A Phase II Clinical Trial Platform of Sensitization Utilizing Total Neoadjuvant Therapy (TNT) in Rectal Cancer
Phase: PHASE2
Conditions: Rectal Adenocarcinoma, Stage II Rectal Cancer AJCC v7, Stage III Rectal Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

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NRG ONCOLOGY 
NRG-GI002 
(ClinicalTrials.gov NCT02921256) 
A Phase II Clinical Trial Platform of Sensitization Utilizing 
Total Neoadjuvant Therapy (TNT) in Rectal Cancer 
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, and SWOG/SWOG. 
TNT PLATFORM LEADERSHIP TEAM 
Coordinating Center 
NRG Oncology 
 
 
Principal Investigator/ 
Medical Oncology Chair 
 
University of Florida 
 
 
Phone: 
  
Email: 
 
For eligibility and clinical questions: 
Phone: 
 
E-mail: 
 
Medical Oncology Protocol Officer 
 
NRG Oncology, Nova Tower 2 
Phone: 
 
Email: 
 
Colorectal Surgery Co-Chair 
 
VA Greater Los Angeles Healthcare System 
Phone: 
 
E-mail: 
 
Pathology Co-Chair 
 
NRG Oncology 
Biospecimen Bank – Pittsburgh 
 
 
Phone: 
 
E-mail: 
 
Translational Science Co-Chair 
 
MD Anderson Cancer Center 
Phone: 
 
E-mail: 
  
Radiation Therapy Co-Chair 
 
Massachusetts General Hospital 
Phone: 1-800-477-7227 
E-mail: ccdPGH@nrgoncology.org 
Medical Physics Co-Chairs 
 
McGill University Health Centre 
Phone: 
 
E-mail: 
 
Protocol Statistician 
 
NRG Oncology  
Statistics and Data Management Center 
 
 
 
Phone: 
 
Email: 
 
Diagnostic Radiology Co-Chair 
 
Memorial Sloan Kettering Cancer Center 
Phone: 
 
E-mail: 
 
 
 

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NRG Oncology Colorectal Committee Chair 
 
STUDY LEAD(S): ARM 2 
Principal Investigator 
 
University of Florida 
 
 
Phone: 
  
Email: 
 
 
 
 
 
 
 
 
STUDY LEAD(S): ARM 3 
Principal Investigator 
 
Dana-Farber Cancer Institute 
 
 
Phone: 
 
Email: 
  
 
BIOIMAGING CORRELATIVE TEAM 
Principal Investigator 
 
Medical College of Wisconsin 
 
University of Florida 
 
 
University of Pennsylvania 
 
Memorial Sloan Kettering Cancer Center 
 
Baylor University Medical Center at Dallas 
 
 

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The following NCTN Group Study Champions have been added to this trial: 
ALLIANCE: 
 
Dana-Farber Cancer Institute 
ECOG-ACRIN: 
 
Fox Chase Cancer Center 
SWOG: 
 
Vanderbilt-Ingram Cancer Center 
 
STUDY MANAGEMENT PERSONNEL 
Clinical Coordinating Department (CCD) 
 
 
NRG Oncology 
 
 
 
Phone: 
 
E-mail: 
 
Protocol Coordinator 
 
 
Department of Regulatory Affairs 
 
NRG Oncology 
 
 
Phone: 
 
E-mail: 
  
Data Manager 
 
NRG Statistics and Data Management Center  
 
 
 
Phone: 
 
Fax: 
 
Image and Radiation Oncology Core (IROC) 
 
 
 
 
IROC Philadelphia Imaging QA Center 
 
 
Phone: 
 
Email: 
  
Image and Radiation Oncology Core (IROC) 
 
 
 
 
Phone 
 
Email: 
  
Image and Radiation Oncology Core (IROC) 
 
IROC Houston 
Phone: 
 
Email: 
 
 
 
 

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NRG ONCOLOGY 
NRG-GI002 
A Phase II Clinical Trial Platform of Sensitization Utilizing 
Total Neoadjuvant Therapy (TNT) in Rectal Cancer 
Protocol Agents 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Capecitabine 
Commercial 
712807 
131922 
DCTD, NCI 
Oxaliplatin 
Commercial 
266046  
5-Fluorouracil 
Commercial 
19893  
Leucovorin 
Commercial 
3590  
Veliparib (ABT-888) 
Investigational 
737664 
MK-3475 
(Pembrolizumab) 
Investigational 
776864 
Participating Sites 
☒ U.S. 
☐ Canada 
☐ Approved International Member Sites 
Document History 
 
Version Date 
Amendment 5 
February 20, 2020 
Amendment 4 
November 18, 2019 
Amendment 3 
June 4, 2019 
Amendment 2 
June 25, 2018  
Amendment 1 
June 15, 2018 
Pre-activation Revision 
August 22, 2016 
Original 
May 31, 2016 
 
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. 
For detailed information on the 
regulatory and monitoring procedures 
for CTSU sites, please review the CTSU 
Regulatory and Monitoring Procedures 
policy located on the CTSU Member 
website at https://www.ctsu.org 
>resources tab> CTSU Operations 
Information. 
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, treatment, or clinical data 
submission), 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 data submission questions, contact the GI002 Data Manager at the NRG Oncology Statistics and 
Data Management Center by calling 412-624-2666. 
For detailed information on the regulatory and monitoring procedures for CTSU sites, please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU Member website 
at https://www.ctsu.org >resources tab> CTSU Operations Information. 
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 ...................................................... 5 
1.0 
OBJECTIVES ................................................................................................................................ 10 
1.1 
Primary Objective ............................................................................................................. 10 
1.2 
Secondary Objectives ....................................................................................................... 10 
1.3 
Tertiary Objectives ........................................................................................................... 10 
1.4 
Exploratory Objectives ..................................................................................................... 10 
2.0 
BACKGROUND ........................................................................................................................... 11 
2.1 
Introduction ....................................................................................................................... 11 
2.2 
Neoadjuvant Rectal Cancer (NAR) Score ........................................................................ 11 
2.3 
Current Arms, Future Intent .............................................................................................. 12 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ............................ 15 
3.1 
Eligibility Criteria ............................................................................................................. 15 
3.2 
Ineligibility Criteria .......................................................................................................... 16 
4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP....................... 19 
5.0 
TREATMENT REGIMENS .......................................................................................................... 26 
5.1 
Treatment regimen for Arm 1 (mFOLFOX6 followed by RT + capecitabine) ................ 26 
5.2 
Treatment regimen for Arm 2 (mFOLFOX6 followed by RT + capecitabine + veliparib)
 .......................................................................................................................................... 27 
5.3 
Treatment regimen for Arm 3 (mFOLFOX6 followed by RT + capecitabine + MK-3475 
(pembrolizumab) ............................................................................................................... 28 
5.4 
Dose determinations ......................................................................................................... 29 
5.5 
Radiation therapy .............................................................................................................. 29 
5.6 
General Concomitant Medication and Supportive Care Guidelines ................................. 35 
5.7 
Duration of Therapy .......................................................................................................... 38 
5.8 
Surgery .............................................................................................................................. 38 
5.9 
Adjuvant Therapy ............................................................................................................. 38 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT ................................................................. 39 
6.1 
General instructions .......................................................................................................... 39 
6.2 
Treatment management radiation therapy ........................................................................ 39 
6.3 
Treatment management mFOLFOX6 ............................................................................... 39 
6.4 
Treatment management capecitabine (Arm 1) .................................................................. 44 
6.5 
Treatment management capecitabine and veliparib (Arm 2) ............................................ 47 
6.6 
Treatment management capecitabine and MK-3475 (pembrolizumab) (Arm 3) .............. 50 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS .............................................................. 59 
7.1 
Study Agents ..................................................................................................................... 59 
7.2 
Adverse Events and Serious Adverse Events ................................................................... 59 
7.3 
Adverse Events for the Study Agents ............................................................................... 60 
7.4 
Expedited Reporting of Adverse Events ........................................................................... 67 
7.5 
Routine Reporting of Adverse Events .............................................................................. 70 
7.6 
Reporting Rectal Cancer Progression/Recurrence and Second Primary Cancer .............. 71 
8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES .......................... 72 
8.1 
Cancer Therapy Evaluation Program registration Procedures .......................................... 72 
8.2 
Cancer Trials Support Unit Registration Procedures ........................................................ 73 
8.3 
RT Credentialing Requirements ....................................................................................... 75 
8.4 
Patient Enrollment ............................................................................................................ 77 

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8.5 
Study Withdrawal ............................................................................................................. 78 
9.0 
DRUG INFORMATION ............................................................................................................... 79 
9.1 
Agent Ordering and Agent Accountability ....................................................................... 79 
9.2 
PMB policies and guidelines: ........................................................................................... 79 
9.3 
Commercial Agents .......................................................................................................... 80 
9.4 
CTEP IND Agents ............................................................................................................ 80 
10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..................................................... 84 
10.1 
Specimen Submissions ..................................................................................................... 84 
10.2 
Use of specimens .............................................................................................................. 85 
10.3 
Specimen submissions ...................................................................................................... 88 
11.0 
MODALITY REVIEWS ............................................................................................................... 89 
12.0 
ASSESSMENT OF EFFECT ........................................................................................................ 90 
12.1 
Clinical complete response (cCR) .................................................................................... 90 
12.2 
Pathologic complete response (pCR) ................................................................................ 90 
12.3 
Central review ................................................................................................................... 90 
13.0 
DOCUMENTATION OF RECTAL CANCER PROGRESSION/RECURRENCE AND  
OTHER CANCER EVENTS ......................................................................................................... 91 
13.1 
Abdominal and/or pelvic sites .......................................................................................... 91 
13.2 
Nonabdominal and nonpelvic sites ................................................................................... 92 
13.3 
Secondary malignancy ...................................................................................................... 92 
13.4 
Second primary cancer ...................................................................................................... 93 
13.5 
Documentation requested following death ....................................................................... 93 
14.0 
DATA AND RECORDS ............................................................................................................... 94 
14.1 
Data Reporting .................................................................................................................. 94 
14.2 
Summary of Data Submission .......................................................................................... 95 
14.3 
Global Reporting /Monitoring .......................................................................................... 95 
15.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 96 
15.1 
Study Design ..................................................................................................................... 96 
15.2 
Primary Endpoint .............................................................................................................. 96 
15.3 
Secondary Endpoints ........................................................................................................ 96 
15.4 
Tertiary Endpoints ............................................................................................................ 96 
15.5 
Exploratory Endpoints ...................................................................................................... 96 
15.6 
Primary Hypothesis ........................................................................................................... 96 
15.7 
Statistical Analyses ........................................................................................................... 98 
15.8 
Study Monitoring .............................................................................................................. 98 
15.9 
Secondary Elements .......................................................................................................... 99 
15.10 Gender/Ethnicity/Race Distribution .................................................................................. 99 
16.0 
COLLABORATIVE AGREEMENTS ........................................................................................ 100 
17.0 
REFERENCES ............................................................................................................................ 102 
 
Figure 1 
NRG-GI002 Schema ........................................................................................................... 9 
Table 1 
Tests, Exams, and Other Requirements Prior to Randomization ...................................... 19 
Table 2 
For Arm 1 and Arm 2 Patients Only: Tests, Exams, and Other Requirements During 
Study Therapy and Through Year 3 .................................................................................. 20 

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Table 3 
For Arm 3 Patients Only: Tests, Exams, and Other Requirements During Study  
Therapy and Through Year 3 ............................................................................................ 23 
Table 4 
Treatment Regimen for Arm 1 (mFOLFOX6 Followed by RT + Capecitabine) ............. 26 
Table 5 
Treatment Regimen for Arm 2 (mFOLFOX6 Followed by RT + Capecitabine + 
Veliparib) .......................................................................................................................... 27 
Table 6 
Treatment Regimen for Arm 3 (mFOLFOX6 Followed by RT + Capecitabine  
+ MK-3475 (Pembrolizumab) .......................................................................................... 28 
Table 7 
mFOLFOX6 Dose Levels ................................................................................................. 40 
Table 8 
Treatment Management for mFOLFOX6  (See Table 9 For Oxaliplatin-Specific 
Toxicities) ......................................................................................................................... 40 
Table 9 
Treatment Management for Oxaliplatin-Specific Toxicities ............................................ 43 
Table 10 
Capecitabine Dose Levels ................................................................................................. 44 
Table 11 
Treatment Management for Capecitabine (Arm 1) ........................................................... 45 
Table 12 
Capecitabine and Veliparib Dose Levels .......................................................................... 47 
Table 13 
Treatment Management for Capecitabine and Veliparib (Arm 2) .................................... 48 
Table 14 
Capecitabine Dose Levels ................................................................................................. 50 
Table 15 
Treatment Management for Capecitabine (Arm 3) ........................................................... 51 
Table 16 
Treatment Management and Supportive Care Guidelines for Related Adverse Events 
for MK-3475 (Pembrolizumab) ........................................................................................ 54 
Table 17 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for ABT-888 
(Veliparib) 
61 
Table 18 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for MK-3475 
(Pembrolizumab) .............................................................................................................. 63 
Table 19 
Expedited Reporting Requirements for Adverse Events that Occur on Studies Under 
an IND1............................................................................................................................. 68 
Table 20A 
Sample Submissions for ALL PATIENTS ....................................................................... 84 
Table 20B 
Sample Submission for TNT PLUS SITE PATIENTS ONLY ........................................ 84 
Table 21 
Gender/Ethnicity/Race Distribution .................................................................................. 99 
Appendix A 
Assessment of Performance Status and Activities of Daily Living ................................ 105 
Appendix B 
Clinical Management of Diarrhea ................................................................................... 106 
Appendix C 
Creatinine Clearance Calculation (Cockroft-Gault Formula) ......................................... 107 
Appendix D 
Levoleucovorin Drug Dose and Administration Instructions ......................................... 108 
Appendix E 
Patient Diary ................................................................................................................... 109 
Appendix E 
Patient Diary ................................................................................................................... 110 
Appendix F 
Patient Drug Information Handout and Wallet Card ...................................................... 112 
Appendix G 
Recommended Radiology Magnetic Resonance Imaging (MRI) PROTOCOL 
Specifications .................................................................................................................. 114 
 
 

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Stage II or Stage III locally advanced 
(see Section 3.1.5)
adenocarcinoma of the rectum
Arm 1 (control)
mFOLFOX6*
x 8 cycles
Followed by
RT**
+
Capecitabine
825 mg/m2 PO BID
on days that RT is 
given
*modified FOLFOX6 regimen: oxaliplatin 85mg/m2 IV Day 1 + leucovorin 400mg/m2 IV Day 1
+ 5-FU 400mg/m2 IV bolus followed by 5-FU 2400 mg/m2 continuous infusion over 46 hours 
every 2 weeks for 8 cycles
**RT starts 3-4 weeks following last dose of mFOLFOX6
4500 cGy in 25 fractions over 5 weeks + 540 cGy boost in 3 fractions; IMRT is allowed
(institutional credentialing for IMRT is required).
‡ Surgery performed 8-12 weeks following last dose of radiotherapy (see Section 5.9)
     
Note: Adjuvant therapy is not recommended but allowed (see Section 5.10).
SURGICAL PATHOLOGIC ASSESSMENT‡
RANDOMIZATION (1:1:1) TO A PREOPERATIVE REGIMEN
STRATIFICATION
•
Tumor stage based on clinical evaluation (T1 or T2; T3; T4)
•
Nodal stage based on clinical evaluation (N0; N1; N2)
Arm 2
mFOLFOX6* 
x 8 cycles
Followed by
RT**
+
Capecitabine
825 mg/m2 PO BID
on days that RT is given
+
Veliparib
400 mg PO BID 
beginning on Day 1 of RT 
and continuing 
throughout RT
Arm 3
mFOLFOX6*
x 8 cycles
Followed by
RT**
+
Capecitabine
825 mg/m2 PO BID
on days that RT is given
+
MK-3475 
(pembrolizumab) 
200 mg IV every
3 weeks beginning on
Day 1 of RT for
6 total doses
Figure 1.  NRG-GI002 SCHEMA
Note: Arm 2 was closed to accrual on February 12, 2018 and Arm 3 was closed to accrual on May 13, 
2019 which is indicated by the light gray shaded box.

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1.0 
OBJECTIVES 
1.1 
Primary Objective 
To demonstrate an absolute improvement in Neoadjuvant Rectal Cancer (NAR) score for the 
experimental regimen as compared to concurrently randomized control patients. 
1.2 
Secondary Objectives 
1.2.1 
To compare overall survival (OS) 
1.2.2 
To compare disease-free survival (DFS) 
1.2.3 
To compare the rate of pathologic complete response (nodes and tumor) 
Pathologic response to preoperative therapy will be determined at the time of surgical resection. 
Pathologic complete response (pCR) is defined as no evidence of invasive tumor cells on 
pathologic examination of the primary rectal cancer (or tissue from the area where the tumor had 
been if there is a complete clinical response). 
1.2.4 
To compare the rate of sphincter preservation 
1.3 
Tertiary Objectives 
1.3.1 
To compare the proportion of patients who have a tumor resection overall, conditional on 
beginning induction chemotherapy, and conditional on beginning chemoradiotherapy 
1.3.2 
To compare time from initiation of chemoradiotherapy to surgery in the subset of patients with 
tumor resection 
1.4 
Exploratory Objectives 
1.4.1 
To estimate the rate of disease progression during chemotherapy (prior to chemoradiation) 
1.4.2 
To compare the rate of clinical complete response rate (cCR) 
Presence or absence of complete clinical response will be assessed immediately prior to surgery 
by perioperative digital rectal exam and either sigmoidoscopy or proctoscopy.  Clinical complete 
response (cCR) is defined as no visible or palpable rectal primary tumor. 
1.4.3 
To compare the rate of negative circumferential margin 
1.4.4 
To compare the rate of completion of all cycles of neoadjuvant chemotherapy 
1.4.5 
To compare the rate of completion of full course of chemoradiation 
1.4.6 
To compare the toxicity and safety between interventions 
1.4.7 
To explore the correlative molecular predictors of response and distant failure 
1.4.8 
To explore the relationship between radiographic findings and pathologic outcomes 

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2.0 
BACKGROUND  
2.1 
Introduction 
Multiple attempts to improve outcomes in rectal cancer through enhancement of 
radiosensitization by adding agents such as oxaliplatin to 5-FU have demonstrated no clinical 
benefit but added toxicity (O'Connell 2014; Aschele 2011; Gérard 2012).  However, there is a 
strong preclinical rationale as well as limited clinical studies supporting the hypothesis of 
radiosensitization.  Additionally, 25-70% of patients treated with neoadjuvant chemoradiotherapy 
and surgery fail to obtain appropriate adjuvant systemic chemotherapy (O'Connell 2014; 
Khrizman 2013; Roh 2009; Sauer 2004).  This proposed study is a randomized phase II platform 
with parallel, non-comparative experimental arms in locally advanced and high-risk rectal cancer.  
It will provide a systematic approach to study novel radiosensitizers, personalized treatment 
selection using novel targeted systemic therapeutics and identify patients at exceptionally high 
risk for recurrence.  Thus, the TNT protocol provides the basis for more definitive randomized 
controlled studies after demonstration of substantive activity. 
This trial platform holds the promise of rapidly and prospectively determining the worth of novel 
radiosensitizers, novel systemic therapies or other therapeutic interventions in the setting of 
locally advanced rectal adenocarcinoma.  Development of more potent radiosensitizers in rectal 
cancer represents a scientific strategy with important clinical significance vis a vis patients with 
advanced pelvic disease who may benefit from more effective local control, those with earlier 
stage disease who may benefit from non-surgical or less radical interventions and a greater 
likelihood of organ (sphincter) preservation.  Likewise, testing of novel systemic therapy 
interventions in this population allows for demonstration of in vivo response, correlative 
biomarker refinement, and identification of potential mechanisms of resistance. 
Rectal cancer represents a tumor type that allows serial biopsies during clinical care without 
significant risk to the patient.  This affords an opportunity for scientific discovery, correlating 
clinical outcomes with molecular and biomarker interrogation. 
2.2 
Neoadjuvant Rectal Cancer (NAR) Score 
Yothers, et al developed the Neoadjuvant Rectal Cancer (NAR) score as a short term clinical trial 
surrogate endpoint to take variables associated with treatment effect beyond pCR into 
consideration (Yothers 2014; George 2015).  This composite score was built upon the Valentini 
nomogram as a research tool to predict local recurrence, distant metastases and overall survival 
for patients with locally advanced rectal cancer treated with neoadjuvant therapy (Valentini 
2011).  The NAR score is based upon the degree of downstaging noted between the initial cT/pT 
and pN positivity and was validated in NSABP R-04.  By using variables commonly available in 
rectal cancer neoadjuvant clinical trials, it was proven to predict recurrence free and overall 
survival more accurately than pCR.  This surrogate clinical trial endpoint was subsequently 
independently and externally validated in an international dataset providing further evidence of 
utility as a short term surrogate (Raissouni 2014).  A detailed analysis of NAR scores was also 
undertaken in several studies to confirm the appropriateness of this surrogate in trials which 
incorporate neoadjuvant systemic therapy.  In the CONTRE and GCR3 (induction arm) studies 
(Perez 2014; Fernandez-Martos 2015), the NAR score performed similar to that of NSABP R-04, 
including in the subsets of patients with locally advanced or low lying tumors that would 
otherwise be eligible for this protocol (Yothers personal communication). 
 

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2.3 
Current Arms, Future Intent 
The intent of this study is to serve as a platform to test novel agents or hypotheses in neoadjuvant 
treatment of rectal cancer.  Additional experimental arms will be considered through protocol 
amendments after formal review including information specific to that arm as well as a statistical 
plan for control arm comparison.  Success of any given experimental arm will be determined by 
achievement of pathologic endpoints included in the NAR score reduction supporting a higher 
likelihood of success in subsequent definitive randomized controlled studies. 
2.3.1 
RT + capecitabine (Arm 1/control arm) 
Fluoropyrimidine therapy concurrent with radiotherapy for rectal cancer currently represents the 
standard of care for this disease (NCCN Guidelines [Rectal Cancer] 2014).  The Gastrointestinal 
Tumor Study Group showed that adjuvant combined modality therapy with radiotherapy and  
5-fluorouracil (5-FU)-based chemotherapy improved outcomes in patients with rectal cancer both 
in terms of local control and overall survival compared to postoperative radiotherapy alone 
(Krook 1991).  The incorporation of protracted infusional 5-FU with radiotherapy further 
improved clinical outcomes (O'Connell 1994).  NSABP R-04 demonstrated similar clinical 
outcomes between capecitabine and continuous infusion 5-FU when added to radiotherapy for 
rectal cancer.  Pathologic complete responses were similar between the two arms (22.2 vs 18.8%; 
p=0.12) while toxicity clinically favored capecitabine (O'Connell 2014).  This control arm is 
included to provide contextual and contemporary reference for the experimental arms and 
biomarker substudies.  It will also facilitate secondary validation of the NAR score as a surrogate 
for survival in patients treated with trimodality therapy in a completely neoadjuvant fashion. 
2.3.2 
RT + capecitabine + veliparib (Arm 2) 
As DNA is continually damaged, it is repaired by a distinct integrated network of DNA repair 
mechanisms.  Double-stranded DNA breaks, which typically occur with radiation, (Takahashi 
2005) recruit homologous recombination and non-homologous end-joining pathways to repair 
these double-strand breaks.  Single-strand breaks utilize another pathway including  
nucleotide-excision repair, base-excision repair and mismatch repair.  Poly(ADP-ribose) 
polymerase (PARP) is a nuclear enzyme that rapidly recognizes and binds to single strand breaks 
and facilitates single strand DNA repair.  Since there are at least two sets of mechanisms leading 
to DNA repair, the disruption of one pathway may not lead to cell death; however, when both 
pathways are disrupted the accumulated genomic instability leads to loss of viability.  This 
concept, known as synthetic lethality, is supported by clinical studies in BRCA deficient cancers 
and triple negative breast cancer (O'Shaughnessy 2011; Fong P 2009).  In preclinical studies, it 
has been observed that PARP knock-out mice develop normally but exhibit an extreme sensitivity 
to high doses of gamma-radiation.  This observation suggests that specific inhibition of PARP 
would sensitize cells to radiation and be non-toxic to unirradiated tissues (de Murcia 1997).  
Using cell lines and a clonogenic survival assay, PARP-1 inhibitors have been shown to enhance 
the efficacy of radiotherapy regimens by interfering with DNA repair mechanisms (Chalmers 
2004; Brock 2004).  Veliparib (ABT-888) in combination with radiation in HCT-116 colon 
carcinoma xenograft model showed a near doubling in median survival compared to radiation 
alone while ABT-888 alone was no better than vehicle (Donawho 2007).  A similar synergistic 
effect was demonstrated when veliparib was combined with 5-FU and RT compared to 5FU and 
RT alone in preclinical colorectal cancer xenograft models (Shelton 2013). 
In a first phase 0 trial of its kind in oncology drug development, 13 patients with advanced 
malignancies received veliparib and demonstrated good oral bioavailability and statistically 

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significant inhibition of poly (ADP-ribose) levels in tumor biopsies and peripheral blood 
mononuclear cells at 25 mg and 50 mg dose levels.  Greater than 90% inhibition of PAR (poly 
[ADP-ribose]) levels was observed 3 to 6 hours post-drug administration, with recovery at 24 
hours in both xenograft models and in the clinical trial.  A single dose of veliparib resulted in 
significant inhibition of PAR in tumor biopsies.  This suggests a twice-daily schedule for 
veliparib administration to be ideal (Kummar 2009).  There are a number of ongoing phase I and 
II studies with veliparib either alone or in combination with chemotherapy.  However, a recently 
reported phase I study testing the safety and tolerability of veliparib with capecitabine and RT in 
locally advanced rectal cancer is relevant to this proposal.  Patients with stage II-III rectal cancer 
received standard neoadjuvant chemoRT with capecitabine (825 mg/m2 BID) on days of RT 
(50.4 Gy/1.8Gy/fraction) with the addition of veliparib during the treatment at varying dose 
cohorts (NCT01589419).  Surgery was undertaken 5-10 weeks after completion of therapy.  
Thirty-two patients received study treatment with 30 being available for analysis.  Seventy-three 
percent of patients had histologic downstaging at the time of surgery, including 28% ypCR.  The 
NAR score for patients treated in the full dose cohort was 12.8.  There were two documented 
DLTs (diarrhea and skin toxicity), neither of which compromised therapy.  Twenty-eight percent 
of patients experienced any grade 3 of 4 AE with diarrhea (9%) being the most common.  There 
were no surgical complications attributed to the treatment.  The recommended dose for this phase 
II study is 400 mg PO BID throughout chemoRT.  Pharmacokinetic studies confirmed no benefit 
to dose escalation beyond this level and did not interfere with fluoropyrimidine therapy (Michael 
2015). 
2.3.3 
RT + capecitabine + MK-3475 (pembrolizumab/Arm 3) 
Increasing evidence has been mounting to suggest that the immune system plays a major role in 
controlling tumor progression in a variety of tumors including colorectal cancer (Maas 2011).  
The immune score, first described in colorectal cancer by Galon et al, was calculated based on the 
combined analysis of CD8+ plus CD45RO+cells in the center of the tumors and at the invasive 
margins, and was found to correlate with prognosis (Pages 2009, Galon 2006).  Interestingly, 
patients with colorectal tumors that had greater numbers of infiltrating CD8 and granzyme B-
expressing T-cells (activated T-cells) had better survival compared to those with tumors that had 
lower numbers of infiltrating CD8 cells.  Chemotherapeutic agents and radiation can increase the 
immunogenic properties of tumor cells by enhancing MHC class I expression, thereby increasing 
their vulnerability to cytotoxic lymphocytes.  Another frequent effect of DNA damage inflicted 
by radiotherapy or chemotherapy is the increase in the expression of death receptors, enabling 
lysis of the tumor cells by Fas/CD95 ligand and TRAIL-positive immune effectors (Devaud 
2013).  The immunological impact of neoadjuvant chemoradiation in patients with rectal cancer 
was recently evaluated by Shinto et al.  Pre-treatment biopsy and post- chemoradiation resected 
specimens from 93 rectal cancer patients who underwent neoadjuvant chemoradiation and radical 
resection were immunostained for CD8 and FOXP3, and the densities of stromal (STL) and 
intraepithelial (IEL) immunopositive TILs were determined separately.  CD8+ STL density 
doubled after chemoradiation therapy, whereas FOXP3+ STL counts remained stable.  High post- 
chemoradiation CD8 + STL density was associated with better prognosis and a high pre-treatment 
CD8/FOXP3 IEL ratio was a predictor of favorable tumor regression (Shinto 2014). 
Furthermore, strong PD-L1 expression was observed in 30% of colorectal patients and was found 
to correlate with infiltration by CD8 (+) lymphocytes which did not express PD-1 (Droeser 2013).  
Both radiation and 5-FU induce the expression of PD-L1 on tumor cells through IFNγ production 
by CD8(+) T cells leading to an immune-suppressive environment and promoting PD-L1-
mediated T-cell apoptosis (Dovedi 2014, Zhang 2008).  The concomitant administration of 
stereotactic radiotherapy and anti PD-1 antibodies in B16-OVA melanoma or 4T1-HA breast 

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carcinoma tumors resulted in the development of antigen-specific T cell– and B cell–mediated 
immune responses that translated to better tumor response compared to either modality alone 
(Sharabi 2015).  Specifically, in colorectal cancer xenograft model concomitant but not sequential 
administration of fractionated radiotherapy in combination with αPD-1 or αPD-L1 antibodies 
generated efficacious CD8(+) T-cell responses leading to better tumor response and survival 
compared to either modality alone  (Dovedi 2014).  These results could explain the adaptive 
response by tumor cells that mediates resistance to fractionated radiotherapy by expressing PD-
L1 and therefore blocking PD-1/PD-L1 represents a valid strategy to overcome the adaptive 
tumor resistance to radiotherapy.  Accordingly, we hypothesized that the addition of anti-PD-1 to 
neoadjuvant chemoradiation in rectal cancer could increase the CD8 TILs leading to a better 
pathological response rate. 
Therefore, we propose to further study total neoadjuvant therapy with systemic chemotherapy 
(FOLFOX x 8 cycles) followed by novel radiosensitization with a targeted inhibitor or immune 
modulating agent plus fluoropyrimidine in a randomized phase II study platform for stage II and 
III rectal cancer.  Experimental arms will be compared directly to a control arm (Arm 1) and not 
to each other.  Arm 2 will use veliparib, 400 mg PO BID throughout neoadjuvant chemoRT, with 
capecitabine (825 mg/m2 PO BID on days of radiotherapy), while Arm 3 will use MK-3475 
(pembrolizumab), 200 mg IV every 3 weeks beginning on day 1 of RT for 6 total doses with 
capecitabine, 825 mg/m2 PO BID on days of radiotherapy, as part of this Total Neoadjuvant 
Therapy clinical trial platform. 
 

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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 the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
Capecitabine is required for all patients.  Consideration of prescription and procurement of 
capecitabine should be planned prior to study enrollment. 
Submission of tumor tissue (FFPE) and blood is required for all patients who agree to the 
optional biobanking portion of this study.  Investigators should check with their site Pathology 
department regarding release of tissue before approaching patients about participation in the trial.  
(See details of FFPE tumor sample submissions in Section 10.0.) 
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, 1, or 2 (see Appendix A). 
3.1.4 
Diagnosis of adenocarcinoma of the rectum with the major portion of the tumor intact. 
Note: Prior to randomization, the investigator must specify and document each of the following: 
- 
distance of the lowest tumor margin from the anal verge; and 
- 
intent for sphincter sparing or non-sphincter sparing surgical resection according to 
the primary surgeon; and 
- 
the majority of the untreated tumor must be < 12 cm from the anal verge or below the 
peritoneal reflection as determined by the treating surgeon. 
3.1.5 
The tumor must be clinically determined to be locally advanced Stage II or Stage III rectal cancer 
and must also meet any ONE of the following criteria: 
• 
distal location (as defined by measurement on MRI, ERUS/pelvic CT [with IV contrast] scan 
or palpable on digital rectal exam [DRE]): cT3-4 ≤ 5 cm from the anal verge, any N 
• 
bulky: any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm of) the 
mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan 
• 
high risk for metastatic disease with 4 or more regional lymph nodes (cN2).  Clinical Nodal 
or "cN" status for eligibility includes the total number of nodes (N2 = 4 or more) in the 
mesorectal and superior rectal stations measuring ≥ 1.0 cm in any axis on cross sectional or 
endoscopic imaging.  Nodes must measure 1.0 cm or greater to be considered positive for this 
eligibility requirement. 
• 
not a candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy (as 
planned by the primary surgeon) 
Note: Clinical stage of the primary tumor and nodes may be determined locally by rectal 
endoscopic ultrasound or pelvic MRI (pelvic MRI is strongly preferred; see Appendix G.  CT 
scan with IV contrast is acceptable provided there is evidence of T4 and/or N2 disease. 
3.1.6 
Patients must have the ability to swallow and retain oral medication. 

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3.1.7 
Adequate hematologic function within 28 days before randomization defined as follows: 
• ANC must be  1200/mm3; 
• Platelet count must be  100,000/mm3; and 
• Hemoglobin must be  10 g/dL. 
3.1.8 
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 
bilirubin elevation  ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome 
involving slow conjugation of bilirubin; and 
• 
alkaline phosphatase must be  3 x ULN for the lab; and 
• 
AST must be  3 x ULN for the lab. 
Note: If ALT is performed instead of AST (per institution's standard practice), the ALT value 
must be  3 x ULN; if both were performed, the AST must also be  3 x ULN.  If AST and/or 
ALT is ≥ ULN but  3 x ULN, serologic testing for Hepatitis B and C must be performed and 
results for viral infection must be negative. 
3.1.9 
Adequate renal function within 28 days before randomization defined as serum creatinine  ULN 
for the lab and measured or calculated creatinine clearance  60 mL/min (see Appendix for 
instructions regarding calculation of creatinine clearance). 
3.1.10 Serum potassium, magnesium, and calcium levels within 28 days before randomization must be 
within normal limits (WNL) for the lab. 
3.1.11 International normalized ratio of prothrombin time (INR) within 28 days before randomization 
must be ≤ ULN for the lab.  Patients who are therapeutically treated with an agent such as 
warfarin may participate if they are on a stable dose and no underlying abnormality in 
coagulation parameters exists per medical history. (See Section 5.6.9 for coumarin-derivative 
drug/drug interactions). 
3.1.12 Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human 
immunodeficiency virus (HIV) disease must: 
• 
Have a CD4 count  200 cells/L within 30 days before randomization, 
• 
Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days before 
randomization, and 
• 
Have no evidence of opportunistic infections. 
3.1.13 Pregnancy test (urine or serum beta-HCG) done within 72 hours before randomization must be 
negative (for women of childbearing potential only).  If urine pregnancy results are positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
3.2 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this study. 
3.2.1 
Rectal cancer histology other than adenocarcinoma (i.e., sarcoma, lymphoma, squamous cell 
carcinoma, mucosal melanoma, etc.). 
 

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3.2.2 
Definitive clinical or radiologic evidence of metastatic disease.  Required imaging studies must 
have been performed within 28 days prior to randomization.  Note: Distant clinical staging to 
exclude patients with overt metastatic disease is determined by: 
• 
Chest: CT scan (preferred); chest x-ray PA and lateral (acceptable); or PET scan (acceptable) 
• 
Abdomen: CT scan with IV contrast (preferred); or MRI (acceptable) 
• 
Pelvis: MRI (preferred; see Appendix G); or CT scan with IV contrast (acceptable) 
(It is recommended that the same imaging tests that are performed before randomization be used 
at follow-up time points.  Note: CT scans of the abdomen and pelvis must be performed with IV 
contrast.) 
3.2.3 
History of prior invasive rectal malignancy, regardless of disease-free interval. 
3.2.4 
Cardiac disease that would preclude the use of any of the drugs included in the GI002 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. 
• Second- or third-degree atrioventricular (AV) block unless treated with a permanent 
pacemaker 
• Complete left bundle branch block (LBBB) 
• History of long QT Syndrome 
• QTc ≥ 450ms. 
3.2.5 
Sensory or motor neuropathy ≥ grade 2. 
3.2.6 
History of, or any evidence of, active non-infectious pneumonitis. 
3.2.7 
Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who 
are symptomatic) or have a history of abdominal surgery or other medical condition that may, in 
the opinion of the treating physician, interfere with gastrointestinal motility or absorption. 
3.2.8 
Active autoimmune disease that has required systemic treatment within the past 2 years (i.e., with 
use of modifying agents, corticosteroids, or immunosuppressive drugs).  Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
3.2.9 
History of active TB (Bacillus Tuberculosis). 
3.2.10 Active or chronic infection requiring systemic therapy. 
3.2.11 Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study therapy.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the study PI. 
3.2.12 Active seizure disorder uncontrolled by medication. 
3.2.13 Any antineoplastic therapy for this cancer before randomization. 
3.2.14 Synchronous colon cancer. 
3.2.15 Other invasive malignancy within 5 years before randomization.  Exceptions are colonic polyps, 
non-melanoma skin cancer or carcinoma-in-situ of the cervix. 

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3.2.16 Antineoplastic therapy (e.g., chemotherapy or targeted therapy) for other invasive malignancy 
within 5 years before randomization.  (For the purposes of this study, hormonal therapy is not 
considered chemotherapy.) 
3.2.17 Prior treatment with an investigational compound being tested in this study (e.g., PARP inhibitor, 
anti-PD-1, anti-PD-L1, or anti-PD-L2). 
3.2.18 Receipt of live vaccination within 28 days before randomization.  Seasonal flu vaccines that do 
not contain live virus are permitted. 
3.2.19 Major surgery within 4 weeks before randomization. 
3.2.20 Any therapeutic pelvic radiation. 
3.2.21 Known homozygous DPD (dihydro pyrimidine dehydrogenase) deficiency. 
3.2.22 Any of the following because this study involves agents that have known or potential genotoxic 
or mutagenic, and teratogenic effects: 
• 
pregnant women 
• 
nursing women who are unwilling to discontinue nursing 
• 
men or women of childbearing potential who are unwilling to employ adequate contraception 
(e.g., hormonal or barrier method of birth control; abstinence) for the duration of study 
treatment and for 4 months after the last dose of study therapy.  (See Section 6.6.3) 
3.2.23 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 or interfere 
significantly with the proper assessment of safety and toxicity of the prescribed regimens or 
prevent required follow-up. 
 

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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 and Table 3. 
Table 1. Tests, exams, and other requirements prior to randomization 
Required Assessments 
Before randomization 
(see footnote a) 
Consent form signed by the patient 
X 
Determination of availability for release of primary tumor tissue from 
the diagnostic block (see Section 3.0 ) 
X 
History & physical examb 
X 
Within 28 days 
 
Assessment of concurrent medicationsc 
X 
Performance status (Appendix A) 
X 
Height & weight 
X 
CEA 
X 
CBC/differential/platelet count 
X 
Total bilirubin/AST/Alkaline phosphatased 
X 
Serum chemistries: glucose, BUN, sodium, potassium, chloride, 
bicarbonate or carbon dioxide, calcium, serum creatinine, magnesium 
X 
Triiodothyronine (T3) or free triiodothyronine (FT3), and free 
thyroxine (FT4), and thyroid stimulating hormone (TSH) 
X 
INR 
X 
Creatinine clearance (calculated or measured)e 
X 
12 Lead ECG with QTc interval measurement  
X 
Local disease stagingf 
X 
Distant disease stagingg  
X 
Pregnancy test – Urine or Serum beta HCGh 
X 
Within 72 hours 
Submission of archived primary tumor tissuei 
 X 
Within 60 days after 
study entry 
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 Complete history and physical by a physician or other healthcare professional. 
c Include all prescribed and over-the-counter medications, supplements, herbal therapies. 
d ALT may be substituted for AST if required by the institution's standard practice. 
e Both serum creatinine and creatinine clearance must be performed within 28 days prior to randomization. 
f For local staging: May be either rectal endoscopic ultrasound or pelvic MRI; pelvic MRI is strongly 
preferred (see Appendix G)and requires submission via TRIAD (see Section 8.3.2) CT scan with IV 
contrast is acceptable if there is evidence of T4 and/or N2 disease (see Section 3.1.5). 
g For distant (metastatic) staging:  It is recommended that the same imaging tests performed before 
randomization be used at follow-up time points (see Section 3.2.2 for preferred and acceptable imaging 
tests).  MRI imaging requires submission through TRIAD (see Section 8.3.2 and Appendix G). 
h For women of childbearing potential only.  If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required. 
i For patients who agree to the optional biobanking portion of this study.  See Section 10.0; the  
NRG-GI002 Pathology and Correlative Science Instructions.  

 
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Table 2. For Arm 1 and Arm 2 Patients Only: Tests, exams, and other requirements during study therapy and through Year 3 
Required assessments 
(See footnote a) 
After 
randomization 
but before 
initiation of 
mFOLFOX6 
During 
mFOLFOX6 
Within 3 days  
before starting 
chemoradiation 
(see footnote b) 
Weekly during 
chemoradiation 
(unless otherwise 
indicated) 
30 days (+/- 7 
days) after the 
last dose of 
chemoradiation  
Preoperative 
(At surgery 
or within 14 
days before 
surgery) 
From surgery 
through  
Year 3* 
from 
randomization 
History & physical 
examc 
 
X 
X 
X 
X 
X 
(see  
footnote c) 
X 
(every 6 
months) 
Adverse event 
assessmentd 
 
X 
X 
X 
X 
X 
 
Assessment of 
concurrent 
medicationse 
 
Xe 
X 
X 
X 
 
 
CBC/differential/ 
platelet count 
 
X 
X 
X 
  
Xf 
X 
 
Total bilirubin/ 
AST/Alk phosg 
 
X 
X 
 
Every other week 
beginning with  
Day 1 of chemoRT 
 
X 
X 
 
Serum chemistries: 
glucose, BUN, 
creatinine, sodium, 
chloride, bicarbonate or 
carbon dioxide 
Potassium, magnesium, 
and calcium 
 
 
X 
X 
Arm 2 only 
X 
 
 
INR 
 
 
 
X 
(see footnoteh) 
 
 
 
CEA 
 
X 
(cycle 4 
only) 
X 
 
 
X 
X 
(every 6 
months) 
Table continued on next page 
 

 
NRG-GI002 
 
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Table 2. For Arm 1 and Arm 2 Patients Only: Tests, exams, and other requirements during therapy and through Year 3 (continued) 
Required assessments 
(See footnote a) 
After 
randomization 
but before 
initiation of 
mFOLFOX6 
During 
mFOLFOX6 
Within 3 days 
before starting 
chemoradiation 
(see footnote b) 
Weekly during 
chemoradiation 
(unless 
otherwise 
indicated) 
30 days (+/-7 
days) after the 
last dose of 
chemoradiation 
but before 
surgery 
Preoperative 
(At surgery or 
within 14 days 
before 
surgery) 
From surgery 
through  
Year 3*  
from 
randomization 
Thyroid function 
tests: 
triiodothyronine (T3) 
or free 
triiodothyronine 
(FT3), and free 
thyroxine (FT4), and 
thyroid stimulating 
hormone (TSH)  
 
 
 
 
 
X 
 
 
Pregnancy testing i 
 
 
 
 
X 
Arms 1 and 2 
 
 
Disease imaging j 
 
 
X 
local and 
distant disease 
 
 
X 
local and 
distant 
diseasek 
X 
distant disease 
only 
every 6 
months 
12 Lead ECG with 
QTc interval 
measurement  
 
 
 
 
X 
Arm 2 only 
 
 
Tumor (FFPE)l 
(see Table 1) 
 
 
 
 
X 
(at surgery) 
 
Whole Blood  
X 
X 
(Within 3 days 
of Cycle 5 
only) 
X 
 
 
X 
Xl 
(At 6 months 
post surgery) 
a History and physical, blood tests, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b Chemoradiation (chemoRT): RT plus capecitabine (Arm 1); RT plus capecitabine plus veliparib (Arm 2); .  Note: A minimum of 4 daily RT 
treatments are required in any given week.  
Table continued on next page 
 

 
NRG-GI002 
 
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Table 2. For Arm 1 and Arm 2 Patients Only: Tests, exams, and other requirements during therapy and through Year 3 (continued) 
c Updated history and physical with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and 
follow-up evaluations.  A formal assessment documenting clinical response of the primary rectal tumor (via digital rectal exam and 
proctoscopic or sigmoidoscopic exam) must be included with the preoperative assessment but may be done immediately before 
surgery (see Section 12.1.1). 
d See Section 7.0 for instructions adverse events reporting requirements. 
e Include all prescribed and over-the-counter medications, supplements, herbal therapies and verify study therapy compliance through the 
review of patient's diary (Appendix F) and number of study drug tablets returned. 
f For patients treated with veliparib (Arm 2 only), if cytopenias are documented that aren't attributable to another etiology, patients should be 
re-evaluated at the pre-operative visit.  If persistent at that time and the cytopenia isn't attributable to another etiology, a hematology 
consultation and bone marrow biopsy could be considered post-operatively. 
g ALT may be substituted for AST if required by the institution's standard practice (all Arms). 
h 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 5.6.9). 
i For women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.  Pregnancy testing is not required after completion of investigational product unless required by institutional standards. 
j All imaging results performed during this study must be recorded in the data collection forms.  It is recommended that the same imaging tests 
performed before randomization be used at all follow-up time points.  For local imaging of tumor/nodes, pelvic MRI is strongly preferred. 
MRI imaging requires submission through TRIAD (see Sections 8.3.2 and 14.2, and Appendix G).  Clear evidence of distant (metastatic) 
disease development must be reported as progressive disease if before surgery or recurrent disease if after surgery. 
k Imaging performed between chemoRT and surgery must be completed no earlier than 4 weeks and no later than 2 weeks before surgery 
after completion of chemoRT.  Clear evidence of distant (metastatic) disease development must be reported as progressive disease if before 
surgery or recurrent disease if after surgery. 
l Submission of blood at the defined time points and tumor (FFPE) from the diagnostic biopsy and from surgically resected primary tumor (or 
residual scar in the setting of pCR) is required for patients who agree (submit FFPE within 60 days after surgery).  Postoperatively, research 
blood collection should occur at the first imaging visit (6 months) (see Section 10.0, the NRG-GI002 Pathology and Correlative Science 
Instructions). 
*Note: Following documented disease progression/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 survival and available cancer specimens (FFPE) will be 
collected (see Section 10.0) from patients who agree to optional biobanking. 
 
 

 
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Table 3. For Arm 3 Patients Only: Tests, exams, and other requirements during study therapy and through Year 3 
Required 
assessments 
(See footnote a) 
After 
randomization 
but before 
initiation of 
mFOLFOX6 
Within 3 
days before 
Day 1 of 
each cycle of 
mFOLFOX6 
 (beginning 
with Cycle 2) 
Within 3 days 
before starting 
chemoradiation 
(see footnote b) 
Weekly during 
chemoradiation 
(unless otherwise 
indicated) 
30 days (+/- 7 
days) after the last 
dose of 
chemoradiation  
 
30 days (+/- 3 
days) and 90 days 
(+/-7 days) after 
the last dose of 
MK3475 
(pembrolizumab) 
Preoperative 
(Must be after 
last dose of 
MK3475 
(pembrolizumab) 
but at surgery or 
within 14 days 
before surgery) 
From surgery 
through  
Year 3*  
from 
randomization 
History & physical 
examc 
 
X 
X 
X 
X 
 
X 
(see  
footnote c) 
X 
(every 6 
months) 
Adverse event 
assessmentd 
 
X 
X 
X 
X 
Xd 
Xd 
 
CBC/differential/ 
platelet count 
 
X 
X 
Xe 
X 
 
X 
 
Assessment of 
concurrent 
medicationsf 
 
X 
X 
X 
X 
X 
 
 
Total bilirubin/ 
AST/Alk phosg 
 
X 
X 
 
Beginning 
Day 1 of 
chemoRT (see 
footnotee)  
X 
 
X 
 
Serum chemistries: 
glucose, BUN, 
creatinine, sodium, 
chloride, 
bicarbonate or 
carbon dioxide 
Potassium, 
magnesium, and 
calcium 
 
 
X 
 
X 
 
 
 
INR 
 
 
 
Xh 
(see footnote 
h) 
 
 
 
 
CEA 
 
X 
(cycle 4 
only) 
X 
 
 
 
X 
X 
(every 6 
months) 
Table continued on next page 
 

 
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Table 3: For Arm 3 Patients Only: Tests, exams, and other requirements during therapy and through Year 3 (continued) 
Required 
assessments 
(See footnote a) 
After 
randomization 
but before 
initiation of 
mFOLFOX6 
Within 3 
days before 
Day 1 of each 
cycle of 
mFOLFOX6 
(beginning 
with Cycle 2) 
Within 3 days 
before starting 
chemoradiation 
(see footnote b) 
Weekly during 
chemoradiation 
(unless otherwise 
indicated) 
30 days (+/-7 
days) after the 
last dose of 
chemoradiation 
30 days (+/- 3 
days) after the 
last dose of 
MK3475 
(pembrolizumab) 
Preoperative 
(Must be after 
last dose of 
MK3475 
(pembrolizumab) 
but at surgery or 
within 14 days 
before surgery) 
From surgery 
through  
Year 3*  
from 
randomization 
Thyroid function 
tests: 
triiodothyronine 
(T3) or free 
triiodothyronine 
(FT3), and free 
thyroxine (FT4), 
and thyroid 
stimulating 
hormone (TSH)  
 
 
X 
 
X 
Every 3 weeks 
(before each dose 
of 
MK-3475 
(pembrolizumab) 
(see footnotee) 
 
 
 
X 
 
 
Pregnancy 
testingi 
 
 
 
 
 
 
Disease imagingj 
 
 
X 
local and 
distant 
diseasej 
 
 
 
X 
local and 
distant 
diseasek 
X 
distant 
disease only 
every 6 
months 
12 Lead ECG 
with QTc interval 
measurement  
 
 
 
 
 
 
 
 
Tumor (FFPE)l 
(see Table 1) 
 
 
 
 
 
X 
(at surgery) 
 
Whole Blood  
X 
X 
(Within 3 
days of 
Cycle 5 
only) 
X 
 
 
 
X 
Xl 
(At 6 
months post 
surgery) 

 
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a History and physical, blood tests, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b Chemoradiation (chemo RT) plus capecitabine plus MK-3475 (pembrolizumab) (Arm 3).  Note:  A minimum of 4 daily RT treatments are required in any given 
week. 
c Updated history and physical with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and follow-up evaluations.  
A formal assessment documenting clinical response of the primary rectal tumor (via digital rectal exam and proctoscopic or sigmoidoscopic exam) must 
be included with the preoperative assessment but may be done immediately before surgery (see Section 12.1.1). 
d See Section 7.0 for instructions adverse events reporting requirements. 
Note: Preoperative adverse event assessment: 
• 
for patients completing MK-3475 (pembrolizumab) and going to surgery:  the day before surgery. 
• 
for patients completing MK-3475 (pembrolizumab) and NOT going to surgery: 30 days from last MK-3475 (pembrolizumab) dose. 
• 
for patients discontinuing MK-3475 (pembrolizumab) early and going to surgery: 8 weeks from RT+capecitabine or 30 days from last MK-3475 
(pembrolizumab) dose, whichever is the latest, but not later than the day before surgery. 
• 
for patients discontinuing MK-3475 (pembrolizumab) early and NOT going to surgery:8 weeks from RT+capecitabine or 30 days from last MK-3475 
(pembrolizumab), whichever is the latest. 
All patients will have an adverse event assessment at 90 days after the last dose of MK3475 (pembrolizumab). 
e Following completion of chemoRT, continue to obtain CBC, LFTs, chemistries, thyroid function and pregnancy testing within 3 days before each dose of MK-
3475 (pembrolizumab). 
f Include all prescribed and over-the-counter medications, supplements, herbal therapies and verify study therapy compliance through the review of patient's diary 
(Appendix F) and number of study drug tablets returned. 
g ALT may be substituted for AST if required by the institution's standard practice (all Arms). 
h 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 5.6.9). 
i For women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  Pregnancy testing 
is not required after completion of investigational product unless required by institutional standards. 
j All imaging results performed during this study must be recorded in the data collection forms.  It is recommended that the same imaging tests performed before 
randomization be used at all follow-up time points.  For local imaging of tumor/nodes, pelvic MRI is strongly preferred. MRI imaging requires submission 
through TRIAD (see Sections 8.3.2 and 14.2, and Appendix G).  Clear evidence of distant (metastatic) disease development must be reported as progressive 
disease if before surgery or recurrent disease if after surgery. 
k The imaging due prior to initiation of chemo/RT should be done 3-4 weeks after completion of mFOLFOX6 but must be done prior to initiation of chemo/RT.  
Imaging performed between chemoRT and surgery must be completed no earlier than 4 weeks and no later than 2 weeks before surgery after completion of 
chemoRT.  Clear evidence of distant (metastatic) disease development must be reported as progressive disease if before surgery or recurrent disease if after 
surgery. 
l Submission of blood at the defined time points and tumor (FFPE) from the diagnostic biopsy and from surgically resected primary tumor (or residual scar in the 
setting of pCR) is required for patients who agree (submit FFPE within 60 days after surgery).  Postoperatively, research blood collection should occur at the first 
imaging visit (6 months) (see Section 10.0, the NRG-GI002 Pathology and Correlative Science Instructions). 
*Note: Following documented disease progression/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 survival and available cancer specimens (FFPE) will be collected (see Section 10.0) from 
patients who agree to optional biobanking. 

 
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5.4 
Dose determinations 
5.4.1 
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. 
5.4.2 
Rounding Doses 
Rounding of drug doses is optional.  If the treating physician decides to round the dose(s), follow 
these guidelines.  (These also apply to dose modifications.) 
• 
Oxaliplatin (85 mg/m2 IV) 
Doses should be rounded to the nearest 1 mg. 
• 
5-Fluorouracil (400 mg/m2 IV and 2400 mg/m2 IV) 
Doses should be rounded to the nearest 50 mg. 
• 
Leucovorin (400 mg/m2 IV) 
Doses should be rounded to the nearest 25 mg. 
• 
Capecitabine (825 mg/m2 PO) 
Doses should be rounded down to the nearest 500 mg or 150 mg. 
• 
Veliparib (400 mg PO) 
Fixed dose; rounding is not applicable 
• 
MK-3475 (pembrolizumab) (200 mg total dose) 
Fixed dose; rounding is not applicable. 
5.5 
Radiation therapy 
This protocol allows, but does not require, the use of Intensity Modulated Radiation Therapy 
(IMRT).  Institutions using IMRT must be credentialed for IMRT for the modality chosen for 
treatment as specified by IROC Houston (Section 8.3).  IGRT credentialing is not required; 
however, a facility questionnaire must be completed.  Credentialing requirements can be found in 
Section 8.3. 
Radiation Therapy Schema: 
The treatment is delivered in 2 phases, an initial phase to treating the entire PTV_4500 including 
the PTV_5040 volume to 45 Gy, followed by a boost phase, treating the PTV_5040 with an 
additional 5.4 Gy to a total of 50.4 Gy.  The fraction size is 1.8 Gy for all phases. 
 

 
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Examples of contoured patients (anorectal atlas) are available for review on the NRG Oncology 
website (https://www.nrgoncology.org/ciro-gastrointestinal; Anorectal Atlas Link).  These 
examples are excellent resources for the contouring of normal structures as well as GTV, CTV 
and PTV design, and their use is strongly encouraged. 
Standard 
Name 
Description 
Validation Required/Required 
when applicable/Optional 
GTV_5040 
GTV to receive 50.4 Gy 
Required 
PTV_5040 
PTV to receive 50.4 Gy 
Required 
CTV_4500 
CTV to receive 45 Gy 
Required 
PTV_4500 
PTV to receive 45 Gy 
Required 
Detailed specification: 
Gross tumor volume (GTV): This includes the primary tumor and any pelvic nodes felt involved 
grossly with metastatic disease.  Assessment of the primary tumor and nodal disease may be 
made on the basis of endoscopy, CT, PET-CT, MRI, or transrectal ultrasonography.  The entire 
rectal circumference at the level of the tumor should be included as GTV_5040. 
Clinical target volume (CTV_4500): This includes the GTV and the following nodal groups: 
perirectal nodes; presacral nodes; internal iliac; and common iliac nodes below the L5-sacral 
junction. 
Planning target volume 4500 (PTV_4500): This will provide a margin around the CTV_4500 to 
compensate for the inter- and intra-fraction uncertainty consequent to daily setup uncertainty and 
to potential internal organ motion.  By definition, the PTV_4500 will consist of a symmetrical  
7 mm expansion around the CTV_4500.  In the event that a PTV_4500 extends outside of the 
skin surface, the clinician should manually trim the PTV_4500 contours to be 3 mm inside the 
outer skin (unless there is direct skin involvement). 
The following are guidelines for generating the CTV_4500 and PTV_4500 and PTV_5040. The 
CTV_4500 can be formed from the following CTV sub-volumes: 
• 
CTV_rectal = Rectal GTV +1.5 cm radially, +2.5 cm craniocaudally along the mucosal 
surface.  The radial expansion can be shrunk to within the mesorectal fascia and off 
organs/sidewall if no clinical/radiographic evidence of an involved mesorectal fascia OR T4 
disease. 
• 
CTV_nodal = Nodal GTV + 1.5cm symmetrical expansion.  The symmetric expansion can be 
shrunk to within the mesorectal fascia and off organs/sidewall if no clinical/radiographic 
evidence of an involved mesorectal fascia. 
• 
CTV_vessels = Uninvolved iliac vessels + 1.0 cm.  This expansion can be trimmed off pelvic 
sidewall/bowel. 
• 
CTV_presacral = the entire sacral hollow from mid S1-S5 and 8 mm tissue anterior to the 
anterior border of the sacral bone. 
• 
CTV_perirectal = The mesorectum and perirectal lymphatic CTV should be identified on 
cross-sectional imaging and is best seen on an MRI.  If the fascia cannot be confidently 
visualized, it can be generated by utilizing anatomic landmarks: 
− 
Posterior Border: anterior border of the sacrum and gluteus maximus 
− 
Lateral Border: ileum, piriformis and obturator muscles 

 
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− 
Anterior Border: should include the interface with the bladder, vagina, uterus or prostate 
− 
Inferior Border: the levators 
• 
The PTV_4500 is generated by expanding all of the above structures by 0.7 cm 
symmetrically and unifying them into one 3-dimensional volume for planning purposes. 
• 
The PTV_5040 is an expansion of the GTV_5040 by 3 cm and the presacrum, this volume 
should not extend beyond PTV_4500. 
5.5.4 
Definition of critical structures 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan.  Structures marked as “Required when applicable” must be contoured and 
submitted when applicable. 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
Standard Name 
Description 
Validation 
Required/Required when 
applicable/Optional 
Bladder 
Bladder 
Required 
Femur_R 
Right femur 
Required 
Femur_L 
Left femur 
Required 
Bowel_Small 
Small Bowel 
Required 
Notes from RTOG Anorectal Atlas for contouring of normal structures: 
Small Bowel: 
The small and large bowel are important structures to consider when planning treatment.  To 
avoid unnecessary time spent contouring the entire abdominal contents, they only need to be 
contoured up to ~ 1 cm above the PTV.  This, in turn, implies that absolute volume of bowel  
(in cc) is more important than relative volume (in %). Otherwise cases with good exclusion of 
small bowel from the pelvis (e.g., with a belly board) will be unfairly penalized. 
Femoral Heads: 
The femoral head and neck should be avoidance structures.  Only the femoral heads, not the neck 
should be drawn. 
5.5.5 
Dose prescription 
Target 
Standard Name 
Dose (Gy) 
Fraction Size (Gy) 
# of fractions 
Dose specification 
technique 
PTV_4500 
45 
1.8 
25 
Covering  
95% of PTV 
PTV_5040 
50.4 
1.8 
3 
Covering  
95% of PTV 
 
 

 
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5.5.7 
Planning technique 
A 3D conformal radiotherapy planning technique must be used.  If not using IMRT, field edges 
and MLC blocking must be conformal to the PTVs.  The dose distributions must include 
corrections for tissue density heterogeneities.  Regardless of planning technique, the dose 
prescription criteria specified in the section on compliance criteria (Section 5.5.7) must be used. 
5.5.8 
Compliance criteria 
The compliance criteria listed here will be used to score each case.  Given the limitations inherent 
in the treatment planning process, the numbers given in this section can be different than the 
prescription table.  The Per Protocol and Variation Acceptable categories are both considered to 
be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable 
category can include more challenging plans that do not fall at or near the ideal results.  A final 
category, called Deviation Unacceptable, results when cases do not meet the requirements for 
either Per Protocol or Variation Acceptable.  Plans falling in this category are considered to be 
suboptimal and additional treatment planning optimization is recommended. 
VxGy (cc), VxGy (%), Vx%(cc), Vx%(%): Volume (cc or %) receiving Dose (Gy, or %) 
Dvcc(Gy), Dvcc(%), Dv%(Gy), Dv%(%): Dose (Gy or %) to Volume (cc or % of total volume) 
Dmin(Gy) or Dmin(%):  Minimum dose is defined to a volume that is the total volume minus  
0.03 cc 
D0.03cc(Gy) or D0.03cc(%): Maximum dose is defined to a volume of 0.03 cc 
Dmean(Gy) or Dmean(%): Mean dose in Gy or % 
For Normalization purposes two treatment plans are generated, one for each phase of treatment 
(initial 45 Gy, and subsequent boost volume to 50.4 Gy), each plan normalized to a PTV covering 
isodose volume of 95% as described in the prescription section (Section 5.5.5), V95%= 100%.  A 
combination (plan sum) is required to evaluate the dosimetric compliance criteria for critical 
structures. 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met. 
5.5.9 
Target Volume Constraints and Compliance Criteria 
Name of Structure 
Dosimetric parameter* 
Per Protocol 
Variation Acceptable 
PTV_4500 
D95% (%) 
≥95 
≥90 
PTV_5040 
D95% (%) 
D10(%) (%) 
≥95 
≤110 
≥90 
≤120 
*Note: Percentiles are normalized to prescription doses of 45 Gy and 50.4 Gy respectively. 
 
 

 
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Structure Constraints and Compliance Criteria 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation Acceptable 
Bowel_Small 
D150cc(Gy) 
≤15 
≤16.5 
 
D120cc(Gy) 
≤35 
≤38.5 
 
D70cc(Gy) 
≤40 
≤44 
 
D35cc(Gy) 
≤45 
≤49.5 
 
D0.03cc(Gy) 
≤50 
≤55 
Femur_L & Femur_R 
D50%(Gy) 
≤30 
≤33 
 
D40%(Gy) 
≤40 
≤44 
 
D5%(Gy) 
≤45 
≤49.5 
 
D0.03cc(Gy) 
≤50 
≤55 
Bladder 
Dmean(Gy) 
≤40 
≤44 
E-PTVs 
D1cc(Gy) 
≤49.5 
≤54.5 
E-PTVs include any non-PTV tissues. 
Note: Constraints related to bowel and bladder are recommendations.  Constraints will be scored but any 
Unacceptable Deviations will not affect the overall plan score.  However, all femoral head constraints and 
the D0.03cc (Gy) for the Bowel_Small will be scored an Unacceptable Deviation if parameters are not 
met and will be counted in overall plan score. 
5.5.10 Patient specific QA 
Any patient-specific QA that needs to be acquired should follow institutional guidelines.  For 
photon IMRT plans, patient specific QA is highly recommended.  QA is performed by delivering 
the plan onto a phantom and measuring the dose using an ion chamber array or other 2D/3D 
device.  Typically, measured dose distributions will be compared to planned dose distribution 
using a Gamma criterion of 4% dose difference and 3 mm distance to agreement.  The pass rate 
should be at least 90% measured for the entire plan. 
5.5.11 Daily Treatment Localization/IGRT 
Daily IGRT localization is required for patients treated with IMRT. Either a daily orthogonal kV 
pair, or CBCT (or MVCT) is acceptable.  The boost plan should be imaged with daily CBCT.  
Institutional guidelines should be followed for daily treatment localization and IGRT.  For 
patients not treated with IMRT, patients should be imaged with an Orthogonal kV (2D) image 
pair or CBCT (or equivalent) prior to the first fraction, and weekly henceforth. IGRT 
credentialing is not required for this protocol. 
Management of Radiation Dose to the Patient from IGRT 
NRG Oncology is concerned about the estimated doses given from IGRT, and is committed to 
limiting the imaging dose when IGRT is used in any of its protocols.  This can be accomplished 
by avoiding the use of this technology to make small changes in patient positioning that are 
within the stated PTV margins.  The imaging dose to the patient may become significant if 
repeated studies are done for patients with severe set up problems (e.g. requiring frequent 
corrections that are larger than the PTV margins).  It is recommended that patients demonstrating 
severe set up problems during the first week of treatment be moved to a treatment with larger 
margins. 

 
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5.6 
General Concomitant Medication and Supportive Care Guidelines 
All concurrent/concomitant medications received within 30 days before the first dose of study therapy and 
30 and 90 days after the last dose of study therapy are to be recorded. 
5.6.1 
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 
or at any time during the radiotherapy phase of treatment.  See Section 6.0 for dose 
modifications and delays. 
• 
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. 
5.6.2 
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. 
5.6.3 
Management of diarrhea 
Diarrhea is a commonly occurring toxicity with the therapies included in GI002.  With 
combination chemoradiation, it is anticipated that diarrhea is likely to occur.  Without appropriate 
treatment, diarrhea can be prolonged, severe, and lead to dehydration and other complications. 
(See Appendix B for clinical management of diarrhea.  For patients randomized to Arm 3, also 
see Section 6.6.2 for supportive care guidelines of diarrhea/colitis with potential immunologic 
etiology.) 
Management of diarrhea for patients randomized to Arms 1 and 2; and for patients randomized to 
Arm 3 (if diarrhea is deemed to be related to FOLFOX or CRT): 
• 
Inform patients that they will experience diarrhea while on study therapy and possibly for 
several weeks after study therapy has stopped. 
• 
Patients must be instructed to: 
− 
have ready access to antidiarrheal agents (e.g., loperamide) starting on Day 1 of 
treatment. 
− 
start antidiarrheal therapy at the very first sign of loose or more frequent stools 
− 
continue prophylactic therapy as directed 
− 
promptly report diarrhea symptoms 
− 
record the baseline number of daily stools, the occurrence of loose stools, and any anti-
diarrheal treatment along with the daily dose of study therapy using the GI002 study 
diary (Appendix E).  This record should be reviewed with the patient at each treatment 
visit. 
− 
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.  For patients randomized to Arm 3, also see Section 6.6.2 
for supportive care guidelines of diarrhea/colitis with potential immunologic etiology.) 

 
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Refer to the ASCO Recommended Guidelines for Treatment of Cancer Treatment-Induced 
Diarrhea for additional recommendations regarding diarrhea (Benson 2004). 
Antidiarrheal medications 
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. 
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.  For patients randomized to Arm 3, 
also see Section 6.6.2 for treatment management/supportive care guidelines of diarrhea/colitis 
with potential immunologic etiology. 
Management of diarrhea for Arm 3 (if diarrhea is thought to be related to pembrolizumab): 
− 
Patients should be carefully monitored for signs and symptoms of immune related 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).  In symptomatic patients, 
infectious etiologies should be ruled out, and if symptoms are persistent and/or severe, 
endoscopic evaluation should be considered. 
− 
For patients with severe enterocolitis (Grade 3), MK-3475 (pembrolizumab) will be 
permanently discontinued and treatment with systemic corticosteroids should be initiated at a 
dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When symptoms improve to Grade 1 
or less, corticosteroid taper should be started and continued over at least 1 month. 
− 
For patients with moderate enterocolitis (Grade 2), MK-3475 (pembrolizumab) should be 
withheld. If symptoms are persistent for more than one week, systemic corticosteroids should 
be initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at least 1 month. 
− 
All patients who experience diarrhea should be advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via 
IV infusion. 
For patients randomized to Arm 3, also see Section 6.6.2 for treatment management/supportive 
care guidelines of diarrhea/colitis with potential immunologic etiology. 
5.6.4 
Management of nausea or vomiting (Arm 2) 
Grade 3 nausea and vomiting has been seen in early phase studies with veliparib and 
capecitabine.  Therefore, to optimize dose intensity and maintain quality of life, early initiation or 
prophylactic management with scheduled anti-emetic therapy (5HT-3 antagonists, 
metoclopramide, prochlorperazine) and/or lorazepam should be considered when patients begin 
treatment with veliparib and capecitabine.  In addition, management should include counseling 
regarding these toxicities and may include brief interruption of dosing or dose modification.  
Investigators should also rely on standard clinical practice and guidelines for nausea 
management. 
Antiemetic Therapy (all Arms) 
Antiemetic therapy should be administered according to National Comprehensive Cancer 
Network (NCCN) or American Society of Clinical Oncology (ASCO) clinical practice guidelines. 

 
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5.6.5 
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 9 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. 
5.6.6 
Management of anaphylaxis 
Oxaliplatin may cause anaphylactic reactions.  Management of such reactions is per institutional 
guidelines. 
5.6.7 
Management of injection site reactions 
Injection site reactions, including redness, swelling, and pain, has been reported with oxaliplatin. 
Extravasation, in some cases including soft tissue necrosis has occurred.  Management is per 
institutional guidelines. 
5.6.8 
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 prior to resection of the primary rectal cancer (see Section 5.9). 
• 
Targeted therapy 
Administration of targeted therapy for malignancy is prohibited prior to resection of the 
primary rectal cancer (see Section 5.9). 
• 
Radiation therapy 
Administration of radiation therapy other than the radiation therapy specified in this protocol 
is prohibited.  (Radiation protocol therapy is outlined in Section 5.5.) 
• 
Live vaccines 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  Seasonal 
flu vaccines that do not contain live virus are permitted. 
• 
Systemic glucocorticoids 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Principal Investigator. 
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 per protocol.  (See Section 3.2 for additional medications that are 
prohibited in this trial.) 
 

 
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5.6.9 
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 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. 
5.6.10 Participation in Other Trials 
If a GI002 patient is considering participation in another clinical trial (including supportive 
therapy trials), contact the NRG Oncology Clinical Coordinating Department. 
5.7 
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 progression/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. 
5.8 
Surgery 
Surgery must be performed within 8 to 12 weeks following the last dose of radiotherapy.  
For patients in Arm 3, surgery must be performed within this window.  Do not reschedule missed 
MK-3475 (pembrolizumab) doses.  All doses of MK-3475 (pembrolizumab) must be given prior to 
surgery. 
5.9 
Adjuvant Therapy 
Per protocol, adjuvant therapy is not recommended but allowed at the investigator's discretion.  
Any antineoplastic treatment given after surgical resection of the primary rectal cancer but before 
documentation of rectal cancer recurrence, second primary cancer or secondary malignancy must 
be reported via the GI002 Follow-up Folder in Medidata Rave. 
 

 
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6.0 
TREATMENT MODIFICATIONS/MANAGEMENT 
6.1 
General instructions 
• 
The descriptions and grading scales found in the revised CTCAE v4.0 will be utilized for AE 
reporting until March 31, 2018.  CTCAE version 5.0 will be utilized for AE reporting 
beginning April 1, 2018.  All appropriate treatment areas should have access to a copy of 
CTCAE version 5.0, which can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
• 
Treatment schedule changes for non-medical reasons:  When rescheduling study therapy 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.  (See Section 6.6.2 for instructions specific to MK-3475/pembrolizumab 
treatment delays.) 
• 
In the event of disease progression/recurrence or diagnosis of an invasive second primary 
cancer or secondary malignancy, study therapy will be discontinued; further therapy is at the 
investigator's discretion.  However, patients will continue to be followed off treatment for 
survival, and available cancer specimens (FFPE) will be collected (see Table 20A). 
6.2 
Treatment management radiation therapy 
Treatment interruptions of radiation therapy are discouraged but may be necessitated by acute 
complications.  The reason for and duration of any such interruption must be documented.  A 
minimum of 4 daily radiation therapy treatments are required in any given week.  Any 
missed radiation treatments will be made up at the end of the treatment schedule such that the 
total number of delivered 1.8 Gy fractions remains 28.  If the sum total of radiation interruptions 
exceeds 7 normally scheduled treatment days, for reasons other than toxicity, this would represent 
a minor protocol violation. 
During the chemoradiotherapy phase of treatment, if chemotherapy is held, radiation therapy will 
continue.  If radiation is held, capecitabine will also be held; however, treatment with veliparib 
(Arm 2) and pembrolizumab (Arm 3) will continue unless otherwise contraindicated.  Radiation 
may be held for grade 3 dermatitis radiation, grade 4 neutropenia, or other radiation-associated 
toxicity > grade 3 by CTCAE at the discretion of the treating radiation oncologist.  Radiation 
should be restarted subsequent to recovery at the discretion of the radiation oncologist consistent 
with standard practice. 
6.3 
Treatment management mFOLFOX6 
Chemotherapy dose modifications for all GI002 patients are detailed in Tables 7, 8, and 9.  
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 Tables 7 and 8 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 
progression/recurrence or diagnosis of a second primary cancer or secondary malignancy and 

 
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the patient is able to comply with all other aspects of the trial, timing of additional study 
treatment (RT + radiosensitizer[s]) may continue as planned. 
• 
In the event of disease progression/recurrence or diagnosis of an invasive second primary 
cancer or secondary malignancy during mFOLFOX6, study therapy will be discontinued; 
further therapy is at the investigator's discretion. However, patients will continue to be 
followed off treatment for survival, and available cancer specimens (FFPE) will be collected. 
Table 7. 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 D). 
 
Table 8. Treatment management for mFOLFOX6  (See Table 9 for oxaliplatin-specific toxicities.) 
Important table instructions: 
• Dose modifications for mFOLFOX6 are based on the dose level changes on Table 7. 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present 
on the scheduled Day 1 of Cycles 2-8 (column 3). Refer to other applicable instructions in.  
• Refer to Section 5.6.2 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 v4.0 (until 3/31/18) 
CTCAE v5.0 (beginning 4/1/18) 
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: 
Grade 2 (ANC 1000-1199/mm3); 
Grade 3, 4  
 
Maintain dose 
Consider use of growth factors to 
avoid delay with subsequent cycles. 
Hold until   1200/mm3. If recovery 
takes: 
 1 wk – maintain dose;  
2-3 wks –  one dose level 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Hold until   75,000/mm3.   
If recovery takes: 
1 wk – maintain dose;  
2-3 wks –  one dose level 
Grade 4 
↓ one dose level 
Hold until   75,000/mm3. 
 one dose level 
Table continued on next page 
 

 
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Table 8. Treatment management for mFOLFOX6 (continued) 
CTCAE v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18) 
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) 
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 
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 
Table continued on next page 
 

 
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Table 8. Treatment management for mFOLFOX6 (continued) 
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 6.3 for instructions regarding further study treatment). 
c 
Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
 

 
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6.4 
Treatment management capecitabine (Arm 1) 
Capecitabine dose modifications for GI002 patients randomized to Arm 1 are detailed in Tables 
10 and 11. 
  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 RT is not administered (holiday, weekend, RT related toxicity, etc.), capecitabine is held. 
• 
If capecitabine is held or discontinued, RT continues per protocol unless otherwise 
contraindicated. 
• 
Capecitabine doses that have been reduced may not be escalated. 
• 
In the event of disease progression/recurrence or diagnosis of an invasive second primary 
cancer or secondary malignancy during treatment with capecitabine/RT, study therapy will be 
discontinued; further therapy is at the investigator's discretion.  However, patients will 
continue to be followed off treatment for survival, and available cancer specimens (FFPE) 
will be collected (see Table 20A). 
Table 10. Capecitabine dose levels 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level 
 -1 
(mg/m2) 
Dose Level  
-2 
(mg/m2) 
Dose Level  
-3 
Capecitabine 
825 (BID)  
on days when RT is 
given 
620 (BID)  
on days when RT 
is given 
465 (BID)  
on days when RT 
is given 
Discontinue 
 
 

 
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Table 11. Treatment management for capecitabine (Arm 1) 
Important table instructions: 
•  Dose modifications for capecitabine are based on the dose level changes on Table 10. 
• 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 v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18) 
Adverse Event/Grade 
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
Neutrophil count 
decreased: 
Grades 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  
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  
Table continued on the next page. 
 

 
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Table 11. Treatment management for capecitabine (Arm 1) (continued) 
CTCAE v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18) 
Adverse Event/Grade 
Modifications for AEs that  
REQUIRED DELAY IN TREATMENT 
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. 
 
 

 
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6.5 
Treatment management capecitabine and veliparib (Arm 2) 
Capecitabine and veliparib dose modifications for GI002 patients randomized to Arm 2 are 
detailed in Tables 12 and 13.  
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 RT is not administered (holiday, weekend, RT related toxicity, etc.), capecitabine is held; 
however, veliparib and RT continue per protocol unless otherwise contraindicated. 
• 
If capecitabine and/or veliparib are held or discontinued, RT continues per protocol unless 
otherwise contraindicated. 
• 
Capecitabine doses that have been reduced may not be escalated. 
• 
Veliparib doses that have been reduced may not be escalated. 
• 
In the event of disease progression/recurrence or diagnosis of a second primary cancer or 
secondary malignancy during treatment with capecitabine, veliparib and RT, study therapy 
will be discontinued; further treatment is at the investigator's discretion.  However, patients 
will continue to be followed off treatment for survival, and available cancer specimens 
(FFPE) will be collected (see Table 20A). 
 
Table 12. Capecitabine and veliparib dose levels 
 
Dose Level 
0 
Starting Dose 
(mg/m2) 
Dose Level 
-1 
(mg/m2) 
Dose Level  
-2 
(mg/m2) 
Dose Level  
-3 
Capecitabine 
825 (BID)  
on days when RT is 
given 
620 (BID)  
on days when RT 
is given 
465 (BID)     
on days when RT 
is given 
Discontinue 
 
Dose Level 
0 
Starting Dose 
(total dose) 
Dose Level 
-1 
(total dose) 
Dose Level 
-2 
(total dose) 
Dose Level 
-3 
 
Veliparib 
400mg (BID) 
7 days/week 
300mg (BID) 
7 days/week 
200mg (BID 
7 days/week 
Discontinue 
 
 

 
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Table 13. Treatment management for capecitabine and veliparib (Arm 2) 
Important table instructions: 
• Hold capecitabine and veliparib doses 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. 
• All modifications in dose levels apply to both capecitabine and veliparib unless otherwise noted. 
CTCAE v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18)  
Adverse Event/Grade 
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
Neutrophil count 
decreased: 
Grades 2 (1000-
1199/mm3), 3, and 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 ↓ capecitabine one dose level 
Grade 3 
↓ capecitabine one dose level 
Grade 4 
Discontinue capecitabine 
Vomiting (despite 
antiemetics) 
Grade 2 
 
 
Hold and delay until ≤ grade 1, then ↓ one dose level 
Grades 3, 4 
↓ one dose level or discontinue chemotherapy 
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; then ↓ one dose level 
Grade 3, 4 
Discontinue chemotherapy 
Table continued on the next page.  
 

 
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Table 13. Treatment management for capecitabine and veliparib (Arm 2) (continued) 
CTCAE v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18)  
Adverse Event/Grade 
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
Febrile neutropenia: 
Grade 3 
 
Hold until clinical resolution, then  one dose level 
Grade 4 
Discontinue chemotherapy 
Infection: 
Grade 2 
 
Maintain dose or  one dose level 
Grade 3 
 one dose level 
Grade 4 
 one dose level or discontinue 
Nervous system 
disorders: 
Seizure 
Grades 1, 2, 3, 4 
Any event of seizure, regardless of grade or attribution, requires 
discontinuation of veliparib and discussion with the Medical Oncology 
Chair or Medical Oncology Protocol Officer regarding the decision to 
resume treatment. 
Skin and subcutaneous 
tissue disorders: 
Palmer-planter 
erythrodysesthesia 
syndrome  
 
Grades 2, 3 
 
 
 
 
 
 
1st occurrence −  capecitabine one dose level 
2nd occurrence −  capecitabine one additional dose level 
3rd occurrence − discontinue capecitabine 
Other clinically 
significant AEs:* 
Grade 2 
 
 
Maintain dose or  attributable agent one dose level 
Grade 3 
↓ attributable agent one dose level 
Grade 4 
Discontinue attributable agent 
* Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
 

 
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6.6 
Treatment management capecitabine and MK-3475 (pembrolizumab) (Arm 3) 
• 
Toxicities during chemoRT with capecitabine and MK-3475 (pembrolizumab) may be 
difficult to distinguish when first presenting.  As a result, for any toxicity noted, please refer 
to both Table 15 (capecitabine) AND Table 16 (MK-3475/pembrolizumab) to determine if 
the AE and grade require one or more agent modification.  Table instructions for individual 
agents should be followed independent of one another; however, both tables must be 
referenced for any overlapping toxicities. 
• 
If RT is not administered (holiday, weekend, RT related toxicity, etc.), capecitabine is held; 
however, pembrolizumab continues per protocol unless otherwise contraindicated. 
• 
If capecitabine is held or discontinued for capecitabine related toxicities (see Table 15), 
pembrolizumab and RT continue per protocol unless otherwise contraindicated. 
• 
If pembrolizumab is held or discontinued for pembrolizumab related toxicities (see Table 16), 
capecitabine and RT continue per protocol unless otherwise contraindicated.  Missed or held 
pembrolizumab doses are not to be rescheduled. 
For toxicity-related delays, continue with the next scheduled dose following acceptable resolution 
of the AE.  Note: Surgery must be performed within 8 to 12 weeks following the last dose of 
RT.  For patients in Arm 3, surgery must be performed within this window. .  Do not reschedule 
missed MK-3475 (pembrolizumab) doses.  All doses of MK-3475 (pembrolizumab) must be given 
prior to surgery. 
6.6.1 
Capecitabine dose modification 
Capecitabine dose modifications for GI002 patients randomized to Arm 3 are detailed in  
Tables 14 and 5 (capecitabine).  See Section 6.6.2 and Table 16 for treatment management for 
MK-3475 (pembrolizumab). 
Additionally, the following dose modification instructions must be followed: 
• 
The current CTCAE version (v4.0 until 3/31/18 or v5.0 beginning 4/1/18) must be used to 
grade the severity of AEs.  Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
• 
All dose modifications should be based on the adverse event requiring the greatest dose 
modification. 
• 
Capecitabine doses that have been reduced may not be escalated. 
• 
In the event of disease progression/recurrence or diagnosis of an invasive second primary 
cancer or secondary malignancy during treatment with capecitabine/pembrolizumab/RT, 
study therapy will be discontinued; further therapy is at the investigator's discretion.  
However, patients will continue to be followed off treatment for survival, and available 
cancer specimens (FFPE) will be collected (see Table 20A). 
Table 14. Capecitabine dose levels 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level 
 -1 
(mg/m2) 
Dose Level  
-2 
(mg/m2) 
Dose Level  
-3 
Capecitabine 
825 (BID)  
on days when RT is 
given 
620 (BID)  
on days when RT 
is given 
465 (BID)  
on days when RT 
is given 
Discontinue 
 
 

 
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Table 15. Treatment management for capecitabine (Arm 3) 
 
Important table instructions: 
• Dose modifications must be based on the AE requiring the greatest modification. 
• Hold capecitabine until any AE requiring dose modification returns to  
 grade 1 unless indicated otherwise in the treatment management sections/tables.  For capecitabine, 
if recovery to  grade 1 (or to other level specified) has not occurred after 3 weeks of delay, 
capecitabine must be discontinued. 
• Refer to Section 6.6 and Table 16 for MK-3475 (pembrolizumab) instructions. 
CTCAE v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18)  
Adverse Event/Grade 
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
Neutrophil count 
decreased: 
Grades 2 (1000-
1199/mm3), 3, and 4 
Hold capecitabine 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  
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  
Table continued on the next page. 
 

 
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Table 15. Treatment management for capecitabine (Arm 3) (continued) 
CTCAE v4.0 (until 
3/31/18) 
CTCAE v5.0 (beginning 
4/1/18) 
Adverse Event/Grade  
Modifications for AEs that 
REQUIRED DELAY IN TREATMENT 
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. 
6.6.2 
Treatment Management/Supportive Care Guidelines: MK-3475 (pembrolizumab) (Arm 3) 
Adverse events (both non-serious and serious) associated with MK-3475 (pembrolizumab) exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or several months 
after the last dose of treatment.  MK-3475 (pembrolizumab) must be withheld for drug-related toxicities 
and severe or life-threatening AEs. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not related to 
study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays).  Patients 
should be placed back on study therapy within 3 weeks of the scheduled interruption.  The reason for 
interruption should be documented in the patient's study record.  Note: Surgery must be performed within 
8-12 weeks following the last dose of RT.  If the dose interruption(s) would result in a delay of surgery, 
do not reschedule missed dose(s). 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are also outlined in Table 16.  Where appropriate, these guidelines include the use 
of oral or IV treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care.  The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to MK-3475 (pembrolizumab). 

 
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Note:  If after evaluation, the event is determined not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below).  It may be necessary to perform conditional procedures 
such as bronchoscopy, endoscopy, or skin photography as part of the evaluation of the event. 
 

 
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Table 16. Treatment Management and Supportive Care Guidelines for Related Adverse Events for MK-
3475 (pembrolizumab) 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids.  
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to  
≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up 
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
• Add prophylactic 
antibiotics for 
opportunistic 
infections 
• Monitor participants for 
signs and symptoms of 
pneumonitis 
• Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment 
Recurrent 
Grade2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
• Monitor participants for 
signs and symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (i.e., 
peritoneal signs and 
ileus) 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
 
• Participants with 
≥Grade 2 diarrhea 
suspecting colitis should 
consider GI consultation 
and performing 
endoscopy to rule out 
colitis 
• Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids. If sufficient 
oral fluid intake is not 
feasible, fluid and 
electrolytes should be 
substituted via IV 
infusion 
Table continued on next page.  
 

 
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AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2a 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5-1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline or 
is stable) 
Grade 3b or 4c 
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure 
Withhold d 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
• Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated 
• Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinued 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non-
selective beta-
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
• Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinued 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
• Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
• Monitor for signs and 
symptoms of thyroid 
disorders 
Table continued on next page. 
 

 
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Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 1–
2mg/kg or 
equivalent) 
followed by taper 
• Monitor changes of 
renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids 
• Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Persistent 
Grade 2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids 
• Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
evente 
Recurrent 
Grade3 or 
Grade4 
Permanently 
discontinue 
a AST/ALT: >3.0-5.0 x ULN if baseline normal; >3.0-5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5-3.0 x ULN if baseline normal; >1.5-3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0-20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0-10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin:>10.0xULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician.  If control achieved or ≤Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, 
encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 
 

 
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6.6.3 
Other Considerations 
Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
Contraception and Pregnancy 
Study therapy may have adverse effects on a fetus in utero.  Furthermore, it is not known if the 
study drugs have transient adverse effects on the composition of sperm. 
For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). 
Female patients will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 90 days (Arms 1 and 20 
and 120 days (Arm 3) after the last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity; 
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female patient’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 

 
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†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the patient's preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for patients participating at sites in this 
country/region. 
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study, patients of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 90 days (Arm 1 and Arm 2) 
or 120 days (Arm 3) after the last dose of trial therapy.  If there is any question that a patient of 
childbearing potential will not reliably comply with the requirements for contraception, that 
patient should not be entered into the study. 
Use in Pregnancy (Arm 3) 
If a patient inadvertently becomes pregnant while on MK-3475 (pembrolizumab), the patient will 
immediately be removed from the study.  The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the NCI and to Merck without delay and within 24 
hours to the NCI and within 2 working days to Merck if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the NCI.   If a male patient 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the NCI and to Merck and followed as described above and in  
Section 7.4.7. 
Use in Nursing Women (Arm 3) 
It is unknown whether MK-3475 (pembrolizumab) is excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, patients who are breast-feeding are not eligible for enrollment. 
 

 
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7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Study Agents 
7.1.1 
Investigational agents 
The investigational agents in NRG-GI002 are veliparib (NSC #737664)/ARM 2 and MK-3475 
(pembrolizumab)(NSC #776864)/ARM 3, which are being made available under INDs sponsored 
by the DCTD, NCI. 
7.1.2 
Commercial agents 
The commercial agents in NRG-GI002 are 5-fluorouracil (NSC #19893), leucovorin (NSC 
#3590), 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 
4.0 will be utilized for AE reporting until March 31, 2018.  CTCAE version 5.0 will be utilized 
for AE reporting beginning April 1, 2018.  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 
Harmonisation [ICH] E2A, E6). 
Adverse event reporting encompasses all aspects of the protocol including radiation therapy, 
surgery, and drug. 
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-florouracil, leucovorin, and oxaliplatin): 
Common adverse events (> 20%) include: alopecia, mucositis, anemia, diarrhea, nausea, 
vomiting, infection, palmar-plantar erythrodysesthesia, peripheral motor and sensory 
neuropathies 
Less common events ( 20%) include: photophobia, blurred vision, eyelid function disorder, 
hearing impaired, and high blood pressure 
Rare but serious events (< 3%) include: treatment related secondary malignancy and Reversible 
Posterior Leukoencephalopathy Syndrome (RPLS) 
Capecitabine: 
Common adverse events (> 20%) include: edema, palmar-plantar erythrodysesthesia anemia, 
infection, thrombocytopenia, fatigue, and diarrhea. 
Less common events ( 20%) include: blurred vision, restlessness, and ataxia. 
Rare but serious events (< 3%) include: hypersensitivity reaction, and myocardial 
infarction/ischemia. 
7.3.2 
Investigational agent veliparib (ABT-888) 
For veliparib, expectedness of adverse events is based on the current NCI Specific Protocol 
Exceptions to Expedited Reporting (SPEER) for veliparib. 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 2310 patients. Below is the CAEPR for 
veliparib (ABT-888). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 

 
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Adverse events reported on ABT-888 (Veliparib) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that ABT-888 (Veliparib) caused the adverse 
event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and 
lymphatic system disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Cardiac disorders - Other (Takotsubo cardiomyopathy); Heart failure; Left 
ventricular systolic dysfunction; Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic obstruction; 
Dental caries; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; 
Gastritis; Gastroesophageal reflux disease; Lower gastrointestinal hemorrhage; Mucositis oral; 
Obstruction gastric; Rectal hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; 
Fever; Flu like symptoms; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cirrhosis) 
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; Infections and 
infestations - Other (peritonsillar abscess); Lung infection; Lymph gland infection; Mucosal infection; 
Sepsis; Shingles; Skin infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; 
Radiation recall reaction (dermatologic) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypernatremia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
7.3.3 
Investigational agent MK-3475 (pembrolizumab) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 3793 patients.  Below is the CAEPR for 
MK-3475 (pembrolizumab), NSC 776864). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 

 
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Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Myocardial infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal 
hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; 
Rectal hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema 
limbs; Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general 
physical health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal 
and urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous 
tissue disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
Note: MK-3475 (pembrolizumab) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
7.3.4 
Radiation therapy adverse events 
• Short Term 
Fatigue, loss of appetite, and nausea are anticipated systemic reactions to radiation treatment.  
Skin erythema, desquamation, and diarrhea are potential local reactions. 
• 
Long Term 
Long term effects include bowel obstructions; bowel dysfunction presented as fecal 
incontinence to gas, loose stools, evacuation problems or urgency; and sexual dysfunction. 

 
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7.4 
Expedited Reporting of Adverse Events 
• 
All serious adverse events that meet expedited reporting criteria defined in Table 19 will be 
reported via the CTEP Adverse Event Reporting System (CTEP-AERS), accessed via the 
CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers.  The reporting procedures to be 
followed are presented in the "NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs" which can be 
downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm).     
The reporting timelines are outlined in Table 19. 
• 
For expedited reporting purposes only: AEs for the agent that are bold and italicized in the 
CAEPR (i.e., those listed in the SPEER column [Sections 7.3.2 and 7.3.3]) should be reported 
through CTEP-AERS only if the grade is above the grade provided in the SPEER. 
• 
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 CTEP by telephone at 301-897-7497 and to NRG Oncology by phone at 412-339-5300.  
An electronic report must be submitted 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 19). 
• 
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 19). 
• 
Supporting source documentation is requested by the IND sponsor (CTEP/DCTD) for this 
study as needed to complete adverse event review.  All CTEP-AERS documentation is faxed 
to CTEP at 301-897-7404.  When submitting supporting source documentation, include the 
protocol number, patient ID number, and CTEP-AERS ticket number on each page. 
7.4.2 
Expedited reporting requirements (CTEP-AERS-24, CTEP-AERS) 
Expedited reporting requirements begin with the administration of the first study therapy dose.  
Expedited reporting requirements for all patients are provided in Table 19. 
 

 
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7.4.3 
Additional protocol-specific requirements or exceptions to expedited reporting 
• 
Protocol-specific expedited reporting requirements: For this study, the following 
secondary malignancies require expedited reporting via CTEP-AERS from the first dose of 
study therapy until the end of the patient's follow-up: 
− Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
− Myelodysplastic syndrome (MDS) 
− Treatment-related secondary malignancy 
• 
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. 
− Neoplasms-malignant (i.e., a second primary cancer) determined by the investigator to 
NOT be most probably related or definitely related to treatment for malignancy. 
− AEs following a documented invasive rectal cancer recurrence or tumor progression. 
7.4.4 
Protocol-specific exceptions to expedited reporting of serious adverse events for the 
investigational agents (veliparib and MK-3475 (pembrolizumab) are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the ABT-888 (veliparib) 
CAEPR and the MK-3475 (pembrolizumab) CAEPR.  Reporting to the Site IRB 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) 
responsible for oversight of the patient according to institutional policy. 
7.4.5 
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. 
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 GI002 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. 
7.4.6 
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 GI002 Follow-up folder in Medidata Rave (see Section 7.6). 
7.4.7 
Expedited reporting of pregnancy, fetal death/pregnancy loss, and death neonatal 
Any pregnancy, fetal death/pregnancy loss, or death neonatal occurring in a female patient or 
partner of a male patient from the time of consent to 90 days (Arms 1 and 2) or to 120 days (Arm 

 
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3) following the last dose of study therapy, 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 5.5.6) located at the following CTEP website:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf). 
Upon learning of a pregnancy, fetal death/pregnancy loss, or death neonatal that occurs during 
study or within 3 months following the last dose of study therapy the investigator is required to: 
• 
Immediately discontinue study therapy. 
• 
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 5.5.6): 
− 
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 fax the form to 
CTEP at 301-897-7404. 
• 
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. 
• 
Pregnancy loss is defined in CTCAE as "Death in utero."  Beginning April 1, 2018, report 
pregnancy loss expeditiously as Grade 4 "Pregnancy loss" under the Pregnancy, puerperium 
and perinatal conditions SOC.  A pregnancy loss is not reported as a Grade 5 event. 
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 14.0). 
• 
All  grade 2 adverse events that occurred during study therapy must be reported on the 
GI002 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 GI002 Adverse Event forms through 
Medidata Rave must be maintained in the patient's research record. 
7.5.2 
Schedule for reporting routine adverse events 
Adverse events are to be submitted through Medidata Rave, even if no AEs were experienced 
by the patient.  Submit the GI002 Adverse Event and Treatment forms according to the 
following schedule: 
• 
During mFOLFOX6: at the end of each cycle and 3 to 4 weeks after the last cycle but before 
starting chemoRT; 
• 
During chemoRT: weekly and 30 days (+/- 3 days) after the last dose of chemoRT; 
• 
Before surgery: For Arms 1 and 2: within 14 days before surgery.  If surgery is not 
performed, AE assessment should be submitted 8-12 weeks after the last dose of chemoRT. 
For Arm 3: If patient completed 6 total doses of MK3475 (pembrolizumab): report AEs the 
day before surgery.  If surgery is not performed, AE assessment should be submitted 30 days 
from last dose of MK3475 (pembrolizumab).  If patient discontinues MK3475 
(pembrolizumab) early and if surgery is performed, report AEs 8 weeks from RT and 
capecitabine or 30 days from last MK3475 (pembrolizumab), whichever is the latest, but not 
later than the day before surgery.  If patient discontinues MK3475 (pembrolizumab) early and 
if surgery is not performed, report AEs 8 weeks from RT and capecitabine or 30 days from 
last MK3475 (pembrolizumab), whichever is the latest. 
 

 
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7.6 
Reporting Rectal Cancer Progression/Recurrence and Second Primary Cancer 
Report rectal cancer progression/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 GI002 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 
7.4.5 for reporting instructions for secondary malignancies.) 
 

 
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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. 
 

 
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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: 
• 
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. 
Additional Requirements 
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). 
Protocol Specific Requirements for NRG-GI002 Site Registration 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must be 
aligned to an RTI provider.  To manage provider associations or to add or remove associated 
providers, access the Provider Association page from the Regulatory section on the CTSU 
members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation.  Sites must be linked to 
at least one Imaging and Radiation Oncology Core (IROC) provider to participate on trials with 
an RTI component.  Enrolling sites are responsible for ensuring that the appropriate agreements 
and IRB approvals are in place with their RTI provider.  A primary role on any roster is required 
to update provider associations, though all individuals at a site may view provider associations. 
To find who holds primary roles at your site, please view the Person Roster Browser under the 
RUMS link on the CTSU website. 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston to 
verify credentialing status or to begin a new modality credentialing process. 
To complete protocol-specific credentialing the RTI provider or enrolling site should follow 
instructions in the protocol to submit documentation or other materials to the designated IROC 
Quality Assurance (QA) center.  Upon the IROC QA center approving the RTI provider for the 
study modality, IROC will automatically send the approval to the Regulatory Support System 
(RSS) to comply the protocol specific requirement.  IROC will continue to copy the provider 
and/or enrolling site on modality approvals. 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments.  The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen, and may need to answer additional questions related to treatment in 
the eligibility checklist. 
 

 
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8.2.2 
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 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select NRG, and protocol 
number NRG-GI002; 
• 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.). 
8.2.3 
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. 
8.2.4 
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 given 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 
RT Credentialing Requirements 
For detailed information on the specific technology requirement required for this trial, please 
refer to the table below and utilize the web link provided for detailed instructions. The check 
marks under the treatment modality columns indicate whether that specific credentialing 
requirement is required for this study. Credentialing is not required for 3DCRT.  For IMRT, 
IROC Houston will notify the institution when all credentialing requirements have been met and 
the institution is RT credentialed to enter patients onto this study. 
 

 
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TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will need to install 
the TRIAD application on their workstation.  TRIAD installation documentation is 
available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password and RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
8.4 
Patient Enrollment 
The Oncology Patient Enrollment Network (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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8.4.1 
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-GI002 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 
Study Withdrawal 
8.5.1 
Investigator-initiated discontinuation of study therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study therapy 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 study therapy or other treatments for rectal cancer becomes 
available. 
If study therapy is stopped, study data and other materials should be submitted according to the 
study schedule unless the patient withdraws from the study (see Section 8.5.3). 
8.5.2 
Patient-initiated discontinuation of study therapy 
Even after a patient agrees to take part in this study, he or she may stop study therapy or withdraw 
from the study at any time.  If study therapy 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. 
8.5.3 
Patient-initiated 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), the investigator must provide NRG 
Oncology SDMC with written documentation of the patient’s decision to fully withdraw from the 
study. 
 

 
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9.0 
DRUG INFORMATION 
9.1 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by the responsible investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied investigational agents for 
the study should be ordered under the name of one lead investigator at that institution. 
Patients must be enrolled and randomized to veliparib (Arm 2) or MK-3475 (pembrolizumab) 
(Arm 3) prior to submitting the agent request to PMB. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, dispensing and final disposition of all agents 
received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and ordering 
investigator on this protocol. 
9.1.1 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status and a “current” password.  
Questions about IB access may be directed to the PMB IB Coordinator via email. 
9.2 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm 
Refer to the Policy and Guidelines for Investigational Agent Ordering for order processing time 
and conditions.  Normal order processing time is two business days.  An express courier account 
number must be provided for next-day delivery. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx 

 
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• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/index.jsp 
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov 
• 
PMB IB Coordinator: IBCoordinator@mail.nih.gov 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) 
9.3 
Commercial Agents 
The commercial study agents are 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine. 
9.3.1 
Availability/Supply 
5-fluorouracil (NSC #19893), leucovorin (NSC #3590), oxaliplatin (NSC #266046), and 
capecitabine (NSC #712807) will not be provided and must be obtained by the investigator from 
commercial supply.  Please see Section 5.1 (Table 4), Section 5.2 (Table 5), and Section 5.3 
(Table 6) 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. 
9.3.2 
Adverse Events 
For adverse events and potential risks associated with 5-fluorouracil, leucovorin, oxaliplatin, and 
capecitabine, please refer to Section 7.3.1, to the current FDA-approved package insert provided 
with each drug, and to the site-specific pharmacy. 
9.4 
CTEP IND Agents 
The CTEP IND (investigational) agents are veliparib for patients randomized to Arm 2 and MK-
3475 (pembrolizumab) for patients randomized to Arm 3.  There are no investigational study 
agents in Arm 1. 
9.4.1 
Veliparib Capsule (NSC 737664) 
Chemical Name: 1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl 
Other Names: ABT-888, A-861695.0 
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
CAS Registry Number: 912444-00-9 
Molecular Formula: 
C13H16N4O 
 
M.W.:244.29 
Approximate Solubility: Veliparib is freely soluble at pH < 6.9, soluble at pH 6.9 to 7.1, and 
slightly soluble at pH > 7.1. 
Mode of Action: Veliparib inhibits the formation of poly (ADP-ribose) (PAR) polymers in vitro 
and in vivo.  It inhibits the repair of DNA when the DNA is damaged by cytotoxic agents.  
Veliparib increases antitumor efficacy when added to DNA-damaging therapies such as 
temozolomide, cisplatin, carboplatin, cyclophosphamide, irinotecan, or radiation therapy. 
Description: White to light yellow solid. 
How Supplied: AbbVie supplies and Division of Cancer Treatment and Diagnosis (DCTD) 
distributes veliparib.  Veliparib capsules are available in 100 mg immediate release capsules.  The 

 
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inactive ingredients are microcrystaline cellulose, colloidal silicon dioxide, magnesium stearate, 
gelatin, sodium lauryl sulfate, and titanium dioxide.  It may contain FD&C blue#1, FD&C yellow 
#6, or FD&C yellow #5.  The capsules are packaged in HDPE bottles, and each HDPE bottle 
contains 64 capsules. 
Veliparib capsules may be repackaged from the supplied HDPE bottles into amber (or other low-
actinic) child resistant pharmacy dispensing bottles.  Expiration will be 30 days from the 
repackaging date (or the original retest date, whichever is earlier) when stored at 15°C to 25°C 
(59°F to 77°F). 
Storage: Store the original bottle at 15° to 25° C (59° to 77° F).  If a storage temperature 
excursion is identified, promptly return veliparib to 15° and 25° C and quarantine the 
supplies.  Provide a detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
Stability: Shelf-life stability studies for veliparib capsules are on-going. 
Route(s) of Administration: Oral 
Method of Administration: Administer veliparib orally without regards to meals. 
Potential Drug Interactions (DDIs): Nonclinical studies suggest ABT-888 is a substrate of  
P-gp, OCT2, and MATE1/MATE2K transporters.  Co-administration of ABT-888 with strong 
inhibitors of P-gp, OCT2, and MATE1/MATE2K drugs may result in a decrease of ABT-888 
renal clearance and an increase in ABT-888 plasma concentration. Therefore, use caution when 
administering ABT-888 with strong inhibitors of P-gp, OCT2, and MATE1/MATE2K drugs.  At 
high dose (e.g., 400 mg BID), ABT-888 may inhibit OCT1 in the liver and MATE1/MATE2K in 
the kidney. 
Veliparib is not a potent inhibitor of the major human CYPs and does not significantly induce 
activities of major human CYP isoforms, suggesting a negligible potential for CYP-mediated 
drug-drug interactions as a perpetrator at the anticipated therapeutic concentrations. 
In patients, ABT-888 clears primarily in the urine as intact parent drug along with metabolites 
suggesting that renal function plays an important role in the drug clearance and its metabolites. 
Drug-associated with kidney toxicities or kidney diseases could change ABT-888 
pharmacokinetics.  Use caution when administering concomitantly with oxaliplatin, carboplatin, 
cisplatin, and topotecan in patients with pre-existing renal impairment.” 
Patient Care Implications: Patients may feel fatigue or tiredness. Loss of appetite and losing 
weight are common.  Provide appropriate supportive care for diarrhea.  Avoid long-sun exposure 
as it might exacerbate skin rash. 
 

 
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9.4.2 
 MK-3475 (pembrolizumab) (NSC #776864) 
• 
Other Names: Pembrolizumab, SCH 900475, KEYTRUDA® 
• 
Classification: Anti-PD-1 MAb 
• 
Molecular weight: 148.9-149.5 KDa 
• 
CAS registry number: 1374853-91-4 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor expressed 
by T cells.  When bound to either of its ligands, PD-L1 or PD-L2, activated PD-1 negatively 
regulates T-cell activation and effector function.  The pathway may be engaged by tumor cells to 
suppress immune control.  MK-3475 (pembrolizumab) blocks the negative immune regulatory 
signaling by binding to the PD-1 receptor, inhibiting the interaction between PD-1 and its ligands. 
Description: MK-3475 (pembrolizumab) is a humanized MAb of the IgG4/kappa isotype. 
How Supplied: MK-3475 (pembrolizumab) is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 100 mg vials containing a 
sterile, non-pyrogenic, clear to opalescent aqueous solution (25 mg/mL).  Proteinaceous particles 
may be present.  MK-3475 (pembrolizumab) solution for infusion is formulated in 10mM 
histidine buffer, pH 5.2-5.8, containing 7% sucrose and 0.02% polysorbate 80, supplied in Type I 
glass vials with a cap color of red, salmon, or blue. 
Preparation: MK-3475 (pembrolizumab) solution for infusion must be diluted prior to 
administration.  Allow the required number of vials to equilibrate to room temperature.  Do not shake 
the vials.  Do not use if opaque or extraneous particulate matter other than translucent to white 
proteinaceous particles is observed.  Do not use if discolored.  To prepare the infusion solution add 
the dose volume of MK-3475 (pembrolizumab) to an infusion bag containing 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP.  Gently invert the bag 10-15 times to 
mix the solution.  The final concentration must be between 1 mg/mL to 10 mg/mL. 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, or PE 
lined polyolefin 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from light by 
storing in the original box. 
If a storage temperature excursion is identified, promptly return MK-3475 (pembrolizumab) to 
between 2-8°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Stability testing of the intact vials is on-going. 
Administer prepared solutions immediately after preparation.  If not administered immediately, 
prepared solutions may be stored refrigerated for up to 20 hours.  MK-3475 (pembrolizumab) solutions 
may be stored at room temperature for a cumulative time of up to 4 hours.  This includes room 
temperature storage of liquid drug product solution in vials, room temperature storage of infusion 
solution in the IV bag, and the duration of infusion. 
Route of Administration: IV infusion only.  Do not administer as an IV push or bolus injection. 

 
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Method of Administration: Infuse over approximately 30 minutes (range: 25 - 40 minutes) using an 
infusion set containing a low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone or 
polysulfone.  Infusion rate should not exceed 6.7 mL/min.  A central line is not required; however, 
if a subject has a central venous catheter in place, it is recommended that it be used for the infusion.  
Do not co-administer other drugs through the same infusion line.  Following the infusion, flush the IV 
line with normal saline. 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-(2-
ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
Patient Care Implications: Refer to the protocol for information on evaluation and management 
of potential immune-related adverse events. 
Availability: MK-3475 (pembrolizumab) is an investigational agent supplied to investigators by 
the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
MK-3475 (pembrolizumab) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 16.0 ) 
 

 
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10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
10.1 
Specimen Submissions 
All patients will be asked to consent to the optional biobanking of biologic samples for future 
research.  For patients who agree, sample collection is a protocol requirement.  Patient samples 
for all patients will be collected at the specified timepoints outlined in Table 20A.  Please note 
that the additional optional collections for patients treated at designated TNT Plus sites  
(see Table 20B) are no longer to be collected after November 30, 2019. 
Tables 20A and 20B. Summary of patient sample submissions 
Table 20A: Sample Submissions for ALL PATIENTS 
Sample 
submissions: 
Baseline 
During and post 
mFOLFOX6 
During 
chemoradiation 
(chemoRT) 
Before or at the 
time of surgery 
Post 
surgery 
Archived 
primary tumor 
tissue (FFPE) 
Xa 
From diagnostic 
biopsy; must be 
submitted within  
60 days after study 
entry. 
 
 
Xb 
At surgery 
From surgical 
resection; must 
be submitted 
within 60 days 
after surgery. 
(See 
footnote d) 
Whole bloodc 
X 
After 
randomization; 
before 
mFOLFOX6 
begins 
X 
 Within 3 days 
before mFOLFOX6 
administration for 
Cycle 5 AND 
within 3 days 
before starting 
chemoRT 
 
 
 
X 
Within 14 days 
before surgery 
X 
At 6 month 
visit, in 
alignment 
with repeat 
imaging 
Table 20B: Sample Submission for TNT PLUS SITE PATIENTS ONLY (As of November 30, 2019, 
no additional blood or tissue specimens should be obtained.) 
In addition to the sample submissions for "All patients," the following tissue and blood samples are to 
be submitted for patients who are treated at designated TNT Plus Sites and agree to these optional 
collections: 
Sample 
submissions: 
Baseline 
During and post 
mFOLFOX6 
During 
chemoradiation 
(chemoRT) 
Before or at the 
time of surgery 
Post 
surgery 
Fresh tissue 
 
X 
 
X 
 Within 3 days 
before starting 
chemoRT  
 
X 
At surgery 
 
 
Blood samples 
X 
After 
randomization; 
before 
mFOLFOX6 
begins 
X 
Within 3 days 
before mFOLFOX6 
administration for 
Cycle 5 AND 
within 3 days 
before starting 
chemoRT 
X 
Week 3 
AND 
Week 5 only 
(Arms 1 and 2) 
or 
Week 6 
(Arm 3) 
X 
Within 14 days 
before surgery 
X 
30 days 
AND  
6 months 
after 
surgery 
Table continued on next page 
 

 
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Tables 20A and 20B.  Summary of patient sample submissions (continued) 
a Submit an archived paraffin block (FFPE) of at least two (2) core biopsy specimens of primary 
untreated tumor tissue from the diagnostic biopsy. 
b Submit an archived paraffin block (FFPE) of surgically resected primary tumor tissue (or residual 
scar in the setting of pCR). 
c Collect three tubes of blood: one (1) 10 mL red/grey top serum separator tube and one (1) 10 mL 
purple top tube (EDTA), and one (1) 10 ml Streck tube at each of these time points during a routine 
phlebotomy procedure for other standard labs. 
d In the event of disease progression/recurrence or diagnosis of a second primary cancer or secondary 
malignancy, study therapy will be discontinued; however, for patients who agree to the optional 
biobanking portion of this study, available cancer specimens (FFPE) will be collected through Year 3 
from randomization. 
Note: Refer to the NRG-GI002 Pathology and Correlative Science Instructions for tumor and blood 
sample collection, alternative sample submission, processing, and submission instructions. 
10.2 
Use of specimens 
10.2.1 All patients 
Any plan to analyze biomarkers collected from patient biospecimens in this protocol, including 
FFPE and blood samples from patients treated at TNT Plus sites (see Tables 20A and 20B) will 
be submitted for approval by the NCI CCSC after study closure and before analysis of samples. 
In general, the correlative analyses will leverage the annotated clinical data and companion 
radiographic images (supported through BISQPF 5U10CA180868-03; PI: Wolmark) and 
assessment of predictors or surrogates of response and resistance.  Proposed correlative studies 
include the association of matched pair tumor samples (baseline and surgical) to identify 
predictive markers of sensitivity to treatment or potential markers of resistance.  Tissue-based 
assessments will also be characterized and correlated with bioimaging findings such that 
radiographic surrogacy for treatment response or resistance may be identified.  At a minimum, 
assays to characterize the molecular profile of tumor tissues through NGS and other 
comprehensive DNA and RNA platforms will be conducted.  Additionally, assessment of the 
immunogenic state of the patient, molecular determinants or evidence of DNA repair deficiency, 
circulating cell free DNA and circulating tumor cell kinetics, dynamics and correlation with 
treatment response (all arms) are proposed via exploratory post-hoc, but pre-planned analyses. 
• 
To establish a circulating and tumor-based biomarker program for exploratory secondary 
analyses related to predicting response across and specific-to novel therapeutic agents. 
Owing to the serial nature of blood and tissue collection and analyses, the TNT platform 
allows for robust assessment of in-vivo response and biomarker predictors to chemotherapy 
and chemoradiotherapy response.  This can be analyzed both in generic treatment terms as 
well as for specific modalities (e.g., radiotherapy) and specific novel therapeutic 
interventions. 
Blood will be collected in appropriate tubes for the assessment of serum, plasma, and buffy 
coat and will be used for sequencing, cytokine, and biomarker assessment.  Blood collection 
and processing time points will facilitate assessment of baseline, post-treatment and recovery 
changes in these variables in response to treatment interventions and biologic response 
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Exploratory biomarkers of treatment effect: Relevant to blood collected during chemoRT, 
DNA Damage Repair proteins, peripheral blood γ-H2AX assay and apoptotic assessments are 
planned.  While there are very few clinical biomarkers available that currently predict 
response to the agent being actively studied, tumor homologous recombination deficiency 
(HRD) assessment for patients in the veliparib arm is planned.  These biomarkers will be 
processed and analyzed after study completion in a post-hoc batch manner. 
• 
To determine if genomic signatures can predict local response to chemotherapy and 
chemoradiotherapy in high-risk rectal adenocarcinoma.  This specifically is proposed to 
include, but may not be limited to, the Radiosensitivity Index (RSI; Cvergenx, Inc.). 
The NCI has recently created the Clinical Assay Development Program (CADP) to foster the 
commercial development of promising molecular diagnostics that will advance personalized 
medicine.  The Radiosensitivity Index (RSI), a clinically-validated molecular signature of 
rectal tumor intrinsic radiosensitivity, has been recently selected by NCI for commercial 
development through this program.  In this commercial partnership, the NCI will lead efforts 
to develop a commercial-grade FDA ready analytically-validated diagnostic platform for RSI.  
The efforts will focus on developing an FFPE/RT-PCR-based diagnostic platform in rectal 
cancer.  We anticipate that this project will be complete prior to the initiation of this analysis. 
Once the CADP assay is complete, we believe the next step in development is testing the 
commercial platform for RSI in a multi-institutional collaborative study.  Previously obtained 
FFPE specimens from NSABP R-03 and potentially R-04 are being similarly tested to refine 
the RSI signature in the rectal cancer patient population.  Using baseline specimens obtained 
in this protocol, the central hypothesis of this correlative subproject is that RSI can be utilized 
to identify patients with high (high prevalence of complete pathological responders), 
intermediate (high prevalence of partial pathological responders) and low (low prevalence of 
any pathological response) likelihood of therapeutic response to preoperative chemoradiation.  
The development of an accurate approach to identify these three populations would have 
significant impact on clinical management of patients with rectal cancer.  For example, 
patients that are deemed to have a high probability of complete pathological response might 
be candidates for non-surgical management.  Patients with intermediate and low probability 
of response might be excellent candidates for studies testing novel therapies or local 
treatment intensification.  Therefore, demonstrating the clinical utility of RSI within a 
prospective multi-institutional study is of significant clinical importance. 
We intend to categorize patients as high, intermediate, or low likelihood of response based on 
the RSI score from FFPE tissue using cutoffs that result from the CADP process. 
The TNT platform will support the continued development of tumor-based predictive 
signatures that may be capable of identifying non-response to standard therapy and serve as 
an integral biomarker in the future for targeting patients with novel therapies who are at 
exceptionally high risk for recurrence. 
• 
To determine the effect of FOLFOX and CRT with or without the combination with PD-1 
blockade on the density of TILs and T-cell subpopulations in the tumor microenvironment. 
• 
To identify different immune cell populations (effector/memory/ CD8 cells and T regulatory 
cells) Multiplex ImmunoFluorescence (IF) staining or other relevant technologies may be 
performed on FFPE tumor slices using the following panels and antibodies: Panel 1 
(Cytokeratin (tumor marker), CD4, CD8, CD45RO+cells, FoxP3 and DAP). Panel 2 
(Cytokeratin, CD4, CD8, Granzyme B (activation marker) and Ki67 (proliferation marker) 
and DAPI. Cytotoxic (CD8), memory (CD45RO), and T-regulatory (FOXP3) T cells will be 

 
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quantified from the center (CT) and the invasive margin (IM). All Multiplex IF stained slides 
will be scanned by an automated scanning microscope (Vectra 3, PerkinElmer Inc.) and 
tumor areas will be marked by a pathologist to exclude non-neoplastic areas, such as stroma, 
normal epithelial and necrotic regions.  Image Analysis will be performed with Inform2.1 
image analysis software (PerkinElmer, Inc.) and scoring will be confirmed manually by a 
pathologist. Immune score will be calculated the center (CT) and the invasive margin (IM) as 
described before (Pages 2009; Galon 2006).  The ratio of effector CD4 and CD8 T-cells/T-
regs will be also analyzed. 
• 
To determine the effect of FOLFOX and CRT with or without the combination with PD-1 
blockade on PD-L1 and other immune checkpoints expression and whether the combination 
of CRT and MK-3475 (pembrolizumab) can overcome immune editing. 
Multiplex IF using the following Panel (Cytokeratin, PD-L1, TIM3, LAG3 and DAPI) or 
other relevant technologies may be performed on all samples.  All Multiplex IF stained slides 
will be scanned by an automated scanning microscope (Vectra 3, PerkinElmer Inc.) and 
tumor areas will be marked by a pathologist to exclude non-neoplastic areas, such as stroma, 
normal epithelial and necrotic regions. Image Analysis will be performed with Inform2.1 
image analysis software (PerkinElmer, Inc.).  The Image Analysis software will be used to 
quantify and assess the percentage of Cytokeratin+ tumor cells that co-express PD-L1, TIM3, 
or LAG3. Protocols of these antibodies have been optimized, standardized to minimize 
staining variance (Chen 2013.  Tumor will be considered positive if >5% (CD274 or PD-L1).  
Data will be compared with that of manual counting by a pathologist to exclude tissue 
artifacts that cannot be recognized by computer image software. 
• 
To determine the effect of chemotherapy (FOLFOX) and CRT with or without the 
combination with PD-1 blockade on T-cell repertoire in the periphery and correlate these 
finding with the effect in the tumor microenvironment. 
Peripheral blood mononuclear cells (PBMCs) will be collected from whole blood to assess 
immune cell populations. Surface staining with a panel of antibodies (CD3, CD4, CD8, 
CD19, CD25, FoxP3, CD11c, CD83, CD86, CD56) and intracytoplasmatic cytokine staining, 
followed by flow cytometry will be performed in order to identify different T cell 
populations, their activation status, myeloid-derived suppressor cells (CD11b, CD14, CD19, 
CD33, HLA-DR) and the production of different cytokines as well as other immune cell 
population.  Absolute lymphocyte count (ALC) will be monitored.  We will specifically 
analyze changes as a function of treatments for CCR7+/-/CD45RO+ cell populations for both 
the CD4+ and CD8+ compartments.  The following immune cell populations will be detected 
in PBMCs using specific marker antibodies and flow cytometry gating strategies: Regulatory 
T cells (CD4+/CD25+/FoxP3+), Effector T cells (CD4+/CD69+), Naïve T cells 
(CD4+/CD69-), Memory T cells (CCR7+/CD45RO+), CD8 Cytotoxic cells (CD8+/CD3+), 
Plasmocytoid Dendritic cells (CD123+/CD303+), Myeloid Dendritic cells 
(CD11c+/CD141+), Natural Killer cells (CD3-/CD56+), Natural Killer T cells 
(a/bTCR+/NKG2D+), Classic Monocytes (CD14+), and Monocytic Myeloid-Derived 
Suppressor cells (CD14+/HLADR-).  A panel of cytokines and chemokines may be tested in 
serum using Luminex cytokine assay or other relevant technology.  Changes in cytokine 
production in immune cell subsets as a function of treatment will be determined by ELISA 
and intracellular cytokine staining.  Plasma from heparin treated blood will be collected, 
aliquoted and stored at -80C.  Via Cytokine/Chemokine Multiplex assays, concentration 
levels will be assessed for up to 50 biomarkers including (but not limited to) the following 
inflammatory mediators: IL-6, IFNg, TNFa, IL-10, IP-10, IL-1b, CXCL16, VEGF, and Ang1. 

 
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The assays will be performed following manufacturer Standard Operating Procedures for 
each biomarker group panel. 
10.2.2 TNT-Plus patients 
Objectives: 
• 
To establish feasibility in obtaining serial blood and tumor specimens from patients with 
colorectal cancer across a multi-site NCTN study. 
In conjunction with the NRG Oncology/NCI U10 Translational Science Center, we aim to 
establish a scalable and systematic program to collect, process, analyze and store serial 
biospecimens collected as part of colorectal cancer clinical trials conducted through NRG 
Oncology.  These specimens will be procured through standard operating procedures, 
processed in a consistent manner and annotated with clinical data.  Centralized quality control 
checks and operational adjustments will be undertaken to optimize the workflow and 
translational science capacity of the specimens collected.  Best practices and procedures from 
other disease sites participating in the NRG Oncology U10 TSC will be incorporated, but 
with specific modifications relevant to colorectal cancer tissue collection.  Specific high-
volume sites with capacity to conduct these types of required processes will be identified as 
“TNT Plus” sites and will serve as the core participants for completing this translational 
objective. 
In addition to demonstrating multisite feasibility for such comprehensive specimen collection 
as part of an NCTN protocol, the scientific end result of this process will include the capacity 
to develop patient-derived xenografts and/or cell lines, as well as an integrated colorectal 
cancer multiplex genome and protein kinome assay.  Evaluation of DNA, RNA, and protein 
markers will be assessed with appropriate technologies.  This may necessitate the isolation of 
DNA, RNA, and protein from these tumor specimens.  Alternatively, it may be possible to 
evaluate DNA and RNA utilizing tumor lysates.  Currently, HTG Molecular Diagnostics and 
Nanostring are able to assess RNA levels utilizing tissue lysates.  HTG Molecular plans to 
launch a test for DNA analysis with their technology.  These specimens will undergo DNA 
and protein analysis with possible analysis in the future of the transcriptome and the immune 
microenvironment.  Through subsequent studies, we plan to assess serial tissue and cell-free 
circulating tumor mutational and proteomic expression changes associated with treatment, 
recovery and clinical outcomes. 
10.3 
Specimen submissions 
All sites − refer to the NRG-GI002 Pathology and Correlative Science Instructions for 
complete tumor and blood sample collection and submission procedures for all patients. 

 
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11.0 
MODALITY REVIEWS 
The Radiation Therapy Co-Chair will perform an RT Quality Assurance Review after 
IROC-Philadelphia has received complete data.  These reviews will be completed 
remotely and will be ongoing.  The final cases will be reviewed within 6 months after this 
study has reached the target accrual or as soon as IROC-Philadelphia RT has received 
complete data for all cases enrolled, whichever occurs first.  The scoring mechanism is: 
Per Protocol; Acceptable Variation; and Unacceptable Deviation. 
 

 
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12.0 
ASSESSMENT OF EFFECT 
12.1 
Clinical complete response (cCR) 
12.1.1 Timing of assessments 
For the purposes of this study, patients must have a formal perioperative assessment documenting 
clinical response of the primary rectal tumor via digital rectal exam (DRE) and proctoscopic or 
sigmoidoscopic exam. DRE and proctoscopic or sigmoidoscopic exam may be done immediately 
before surgery. 
12.1.2 Definition of cCR 
No visible or palpable rectal tumor on direct examination.  Nodes are not included in this 
definition. 
12.2 
Pathologic complete response (pCR) 
12.2.1 Timing of assessments 
Presence or absence of pCR will be determined following gross and microscopic examination of 
tissue removed at the time of surgery according to methods outlined in Section 12.2.2. 
12.2.2 Definition of pCR 
No histologic evidence of invasive tumor cells in the surgical specimen at the site of the primary 
tumor and associated regional lymph nodes. 
Accurate and uniform assessment of radial margins and pCR is critical for optimal evaluation of 
GI002 endpoints.  Forms must be completed accurately (preferably by the pathologist) and 
submitted with the surgical pathology report.  Specimen processing and pathology examination 
should follow the Protocol for the Examination of Specimens from Patients with Primary Cancer 
of the Colon and Rectum (Washington 2009).  Pathologic tumor (T) and nodal (N) stage along 
with proximal, distal, and circumferential margin status must be assessed as recommended by 
CAP in the "Explanatory Notes" section of the CAP protocol. 
12.3 
Central review  
While central review of tumor tissue is not required at this time, pathology specimens should be 
easily accessible should central review be required in the future.  Submission of MRI imaging 
collected as part of staging or treatment monitoring is required (see Section 8.3.2). 

 
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13.0 
DOCUMENTATION OF RECTAL CANCER PROGRESSION/RECURRENCE AND 
OTHER CANCER EVENTS   
The diagnosis of a rectal cancer progression (before surgery) or recurrence (after surgery) should 
be made only when the clinical and laboratory findings meet the criteria of “acceptable” as 
defined below.  Any progression/recurrence of malignant disease should be proven by biopsy 
whenever possible. 
At the time of rectal cancer progression/recurrence, the investigator should indicate the site of 
tumor progression/recurrence and whether multiple sites are involved. 
Supporting documentation must be submitted with the GI002 Follow-up folder in Medidata Rave 
following diagnosis of rectal cancer progression/recurrence or invasive second cancer.  The 
documentation will be reviewed at the NRG Oncology SDMC to determine the method(s) used to 
document the progression/recurrence, the anastomotic location(s) of the progression/recurrence, 
and the type of second cancer. 
13.1 
Abdominal and/or pelvic sites 
13.1.1 Anastomotic 
 
Acceptable: positive cytology or biopsy 
13.1.2 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. 
13.1.3 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. 
13.1.4 Ascites 
 
Acceptable: positive cytology 
13.1.5 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). 

 
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Note: An elevated CEA level will, as a solitary finding, not be considered acceptable 
evidence of rectal cancer progression/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 rectal cancer progression/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 scan, PET scan, or CEA scan; and/or celiac and mesenteric 
arteriography.  Documentation of corroborative evidence by biopsy is strongly recommended. 
13.1.6 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. 
13.1.7 
Abdominal wall, perineum, and scar 
Acceptable: positive cytology or biopsy 
13.2 
Nonabdominal and nonpelvic sites 
13.2.1 Skeletal 
Acceptable: 
For all suspected bone-only recurrences/progression, a biopsy is required to 
demonstrate progression/recurrence. 
13.2.2 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. 
13.2.3 Bone marrow 
Acceptable: positive cytology, aspirate, biopsy, or MRI scan 
13.2.4 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). 
13.3 
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. 
 

 
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13.4 
Second primary cancer 
Second primary cancer is defined any invasive non-rectal 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. 
13.5 
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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14.0 
DATA AND RECORDS 
14.1 
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. 
o 
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a minimum of an 
AP registration type; 
o 
To hold Rave Investigator role, the individual must be registered as an NPIVR or IVR; 
and 
o 
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 
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 

 
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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. 
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. 
14.2 
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. 
See Section 8.3 for TRIAD account access and installation instructions. 
14.3 
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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15.0 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design 
This is a prospective randomized phase II open label (not blinded) trial.  Patients will be 
randomized with equal allocation (1:1:1) among each of the trial arms.  The primary analysis will 
compare each experimental arm to the concurrently randomized control arm patients. 
Patients will be allocated to treatments by a permuted block randomization algorithm with 
varying block size.  Stratification factors include clinical tumor stage (T1 or T2; T3; T4) and 
clinical nodal stage (N0; N1; N2). 
15.2 
Primary Endpoint 
To demonstrate an absolute improvement in Neoadjuvant Rectal Cancer (NAR) score for the 
experimental regimen as compared to concurrently randomized control patients. 
15.3 
Secondary Endpoints 
15.3.1 To compare overall survival (OS) 
15.3.2 To compare disease-free survival (DFS, time to recurrence, second primary cancer or death) 
15.3.3 To compare the rate of pathologic complete response (nodes and tumor), ypT0 and ypN0 
15.3.4 To compare the rate of sphincter preservation 
15.4 
Tertiary Endpoints 
15.4.1 To compare the proportion of patients who have a tumor resection overall, conditional on 
beginning induction chemotherapy, and conditional on beginning chemoradiotherapy 
15.4.2 To compare time from initiation of chemoradiotherapy to surgery in the subset of patients with 
tumor resection 
15.5 
Exploratory Endpoints 
15.5.1 To estimate the rate of disease progression during chemotherapy (prior to chemoradiation) 
15.5.2 To compare the rate of clinical complete response rate (cCR), ycT0 
15.5.3 To compare the rate of negative circumferential margin 
15.5.4 To compare the rate of completion of all cycles of neoadjuvant chemotherapy 
15.5.5 To compare the rate of completion of full course of chemoradiation 
15.5.6 To compare the toxicity and safety between interventions 
15.5.7 To explore the correlative molecular predictors of response and distant failure 
15.5.8 To explore the relationship between radiographic findings and pathologic outcomes 
15.6 
Primary Hypothesis 
The experimental arm will have reduced (improved prognosis) NAR score as compared to the 
control arm. 
15.6.1 Power Justification 
 
 
 
 

 
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• 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
15.6.2 Expected Sample Size and Accrual Estimates 
Eighty-seven (87) patients per arm are required for a study total between 320 and 348 patients, 
given that the study has already accrued 144 patients to Arms 1 and 2 (as of 20Dec2017).  The 
control arm will be temporally and numerically expanded to account for the addition of Arm 3 
(MK-3475 [pembrolizumab]).  The control arm will include an equal number of concurrently 
randomized patients to compare with the new experimental arm.  Thus, there could be anywhere 
from 59 to 87 additional control patients required depending on the temporal overlap in accrual of 
the two experimental arms. 
We anticipate no accrual during a four month start-up phase followed by 14 months of level 
accrual of 13 patients per month for an eighteen month duration of accrual for the first 
experimental arm (ABT-888 [veliparib]).  The addition of the third arm will result in a temporary 
suspension of accrual anticipated to last 1 month.  The definitive analysis comparing NAR scores 
for the experimental arms to the control arm should occur 2 to 2.5 years after initiation of each 
respective experimental arm. 

 
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15.7 
Statistical Analyses 
15.7.1 Analyses of Data on the Primary Endpoint 
The analysis set is all patients who begin chemoradiotherapy.  Patients will be analyzed according 
to their assigned treatment regardless of treatment actually received.  Each experimental arm will 
be compared to concurrently randomized patients from the control arm for the primary endpoint 
of NAR score in a linear regression model that controls for the stratification factors (cT-Stage and 
cN-Stage).  Mean NAR scores along with standard errors and confidence intervals will be 
reported by treatment. 
15.7.2 Analyses of Data on Secondary Efficacy Endpoints 
Many of the secondary endpoints will be available for reporting immediately following definitive 
surgery along with the primary endpoint.  We anticipate the primary manuscript of each 
experimental arm will include these endpoints.  Most of these endpoints are binary in nature and 
will be analyzed by a logistic regression model that controls for the stratification factors (cT-
Stage and cN-Stage).  Observed proportions along with confidence intervals will be presented by 
treatment. 
The time-to-event endpoints of DFS and OS will require additional follow-up beyond surgery and 
we expect these endpoints will be presented in a second manuscript approximately 3 years after 
the initial results.  These endpoints will be analyzed using the stratified log rank test with strata 
cT-Stage and cN-Stage.  Kaplan-Meier plots will illustrate the distribution of these endpoints by 
treatment.  Cox regression models will be used to estimate hazard ratios and associated 
confidence intervals.  Exploratory analyses of specimens collected will be conducted after review 
and approval by NCI CCSG. 
15.7.3 Analyses of Data on Tertiary Endpoints 
The proportions of patients overall (and conditional on beginning induction chemotherapy, and 
conditional on beginning CRT) will be analyzed by a logistic regression model that controls for 
the stratification factors (cT-Stage and cN-Stage).  Observed proportions along with confidence 
intervals will be presented by treatment. 
Time to surgery (TTS) from initiation of CRT will be analyzed using the stratified log rank test 
with strata cT-Stage and cN-Stage.  Kaplan-Meier plots will illustrate the distribution of TTS by 
treatment.  Cox regression models will be used to estimate hazard ratios and associated 
confidence intervals. 
15.8 
Study Monitoring 
15.8.1 Interim Monitoring of the Primary Objective 
There will be interim futility analyses for each experimental arm when (experimental arm and 
control) 80 patients are evaluable for NAR.  Observed NAR score in the experimental arm must 
be less than the score observed in the control arm (Wieand 1994); otherwise, the Data Monitoring 
Committee (DMC) will consider a recommendation to close the study early.  Since this is purely 
a futility analysis, no alpha is spent. 
15.8.2 Monitoring of Patient Accrual 
The NRG Oncology DMC will review the study twice a year with respect to patient accrual. 

 
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a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm).  Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 30 
days from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media presentations 
must also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 

 
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17.0 
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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 current 
CTCAE version (v4.0 until 3/31/18 or v5.0 beginning 4/1/18) grading criteria are based on ADL: 
• 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
• 
Self-care ADL refer 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.  Positive results from occult blood, fecal 
leukocyte stain, Clostridium difficile, Campylobacter, Salmonella, and Shigella testing, if 
performed, must be reported using the appropriate eCRF. 
− 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, and applesauce, and/or toast. 

 
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APPENDIX C 
 
CREATININE CLEARANCE CALCULATION (COCKROFT-GAULT FORMULA) 
Creatinine clearance must either be measured or estimated using the Cockroft-Gault formula, 
as follows: 
For Women 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) x 0.85 
72 x serum creatinine (mg/dL) 
or 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) x 0.85 
815 x serum creatinine (mmol/L) 
For Men 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) 
72 x serum creatinine (mg/dL) 
or 
Creatinine Clearance (mL/min)  =  (140 – age) x weight (kg) 
815 x serum creatinine (mmol/L) 
 

 
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APPENDIX D 
 
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 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 E:  PATIENT DIARY 
Group 2 Patient Diary (continued)                                                                                             Page 2 of 2 
Protocol: NRG-GI002/Group 2                                    Study Medication: Capecitabine and 
Veliparib  
Week #                  of Radiation Therapy (RT)                                                                                           
Day 
Date 
Time taken 
Number of 
veliparib 
capsules 
taken 
(morning) 
 
Number of 
veliparib 
capsules 
taken 
(evening) 
 
Notes 
Include any side effects 
that you are having 
(especially loose stools and 
any medications that you 
took for the side effects.  If 
you did not receive RT on 
a regularly scheduled day, 
record the reason here. 
Morning 
Evening 
100mg 
capsules 
100mg 
capsules 
Mon 
 
 
 
 
 
 
Tues 
 
 
 
 
 
 
Wed 
 
 
 
 
 
 
Thurs 
 
 
 
 
 
 
Fri 
 
 
 
 
 
 
Sat 
 
 
 
 
 
 
Sun 
 
 
 
 
 
 
 
 
Patient's name: ______________________________   Date: __________________________ 
 
Physician's office will complete this section: 
Total number of veliparib capsules taken this reporting period:  ___________ 
Total number of veliparib capsules returned this reporting period: ____________ 
 
Research Staff Signature/Date: ________________________________________ 
 

 
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APPENDIX F: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the patient at 
the time of enrollment.  Use or modify the text as appropriate for the study agent, so that the patient is 
aware of the risks and can communicate with their regular prescriber(s) and pharmacist.  A convenient 
wallet-sized information card is also included for the patient to clip out and retain at all times.  Please 
note that the information sheet and wallet card will require IRB approval before distribution to patients.] 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug ABT-888 (veliparib).  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient. 
These are the things that you as a prescriber need to know: 
ABT-888 (veliparib) interacts with certain transporter proteins that help move drugs in and out of cells. 
The proteins in question are OCT2, MATE1, MATE2K, and P-gp.  ABT-888 (veliparib) is a substrate of 
P-gp, OCT2, and MATE1/2K and may be affected by other drugs that inhibit these protein transporters. 
ABT-888 is an inhibitor of OATP1B1, OATP1B3, MATE1/2K, OAT1/3and OCT1 and may affect 
transport of other drugs in and out of cells. 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet. 
 
ABT-888 (veliparib) may interact with other drugs which can cause side effects.  For this reason, it is 
very important to tell your study doctors about any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study.  When you talk about your current 
medications with your doctors, include medicine you buy without a prescription (over-the-counter 
remedy), or herbal supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or 
an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical trial. 
These are the things that you and they need to know: 
Use caution when administeringABT-888 (veliparib) with other medicines that need certain transport 
protein to be effective or to be cleared from your system.  Before you enroll onto the clinical trial, 
your study doctor will work with your regular health care providers to review any medicines and herbal 
supplements that are considered “strong inducers/inhibitors" of P-gp, OCT2, and MATE1/2K. 
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference for a list 
of drugs to avoid or call your study doctor before prescribing any new medicine or discontinuing 
any medicine.  Your study doctor’s name is __________________________________ 
He or she can be contacted at ____________________. 
February 2016 

 
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STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental 
study drug ABT-888 (veliparib).  This clinical trial is 
sponsored by the NCI.   ABT-888 (veliparib) may 
interact with drugs that need certain transport proteins in 
your body.   
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines. 
➢ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or pharmacists) 
that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement. 
 
 
 
Use caution as ABT-888 (veliparib) may interact with 
medicines that stop transport proteins MATE1/2K, 
OCT2, and P-gp to process further in the body.  
➢ 
Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care 
providers to review any medicines and herbal 
supplements that are considered “strong 
inducers/inhibitors of P-gp, MATE1/2K, and 
OCT2.” 
➢ 
Before prescribing new medicines, your regular 
prescribers should go to a frequently updated 
medical reference for a list of drugs to avoid or 
contact your study doctor.  
➢ Your study doctor’s name is: 
 __________________________________  
 
Your study doctor can be contacted at: 
 ___________________________________