (see Section 13.0). 
 
All  grade 2 adverse events that occurred during chemotherapy must be reported on the 
GI005 Adverse Event and Treatment forms through Medidata Rave, regardless of whether 
these adverse events are expected or unexpected. 
 
Supporting documentation for each AE reported on the GI005 Adverse Event forms through 
Medidata Rave must be maintained in the patient's research record. 
 

 
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7.5.2 
Schedule for reporting routine adverse events 
Adverse events for Arm 2 patients "ctDNA detected" are to be submitted through Medidata Rave, 
even if no AEs were experienced by the patient.  Submit the GI005 Adverse Event and 
Treatment forms at the end of each cycle and 30 days (+/-7) days after the last dose of 
chemotherapy. 
7.6 
Reporting Colon Cancer Recurrence and Second Primary Cancer 
Report colon cancer recurrence and second primary cancer (a malignancy that is unrelated to the 
treatment of a prior malignancy and which is not a metastasis from the initial malignancy) within 
the GI005 Follow-up folder in Medidata Rave.  Supporting documentation should be uploaded 
into the relevant form in the Follow-up folder in Medidata Rave using available upload fields 
within those forms.  Please upload each document into a different upload field, as any later 
uploads into a given field erases the document that exists there.  (See Section 7.4.4 for reporting 
instructions for secondary malignancies.) 
 

 
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8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
8.1 
Cancer Therapy Evaluation Program registration procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
(https://ctepcore.nci.nih.gov/rcr). 
RCR utilizes five person registration types. 
 IVR — MD, DO, or international equivalent; 
 NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
 AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
 Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
 Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation 
Required
IVR 
NPIVR 
AP
A
AB 
FDA Form 1572

 
 
Financial Disclosure Form 

 
 
NCI Biosketch (education, 
training, employment, 
license, and certification)

 
 
GCP training

 
 
Agent Shipment Form (if 
applicable) 

 
CV (optional) 

 
 
 
 

 
NRG-GI005 
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Version Date: April 7, 2021 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 
Addition to a site roster 
 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
In addition, all investigators act as the Site Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance). 
Additional information is located on the CTEP website at 
< https://ctep.cancer.gov/investigatorResources/default.htm > 
For questions, please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
8.2 
Cancer Trials Support Unit Registration Procedures 
This study is supported by the NCI CTSU. 
8.2.1 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional Review 
Board (NCI CIRB).  In addition, U.S.-based sites must accept the NCI CIRB review to activate 
new studies at the site after March 1, 2019.  Local IRB review will continue to be accepted for 
studies that are not reviewed by the CIRB, or if the study was previously open at the site under the 
local IRB. International sites should continue to submit Research Ethics Board (REB) approval to 
the CTSU Regulatory Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network.  Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by 
emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
 
Local IRB documentation; 
 
IRB-signed CTSU IRB Certification Form; and/or 
 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria to complete processing of the IRB/REB approval 
record: 

 
NRG-GI005 
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Version Date: April 7, 2021 
 
Holds an Active CTEP status; 
 
Rostered at the site on the IRB/REB approval and on at least one participating roster; 
 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
 
Holds the appropriate CTEP registration type for the protocol. 
8.2.2 
Additional Requirements for Protocol NRG-GI005 Site Registration 
Additional requirements to obtain an approved site registration status include: 
 
An active Federal Wide Assurance (FWA) number; 
 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
 
Compliance with all protocol-specific requirements (PSRs). 
8.2.3 
Downloading Site Registration Documents 
Download the site registration forms from the protocol specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a PO on the protocol. 
 
Log on  to the CTSU members' website (https://www.ctsu.org)  using your CTEP-IAM 
username and password; 
 
Click on Protocols in the upper left of your screen 
 
Enter the protocol number in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand, then select NRG, and  
protocol number NRG-GI005 
 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB initiative, IRB data will load automatically to the 
CTSU as described above.) 
8.2.4 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal log on to the CTSU members’ website  Regulatory 
 Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 

 
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8.2.5 
Checking Your Site’s Registration Status 
You can verify your site’s registration status on the members’ side of the CTSU website. 
 
Log on to the CTSU members’ website; 
 
Click on Regulatory  at the top of your screen; 
 
Click on Site Registration; 
 
Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
8.3 
Patient Enrollment 
Patient enrollment will be facilitated using The Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  OPEN is integrated with 
CTSU regulatory and roster data and with the Lead Protocol Organization (LPOs) 
registration/randomization systems or Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI's clinical data management system, Medidata Rave. 
Requirements for OPEN access:  
 
A valid CTEP-IAM account; 
 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must hold 
the OPEN Registrar task on the DTL for the site; and 
 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, 
the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 
1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 

 
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8.4 
Reimbursement 
To receive site reimbursement for biospecimen submissions, completion dates must be entered in 
the OPEN Funding screen post registration.  Please refer to the NRG-GI005 specific funding page 
on the CTSU members' website for additional information.  Timely entry of completion dates is 
recommended as this will trigger site reimbursement for CTEP funding. 
Further instructional information is provided on the OPEN tab of the CTSU Member side of the 
CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
8.5 
Investigator-Initiated Discontinuation of chemotherapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue chemotherapy if one of the following occurs: 
 
the patient develops a serious side effect that he or she cannot tolerate or that cannot be 
controlled with other medications, 
 
the patient's health gets worse, 
 
the patient is unable to meet the study requirements, or 
 
new information about the chemotherapy or other treatments for colorectal cancer becomes 
available. 
If chemotherapy is stopped, study data and other materials should be submitted according to the 
study schedule unless the patient withdraws from the study (see Section 8.7). 
8.6 
Patient-Initiated Discontinuation of Chemotherapy 
Even after a patient agrees to take part in this study, he or she may stop chemotherapy or 
withdraw from the study at any time.  If chemotherapy is stopped but the patient still allows the 
investigator to submit information, study data and other materials should be submitted according 
to the study schedule. 
8.7 
Patient-Initiated Consent Withdrawal from the Study 
If a patient chooses to have no further interaction regarding the study (i.e., allow no future  
follow-up data to be submitted to NRG Oncology SDMC), consent withdrawal form is to be 
completed via the Add-Event function in Medidata Rave. 
8.8 
ctDNA Testing Outside of the Conduct of the GI005 Study 
Patients participating in the GI005 study are permitted to pursue ctDNA testing outside of the 
conduct of the GI005 study.  Patients who elect to pursue ctDNA testing outside the conduct of 
this study will be allowed to stay on study.  Patients will continue to follow study requirements 
according to the study schedule.  Patients in Arm 1 will be monitored for treatment with 
chemotherapy received outside the conduct of this study. 
 

 
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9.0 
DRUG INFORMATION 
9.1 
Commercial Agents 
The commercial study agents are 5-fluorouracil, leucovorin, levoleucovorin, oxaliplatin, and 
capecitabine.  There are no investigational agents for NRG-GI005. 
9.1.1 
Availability/Supply 
5-fluorouracil (NSC #19893), leucovorin (NSC #3590), levoleucovorin (NSC #807037), 
capecitabine (NSC #712807) and oxaliplatin (NSC #266046) will not be provided and must be 
obtained by the investigator from commercial supply.  Please see Section 5.2 (Table 3) and 
(Table 4), for administration instructions.  Refer to the current FDA-approved package insert 
provided with each drug and the site-specific pharmacy for instructions for standard drug 
preparation, handling, and storage. 
9.1.2 
Adverse Events 
For adverse events and potential risks associated with 5-fluorouracil, leucovorin, levoleucovorin, 
capecitabine, and oxaliplatin, please refer to Section 7.3.1, to the current FDA-approved package 
insert provided with each drug, and to the site-specific pharmacy. 
 

 
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10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
10.1 
Specimen Submissions 
Submission of whole blood for ctDNA analysis, archived resected primary tumor tissue 
(FFPE), and uninvolved margin of resection (normal tissue) (FFPE) is required for all 
patients who consent to enrollment in NRG-GI005.  Submission of optional tumor tissue and 
blood specimens is only required for patients who agree to submission of optional tumor tissue 
and blood in the GI005 consent form.  Tumor and blood samples for all patients will be 
collected at the specified timepoints outlined in Table 11. 
Table 11. Mandatory and optional sample requirements 
Specimen Type 
Collection Time Points 
Shipping 
Archived resected 
primary tumor tissue and 
uninvolved margin of 
resection (normal 
tissue)(FFPE) 
(mandatory)a 
 
All patients 
Must be submitted within 60 days 
 after randomization 
NSABP Division of Pathology 
NRG Oncology 
Biospecimen Bank-Pittsburgh 
1307 Federal Street 
Suite 303 
Pittsburgh, PA 15212 
Whole blood for ctDNA 
(mandatory)b, e 
 All patients 
Baseline (before or after 
randomization) 
Note: Do not ship sample until patient 
ID is obtained at randomization. 
Guardant Health, Inc. 
505 Penobscot Dr. 
Redwood City, CA 94063 
 
 All Arm 1 and Arm 2 patients with 
"ctDNA not detected" 
6 months from randomization e 
 Arm 2 patients with "ctDNA 
detected" 
Prior to administration of last cycle of 
chemotherapy e 
Unstained slides at time 
of recurrence/secondary 
malignancy 
(optional)c 
 All patients 
At recurrence or second 
primary/secondary malignancy 
NSABP Division of Pathology 
NRG Oncology 
Biospecimen Bank-Pittsburgh 
1307 Federal Street 
Suite 303 
Pittsburgh, PA 15212 
Table continued on next page 
 

 
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Table 11. Mandatory and optional sample requirements (continued) 
Whole blood  
(optional) d 
 All patients 
Baseline (before or after 
randomization) 
Note: Do not ship sample until patient 
ID is obtained at randomization. 
 
 
 
 
Baylor College of Medicine 
NRG Oncology Serum Bank 
Room N1111 
One Baylor Plaza 
Houston, TX 77030 
 All Arm 1 and Arm 2 patients with 
"ctDNA not detected" 
- 3 months from randomization  
- 6 months from randomization  
 Arm 2 patients with "ctDNA 
detected" 
- Prior to week 13 administration of 
chemotherapy 
- Prior to administration of last cycle 
of chemotherapy 
 All patients 
- 12 months from randomization 
 
a Submit an archived paraffin block (FFPE) or one H & E slide with an additional  15 unstained 
slides from resected primary tumor tissue and submit an archived paraffin block (FFPE) or one 
H & E slide with at least 15 unstained slides from an uninvolved margin of resection (normal 
tissue). 
b Collect four (4) 10 mL Streck cell-free BCT tubes, at each of these time points during a routine 
phlebotomy procedure for other standard labs.  All mandatory specimens should be collected in 
their entirety prior to collection of any optional sample collection.  Mandatory blood specimen at 
baseline cannot be collected until informed consent is obtained.  Note: A failed assay at baseline 
will require a blood redraw, and testing should be completed within 4 weeks following 
randomization. 
c If a biopsy was done anytime through Year 3 from randomization as part of routine care at the time 
of disease recurrence or diagnosis of a second primary cancer or secondary malignancy, submission 
of one H & E slide with an additional  15 unstained slides is required for patients who have agreed 
to the optional biobanking portion of this study. 
d For patients participating in the optional specimen collection, collect five (5) 10 mL purple top 
tubes (EDTA) before or after randomization and collect two (2) 10 mL purple top tubes (EDTA), at 
each of the other time points during a routine phlebotomy procedure for other standard labs.  Note: 
Optional blood specimen at baseline cannot be collected until informed consent is obtained. 
e Patients who recur or have a second primary/second malignancy prior to 6 months from 
randomization or prior to last cycle of chemotherapy should have a whole blood draw for ctDNA at 
that time to replace the 6 months or prior to last cycle of chemotherapy timepoint. 
Note: Refer to the NRG-GI005 Pathology and Correlative Science Instructions for tumor and blood 
sample collection, alternative sample submission, processing, and submission instructions. 
 
 

 
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10.2 
Integrated Correlative Studies 
10.2.1 ctDNA Analysis 
For all patients enrolled in the study, it is mandatory that blood is collected before randomization 
and 6 months after randomization specifically to perform necessary ctDNA analyses required for 
the primary and secondary objectives.  Patients who recur prior to 6 months from randomization 
would have mandatory blood drawn at the time of recurrence in place of the 6-month time point.  
For those patients randomized to Arm 2, the specimen collected at baseline will be analyzed in 
near-real-time, with results reported back to sites via SDMC as “ctDNA detected” or ctDNA not 
detected”.  All other mandatory specimens will be analyzed in batch processes as part of listed 
endpoints associated with the study protocol.  These results will not be reported back to the 
patient or the patient’s provider. 
Additional analyses from all samples will be performed to refine and optimize the Guardant 
LUNAR test.  These analyses include, but are not limited to, assessment of individual genetic and 
epigenetic signals, ctDNA kinetics with regards to change in variant allele frequency, ctDNA 
clearance following treatment, analyses of other blood components, and association with patient 
and tumor characteristics and clinical outcomes. 
The Guardant Health LUNAR test is designed to detect mutations and epigenetic signals from 
circulating tumor DNA agnostic of mutation profiling in associated tumor tissue.  However, in 
order to compare ctDNA findings with those in the corresponding tumor tissue, for all patients 
enrolled in the study, primary tumor tissue (FFPE) obtained at surgical resection may be utilized 
in a pre-planned (but retrospective) analysis to explore the representation of genetic and/or 
epigenetic features in circulation as compared to tissue.  This may be used for refinement 
purposes of assay performance, standards and determination of false positive or false negative 
ctDNA rates. 
10.2.2 
Location of testing 
Guardant Health, Inc. 
505 Penobscot Dr. 
Redwood City, CA 94063 
10.3 
Exploratory Correlative Studies 
For patients who elect to enroll in the optional biobanking associated with this trial and provide 
written consent, any additional biospecimen material remaining from the required specimens will 
be made available for additional research.  Funding for the optional tissue biopsy at the time of 
recurrence will depend upon securing external financial support in the future for prospective 
collection.  However, it is possible that patients may undergo a tissue biopsy for standard-of-care 
practice at the time of recurrence/progression.  If so, one H&E slide and 15 unstained slides may 
be submitted for biobanking, regardless of the securing of external funding.  Additional blood 
samples will be collected and stored for future analyses (See Table 11). 
These correlative specimens will serve as an invaluable resource for future ctDNA assay 
refinement or validation, biomarker discovery, and other analyses associated with personalized 
treatment determinations.  These EDTA specimens will be adequate to allow for analyses of 
ctDNA kinetics and temporal dynamics associated with clearance, recurrence, and concurrent 
imaging assessments and exploratory endpoints. 
An amendment or proposal for any correlative science studies to be performed on any of these 
biological samples will be submitted to CTEP, NCI for review and approval according to NCTN 
guidelines.  Amendments to the protocol and/or proposals for use of banked tissue will include 
the appropriate background, experimental plans with assay details, and a detailed statistical 
section.  Samples for testing will not be released for testing until the appropriate NCI approvals 
have been obtained. 
 

 
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11.0 
SPECIAL STUDIES (NON-TISSUE) 
Resource utilization, such as anti-cancer therapy, medications, procedures, laboratories, imaging, 
and hospital stays, will be collected using standard resource utilization data collection forms. 
The timing of the collection of utility and resource utilization will be more frequent for some 
patients when they receive adjuvant chemotherapy and/or at relapse in order to capture adequate 
data. 
The analyses will take the payers’ perspective. Discounting will be based on country-specific 
discounting rate (e.g. 3% in US and 1.5% in Canada) with sensitivity analysis exploring 0%, 
1.5%, 3% and 5%. 
The robustness of the model results will be assessed using one-way and multi-way sensitivity 
analyses. Major drivers of medical care costs, namely hospitalization, drugs and survival, will be 
varied ± 20%, to examine the impact on the base-case incremental cost effectiveness ratios 
(ICERs).  Bootstrapping and the development of a cost-effectiveness acceptability curve will also 
be conducted to assess the magnitude of uncertainty of the results. 
Subgroup analyses based on stratified factors or any future identified clinically beneficial 
subgroups (either based on clinical factors or biomarkers) will be conducted. 
To assess for the cost-effectiveness and the cost-utility of the strategy of testing for ctDNA with a 
life-time horizon, recognizing that the trial time horizon is 56 months only, a companion state 
transition model will be constructed with inputs from data collected prospectively in the trial and 
supplemented by published literature regarding the downstream cost, utility and survival in the 
recurrent/advanced health states.  Probabilistic analysis will be conducted as the base-case and 
scenario analyses will be conducted for clinically relevant/beneficial subgroups. 
 

 
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12.0 
DIAGNOSIS OF COLON CANCER RECURRENCE 
The diagnosis of a first colon cancer recurrence should be made only when the clinical and 
laboratory findings meet the criteria of “acceptable” as defined below.  Any recurrence of 
malignant disease should be proven by biopsy whenever possible. 
At the time of colon cancer recurrence, the investigator should indicate the site of tumor 
recurrence and whether multiple sites are involved. 
Supporting documentation must be submitted with the GI005 Follow-up folder in Medidata Rave 
following diagnosis of colon cancer recurrence or invasive second cancer.  The documentation 
will be reviewed at the NRG Oncology SDMC to determine the method(s) used to document the 
recurrence, the anastomotic location(s) of the recurrence, and the type of second cancer. 
12.1 
Abdominal and/or pelvic sites 
12.1.1 Anastomotic 
 
Acceptable: positive cytology or biopsy 
12.1.2 Abdominal, pelvic, and retroperitoneal nodes 
 
Acceptable: positive cytology or biopsy; progressively enlarging node(s) as evidenced by two CT 
or MRI scans separated by at least a 4-week interval; ureteral obstruction in the presence of a 
mass as documented on CT or MRI scan; or a single CT or MRI scan showing a definite mass 
which is confirmed to be malignant by a positive PET scan at that site. 
12.1.3 Peritoneum (including visceral and parietal peritoneum or omentum) 
 
Acceptable: positive cytology or biopsy; 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. 
12.1.4 Ascites 
 
Acceptable: positive cytology 
12.1.5 Liver 
Acceptable: positive cytology or biopsy or three of the following that are not associated with 
benign disease: 
 
recent or progressive hepatomegaly, abnormal liver contour; 
 
positive radionucleotide liver scan, or sonogram; 
 
positive CT scan or MRI scan; 
 
positive PET scan which confirms abnormal CT scan or MRI scan and is associated with a 
rising CEA; 
 
abnormal liver function studies; or 
 
elevated CEA, i.e., a persistent rise in CEA titer of 10 times 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: contrast and/or endoscopic exam; abdominal and pelvic CT scan, sonogram, MRI 

 
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scan, PET scan, or CEA scan; and/or celiac and mesenteric arteriography. Documentation of 
corroborative evidence by biopsy is strongly recommended. 
12.1.6 Pelvic mass not otherwise specified (NOS) 
Acceptable: positive cytology or biopsy; progressively enlarging intrapelvic solid mass as 
evidenced by two CT or MRI scans separated by at least a 4-week interval; or a 
solid mass on a single CT scan confirmed by a positive PET scan at that site. 
12.1.7 
Abdominal wall, perineum, and scar 
Acceptable: positive cytology or biopsy 
12.2 
Non-abdominal and non-pelvic sites 
12.2.1 Skeletal 
Acceptable: 
For all suspected bone-only recurrences, a biopsy is required to demonstrate 
recurrence. 
12.2.2 Lung 
Acceptable: 
positive cytology, aspirate, or biopsy or 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, or MRI scan, further investigations such as biopsy, needle 
aspiration, or resection should be performed.  Proof of neoplastic pleural effusion 
should be established by cytology or pleural biopsy. 
12.2.3 Bone marrow 
Acceptable: positive cytology, aspirate, biopsy, or MRI scan 
12.2.4 Central nervous system 
Acceptable: positive CT or MRI scan, usually in a patient with neurologic symptoms, or biopsy 
or cytology (for a diagnosis of meningeal involvement). 
12.3 
Secondary malignancy 
Secondary malignancy is defined as a cancer that is caused by a treatment for previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy).  
A secondary malignancy is not considered a metastasis of the initial neoplasm.  The diagnosis of 
a secondary malignancy must be confirmed histologically.  Representative slides are not required 
unless requested by the NRG Oncology SDMC for review. 
12.4 
Second primary cancer 
Second primary cancer is defined any invasive non-colon cancer other than squamous or basal 
cell carcinoma of the skin. The diagnosis of an invasive second cancer must be confirmed 
histologically whenever possible.  Representative slides are not required unless requested by the 
NRG Oncology SDMC for review. 
12.5 
Documentation requested following death 
 Autopsy reports should be secured whenever possible and should be submitted to the NRG 
Oncology SDMC. 
 A copy of the death certificate should be forwarded to the NRG Oncology SDMC if it is 
readily available or if it contains important cause-of-death information not documented 
elsewhere. 
 Please submit the last clinic/office note before the death or the physician's note summarizing 
the death. 
 

 
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13.0 
DATA AND RECORDS 
13.1 
Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 
 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account; and 
 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site: Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a minimum of an 
AP registration type; 
 
To hold Rave investigator role, the individual must be registered as an NPIVR or IVR, 
and 
 
To hold Rave Read Only role, site staff must hold an Associates (A) registration type. 
If the study has a Delegation of Tasks Log (DTL), individuals requiring write access to Rave 
must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be able 
to access the study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in 
iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website in the 
Rave section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance).  Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com 
Rave CTEP AERS Integration 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting, and facilitates entry in 
CTEP-AERS for those AEs requiring expedited reporting. 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 

 
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Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline Adverse Events 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 The reporting period (course/cycle) is correct; and 
 AEs are recorded and complete (no missing fields) and the form is query free 
(fields added to the form during study build do not need to be query free for the 
integration call with CTEP-AERS to be a success). 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence, that Internet connectivity is lost; a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
 Study specific documents: Protocols > Documents> Education and Promotion; 
and 
 Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides. 
NCI requirements for SAE reporting are available on the CTEP website: 
 NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 

 
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The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP.  A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details and reports to be available on the DQP.  
Site staff should contact the LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality. 
13.2 
Summary of Data Submission 
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 the trial using Medidata Rave.  Additionally, certain adverse events must be reported 
in an expedited manner for timelier monitoring of patient safety and care.  See Sections 7.4 and 
7.5 for information about adverse event reporting. 
Summary of Data Submission: Refer to the CTSU Member website for the table of Required 
Forms and Materials. 
13.3 
Global Reporting /Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol and patient-specific CDUS data will be submitted electronically to CTEP on 
a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 31, and 
October 31.  Instructions for submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov). 
 

 
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14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Abstract 
This is a phase II-III prospectively randomized clinical trial comparing ctDNA assay-directed 
therapy (chemotherapy for "ctDNA detected" patients, SOC for "ctDNA not detected" patients) to 
standard of care (SOC, observation after surgery) with equal allocation to treatment arm (1:1).  
Treatment assignment is not blinded, however, assay results will be blinded for patients assigned 
to the SOC therapy arm (not assay-directed). 
14.2 
Endpoint(s) 
14.2.1 Primary Endpoints 
Phase II: Clearance of ctDNA (to undetectable levels) for the "baseline ctDNA detected" patient 
subset at 6 months.  Patients who recur prior to 6 months should have a blood draw for 
assessment as soon as possible after diagnosis.  Patients with recurrence who fail to provide a 
blood draw at recurrence will be considered “failure to clear” for analysis purposes. 
Phase III: Recurrence-free survival (RFS, time to recurrence or death) for the "baseline ctDNA 
detected" patient subset.  Censoring will be at last patient contact. 
14.2.2 Secondary Endpoints 
 
RFS according to ctDNA marker status and treatment 
 
Overall Survival (OS) according to ctDNA marker status and treatment 
 
Time to Recurrence (TTR) according to ctDNA marker status and treatment.  Censoring will 
be at last patient contact or death. 
 
Compliance with adjuvant chemotherapy and/or active surveillance 
 
Incidence (presence or absence) of ctDNA in blood following resection of stage II colon 
cancer 
14.2.3 Exploratory Endpoints 
 
Quantitative ctDNA levels association with time to event outcomes (RFS, OS, and TTR) by 
treatment received. 
 
To characterize genomic profiles associated with TTR using a ctDNA assay in patients with 
resected stage IIA colon cancer. 
 
Cost effectiveness of the use of ctDNA versus standard of care in this setting. 
14.3 
Stratification and randomization 
There is no stratification on this trial.  Patients will be randomized 1:1 between standard of care 
(Arm 1) and assay-directed therapy (Arm 2).  An adaptive randomization scheme that avoids 
imbalance within participating institutions will be employed.  We use an algorithm based on the 
method described by White and Freedman (White 1978) that incorporates Efron's (Efron 1971) 
biased coin approach.  Our algorithm computes a score for each treatment arm as the weighted 
sum of the number of patients on that treatment arm in the randomizing institution.  When the 
treatment scores differ by less than a pre-defined tolerance, patients are randomly assigned 
treatment in an unbiased fashion (treatment equally likely).  When the treatment scores differ by 
more than a pre-defined tolerance, patients are randomly assigned treatment using a biased-coin 
approach where the bias depends on the difference in scores. 
 

 
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14.4 
Patient Cohorts 
Patients will be analyzed by intention to treat (ITT), that is, patients will be analyzed according to 
their randomly assigned treatment regardless of treatment actually received.  Patients not at risk 
for recurrence of colon cancer (determined not to have had colon cancer in the first place) will be 
excluded from the ITT cohort.  The "baseline ctDNA detected" cohort is determined by the assay 
of the pre-randomization blood draw. 
14.5 
Patient Accrual 
We anticipate 4 months of zero accrual after initiation of the study followed by level accrual of 30 
patients per month thereafter. 
14.6 
Sample Size Determination 
For this phase II/III study, a total of 1408 patients will be randomized between the two arms in a 
1:1 distribution (704 patients/arm) over a period of 47months (30 pts/month).  Patients will be 
followed for an additional 18 months for a total study duration of 65 months.  The analysis of 
RFS between the two arms for the phase III endpoint will occur in the "ctDNA detected" subset 
(estimated N=76 for both arms combined) when 55 RFS events have been observed.  The sample 
size for this primary phase III analysis was calculated using a one-sided α=.025 and a power of 
92%.  One percent annual loss to follow-up is assumed for each arm.  Here, we assume that 
5.45% of patients will be "ctDNA detected", and that untreated patients in this subset will have a 
25% RFS at 24 months.  We assume that, for the "ctDNA detected" subset, administration of 
adjuvant chemotherapy will reduce the RFS event rate by 60% (HR .40).  The unstratified two-
sample logrank test is used for the treatment comparison. 
14.7 
Study Monitoring 
14.7.1 Phase II/III Futility rule 
The initial phase II study aims to ascribe the ability of chemotherapy to clear ctDNA in patients 
with stage IIA colon cancer.  When 16 "ctDNA detected" patients have been on study for 6 
months (time to complete chemotherapy) and have completed the 6 month blood draw, we will 
compare the rates of clearance in the "ctDNA detected" patients by arm (assay -directed therapy 
versus active surveillance).  This analysis is anticipated to occur when 540 of 1408 patients have 
been accrued (~22 months into study).  The decision rule is as follows: 
 
If the p-value from a one-sided Fisher exact test is > 0.35 (i.e., with no improvement in 
ctDNA clearance definitively detected with chemotherapy), then we will stop early for 
futility. 
 
If the p-value is less than  or equal to 0.35, then we plan to proceed to the phase III study 
in order to gather more definitive data on the relationship between treatment and 
recurrence-free survival.  Assuming the 16 "ctDNA detected" patients break down as 8 
per arm, this decision rule can be illustrated as follows in Figure 2 where we plot the 
Fisher’s exact p-value as a function of the observed clearance rates in the two arms: 
 
The operating characteristics of the test are as follows: 
 

 
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P clear 
control 
P clear 
experimental 
Power 
Comment 
0.1 
0.1 
7.2% 
Null hypothesis 
0.1 
0.3 
46.4% 
 
0.1 
0.4 
65.7% 
 
0.1 
0.5 
79.1% 
 
0.1 
0.6 
90.9% 
Alternative hypothesis 
0.2 
0.2 
13.8% 
 
0.2 
0.3 
30.0% 
 
0.2 
0.4 
45.2% 
 
0.2 
0.5 
63.4% 
 
0.2 
0.6 
77.3% 
 
 
Figure 3: Phase II/III futility rule of ctDNA clearance 
 
It is important to note that differences in clearance rates roughly less than 25% correspond to 
stopping for futility (pink shading), and rate differences below 25% or more (yellow shading) 
imply continued equipoise as to the value of treatment in this subset. 
14.7.2 Interim analysis of the primary phase III endpoint 
When 26 RFS events have been observed in the "ctDNA detected" subset (50% information, ~ 40 
months), we will compare RFS and proceed if the hazard ratio favors the assay directed therapy 
arm (Wieand 1994).  If the one-sided p-value favoring the assay directed therapy arm is less than 
0.001 the DMC will consider a recommendation to stop the trial early for efficacy (Haybittle-Peto 
rule) (Haybittle 1971). 
 
Chemotherapy
Number
cleared
0
1
2 
3
4
5
6
7
8
%
cleared
0%
13%
25%
38%
50%
63%
75%
88% 
100%
0
0%
1.0000
0.5000 
0.2333
0.1000 
0.0385
0.0128
0.0035
0.0007
0.0000
1
13%
1.0000
0.7667 
0.5000
0.2846 
0.1410
0.0594
0.0203
0.0051
0.0007
2
25%
1.0000
0.9000 
0.7154
0.5000 
0.3042
0.1573
0.0660
0.0203
0.0035
Rule
3
38%
1.0000
0.9615 
0.8590
0.6958 
0.5000
0.3096
0.1573
0.0594
0.0128 Stop futility
p > 0.35
4
50%
1.0000
0.9872 
0.9406
0.8427 
0.6904
0.5000
0.3042
0.1410
0.0385 Continue 
p <= 0.35
5
63%
1.0000
0.9965 
0.9797
0.9340 
0.8427
0.6958
0.5000
0.2846
0.1000
6
75%
1.0000
0.9993 
0.9949
0.9797 
0.9406
0.8590
0.7154
0.5000
0.2333
7
88%
0.5000
8
100%
Figure 3: Phase II/III Futility Rule for ctDNA Clearance
Rule illustrated assuming 8 ctDNA+ patient per arm
O
b 
s
e
r
v
a
t
i
o 
n 

 
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14.7.3 Monitoring of Patient Accrual 
The NRG Oncology DMC will review the study twice a year with respect to patient accrual. 
14.7.4 Monitoring of Protocol Treatment 
The NRG Oncology DMC will review the study twice a year with respect to compliance with 
assigned therapy. 
14.7.5 Further Monitoring 
The NRG Oncology DMC will review morbidity, serious adverse events, and loss to follow-up.  
We expect that the annual loss to follow-up is at most 2%.  If the annual lost to follow-up is more 
than 2% at 3 years or more after the initiation of this study, we will study the loss to follow-up 
data, identify possible causes, and take actions to reduce loss to follow-up. 
All study participants, regardless of arm of randomization or ctDNA status (if tested off protocol), 
will be monitored for treatment with chemotherapy.  If >15% of participants randomized to Arm 
1 receive chemotherapy outside of study conduct, then the NRG Oncology DMC will discuss 
whether or not to continue with study conduct. 
14.8 
Analysis 
14.8.1 Primary Endpoints 
Phase II: Clearance of ctDNA (to undetectable levels) for the baseline "ctDNA detected" patient 
subset. 
The first 16 patients in the cohort “ctDNA detected” at baseline and the ITT cohort with assay 
results from the 6-month blood draw or recurrence prior to the 6-month blood draw will be 
categorized as “cleared” if the 6-month blood draw result is "ctDNA not detected" or “failed to 
clear” otherwise (assay of "ctDNA detected" or "Failed" or early recurrence).  A two by two 
contingency table of clearance by treatment arm will be created.  The one-sided Fisher exact p-
value will be used to determine futility based on the rule specified in Section 14.7.1.  Degenerate 
tables where the Fisher p-value cannot be calculated (no patients clear on either arm or all 
patients clear on both arms) will count as a failure and a recommendation for early termination. 
Phase III: Recurrence-free survival 
RFS will be compared by treatment arm using the logrank test with no stratification in the ITT 
cohort.  Kaplan Meier curves will be computed to describe the distribution of time to event.  A 
summary hazard ratio and associated confidence interval will be computed from a Cox model 
with treatment arm as the only covariate. 
14.8.2 Secondary Endpoints 
 
RFS according to ctDNA marker status and treatment 
Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment 
combination. 
 
Overall Survival (OS) according to ctDNA marker status and treatment  
Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment 
combination.  The unstratified logrank test will be used to compare treatments for patients 
“ctDNA Positive” at baseline and a Cox model will estimate the hazard ratio. 
 
Time to Recurrence (TTR) according to ctDNA marker status and treatment.  
Kaplan Meier analyses to describe the distribution of time to event for each marker-treatment 
combination.  The unstratified logrank test will be used to compare treatments for patients 
“ctDNA Positive” at baseline and a Cox model will estimate the hazard ratio. 

 
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 
Compliance with adjuvant chemotherapy and/or active surveillance. 
The duration of chemotherapy will be categorized as None, less than 3 months, and at least 3 
months by treatment arm and baseline ctDNA status.  Arms will be compared by a chi square 
test within each baseline ctDNA status. 
 
Incidence (detection or no detection) of ctDNA in blood following resection of stage IIA 
colon cancer 
 
Combined baseline rate of "ctDNA detected" for all patients in the ITT cohort. 
14.9 
Gender/Ethnicity/Race Distribution 
Possible racial and ethnic variation assuming 1408 patients are randomized: 
The prognostic effect of race/ethnicity will be evaluated using statistical models.  Unfortunately, 
because of power limitations, we will not be able to compare effects separately for the different 
cultural or racial groups.

 
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Table 12. Gender/Ethnicity/Race Distribution 
DOMESTIC PLANNED ENROLLMENT REPORT
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male
American 
Indian/ Alaska 
Native 
3 
5 
0 
0 
8 
Asian
27 
25
0
0
52
Native 
Hawaiian or 
Other Pacific 
Islander 
1 
1 
0 
0 
2 
Black or 
African 
American
66 
69 
0 
0 
135 
White
323
339 
85
89
836
More Than One 
Race
6 
6 
6 
6 
24 
Total 
426
445 
91
95
1057
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male
American 
Indian/ Alaska 
Native 
25 
45 
0 
0 
70 
Asian
1 
0
0
0
1
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or 
African 
American
1 
2 
0 
0 
3 
White
97 
180 
0
0
277
More Than One 
Race
0 
0 
0 
0 
0 
Total 
124
227 
0
0
351
 
 

 
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15.0 
REFERENCES 
Benson AB III, Ajani JA, Catatano RB, et al.  Recommended guidelines for the treatment of 
cancer treatment-induced diarrhea.  J Clin Oncol. 2004;22(14):2918-2926. 
Diehn M, Alizadeh AA, Adams HP, et al.  Early prediction of clinical outcomes in resected stage 
II and III colorectal cancer (CRC) through deep sequencing of circulating tumor DNA (ctDNA).  
J Clin Oncol. 2017; 35.15_suppl.abstr.3591. 
Efron B. Forcing sequential experiments to be balanced.  Biometrika 1971; 58:403-441. 
Haybittle, JL.  Repeated assessments of results in clinical trials of cancer treatment.  Br. J. 
Radiol.1971; 44 (526):793–797. 
Hesketh PJ, Kris MG, Basch E, et al. Antiemetics:  American Society of Clinical Oncology 
Clinical Practice Guideline Update. J Clin Oncol. 2017; 35(28):3240-3261. 
Kumar A, Kennecke HF, Renouf DJ, et al.  Adjuvant chemotherapy use and outcomes of patients 
with high-risk versus low-risk stage II colon cancer.  Cancer 2015; 121(4):527-534. 
NCCN Clinical Practices Guidelines in Oncology:  Colon Cancer 2018; 
https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. 
O'Connor ES, Greenblatt DY, LoConte NK, et al.  Adjuvant chemotherapy for stage II colon 
cancer with poor prognostic features.  J Clin Oncol  2011; 29(25):3381-3388. 
Schrag D, Rifas-Shiman S, Saltz L, Bach PB, Begg CB.  Adjuvant chemotherapy use for 
Medicare beneficiaries with stage II colon cancer.  J Clin Oncol 2002; 20(19):3999-4005. 
Tie J, Wang Y, Tomasetti C, et al.  Circulating tumor DNA analysis detects minimal residual 
disease and predicts recurrence in patients with stage II colon cancer.  Sci Transl Med  2016; 8 
(346):346ra392. 
White SJ, Freedman LS.  Allocation of patients to treatment groups in a controlled clinical study.  
Br J Cancer 1978; 37:849-857. 
Wieand S, Schroeder G, O'Fallon JR.  Stopping when the experimental regimen does not appear 
to help.  Stat Med 1994; 13(13-14):1453–1458. 
 

 
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APPENDIX A 
 
ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING 
1.0 
PERFORMANCE STATUS 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on all 
pre-disease performance without 
restriction 
90-100% 
1 
Restricted in physically 
strenuous activity but 
ambulatory 
70-80% 
2 
Ambulatory and capable of  
self-care; but unable to carry out 
any work activities 
50-60% 
3 
Capable of only limited self-
care; confined to bed or chair 
more than 50% of waking hours 
30-40% 
4 
Completely disabled 
10-20% 
2.0 
ACTIVITIES OF DAILY LIVING 
The following definitions for activities of daily living (ADL) should be used when the  
CTCAE v5.0 grading criteria are based on ADL: 
 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
 
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.

 
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APPENDIX B 
 
CLINICAL MANAGEMENT OF DIARRHEA 
Pharmacologic diarrhea management 
 For patients with persistent grade 1 diarrhea on loperamide, diphenoxylate hydrochloride and 
atropine sulfate (Lomotil) 1 tablet every 6 to 8 hours may be added. 
 For  grade 2 diarrhea despite intensive antidiarrheal therapy, consider adding octreotide 
(short acting) 150 micrograms subcutaneous injection as needed up to three times per day; or 
after the initial dose of short acting octreotide, if well tolerated, a single dose of octreotide 
LAR 20 mg IM. 
 For grade 3 or grade 4 diarrhea with complicating features (dehydration, fever, and/or grade 
3-4 neutropenia) 
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) every 4 hours or after every unformed stool 
(maximum 16 mg a day) and continue loperamide at this frequency until diarrhea free for 
12 hours.  Then titrate the amount of loperamide used to keep diarrhea controlled (< 4 
stools/day). 
 Administer octreotide (100-150 µg SC BID or [25–50 µg/hr IV if dehydration is severe, 
with dose escalation up to 500 µg SC TID). 
 Use IV therapy as appropriate. 
 Stool cultures should be done to exclude infectious causes of grade 3 or 4 diarrhea or 
diarrhea of any grade with complicating features (dehydration, fever, and/or grade 3 or 4 
neutropenia) per the Investigator’s discretion. 
 Consider prophylactic antibiotics as needed (e.g., fluoroquinolones) especially if diarrhea 
is persistent beyond 24 hours or there is fever or grade 3-4 neutropenia. 
 Patients should be monitored for constipation and prophylaxis adjusted accordingly.  Do not 
discontinue antidiarrheals completely; doses may be adjusted. 
 For the second and subsequent cycles, the dose of loperamide should be titrated to keep 
diarrhea controlled to  4 stools a day. 
Dietary management 
Instruct patients to: 
 Stop all lactose-containing products (milk, yogurt, cheese, etc.). 
 Drink 8-10 large glasses (64-80 ounces) of clear liquids per day. 
 Eat frequent small meals. 
 Maintain a low fat diet enriched with rice, bananas, applesauce, and/or toast. 
 

 
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APPENDIX C 
 
LEVOLEUCOVORIN DRUG DOSE AND ADMINISTRATION INSTRUCTIONS 
Levoleucovorin can be substituted for racemic leucovorin (leucovorin) throughout this protocol, per 
institutional practice or as needed for drug availability. 
Dose: 
Levoleucovorin 200 mg/m2 
(Note: The levoleucovorin dose is one-half the dose of leucovorin.) 
Reconstitute as described in the manufacturer’s full prescribing information.  Do not round the dose. 
Administration: 
Further dilute the reconstituted levoleucovorin dose with 250 mL D5W. 
Using separate infusion bags and separate lines utilizing Y-connector tubing, administer 
levoleucovorin IV over 2 hours concurrently with oxaliplatin (mFOLFOX6).  If oxaliplatin is 
held, administer levoleucovorin over 2 hours (preferred); however, administration time for all 
chemotherapy in this protocol per institutional practice is permitted. 
Due to poor absorption at doses greater than 50 mg, the use of oral leucovorin is not permitted. 
The decision and rationale for administering levoleucovorin must be documented in the patient’s medical 
record. 
Changing the patient’s treatment in any way other than as stated above will be considered non-protocol 
therapy and result in a protocol violation. 
 

 
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APPENDIX D 
 
PATIENT DIARY 
Page 1 of 1 
Protocol: NRG-GI005                                                                         Study Medication: 
Capecitabine                                                                                                                     
Cycle #__________                                                                                                                                      
Prescribed dose: capecitabine ____________mg twice each day on days 1 to 14 of each 21 day cycle  
 Please record information daily. 
 Use a new page for each week. 
 Take capecitabine in the morning and evening (within 30 minutes after eating breakfast and dinner). 
 Please remember to bring this diary (all pages) and your capecitabine containers (even if they are 
empty) to each visit with your study team.
Day 
Date 
Time taken 
Number of 
capecitabine 
tablets taken 
(morning) 
Number of 
capecitabine 
tablets taken 
(evening) 
Notes 
Include any side 
effects that you are 
having (especially 
loose stools and any 
medications that 
you took for the side 
effects. 
Morning 
Evening 
150mg 
500mg 
150mg 500mg
Mon. 
 
 
 
 
 
 
 
 
Tues. 
 
 
 
 
 
 
 
 
Wed. 
 
 
 
 
 
 
 
 
Thurs. 
 
 
 
 
 
 
 
 
Fri. 
 
 
 
 
 
 
 
 
Sat. 
 
 
 
 
 
 
 
 
Sun. 
 
 
 
 
 
 
 
 
Patient's name: ______________________________ 
 
Date: ____________________ 
Physician's office will complete this section 
Total number of capecitabine tablets taken this reporting period: 150 mg _____500 mg _______ 
Total number of capecitabine tablets returned this reporting period: 150 mg _____ 500 mg ______ 
Research Staff Signature/Date: ___________________________________________