Conditions: Locally Advanced Rectal Carcinoma Rectal Adenocarcinoma Stage II Rectal Cancer AJCC v8 Stage III Rectal Cancer AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of ropidoxuridine and how well it works when added to the usual chemotherapy treatment (capecitabine) during radiation therapy for the treatment of patients with stage II-III rectal cancer. Ropidoxuridine may help radiation therapy work better by making cancer cells more sensitive to the radiation therapy. Chemotherapy drugs, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This study is being done to find out whether ropidoxuridine in addition to capecitabine and radiation therapy works better in treating patients with rectal cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of oral (PO) ropidoxuridine (IPdR) when administered with capecitabine (825 mg/m\^2 twice daily \[BID\]) and radiation therapy (RT) (50.4 Gy in 28 fractions).

II. To determine the toxicities Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 of the combined modality therapy, IPdR + capecitabine + RT.

SECONDARY OBJECTIVES:

I. To establish the pharmacokinetics (PK) of once daily (QD) IPdR when combined with capecitabine.

II. To evaluate iododeoxyuridine (IUdR) incorporation in circulating granulocytes and correlate these levels with IPdR plasma PK and clinical/laboratory toxicities.

III. To assess IUdR incorporation in tumor cells obtained from the surgical resection specimen and correlate IUdR incorporation in tumor cells with IPdR PK.

IV. To assess IUdR incorporation in tumor cells obtained from the surgical resection specimen and correlate IUdR incorporation in tumor cells with tumor response as measured by pathological complete response (pCR) rate and neoadjuvant rectal (NAR) score.

V. To determine the pCR rate of IPdR + capecitabine + RT at the IPdR MTD as a measure of anti-tumor activity.

VI. To determine the NAR score of IPdR + capecitabine + RT at the IPdR MTD.

EXPLORATORY OBJECTIVES:

I. To explore the relationship between extent of exposure to RT and the development and severity of adverse events.

II. To explore the drug/drug/metabolite interactions between capecitabine, IPdR, and their metabolites.

OUTLINE: This is a phase IA, dose-escalation study of ropidoxuridine followed by a phase IB study.

Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6 days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients undergo standard of care surgery.

After completion of study treatment, patients are followed up at 4 and 8-12 weeks following chemoradiation therapy.

Arms:
arm 1: Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6 days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients undergo standard of care surgery.

Interventions: intervention 1: Capecitabine intervention 2: Radiation Therapy intervention 3: Ropidoxuridine
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo radiation therapy intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
i 
To:  
CTEP Protocol and Information Office  
From:  
Timothy Kinsella, M.D. 
Date:  
June 2, 2022 
Re: 
Change of PI for Protocol #10410: “A Phase 1 Study of IPdR in Combination with 
Capecitabine and Radiotherapy in Rectal Cancer” 
 
I. Summary of Changes: 
# 
Section 
Comments 
1. Title 
page 
PI information has been updated. PI transfer information is below: 
 
Current PI: Dr. Timothy Kinsella, Lifespan (via North American Star Consortium) 
New PI: Dr. Charles Kunos, University of Kentucky (via Ohio State University 
Consortium) 
2. Title 
page 
Updated revision numbers and dates in the Protocol Type / Version # / Version 
Date section to match CTEP release dates: 
 
Amended: Revision 7 / January 24, 2022 
Inserted: Revision 8 / April 25, 2022 
 
   Revision 9 / June 2, 2022 
3. Title 
page 
Updated study coordinator and responsible research nurse from Patrick Marban to 
Jeri Reynolds, and responsible data manager staff from Patrick Marban to Charles 
Kunos. 
4. Title 
page 
Updated Coordinating Center information from LAO-11030 / University Health 
Network Princess Margaret Cancer Centre LAO to LAO-OH007 / Ohio State 
University Comprehensive Cancer Center LAO 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
1 
NCI Protocol #: 
10410 
 
Local Protocol #: 
TBD 
 
ClinicalTrials.gov Identifier: NCT04406857 
 
TITLE:  A Phase 1 Study of IPdR in Combination with Capecitabine and Radiotherapy in 
Rectal Cancer 
 
Coordinating Center: 
LAO-OH007 / Ohio State University Comprehensive 
Cancer Center LAO  
 
 
Principal Investigator: 
Charles Kunos, MD, PhD 
 
Department of Radiation Medicine 
 
Markey Cancer Center, University of Kentucky  
800 Rose Street, PAV H C111 
Lexington, KY  40536 
Phone: 859-562-0210 
Fax: 859-257-4060 
Email: charles.kunos@uky.edu  
 
Translational PI: 
Jerry M. Collins, Ph.D. 
Developmental Therapeutics Program 
Division of Cancer Treatment and Diagnosis 
9609 Medical Center Drive, Rm 4W632, MSC 9735 
Bethesda, MD, 20892-9735 USA 
Phone: 240-276-5949 
Email: collinsje@mail.nih.gov  
 
Co-Investigator: 
Howard Safran, M.D. 
Department of Medicine 
Rhode Island Hospital 
110 Lockwood Street 
Providence, RI 02903 
Phone: 401-793-2920 
Email: hsafran@lifespan.org 
 
Statistician: 
Adam Olszewski, M.D. 
593 Eddy Street 
Providence RI, 02903 USA 
Phone:  401-429-3151 
Fax:  401-444-8441 
Email: aolszewski@lifespan.org  
 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
2 
 
Study Coordinator: 
 
Responsible Research Nurse: 
Jeri Reynolds, RN, BSN, CCRC 
Jeri Reynolds, RN, BSN, CCRC 
Study Coordinator/Research Nurse  
Study Coordinator/Research Nurse 
University of Kentucky  
University of Kentucky  
Healthy Kentucky Research Building  
Healthy Kentucky Research Building  
760 Press Avenue, Room 541  
760 Press Avenue, Room 541  
Lexington, KY  40536  
Lexington, KY  40536 
 
Email: jzreyn0@uky.edu  
Email: jzreyn0@uky.edu 
Phone: 859-218-0131 
Phone: 859-218-0131 
Fax: 859-257-0100 
Fax: 859-257-0100 
 
 
Responsible Data Manager:  
Charles Kunos, MD 
Principal Investigator/Data Manager 
Markey Cancer Center  
University of Kentucky Medical Center 
800 Rose Street, PAV H C111  
Lexington, KY 40536 
 
Email: charles.kunos@uky.edu 
Phone: 859-562-0210 
Fax: 859-257-4060 
 
 
 
Participating Organizations:   
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
NCI-Supplied Agent:  5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) (NSC726188) 
Commercial Agent:  Capecitabine (Xeloda) (NSC712807) 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
3 
 
IND #:   
IND Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
Original / February 26, 2020 
 
 
 
 
Revision 1 / April 14, 2020 
 
 
 
 
Revision 2 / April 27, 2020 
 
 
 
 
Revision 3 / May 11, 2020 
 
 
 
 
Revision 4a / June 12, 2020 
 
 
 
 
Revision 5 / July 7, 2020 
 
 
 
 
Revision 6a / July 13, 2020 
 
 
 
 
Revision 6 / July 30, 2020 
 
 
 
 
Revision 7 / January 24, 2022 
 
 
 
 
Revision 8 / April 25, 2022 
 
 
 
 
Revision 9 / June 2, 2022 
 
 
 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
4 
SCHEMA 
 
This is a phase 1 dose escalation study of 5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) in 
combination with capecitabine and radiation therapy (RT) that consists of two parts, Part IA and 
Part IB.  
 
Part IA: 
Part IA uses an accelerated titration design with a single patient cohort, and a 100% dose 
escalation between patient cohorts until a treatment-related Grade 2 non-hematologic toxicity or 
grade 3 neutropenia or thrombocytopenia is observed.  The accelerated titration design may 
reduce the number of patients potentially undertreated by receiving oral (PO) IPdR doses that are 
not expected to result in clinically relevant radiosensitization.  
 
Part IA dose escalation schema 
Dose Level 
Total radiation Gy (45 
Gy primary field, 5.4 
Gy boost @1.8 
Gy/fraction/day) 
Capecitabine (mg/m2 
BID)  
Monday am – Friday 
pm throughout RT 
IPdR (mg BID) 
Administered 
throughout radiation 
1A 
50.4 
825 mg/m2 BID 
75 mg 
BID 
2A 
50.4 
825 mg/m2 BID 
150 mg BID 
3A 
50.4 
825 mg/m2 BID 
300 mg BID 
4A 
50.4 
825 mg/m2 BID 
600 mg BID 
5A 
50.4 
825 mg/m2 BID 
1,200 mg BID 
BID – Twice Daily, RT – Radiation therapy 
 
Part IA is closed to further accrual. 
 
Part IB: 
Part IB will commence when toxicity is encountered in Part IA.  Cohorts of 3-6 patients will be 
entered per dose level until dose-limiting toxicity (DLT) is reached, and the maximum tolerated 
dose (MTD) is defined.  An IPdR dose of 2,400 mg QD is the maximum allowed dose. Dose 
escalation between dose levels will be adjusted to accommodate the availability of 75mg and 
600mg IPdR capsules. 
 
Part IB dose escalation schema 
Dose Level 
Total radiation Gy (45 
Gy primary field, 5.4 Gy 
boost @1.8 
Gy/fraction/day) 
Capecitabine (mg/m2 BID) 
Monday am – Friday pm 
throughout RT 
IPdR (mg QD) 
Administered throughout 
radiation1,2 
1B 
50.4 
825 mg/m2 BID 
75mg QD 
2B 
50.4 
825 mg/m2 BID 
150mg QD 
3B 
50.4 
825 mg/m2 BID 
300mg QD 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
5 
Part IB dose escalation schema 
Dose Level 
Total radiation Gy (45 
Gy primary field, 5.4 Gy 
boost @1.8 
Gy/fraction/day) 
Capecitabine (mg/m2 BID) 
Monday am – Friday pm 
throughout RT 
IPdR (mg QD) 
Administered throughout 
radiation1,2 
4B 
50.4 
825 mg/m2 BID 
600mg QD 
5B 
50.4 
825 mg/m2 BID 
1200mg QD 
6B 
50.4 
825 mg/m2 BID 
1800mg QD 
7B 
50.4 
825 mg/m2 BID 
2400mg QD 
QD – Once Daily, BID – Twice Daily, RT – Radiation therapy 
1 The maximum allowed dose of IPdR is 2,400mg QD 
2 Actual doses will be rounded to account for availability of only 75 mg and 600 mg IPdR capsules 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Study 
Length 
IPdR 
Take on an empty 
stomach, either 1 
hour before or 2 
hours after meals. 
Dose as appropriate 
for the assigned 
dose level. 
PO 
QDA 
38 days 
(6 
weeks) 
 
 
 
Capecitabine 
Take within 30 
minutes after a meal 
(breakfast and 
dinner). 
825 mg/m2C 
PO 
BID 
Monday morning 
through Friday evening 
on RT days B,C 
RT 
 
1.8 Gy/fraction/day × 28 
doses (50.4 Gy total dose) 
5 doses per week until 
week 5 and 3 doses 
during Week 6D 
AOn the days of radiation therapy, the daily dose of IPdR will be administered within 30 min - 2 hours prior to 
radiation.Patients may take dose at home if the timing allows. 
BCapecitabine will be taken Monday morning through Friday evening each week of RT. 
CDosing will be with 150 mg and 500 mg tablets 
DRT will be given only Monday through Friday 
QD – Once Daily, BID – Twice Daily, PO – Oral, RT – Radiation therapy 
 
Patients will be assessed 4 weeks following completion of study treatment (Week 10 unless there 
were delays in therapy).  This will be the final assessment for study-related toxicity.  Patients 
will undergo surgical resection 8-12 weeks following completion of chemoRT (IPdR), and 
study-related response will be assessed at that time. 
 


NCI Protocol #: 10410 
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6 
TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Rectal Adenocarcinoma ...........................................................................................9 
2.2 
CTEP IND Agent ...................................................................................................13 
2.3 
Other Agents ..........................................................................................................20 
2.4 
Rationale ................................................................................................................21 
2.5 
Correlative Studies Background ............................................................................23 
3. 
PATIENT SELECTION ....................................................................................................24 
3.1 
Eligibility Criteria ..................................................................................................24 
3.2 
Exclusion Criteria ..................................................................................................26 
3.3 
Inclusion of Women and Minorities ......................................................................28 
4. 
REGISTRATION PROCEDURES ...................................................................................28 
4.1 
Investigator and Research Associate Registration with CTEP ..............................28 
4.2 
Site Registration .....................................................................................................30 
4.3 
Patient Registration ................................................................................................32 
4.4 
General Guidelines .................................................................................................34 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................34 
5.1 
Summary Table for Specimen Collection ..............................................................34 
5.2 
Specimen Procurement Kits and Scheduling .........................................................34 
5.3 
Specimen Tracking System Instructions ................................................................35 
5.4 
Specimen Collection ..............................................................................................38 
5.5 
Shipping Specimens from Clinical Site to the ETCTN Biorepository ..................39 
5.6 
Shipping Specimens from Clinical Sites to Other Laboratories ............................41 
5.7 
Biomarker Plan ......................................................................................................41 
5.8 
Integrated Correlative Studies ................................................................................44 
6. 
TREATMENT PLAN ........................................................................................................45 
6.1 
Agent Administration .............................................................................................45 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................55 
6.3 
Dose Expansion Cohorts: .......................................................................................56 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................56 
6.5 
Duration of Therapy ...............................................................................................59 
6.6 
Surgery ...................................................................................................................60 
6.7 
Adjuvant Therapy ..................................................................................................60 
6.8 
Duration of Follow-Up ..........................................................................................60 


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7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................60 
7.1 
IPdR Treatment Management ................................................................................61 
7.2 
RT Treatment management ....................................................................................61 
7.3 
IPdR and Capecitabine treatment management .....................................................62 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................65 
8.1 
CTEP IND Agent ...................................................................................................65 
8.2 
Capecitabine ...........................................................................................................68 
9. 
STATISTICAL CONSIDERATIONS...............................................................................68 
9.1 
Study Design/Endpoints.........................................................................................68 
9.2 
Sample Size/Accrual Rate ......................................................................................69 
9.3 
Stratification Factors ..............................................................................................70 
9.4 
Analysis of Secondary Endpoints ..........................................................................70 
9.5 
Analysis of Exploratory Endpoints ........................................................................70 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................70 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................71 
10.2 
Adverse Event Characteristics ...............................................................................73 
10.3 
Expedited Adverse Event Reporting ......................................................................73 
10.4 
Routine Adverse Event Reporting .........................................................................76 
10.5 
Pregnancy ...............................................................................................................77 
10.6 
Secondary Malignancy ...........................................................................................77 
10.7 
Second Malignancy ................................................................................................77 
11. 
STUDY CALENDAR .......................................................................................................77 
12. 
MEASUREMENT OF EFFECT........................................................................................80 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................80 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................81 
13.1 
Study Oversight .....................................................................................................81 
13.2 
Data Reporting .......................................................................................................81 
13.3 
Data Quality Portal ................................................................................................83 
14. 
REFERENCES ..................................................................................................................85 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................91 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE .....................................................................................................92 
APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD .....................................93 
APPENDIX D 
PATIENT MEDICATION DIARY ...........................................................94 
APPENDIX E 
MODIFIED FOLFOX6 .............................................................................98 


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8 
APPENDIX F 
CLINICAL MANAGEMENT OF DIARRHEA .......................................99 
APPENDIX G 
PATIENT-FRIENDLY DIARRHEA management GUIDE ...................101 
 
 
 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
9 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To determine the maximum tolerated dose (MTD) of oral (PO) IPdR when administered 
with capecitabine (825 mg/m2 BID) and radiation therapy (RT) (50.4 Gy in 28 fractions) 
 
1.1.2 To determine the toxicities Common Terminology Criteria for Adverse Events (CTCAE) 
v5) of the combined modality therapy, IPdR + capecitabine + RT 
 
1.2 
Secondary Objectives 
 
1.2.1 To establish the pharmacokinetics (PK) of QD IPdR when combined with capecitabine. 
 
1.2.2 To evaluate IUdR incorporation in circulating granulocytes and correlate these levels 
with IPdR plasma PK and clinical/laboratory toxicities. 
 
1.2.3 To assess IUdR incorporation in tumor cells obtained from the surgical resection 
specimen and correlate IUdR incorporation in tumor cells with IPdR PK. 
 
1.2.4 To assess IUdR incorporation in tumor cells obtained from the surgical resection 
specimen and correlate IUdR incorporation in tumor cells with tumor response as 
measured by pCR rate and Neoadjuvant Rectal (NAR) score. 
 
1.2.5 To determine the pCR rate of IPdR + capecitabine + RT at the IPdR MTD as a measure 
of anti-tumor activity.  Although the clinical benefit of IPdR has not yet been established, 
the intent of offering this treatment is to provide a possible therapeutic benefit, and thus 
the patient will be carefully monitored for tumor response and symptom relief in addition 
to safety and tolerability. 
 
1.2.6 To determine the NAR score of IPdR + capecitabine + RT at the IPdR MTD. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To explore the relationship between extent of exposure to RT and the development and 
severity of adverse events. 
 
1.3.2 To explore the drug/drug/metabolite interactions between capecitabine, IPdR, and their 
metabolites. 
 
2. 
BACKGROUND 
 
2.1 
Rectal Adenocarcinoma 
 
There are approximately 43,000 new cases of rectal cancer diagnosed each year in the United 
States (Seigel et al., 2020).  Stage-for-stage, recurrence rates are higher in rectal cancer in 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
10 
comparison to colon cancer (Heald et al., 1982). 
 
2.1.1 Standard-of-care treatment for Locally Advanced Rectal Cancer (LARC):  
 
2.1.1.1 
Neoadjuvant chemoradiotherapy (chemoRT):  
 
The use of neoadjuvant chemoRT is the established standard-of-care for LARC.  Studies 
performed in the early 2000’s demonstrated improved local control with less toxicity for 
neoadjuvant chemoRT compared with postoperative chemoRT (Sauer et al., 2004, Roh et al., 
2009).  The goals of neoadjuvant chemoRT are to improve local control, increase the likelihood 
of sphincter preservation, and increase the rate of relapse-free survival by acting on gross tumor 
volume and micrometastatic disease.  Efforts to improve local control, disease-free survival 
(DFS) and overall survival (OS) are currently focused on enhancing the benefits of the 
chemotherapy (systemic) and chemoradiotherapy components of therapy for patients with 
LARC. 
 
2.1.1.2 
Systemic chemotherapy:  
 
The rationale for the addition of systemic chemotherapy to the treatment regimen for patients 
with LARC was based on the demonstrated benefit of systemic chemotherapy for patients with 
colon cancer.  For patients with LARC, the paradigm of neoadjuvant chemoRT followed by 
surgical resection relegated the use of systemic chemotherapy to the adjuvant setting.  In studies 
where patients with rectal cancer were randomly assigned to postoperative observation or 
adjuvant therapy, the benefit of systemic therapy was as apparent as it is for the treatment of 
patients with colon cancer.  Unfortunately, in the setting of neoadjuvant chemoRT, the 
administration of adjuvant chemotherapy is challenging with large, multicenter clinical trials 
consistently reporting delay, dose reduction, or discontinuation in 25% - 50% of patients 
(Breugom et al., 2015).  To optimize delivery of trimodality therapy, a new sequence of 
administration was developed incorporating all neoadjuvant therapy prior to surgery, so-called 
total neoadjuvant therapy (TNT) (Figure 1). 
 
Figure 1: 
LARC Total Neoadjuvant Therapy (TNT) paradigm 
 
By ensuring delivery of systemic treatment prior to surgery, it is hoped that TNT will address 
early micrometastases, improve tolerability of therapy, and improve tumor response.   Recent 
trials have demonstrated that a TNT approach can improve compliance with systemic therapy 
without compromising a patient’s ability to undergo surgery or increase the risk of surgery, and 
accumulated data from international studies suggest the TNT approach is a safe and feasible 
treatment option.  TNT is now endorsed by the National Comprehensive Cancer Network 
guidelines, and is the framework upon which newer therapies are tested.  Current standard-of 


NCI Protocol #: 10410 
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11 
care TNT for patients with LARC uses a FOLFOX-based regimen (See Appendix E) for the 
neoadjuvant chemotherapy phase and capecitabine + RT for the chemoRT phase, followed by 
surgery (Figure 2). 
 
Figure 2: 
Current Total Neoadjuvant Therapy (TNT) schema 
 
 
2.1.1.3 
Chemoradiotherapy:  
 
Preoperative fluoropyrimidine (FP) chemotherapy, fluorouracil (5-FU) or capecitabine (cape), 
with concurrent radiation therapy (RT) improves survival in patients with rectal cancer 
(Douglass et al., 1986; Krook et al., 1991; and Kollmorgen et al., 1994) and is a standard-of-care 
for LARC (Sauer et al., 2004).  Preoperative chemoRT improves local control and enhances 
tumor shrinkage facilitating improved options for surgical resection (Sauer et al., 2004).  In an 
effort to improve the chemoradiotherapy component of LARC treatment, several large 
randomized phase 3 trials have addressed the potential benefit of adding oxaliplatin (ox) to FP + 
RT regimens based on the rationale that oxaliplatin’s cytotoxic and radiosensitizing effects may 
decrease rates of distant recurrence and local progression (Table 1) (Aschele et al., 2011; Gerard 
et al., 2010; Gerard et al., 2012; Allegra et al., 2015; O'Connell et al., 2014; Rodel et al., 2012; 
Rodel et al., 2015; Haustermans et al., 2014; Schmoll et al., 2018; Jiao et al., 2015, Deng et al., 
2016; Deng et al., 2019).  The clinical results of the addition of ox to FP + RT have been 
disappointing, in part due to the toxicities encountered with this combination.  
 
Table 1: 
Randomized clinical trials of fluoropyrimidine + RT + oxaliplatin 
Trial 
Endpoints 
Yea
r 
N 
Control Arm 
Experimental Arm 
p 
 
Treatment 
pCR 
Treatment 
pCR 
STAR-1 (Aschele 
et al., 2011) 
Primary endpoint: OS 
Planned early endpoint that would 
be analyzed: pCR 
 
2011 
 
747 
 
5FU + RT 
 
16% 
 
5FU + RT + 
ox 
 
16% 
 
NS 
ACCORD 
12/0405 
PRODIGE 2 
(Gerard et al., 
2010, Gerard et 
al., 2012) 
Primary endpoint: pCR (reported 
JCO 2010) 
Secondary endpoints: local 
recurrence rate, OS, DFS (reported 
JCO 2012) 
 
2012 
 
598 
 
Cape + RT 
 
13.9
% 
 
Cape + RT + 
ox 
 
19.2
% 
 
.09 
NSABP R-04 
4 arm study 
cape vs 5FU + ox 
(O'Connell et al., 
2014, Allegra et 
al., 2015) 
Primary endpoints were all 
“surgical endpoints”: pCR, 
sphincter-sparing surgery, and 
surgical downstaging (conversion 
to sphincter-sparing surgery) 
 
2014 
 
1608 
 
5FU or 
cape + RT 
 
17.8
% 
 
5FU or cape 
+ RT + ox 
 
19.5
% 
 
.42 
German 
CAO/ARO/AIO-
04 (Rodel et al., 
Primary endpoint: DFS (reported 
2015) 
 
2015 
 
1236 
 
5FU + RT 
 
13% 
 
5FU + RT + 
ox 
 
17% 
 
.03 


NCI Protocol #: 10410 
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12 
Trial 
Endpoints 
Yea
r 
N 
Control Arm 
Experimental Arm 
p 
 
Treatment 
pCR 
Treatment 
pCR 
2012, Rodel et al., 
2015) 
Secondary endpoints: pCR, 
toxicity, compliance (reported 
2012) 
PETACC-6 
(Haustermans et 
al., 2014, Schmoll 
et al., 2018) 
Primary endpoint: DFS (reported 
2018 JCO abstract only) 
Secondary endpoints: pCR, 
sphincter-sparing surgery, and 
surgical downstaging (conversion 
to sphincter-sparing surgery) 
 
2014 
 
1069 
 
Cape + RT 
 
11% 
 
Cape + RT + 
ox 
 
13% 
 
.31 
Jiao et al., 2015) 
Primary endpoints: DFS, OS 
Secondary endpoints: pCR, 
toxicity, compliance  
 
2015 
 
206 
 
Cape + RT 
 
19% 
 
Cape + RT + 
ox 
 
23% 
 
.49 
FOWARC (Deng 
et al., 2016, Deng 
et al., 2019) 
Primary endpoint: 3-year DFS 
Secondary endpoints: pCR, 
toxicity 
 
2015 
 
495 
 
5FU + RT 
 
14% 
 
mFOLFOX6 
+ RT 
 
27.5
% 
 
.005 
 
 
2.1.2 Pathologic complete response (pCR) as outcome measure in rectal cancer:  
 
In rectal cancer, the absence of viable tumor cells in the resection specimen (primary tumor 
mass, surrounding tissue and lymph nodes) at the time of surgery, termed pathologic complete 
response (pCR), has been shown to correlate with improved outcome (Ryan et al., 2005, Martin 
et al., 2012).  pCR is considered a standard endpoint for LARC clinical trials, although 
correlations of pCR with surgical results (e.g. extent of resection, sphincter preservation, 
downstaging) and OS are needed for definitive documentation of benefit.  pCR rates for FP + RT 
vs. FP + RT + ox from recent phase 3 trials are presented in Table 1.  In these 7 international, 
multi-institutional, randomized phase 3 trials, pCR was a primary or secondary endpoint in every 
trial. 
 
2.1.3 Neoadjuvant Rectal Score (NAR score) as an outcome measure in rectal cancer:  
 
The NAR score was developed by Yothers et al. as a short-term clinical trial surrogate endpoint 
that is particularly sensitive to changes in factors that are affected by neoadjuvant therapy 
(George et al., 2015).  The NAR score was built upon the Valentini nomogram to go beyond 
pCR to predict local recurrence, distant metastases and OS for patients with LARC (Valentini et 
al., 2011).  NAR is calculated based on the clinical T stage (cT), pathological T (pT) and pN 
stages as: 
 
                           NAR = [5pN- 3 (cT- pT) + 12]2 / 9.61 
 
The NAR score has been validated in the randomized NSABP R04 study that evaluated four 
different FP-based radioensitizing regimens in 1479 patients with resectable rectal cancer.  NAR 
score in this dataset was significantly associated with overall survival (George et al., 2015). 
 
2.1.4 NRG Oncology TNT trial (NRG-GI002; NCT02921256): 
 


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The current NRG Oncology TNT trial (NRG-GI002; NCT02921256) is a randomized, phase 2, 
signal-finding platform study, designed with parallel, noncomparative investigational arms and a 
single comparative TNT control group (George et al., 2019b) (Figure 3).  This NCTN multi-arm 
randomized phase 2 modular clinical trial platform utilizes TNT (mFOLFOX6 × 8 cycles, See 
Appendix E) with parallel experimental arms (EA) in LARC.  The EAs are not intended for 
direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and 
homogenous high-risk patient population with correlative biomarkers.  Success of any EA will 
be determined by achievement of pathologic endpoints compared to a control arm.  Target 
accrual is 79 evaluable patients/arm with additional EAs added through protocol amendments.  
NAR score is the primary endpoint used in the NRG-GI002 trial.  The current study will provide 
data to be used to determine the appropriateness of evaluating IPdR as an EA in the NRG-GI002 
trial.  Because patients on the current study will receive identical treatment to those on NRG-
GI002 (minus IPdR), results of this study will facilitate expeditious incorporation of IPdR into 
NRG-GI002 as an EA (George et al., 2019b; George et al., 2019). 
 
Figure 3: 
NRG-G1002 (NCT02921256) TNT Schema (Non-comparative Phase 2 
experimental arms) 
 
The study schema for randomized phase 2 arms of NRG-GI002 (clinicaltrials.gov identifier NCT02921256) is 
illustrated.  Additional arms are added through protocol amendments and are compared with the ongoing control 
arm.  The FOLFOX regimen consists of oxaliplatin  85 mg/m2 intravenously (IV) on Day 1 + leucovorin 400 mg/m2 
IV on Day 1 + 5-fluorouracil (5-FU) 400 mg/m2 as an IV bolus, followed by 5-FU 2400 mg/m2 as a continuous 
infusion over 46 hours every 2 weeks for 8 cycles.  Radiotherapy (XRT) starts 3 to 4 weeks after the last dose of 
FOLFOX, with 4500 centigrays (cGy) delivered in 25 fractions over 5 weeks and a 540-cGy boost in 3 fractions; 
intensity-modulated radiotherapy is allowed.  Surgery is performed 8 to 12 weeks after the last dose of RT. 
 
2.2 
CTEP IND Agent 
 
2.2.1 5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) 
 
2.2.1.1 
Iododeoxyuridine (IUdR)-mediated radiosensitization 
 


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5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) is a prodrug of iododeoxyuridine (IUdR), a 
pyrimidine analog that has been recognized as a radiosensitizing agent since the early 1960’s 
(Kinsella 1996; McGinn et al., 1996b).  The mechanism of IUdR-mediated radiosensitization 
involves the cellular uptake and metabolism of IUdR through the thymidine salvage pathway.  
IUdR undergoes initial intracellular phosphorylation to the monophosphate derivative by the 
rate-limiting enzyme, thymidine kinase, followed by sequential phosphorylation to the 
triphosphate.  Kinsella and others have demonstrated that this modified analog is then utilized 
(i.e. incorporated) by DNA polymerase during scheduled (S-phase) and unscheduled DNA 
synthesis, in competition with thymidine triphosphate (Kinsella et al., 1987; Rieber and Rieber, 
2008).  DNA incorporation is needed for radiosensitization by ionizing radiation (IR), in human 
tumors as well as normal cells, and the extent of radiosensitization correlates directly with the 
%IUdR DNA replacement (Kinsella et al., 1987; Lawrence et al., 1990; Rieber and Rieber, 
2008).  IR-mediated radiosensitization by IUdR results in the generation of highly reactive uracil 
free radicals by IR, which may also damage unsubstituted complementary-strand DNA, resulting 
in increased DNA single strand breaks (SSBs) and increased double strand breaks (DSBs) 
(Kinsella et al., 1987; Fornace et al., 1990; Lawrence et al., 1990; Rieber and Rieber, 2008).  
The repair of IR damage may also be reduced by pre-IR exposure to IUdR.  IUdR is rapidly 
metabolized in both rodents and humans when given as a bolus infusion with a plasma half-life 
of <5 min (Kinsella 1996).  Consequently, prolonged continuous drug infusion over several 
weeks before and during RT is necessary to maximize the proportion of tumor cells that 
incorporate IUdR during the S phase of the cell cycle (Rodriguez et al., 1994; Fowler and 
Kinsella, 1996). 
 
In the 1980-1990s, clinical trials of IUdR as a radiosensitizer were performed, focusing on 
patients presenting with high-grade gliomas (Kinsella et al., 1988; Sullivan et al., 1994; Urtasun 
et al., 1996; Schulz et al., 2004) and sarcomas (Goffman et al., 1991; Robertson et al., 1995).  
These studies demonstrated that the magnitude of radiosensitization correlates directly with 
plasma IUdR levels and the %IUdR-DNA tumor cellular replacement and can serve as 
radiosensitization biomarkers (Kinsella et al., 1984; Speth et al., 1988b).  Additionally, in small 
series of patients with head and neck cancers or liver metastases from colorectal cancer, the 
%IUdR-DNA cellular incorporation in tumors ranged to 5%, but was less than 1% in adjacent 
normal liver tissue, further supporting a therapeutic window for IUdR-mediated 
radiosensitization (Kinsella et al., 1984; Speth et al., 1988b).  Although IUdR has clear activity 
as a radiosensitizer, its development has been limited by the need for prolonged continuous 
infusion before and during RT that results in myelosuppression and gastrointestinal toxicities, 
limiting the tolerated dose and the potential for clinical radiosensitization (Kinsella et al., 1988; 
Sullivan et al., 1994; Urtasun et al., 1996; Schulz et al., 2004). 
 
2.2.1.2 
IPdR 
 
IPdR offers several key advantages compared to IUdR, including a more favorable therapeutic 
index.  IPdR produces minimal cytotoxic effect, and can be considered a classic radiosensitizer.  
IPdR is a prodrug of IUdR that is administered PO and then efficiently converted to IUdR by a 
hepatic aldehyde oxidase (Chang et al., 1992).  Preclinical studies of IPdR as a potential 
radiosensitizer included pharmacology and toxicology studies performed in athymic mice, rats, 
ferrets, and Rhesus monkeys (Kinsella et al., 1994; Kinsella et al., 1998; Kinsella et al., 2000; 


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15 
Kinsella et al., 2000b; Kinsella et al., 2008); and in vivo radiosensitization studies using human 
tumor xenograft models in athymic mice (two colorectal cancer cell lines, HT29 and HCT-116, 
and two glioblastoma [GBM] cell lines, U251 and U87) (Kinsella et al., 1994; Kinsella et al., 
2000; Kinsella et al., 2000b; Seo et al., 2005).  These preclinical studies demonstrated that:  1.) 
IPdR could be administered and tolerated PO using multiple daily dosing; 2.) IPdR is efficiently 
and predictably metabolized into the active metabolite, IUdR; 3.) relatively prolonged plasma 
levels of IUdR can be achieved; 4.) %IUdR-DNA incorporation was demonstrated to be 2-3 
times more in proliferating tumor and 2-3 fold less in proliferating normal tissues (bone marrow 
and GI epithelium) compared to continuous infusion IUdR at the MTD; 5.) radiation sensitizer 
enhancement ratios of 1.3-6 were achieved using human cancer xenograft models, and compared 
favorably with those of continuous infusion IUdR at the MTD (<1.1); and, 6.) systemic toxicity 
was minimal at effective doses.  These data were used to support an Investigational New Drug 
Application and to conduct an initial phase 0 trial of single-dose IPdR at the NCI in patients with 
advanced malignancies that demonstrated that radiosensitizing plasma levels of IUdR could be 
achieved following PO administration of IPdR (Kummar et al., 2013). 
 
Table 2: 
IPdR pre-clinical and early clinical studies 
Study 
Description 
Summary of Findings 
 
IPdR Metabolism by hepatic aldehyde oxidase 
 
Chang et al., 1992 
Metabolism of IPdR vs. IUdR 
Elucidated IPdR metabolism by 
aldehyde oxidase 
Characterized properties of aldehyde 
oxidase 
Kinsella et al., 2000b; Kinsella et al., 
2008 
IPdR Metabolism in rats and ferrets 
Characterized kinetics of IPdR 
metabolism  
 
Pharmacokinetic and toxicology studies 
 
Kinsella et al., 1994; Kinsella et al., 
1998; Kinsella et al., 2000b 
Pharmacokinetics of PO IPdR in mice 
Established absorption, distribution, 
metabolism, and elimination kinetics 
of PO IPdR in mice 
Kinsella et al., 2000  
Pharmacokinetics (PK) and 
toxicity/toxicology of IPdR in ferrets 
(PO) and rhesus monkeys (IV)  
Established distribution, metabolism, 
and elimination kinetics of IPdR in 
non-rodent species.  
Noted mild weight loss at highest 
dose; but no significant hematologic, 
biochemical, or histopathologic 
changes 


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Study 
Description 
Summary of Findings 
Kinsella et al., 2008  
Pharmacokinetics and toxicity/ 
toxicology of PO IPdR in Fischer rats 
 
Established IPdR and IUdR 
concentration-time profiles 
Reported HPLC/tandem mass 
spectroscopy methods for plasma 
IPdR and IUdR levels. 
 
Pre-clinical efficacy studies of IPdR-mediated radiosensitization 
 
Kinsella et al., 1998; Kinsella et al.,  
2000b 
Seo et al., 2004; Seo et al.,  2005 
 
Efficacy/toxicity studies of PO IPdR 
vs. continuous intravenous (ci) IUdR 
using human colorectal and 
glioblastoma tumor xenografts. 
Increased IUdR-DNA incorporation 
in tumors; decreased in normal 
tissues, PO IPdR vs. ci IUdR.  
1.3-1.5 fold enhancement of response 
to RT with PO IPdR  
Kinsella et al., 1994  
Efficacy, PK, toxicity, and DNA 
incorporation of PO IPdR vs. PO 
IUdR in human colon cancer 
xenografts.  
Demonstrated improved therapeutic 
index of PO IPdR vs. PO IUdR for 
IUdR-mediated radiosensitization 
 
Early clinical studies of IPdR 
 
Kummar et al., 2013 
Pharmacokinetics of single-dose PO 
IPdR in humans 
 
Phase 0 study of PO IPdR, 150mg-
2400mg in humans: No toxicities.  
Kinsella et al., 2019 
Phase I and Pharmacology study of 
Ropidoxuridine (IPdR) as prodrug for 
iododeoxyuridine-mediated tumor 
radiosensitization in advanced GI 
cancer undergoing radiation 
 
PO IPdR daily × 28 days with RT is 
feasible and tolerable at doses that 
produce plasma IUdR levels of > 
1µM/L 
 
 
2.2.1.3 
Phase 1 Study of IPdR + RT For GI Malignancies: 
 
The Brown University Oncology Research Group has recently reported results of a phase 1 study 
of IPdR + RT in patients with advanced GI malignancies (NCI #9882; NCT02381561) (Kinsella 
et al., 2019).  Adult patients with locally advanced or metastatic GI cancers referred for palliative 
RT to the chest, abdomen or pelvis were eligible for study.  Patients received IPdR PO once 
daily (QD) × 28 days beginning seven days prior to the initiation of RT and continuing through 
the final day of RT (37.5 Gy in 2.5Gy × 15 fractions).  A two-part dose escalation scheme was 
used, PK studies were performed at multiple time points, and all patients were assessed for 
toxicity and response to Day 56 (Figures 4, Table 3, and Table 4) 
 
Table 3: 
Schema – Phase 1 and pharmacology trial of oral IPdR as a prodrug for 
IUdR-mediated radiosensitization in patients receiving palliative RT for metastatic GI 


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cancers (NCT02381561) (Kinsella et al., 2019) 
 
Week 1 
Days 1-7 
Week 2 
Days 8-14
Week 3 
Days 15-21 
Week 4 
Days 22-28 
Week 5  
Days 29-35 
Week 6 Week 8 
IPdR 
PO QD dose × 28 days, Days 1-28 
 
 
 
RT 
 
2.5 Gy/day  × 15 doses (37.5 Gy total dose) 
Days 8-12, 15-19, 22-26 
 
 
 
PK studies 
plasma levels of 
IPdR, IUdR, IP and 
IU 
Day 1a 
 
 
Day 15b 
Day 22b 
 
 
 
Radiologic 
assessment of 
tumor (CT or MRI) 
Within I 
week of 
study entry 
 
 
 
 
 
4 weeks 
following 
end of 
therapy 
a  Day 1, a pre-study sample was obtained and then sampling was done at 30, 60, 120, 240 minutes and 24 hours (just prior to 
Day 2 IPdR dose) following the initial PO dose of IPdR 
b Days 15 and 22 of the 28-day dosing schedule, samples were obtained just prior to PO IPdR and then at 30, 60, 120, and 240 
minutes following PO IPdR dose   
 
Nineteen patients were enrolled on study and received dosages from 150mg/day to 1800mg/day 
(Kinsella et al., 2019).  The first and second patients received 150 mg and 300 mg PO QD, 
respectively, without toxicity using single-patient-per-cohort dose escalation.  The third study 
patient (600 mg PO QD) developed grade 3 transaminase elevation on Day 22 of study.  This 
event triggered the Stop/Switch rule, and Part II of the dose escalation scheme was initiated.  
Cohorts of three evaluable patients each for dose levels 600 mg, 900 mg, and 1200 mg received 
therapy with IPdR without additional grade 2 or higher treatment related toxicity.  At 1800 mg 
PO QD, two of three patients experienced Grade 3 toxicity deemed probably or definitely related 
to IPdR.  One patient developed grade 3 dehydration and a second patient had grade 3 diarrhea.  
No Grade 4 toxicities were encountered.  The MTD and recommended phase 2 dose (RP2D) of 
IPdR based on this study is 1200 mg PO QD.


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Table 4: 
Phase 1 trial (NCI #9882): Study treatment, toxicity and response (Kinsella et al., 2019) 
 


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Pharmacokinetics analyses: 
 
In the phase 1 trial, PK analyses demonstrated achievable and sustainable levels of plasma IUdR 
>1µM/L (levels previously shown to mediate radiosensitization) at dose levels >600mg/day 
(Figure 4). 
 
Figure 4: 
PK analyses – Phase 1 trial and pharmacology trial of oral IPdR as a 
prodrug for IUdR-mediated radiosensitization in patients receiving palliative RT for 
metastatic GI cancers (NCI #9882) (Kinsella et al., 2019).   
(A) Mean plasma concentrations of IUdR by IPdR dose level.  (B) Plasma concentrations of 
IUdR in individual patients on Days 1, 15, and 22 at 1200 mg dose level (MTD, recommended 
phase 2 dose [RP2D]) 
 
 
 


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Although not the primary objective of the study, all patients had measurable disease at study 
entry.  Evaluation of target lesions within the radiation field 4 weeks following completion of 
therapy (at Week 8), using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 
revealed two Complete Response (CR), three Partial Response (PR), nine Stable Disease (SD), 
and no progressive disease (PD) in these patients.  
 
In conclusion, this first-in-human tolerance study of IPdR confirmed that IPdR is predictably and 
readily absorbed following PO administration, is metabolized to IUdR principally by hepatic 
aldehyde oxidase, and demonstrates PK that compare favorably to those of IUdR.  The 
administration of IPdR PO QD × 28 days with RT is feasible and tolerable at doses that produce 
plasma IUdR levels >1µM/L, achieving plasma IUdR levels that have previously been associated 
with clinically significant radiosensitization.  This phase 1 study supports further testing of IPdR 
as a potential radiosensitizing agent.  In this subsequent trial, we propose evaluating the addition 
of PO IPdR to preoperative capecitabine + RT for patients with rectal cancer.  
 
2.3 
Other Agents 
 
2.3.1 Capecitabine 
 
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity.  It is an orally 
administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-
fluorouracil (5-FU) in vivo.  Both normal and tumor cells metabolize 5-FU to 5-fluoro-2’-
deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).  These 
metabolites cause cell injury by two different mechanisms.  First, FdUMP and the folate 
cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a 
covalently bound ternary complex.  This binding inhibits the formation of thymidylate from 2’-
deoxyuridylate.  Thymidylate is the necessary precursor of thymidine triphosphate (TTP), which 
is essential for the synthesis of DNA, so a deficiency of this compound can inhibit cell division.  
Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine 
triphosphate (UTP) during the synthesis of RNA.  This metabolic error can interfere with RNA 
processing and protein synthesis. 
 
2.3.1.1 
Capecitabine + RT:  ChemoRT phase of LARC therapy: 
 
Fluoropyrimidine therapy concurrent with RT for rectal cancer currently represents the standard 
of care for this disease (Sauer et al., 2004).  The Gastrointestinal Tumor Study Group showed 
that adjuvant combined modality therapy with RT and 5-fluorouracil (5-FU)-based 
chemotherapy improved outcomes in patients with rectal cancer both in terms of local control OS 
compared to postoperative RT alone (Krook et al., 1991).  The incorporation of protracted 
infusional 5-FU with RT further improved clinical outcomes (O'Connell et al., 1994).  NSABP 
R-04 demonstrated similar clinical outcomes between capecitabine and continuous infusion 5-FU 
when added to RT for rectal cancer (O'Connell et al., 2014).  Pathologic complete responses 
were similar between the two arms (22.2 vs. 18.8%; p=0.12) while toxicity clinically favored 
capecitabine. 
 


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2.4 
Rationale 
 
2.4.1 Mechanism of fluoropyrimidine (FP)-based radiosensitization (RS) and interactions of 
IPdR on FP-based binding (inhibition) of thymidylate synthetase (TS) to enhance FP-RS: 
 
While the precise mechanisms of FP-mediated RS of rectal tumors are not clearly understood, 
we and others have shown experimentally that RS is principally mediated by FP effects on the 
production and balance of intracellular DNA nucleotide pool via binding of the principal FP 
metabolite, FdUMP, to TS causing TS inhibition and depletion of dTTP pools (Bruso et al., 
1990; Miller and Kinsella, 1992).  The level of TS expression in colorectal cancer (CRC) cell 
lines and in patient tumor specimens is of prognostic significance where high TS expression 
correlates with reduced RS (Miller and Kinsella, 1992).  In experimental studies, the addition of 
IPdR further inhibits TS with a greater than additive effect as a result of the generation of the 
intracellular IPdR monophosphate metabolite, IdUMP that further inhibits (by binding) TS 
leading to increased FP-mediated RS (Lawrence et al., 1992; Miller et al., 1995). 
 
2.4.2 FP + IPdR/IUdR:   
 
The phase 1 and clinical pharmacology study combining a fluoropyrimidine (fluorodeoxyuridine, 
FUdR) and a halogenated pyrimidine (HP) analog (IUdR) provides data that may be applied to 
the combination of capecitabine + IPdR proposed in this study (Speth et al., 1988).  FUdR and 
IUdR were administered concomitantly, as 14-day continuous intravenous (IV) infusions with 
standard fractionated RT.  The majority of patients in this study had glioblastoma multiforme 
(GBM), and the trial tested the hypothesis that FP would modulate the extent of cellular %IUdR-
DNA incorporation (Speth et al., 1988).  In retrospect, GBM was a poor choice for testing this 
hypothesis in light of the limited FP cytotoxicity in this tumor.  However, using %IUdR-DNA 
incorporation in circulating granulocytes as a biochemical endpoint and both fixed and escalating 
doses of either FUdR or IUdR, no modulation of %IUdR-DNA incorporation was found in the 
granulocytes.  Indeed, the different MTDs of IUdR and FUdR plotted in an isobologram 
suggested only additive effects (Figure 5).  Additionally, no changes in the expected plasma 
levels of either drug were found.  This clinical study provides data regarding the concomitant use 
of a FP and IUdR as radiosensitizers. 
 


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Figure 5: 
Isobologram of the relationship between the MTDs of FdUrd and IdUrd 
administered as single agents or co-administered in different dosage combinations (Speth et 
al., 1988) 
 
In contrast, RT + FP (using either continuous infusion 5-FU for up to 96 hours or twice daily PO 
capecitabine) is an internationally established treatment for LARC with acceptable acute and late 
normal tissue toxicities (Table 1).  Three in vivo preclinical studies in two representative CRC 
(HT29 and HCT-116) xenograft models supporting the superiority of PO IPdR given daily or up 
to three times a day vs. continuous infusion IUdR (at the MTD) as a radiosensitizer 
demonstrating an improved therapeutic index have been published (Kinsella et al., 1994; 
Kinsella et al., 1998; Seo et al., 2004)  
 
2.4.3 Twice-a-Day Dosing of IPdR:  
 
Based on laboratory studies by Seo et al., 2005 and discussions with Dr. Jerry Collins 
(Developmental Therapeutics Program [DTP], NCI), this protocol will utilize a twice a day 
(BID) dosing schema of IPdR with capecitabine and RT.  Seo et al., evaluated and compared 
four different IPdR treatment schedules: once a day, three-times a day, every-other-day, and 
every third day.  Plasma PK, IUdR-DNA incorporation in tumor and normal proliferating tissues, 
tumor growth delay following irradiation, and body weight loss were used as end points.  The 
three-times-daily schedule with the same total daily doses as the daily schedule improved the 
efficiency of IPdR conversion to IUdR.  This study will initially utilize a twice daily schedule to 
correspond to capecitabine administration. 
. 
 
Based on IPdR’s interactions with FPs and RT in preclinical studies, IPdR is expected to 
improve the efficacy of the chemoRT phase of treatment for patients with LARC.  This phase 1 
study will determine the MTD of the concomitant administration of IPdR with capecitabine + 
RT.  The favorable toxicity profile of IPdR given with concurrent RT in NCI #9882 provides 
support for the expected tolerability of this chemoRT combination (IPdR + capecitabine + RT).  
NRG Oncology TNT trial (NRG-GI002; NCT02921256) is a multi-arm randomized phase 2 
modular clinical trial platform utilizing TNT with parallel experimental arms.  Because patients 
on this trial will receive identical treatment to those on NRG-GI002 (minus IPdR), results of this 


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23 
trial will facilitate expeditious incorporation of IPdR into NRG-GI002 as an experimental arm. 
 
2.5 
Correlative Studies Background 
 
2.5.1 IPdR PK  
 
On Day 8, plasma PK analyses will be performed.  A 10 cc blood sample will be obtained just 
prior to the PO IPdR dose and then at 30, 60, 120, and 240 minutes following the PO dose of 
IPdR.  On Days 21 and 35, 10 cc of blood will be drawn 1-2 hours following the PO dose of 
IPdR for plasma IPdR and IUdR levels. 
 
Methodologies for the PK analyses are those detailed and reported previously (Kummar et al., 
2013) and the same as used in the prior phase 1 trial (Kinsella et al., 2019).  Employing a similar 
schedule for PK sampling in this trial as that used in the prior phase 1 study will allow 
comparison of the results, and the potential impact of concomitant capecitabine dosing.  
 
2.5.2 Capecitabine PK 
 
Levels of capecitabine and its metabolites will be performed on Days 8, 21, and 35 in 
conjunction with the IPdR PK studies, using a portion of the 10-mL blood samples described 
above (Section 2.5.1). 
 
Methodologies for the capecitabine PK analyses are those detailed and reported previously 
(Reigner et al., 2001). 
 
2.5.3 %IUdR-DNA cellular incorporation into tumor biopsy specimen 
 
As the %IUdR-DNA cellular incorporation in human tumor xenografts in athymic mice was 
linearly related to the IPdR dose when given PO QD × 6-14 days (Kinsella et al., 1994; Kinsella 
et al., 2000b; Seo et al., 2004), we will evaluate for correlation between %IUdR-DNA cellular 
incorporation in tumor cells obtained from the surgical resection specimen and the dose of IPdR 
received as a biomarker of tumor radiosensitization.  Evaluation for correlation of tumor 
response using pCR rate and NAR score and the %IUdR-DNA cellular incorporation in tumor 
cells obtained from the surgical resection specimen will also be performed.  
 
2.5.4 %IUdR-DNA cellular incorporation in peripheral (circulating) granulocytes: 
 
%IUdR-DNA cellular incorporation in peripheral (circulating) granulocytes will be performed as 
a biomarker of bone marrow acute normal tissue toxicity.  These analyses will be performed at 
three time points on study, Days 8, 21, and 35.  %IUdR-DNA cellular incorporation in peripheral 
(circulating) granulocytes will be correlated with peripheral blood counts, other systemic 
toxicities (CTCAE v5.0) and plasma PK obtained at the same time points.  This assay was 
originally developed in Dr. J. Collins’ laboratory at NCI (Belanger et al., 1986; Belanger et al., 
1987). 
 
Based on our pre-clinical data regarding %IUdR-DNA cellular incorporation in bone marrow 


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24 
cells harvested directly from the femurs of athymic mice and ferrets following a 14 day exposure 
to PO QD IPdR (Kinsella et al., 1994; Kinsella et al., 2000; Seo et al., 2004; Seo et al., 2005) we 
would not expect a significant correlation between the %IUdR-DNA cellular incorporation in 
circulating granulocytes and PK measurements, peripheral blood counts, or systemic toxicities.  
 
We have used circulating granulocytes as surrogate cells for bone marrow toxicity using the 
%IUdR-DNA cellular incorporation in several clinical trials of continuous intravenous (ci) IUdR 
(Belanger et al.,1986; McGinn et al., 1996; Schulz et al., 2004; Seo et al., 2004).  For example, 
using a 28-day schedule of ci IUdR, we found an increase in the %IUdR-DNA incorporation in 
circulating granulocytes that:  peaked by Day 21 of the 28-day ci treatment; reached nearly 5% at 
the highest dose level (781 mg/m2/day); correlated with steady-state plasma IUdR of 1.5 ± 0.3 
µM; and was associated with Grade 4 neutropenia in 2 of 6 patients and Grade 3 
thrombocytopenia in 1 of 6 patients (Schulz et al., 2004).  In contrast, PO QD dosing of IPdR at 
1 gm/kg/day × 28 days in rats showed no significant myelosuppression and %IUdR-DNA 
incorporation <2% with steady-state plasma IUdR levels of 2-3 ± 0.5 µM.(Schulz et al., 2004) 
 
 
3. 
PATIENT SELECTION 
 
This study involves the chemoradiotherapy phase of treatment for LARC.  The intent is for 
patients to receive treatment as per NRG-GI002 with the addition of IPdR during the 
chemoradiotherapy phase.  As such, patients must have been diagnosed with LARC and received 
8 cycles of mFOLFOX6 (Appendix E) prior to study entry, with the intent to undergo surgical 
resection following chemoradiotherapy. 
 
3.1 
Eligibility Criteria  
 
3.1.1 At diagnosis, patients must have had histologically proven adenocarcinoma of the rectum 
with no evidence of distant metastases. 
 
3.1.2 At diagnosis, the major portion of the tumor must have been intact, and the following 
must be documented: 
• 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. 
 
3.1.3 At diagnosis, the tumor must have been locally advanced Stage II (T3-4 N0) or Stage III 
(N+) rectal cancer with at least one of the following: 
• 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 


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25 
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) 
 
3.1.4 Patients must have received 8 cycles of neoadjuvant mFOLFOX and must have 
completed this therapy at least 3 weeks (and no more than 6 weeks) prior to enrollment 
on this study (see Appendix E). 
 
 
3.1.5 Patients must intend to undergo surgical resection of the rectal primary tumor following 
chemoradiotherapy. 
 
3.1.6 Age ≥18 years.   
 
Because no dosing or adverse event (AE) data are currently available on the use of IPdR 
in combination with Capecitabine and RT in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials.   
 
3.1.7 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.8 Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes  
 
≥3,000/mcL 
− 
absolute neutrophil count 
 
≥1,200/mcL 
− 
platelets  
 
≥100,000/mcL 
− 
hemoglobin 
 
>10 g/dL 
− 
total bilirubin 
 
≤1.5 × institutional upper limit of normal (ULN) 
− 
AST(SGOT)  
 
 
 
≤2.5 × institutional ULN 
− 
ALT(SGPT)  
 
 
 
≤2.5 × institutional ULN 
− 
creatinine  
 
≤1.5 × institutional ULN 
OR 
− 
glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 (see Appendix B) 
− 
alkaline phosphatase 
 
≤3 × institutional ULN 
− 
sodium, potassium,  
chloride, bicarbonate 
 and magnesium 
 
Within institutional normal limits 
 
3.1.9 Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known 
human immunodeficiency virus (HIV) disease must: 
• Have a CD4 count ≥200 cells/µL within 30 days before enrollment, 
• Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days before 


NCI Protocol #: 10410 
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26 
enrollment, and 
• Have no evidence of opportunistic infections. 
 
3.1.10 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured and be receiving no therapy. 
 
3.1.11 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be eligible 
for this trial, patients should be class 2B or better. 
 
3.1.12 Patients must have the ability to swallow and retain oral medication. 
 
3.1.13 The effects of IPdR on the developing human fetus are unknown.  For this reason and 
because radiosensitizing agents as well as other therapeutic agents used in this trial are 
known to be teratogenic, women of child-bearing potential (WOCBP)* and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  WOCBP must 
have a negative urine or serum pregnancy test within 72 hours prior to enrollment.  If 
urine pregnancy results are positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of IPdR administration. 
 
*Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal.  Menopause 
is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence 
of other biological or physiological causes. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document.  
Participants with impaired decision-making capacity (IDMC) who have a legally-
authorized representative (LAR) and/or family member available will also be eligible. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have not recovered from adverse events due to prior mFOLFOX6 
chemotherapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.  
 
3.2.2 Patients who are receiving any other investigational agents.   
 
3.2.3 Patients with impaired GI function or GI disease that may significantly alter the 
absorption of oral IPdR and capecitabine (e.g. ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection).  Patients with 


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27 
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 GI motility or 
absorption.  Patients with colostomies are allowed unless colostomy is for one of the 
precluded reasons above. 
 
3.2.4 Treatment with warfarin is not allowed.  However, therapy with heparin, low molecular 
weight heparin (LMWH), and DOACs (Direct oral anticoagulating agent) such as 
dabigatran (Pradaxa), rivaroxaban, and apixaban [Eliquis] is allowed. 
 
3.2.5 Patients with an active concurrent invasive malignancy.   
 
3.2.6 History of prior invasive rectal malignancy, regardless of disease-free interval. 
 
3.2.7 Patients who have received pelvic RT for rectal cancer, or prior pelvic RT for any other 
malignancy that would prevent the patient from receiving the required RT for this study. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to IPdR or capecitabine. 
 
3.2.9 Patients with uncontrolled intercurrent illness. 
 
3.2.10 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.11 Pregnant women are excluded from this study because IPdR may have the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with IPdR, 
breastfeeding should be discontinued if the mother is treated with IPdR.  These potential 
risks may also apply to other agents used in this study. 
 
3.2.12 Patients that received 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. 
 
3.2.13 Known homozygous DPD (dihydro pyrimidine dehydrogenase) deficiency 
 
3.2.14 History of, or any evidence of, active non-infectious pneumonitis. 
 
3.2.15 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. 
 


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28 
3.2.16 History of active TB (Bacillus Tuberculosis). 
 
3.2.17 Active or chronic infection requiring systemic therapy. 
 
3.2.18 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. 
 
3.2.19 Active seizure disorder uncontrolled by medication. 
 
3.2.20 Synchronous colon cancer. 
 
3.2.21 Other invasive malignancy within 5 years.  Exceptions are colonic polyps, non-melanoma 
skin cancer, or carcinoma-in-situ of the cervix. 
 
3.2.22 Antineoplastic therapy (e.g., chemotherapy or targeted therapy) for other invasive 
malignancy within 5 years (For the purposes of this study hormonal therapy is not 
considered chemotherapy). 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    


NCI Protocol #: 10410 
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29 
 
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges,  
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) 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 (Investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the Clinical Investigator (CI) on 
the DTL must be rostered at the enrolling site with a participating organization. 
 
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. 
 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
30 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet (SSW) for Local Context 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). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record to be completed: 
• Holds an Active CTEP status, 
• Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster, 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s)record, 
• Includes the IRB number of the IRB providing approval in the FDA Form 1572 in the 
RCR profile, 
• Lists all sites on the IRB/REB approval as Practice Sites in the FDA Form 1572 in the 
RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional site 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, 
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory 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 to institutions and its associated investigators and staff on a participating roster. To 
view/download site registration forms: 
 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
31 
• 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 LAO-11030, and 
protocol number 10410, 
• Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration, to download and complete the forms provided.  (Note:  For sites 
under the CIRB initiative, IRB data will load automatically to the CTSU)  
 
4.2.2 Protocol Specific Requirements For 10410 Site Registration 
 
• Site Initiation Teleconference 
• Sites must be credentialed for NRG-GI002 in order to administer pelvic radiation therapy 
to patients enrolled in this trial. 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for training (STS.Support@theradex.com,  
Theradex phone: 609-799-7580). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
regulatory section, and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website.  The Clinical Investigator (CI) is required to review 


NCI Protocol #: 10410 
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32 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study.  To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off.  Any individual at the enrolling site on a 
participating roster may initiate the site DTL.  Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL.  Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU 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 
o 
Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
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 LPOs 
registration/randomization systems or Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment.  OPEN or IWRS 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:  Must be on an LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 


NCI Protocol #: 10410 
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33 
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 
FDA Form 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 Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  IWRS system also sends an email confirmation of the registration. You 
may 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. 
 
4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through Rave user roles:  “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the NCI Early-
Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly 
known as the ETCTN Biorepository).   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section  under the Rave Home tab and then 
under Rave Resource Materials. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 5.3. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN link 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.  


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
34 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
All specimen collections on this study are mandatory. 
 
Time Point 
Specimen 
Send Specimens 
To: 
Day 8 
• Prior to IPdR 
dose; and 
then after 
IPdR dose at 
• 30 min 
• 60 min 
• 120 min 
• 240 min 
• 10 mL blood in sodium heparin tube, 
processed for plasma 
ETCTN 
Biorepository 
• 5 mL blood in EDTA tube (only prior to 
IPdR dose) 
Collins Laboratory 
Day 21 
1-2 hours after 
IPdR dose 
• 10 mL blood in sodium heparin tube, 
processed for plasma 
ETCTN 
Biorepository 
• 5 mL blood in EDTA tube 
Collins Laboratory 
Day 35 
1-2 hours of 
after IPdR dose 
• 10 mL blood in sodium heparin tube, 
processed for plasma 
ETCTN 
Biorepository 
• 5 mL blood in EDTA tube 
Collins Laboratory 
8-12 weeks following completion of study treatment (Surgical Resection) 
 
• Snap-frozen surgical resection specimen1 
ETCTN 
Biorepository 
1A copy of the corresponding anatomic pathology report must be sent with the tissue and 
uploaded to Rave.   
 
5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 Specimen Procurement Kits  
 
Kits for the collection and shipment of frozen specimens to the ETCTN Biorepository can be 


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35 
ordered online via the Kit Management system: 
(https://ricapps.nationwidechildrens.org/KitManagement).  
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kit types per protocol per day (daily max = 6 kits).  
Kits are shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for 
each kit type is located on the Kit Management system website. 
 
5.2.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue:  
 
• Specimens submitted frozen [Surgical resection specimen, plasma] can be collected on 
any day but must be stored frozen and shipped to the ETCTN Biorepository on Monday 
through Thursday.  In the event that frozen specimens cannot be shipped immediately, 
they must be maintained in a -70°C to -90°C or colder freezer. 
 
• Fresh blood specimens [blood in EDTA] may be collected and shipped to Dr. Collins’ 
laboratory Monday through Thursday.  
 
5.3 
Specimen Tracking System Instructions 
 
5.3.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System.  The 
UPID contains no information or link to the treatment protocol.  IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 


NCI Protocol #: 10410 
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36 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s), and the diagnostic pathology report must also be uploaded into Rave.  Important:  
Remove any personally identifying information, including, but not limited to, the patient’s 
name, date of birth, initials, medical record number, and patient contact information from 
the institutional pathology report prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.3.2 Specimen Labeling 
 
5.3.2.1 Blood Specimen Labels  
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date and collection time (to be added by hand) 
 
5.3.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers:  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., Frozen tissue etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number (if applicable)  
• Collection date (to be added by hand) 
 
5.3.2.3 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
37 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.3.3 Overview of Process at Treating Site 
 
5.3.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.3.3.2 Rave Specimen Tracking Process Steps 
 


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Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date and collection time on each label.  
After collection, store labeled specimens as described in Section 5.3.2. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Pathology Verification form (when applicable).  
Return to Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per specimen).  
Uploaded reports should have protected health information (PHI) data, like name, 
mailing address, medical record number or social security number (SSN), redacted.  Do 
not redact SPID, block number or relevant dates (such as collection date), and include the 
UPID and patient study ID on each document.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5:  Print shipping list report and prepare to ship.  
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
5.4 
Specimen Collection  
 


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39 
5.4.1 Collection of Snap-Frozen Resection Tissue 
 
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 30 minutes from 
resection. 
2. Label a 2-mL cryovial(s) according to instructions in Section 5.3.2.  
3. Using clean forceps place the tissue in a pre-chilled cryovial and freeze the vial(s) in 
either vapor phase liquid nitrogen, on dry ice, or by immediate placement in a -70 to -
90°C or colder freezer.  Keep frozen until shipment to the ETCTN Biorepository. 
 
5.4.2 Blood Collection  
 
5.4.2.1 Collection of Blood in Sodium Heparin Tubes for Plasma Processing  
 
1. Label sodium heparin tube(s) according to the instructions in Section 5.3.2.  
2. Collect 10 mL of whole blood in sodium heparin tube(s).  
3. Process plasma by centrifuging for 10 minutes at 1,200 × g at room temperature. 
4. Using a clean transfer pipette, transfer 1 mL of plasma into each of the labeled cryovials 
(using the label printed from the ETCTN Specimen Tracking System or following the 
instructions in Section 5.3.2).  Avoid picking up the blood cells when aliquoting by 
keeping the pipet above the cell layers and leaving a small amount of plasma in the tube.  
Tightly secure the cap of the vials before storage.  Aliquoting and freezing of plasma 
specimens should be completed within 1 hour of centrifugation.  
5. Store plasma cryovials upright in a specimen box or rack in an -70°C to -90°C or colder 
freezer prior to delivering to laboratory.  Do not allow specimens to thaw after freezing.  
 
5.4.2.2 Collection of Whole Blood in EDTA Tubes  
 
1. Label EDTA tubes according to the instructions in Section 5.3.2. 
2. Collect 5 mL blood in EDTA tube(s) and gently invert tube to mix. 
3. Ship on day of collection (whenever possible) according to instructions in Section 
5.6. 
4. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment.  
 
5.5 
Shipping Specimens from Clinical Site to the ETCTN Biorepository  
 
5.5.1 Specimen Shipping Instructions 
 
Frozen specimens may be shipped on Monday through Thursday.  
 
5.5.1.1 
Shipping Frozen Specimens in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 


NCI Protocol #: 10410 
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40 
and time point.  
3. Place the zip-lock bags in the biohazard envelope containing absorbent material.  Expel 
as much air as possible and seal securely.  
4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.  
5. Place frozen specimens in the kit compartment with dry ice.  Layer the bottom of the 
compartment with dry ice until it is approximately one-third full.  Place the frozen 
specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
compartment is almost completely full.  When packaging specimens, ensure that you 
leave enough room to include at least 5 pounds of dry ice in the shipment.  
6. Insert a copy of the required forms into a plastic bag and place in the kit chamber. 
7. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
8. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable sealing 
tape.  Do not completely seal the container. 
9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 
11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.5.2 Shipping Address 
 
Ship to the address below.  Frozen specimens may be shipped on Monday through Thursday.  Do 
not ship specimens the day before a holiday. 
 
ETCTN Biorepository 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The ETCTN Biorepository FedEx Account will not be provided to submitting 
institutions.  There is no central Courier account for this study.  Sites are responsible for all costs 
for shipments to the ETCTN Biorepository. 
 
5.5.3 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
ETCTN Biorepository  


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41 
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
5.6 
Shipping Specimens from Clinical Sites to Other Laboratories 
 
5.6.1 Shipping Blood for IUdR Incorporation to the Collins Laboratory 
 
Fresh blood specimens should be collected and shipped Monday through Thursday. 
 
5.6.1.1 
Shipping Ambient Blood in Your Own Container 
 
Fresh blood for 10410 must be shipped using institutional supplies.  Packaging guidelines for 
sending blood are provided below. 
 
1. Before packaging specimens, verify that the collection tube is labeled according to 
instructions in section 5.3.2. 
2. Place the blood collection tube into a zip-lock bag.   
3. Place zip-lock bag into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.  
4. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
5. Place the specimen(s) and a copy of the shipping manifest into a sturdy shipping 
container. In winter months, please use an insulated container and include extra 
insulation, such as bubble wrap, inside the shipping container to prevent specimens from 
freezing.  
6. Close the container and tape shut. 
7. Attach a shipping label to the top of the shipping container.  
8. Attach an Exempt Human Specimen sticker to the side of the container. 
9. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.1.2 
Shipping Address 
 
Kimberly Hill/Larry Anderson 
FNLCR 
OAD/DTP 
150 Boyles Street; Building 1036/1047 
Frederick, MD 21702 
 
5.6.1.3 
Contact Information for Assistance 
 
Larry Anderson:  Larry.anderson@nih.gov 
 
5.7 
Biomarker Plan  
 
 


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42 
List of Biomarker Assays in Order of Priority 
 
Priority 
Biomarker 
Name 
Assay 
(CLIA:  Y/N) 
Use in the Trial and 
Purpose 
Specimens 
Tested 
Collection Time 
Points 
Mandatory 
or Optional 
Assay Laboratory 
and Lab PI 
Tissue-based Biomarkers 
1 
IUdR 
Incorporation 
IUdR-DNA 
cellular 
incorporation 
CLIA:  N 
Integrated 
To correlate %IUdR 
incorporation in tumor 
cells with IPdR PK and 
clinical tumor response 
Surgical resection 
(snap frozen) 
At 8-12 weeks 
following 
completion of 
therapy 
M 
Clinical Pharmacology 
Branch at 
Developmental 
Therapeutics Program 
(DTP), DCTD, 
National Cancer 
Institute (NCI) 
Jerry Collins, Ph.D. 
collinsje@mail.nih.gov  
Blood-based Biomarkers 
1 
IPdR 
pharmacokinetics 
 
Plasma levels of 
IPdR, IUdR, IP 
and IU 
 
PK 
CLIA:  N 
Integrated 
Plasma levels of IPdR, 
IUdR, IP and IU 
Plasma 
 
(Blood collected 
in sodium heparin 
tubes) 
Day 8 – Prior to 
the PO IPdR dose 
and then at 30, 60, 
120, and 240 
minutes following 
PO IPdR dose 
 
Days 21 and 35 – 
1-2 hrs. following 
PO IPdR dose (at 
the time of 
sampling for 
%IUdR 
incorporation in 
circulating 
granulocytes) 
M 
Clinical Pharmacology 
Branch at 
Developmental 
Therapeutics Program 
(DTP), DCTD, 
National Cancer 
Institute (NCI) 
Jerry Collins, Ph.D. 
collinsje@mail.nih.gov 


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43 
Priority 
Biomarker 
Name 
Assay 
(CLIA:  Y/N) 
Use in the Trial and 
Purpose 
Specimens 
Tested 
Collection Time 
Points 
Mandatory 
or Optional 
Assay Laboratory 
and Lab PI 
2 
IUdR 
incorporation 
(granulocytes) 
IUdR-DNA 
cellular 
incorporation 
CLIA:  N 
Integrated 
To correlate IUdR 
incorporation in 
granulocytes with 
peripheral blood 
counts, other systemic 
toxicities (CTCAE 
v5.0), and plasma PK 
obtained at the same 
time points. 
Blood 
(EDTA) 
Day 8 – Prior to 
the PO IPdR dose  
Days 21 and 35 – 
1-2 hrs. following 
PO IPdR dose 
M 
Clinical Pharmacology 
Branch at 
Developmental 
Therapeutics Program 
(DTP), DCTD, 
National Cancer 
Institute (NCI) 
Jerry Collins, Ph.D. 
collinsje@mail.nih.gov 
3 
Capecitabine 
pharmacokinetics 
Plasma levels of 
capecitabine, 5’-
DFUR, FBAL, 
and 5-FU 
PK 
CLIA:  N 
Exploratory 
Plasma levels of 
capecitabine, 5’-
DFUR, FBAL, and 5-
FU 
Plasma 
 
(collected as part 
of the IPdR PK 
biomarker) 
Day 8 – Prior to 
the PO IPdR dose 
and then at 30, 60, 
120, and 240 
minutes following 
PO IPdR dose 
 
Days 21 and 35 – 
1-2 hrs. following 
PO IPdR dose (at 
the time of 
sampling for 
%IUdR 
incorporation in 
circulating 
granulocytes) 
M 
Clinical Pharmacology 
Branch at 
Developmental 
Therapeutics Program 
(DTP), DCTD, 
National Cancer 
Institute (NCI) 
Jerry Collins, Ph.D. 
collinsje@mail.nih.gov 


NCI Protocol #: 10410 
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44 
 
5.8 
Integrated Correlative Studies 
 
5.8.1 IUdR Incorporation in Surgical Resection Specimen 
 
5.8.1.1 
Specimen(s) Receipt and Processing at the ETCTN Biorepository  
 
At the time of resection, the surgical specimen will be snap-frozen by individual sites according 
to instruction in Section 5.4.1 and sent to the ETCTN Biorepository as soon as possible after 
surgical resection is performed.  The ETCTN Biorepository will accession, barcode, and weigh 
tissue upon receipt.  Frozen tissue will be stored in a liquid nitrogen vapor phase freezer until the 
end of the study, when they are shipped to Dr. Collins’ laboratory in dry ice via overnight 
shipping.  Do not allow specimens to thaw after freezing. 
 
Prior to distribution to Dr. Collins’ laboratory at the end of the study, the Biorepository will 
embed a piece of tissue in OCT media to section and stain for pathology QA review, including 
% tumor vs. stroma, % tumor vs. necrosis, and confirming concordance with the institutional 
diagnosis. 
 
5.8.1.2 
Site Performing Correlative Study 
 
This study will be performed under the supervision of Dr. Jerry Collins in the Clinical 
Pharmacology Branch at Developmental Therapeutics Program (DTP), DCTD. 
 
Actual shipment of specimens from the ETCTN Biorepository should be coordinated with the 
laboratory.  Please contact Larry.anderson@nih.gov for any questions regarding the shipment of 
samples.  
 
Shipping Information: 
 
Kimberly Hill/Larry Anderson 
FNLCR 
OAD/DTP 
150 Boyles Street; Building 1036/1047 
Frederick, MD 21702 
 
5.8.2 IPdR and Capecitabine PK 
 
5.8.2.1 
Specimen(s) Receipt and Processing at the ETCTN Biorepository  
 
Upon receipt, the ETCTN Biorepository will accession, barcode, and bank frozen plasma 
aliquots in a -80°C freezer until distribution.  Plasma samples for each patient should be batched 
and sent to Dr. Collins’ laboratory as soon as the Day 35 sample is received at the Biorepository. 
 
5.8.2.2 
Site Performing Correlative Study 
 


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45 
This study will be performed under the supervision of Dr. Jerry Collins in the Clinical 
Pharmacology Branch at DTP, DCTD. 
 
Actual shipment of specimens from the ETCTN Biorepository should be coordinated with the 
laboratory.  Please contact Larry.anderson@nih.gov for any questions regarding the shipment of 
samples.  
 
Shipping Information: 
 
Kimberly Hill/Larry Anderson 
FNLCR 
OAD/DTP 
150 Boyles Street; Building 1036/1047 
Frederick, MD 21702 
 
5.8.3 IUdR incorporation in granulocytes 
 
5.8.3.1 
Specimen(s) Receipt and Processing at the Collins Laboratory  
 
Upon receipt of fresh blood specimens in EDTA, Dr. Collins’ laboratory will accession and 
barcode the samples prior to processing.  Processing will be according to the methodology 
described in Section 2.5.4, including granulocyte isolation using a histopaque (Sigma Chemical 
Co., St. Louis, MO) 1077/1119 gradient. 
 
5.8.3.2 
Site Performing Correlative Study 
 
This study will be performed under the supervision of Dr. Jerry Collins in the Clinical 
Pharmacology Branch at DTP, DCTD. 
 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported AEs and potential risks are 
described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
6.1.1 IPdR dose escalation schema 
 
This is a phase 1 dose escalation study that consists of two parts, Part IA and Part IB.  Part IA 
uses an accelerated titration design with a single patient cohort, and a 100% dose escalation 
between patient cohorts until a treatment related Grade 2 non-hematologic toxicity or grade 3 
neutropenia or thrombocytopenia is observed.  The accelerated titration design may reduce the 
number of patients potentially undertreated by receiving PO IPdR doses that are not expected to 
result in clinically relevant radiosensitization.  After the completion of part 1A, the protocol will 


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46 
be amended to incorporate the dose levels for part 1B.  Part IB will commence when toxicity is 
encountered in Part IA.  Cohorts of 3-6 patients will be entered per dose level until dose-limiting 
(DLT) is reached, and the MTD is defined.  An IPdR dose of 2400 mg QD is the maximum 
allowed dose. Dose escalation between dose levels will be adjusted to accommodate the 
availability of 75mg and 600mg IPdR capsules. 
 
Part IA: 
 
An initial single patient dose escalation of twice daily PO IPdR × 38 days with concomitant 
capecitabine (825 mg/m2/BID Monday morning through Friday evening on RT days) will be 
conducted in Part IA.  Dosing will be based on the patient’s assigned dose level.  The starting 
dose is 75 mg BID (Dose 1) × 38 days (≅ 1/10th MTD in ferrets, as previously determined 
[Kinsella et al., 2000]).  A 100% dose escalation will be used until a treatment related Grade 2 
non-hematologic toxicity or grade 3 neutropenia or thrombocytopenia is observed.  Two 
additional patients will then be entered at this dose level.  If a second patient of these 3 patients 
experiences a treatment related Grade 2 systemic toxicity (or if a single patient develops 
treatment related > grade 3 toxicity), then a stop/switch rule is invoked for Part IA and Part IB of 
the dose escalation scheme commences.  If not, the dose is incremented to the next level in Part 
IA (after each patient is evaluated for 4 weeks of follow up to assess acute toxicity). 
 
Definitions of “Dose-limiting” and “Moderate” toxicities for Part IA (for exceptions see Section 
6.2) 
 
Grade 2 non-hematologic 
Moderate 
Grade 3 non-hematologic 
DLT 
Grade 4 non-hematologic 
DLT 
Grade 2 ANC and/or Plt 
Moderate 
Grade 3 ANC and/or Plt 
Moderate 
Grade 4 ANC and/or Plt 
DLT 
 
In part IA, if a patient develops: 
• a DLT, the stop/switch rule is invoked, and part IB commences 
• a “moderate” toxicity, two additional patients will be entered at this dose level, and if  
o one of these patients develops a DLT, the stop/switch rule is invoked, and part IB 
commences 
o one of these patients develops a “moderate” toxicity, the stop/switch rule is invoked, 
and part IB commences 
o neither of the two additional patients develops a DLT or “moderate” toxicity, part IA 
recommences at the next dose level 
 
A patient will be considered unevaluable if they receive <67% of their total intended dose of any 
study treatment (IPdR, capecitabine, or RT) for non-protocol required reasons.  Patient 
medication diaries and RT documentation will be reviewed as each patient comes off-study to 
determine the actual total doses of each study treatment they received.  If a patient is deemed 
unevaluable by this definition, they will be replaced by a new patient to be treated at the same 
intended dose level. 


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47 
 
Part IA dose escalation schema 
Dose Level 
Total radiation Gy (45 
Gy primary field, 5.4 
Gy boost @ 1.8 
Gy/fraction/day) 
Capecitabine (mg/m2 
BID)  
Monday am – Friday 
pm throughout RT 
IPdR (mg BID) 
Administered 
throughout radiation 
1A 
50.4 
825 mg/m2 BID 
75 mg 
BID 
2A 
50.4 
825 mg/m2 BID 
150 mg BID 
3A 
50.4 
825 mg/m2 BID 
300 mg BID 
4A 
50.4 
825 mg/m2 BID 
600 mg BID 
5A 
50.4 
825 mg/m2 BID 
1,200 mg BID 
BID – Twice Daily, RT – Radiation therapy 
 
Part IA is closed to further accrual. 
 
Part IB: 
 
Under Part IB of this protocol, cohorts of 3-6 patients will be entered per dose level.  In Part IB, 
3 patients will initially be accrued to a dose level.  If 0 of 3 patients do not experience grade 3 
non-hematopoietic or grade 4 hematopoietic/GI DLT, then dose escalation will proceed.  If a 
DLT is observed in one of the first 3 patients in a dose level cohort, the cohort will be expanded 
to a maximum of 6 patients.  
  
Part IB dose escalation schema 
Dose Level 
Total radiation Gy (45 
Gy primary field, 5.4 Gy 
boost @1.8 
Gy/fraction/day) 
Capecitabine (mg/m2 BID) 
Monday am – Friday pm 
throughout RT 
IPdR (mg QD) 
Administered throughout 
radiation1,2 
1B 
50.4 
825 mg/m2 BID 
75mg QD 
2B 
50.4 
825 mg/m2 BID 
150mg QD 
3B 
50.4 
825 mg/m2 BID 
300mg QD 
4B 
50.4 
825 mg/m2 BID 
600mg QD 
5B 
50.4 
825 mg/m2 BID 
1200mg QD 
6B 
50.4 
825 mg/m2 BID 
1800mg QD 
7B 
50.4 
825 mg/m2 BID 
2400mg QD 
QD – Once Daily, BID – Twice Daily, RT – Radiation therapy 
1 The maximum allowed dose of IPdR is 2,400mg QD 
2 Actual doses will be rounded to account for availability of only 75 mg and 600 mg IPdR capsules 
 


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48 
Patients will be assessed 4 weeks following completion of study treatment (Week 10 unless there 
were delays in therapy).  This will be the final assessment for study-related toxicity.  Patients 
will undergo surgical resection 8-12 weeks following completion of chemoRT (IPdR), and 
study-related response will be assessed at that time. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Study 
Length 
IPdR 
Take on an empty 
stomach, either 1 
hour before or 2 
hours after meals. 
Dose as appropriate 
for the assigned 
dose level. 
PO 
QDA 
38 days 
(6 
weeks) 
 
 
 
Capecitabine 
Take within 30 
minutes after a meal 
(breakfast and 
dinner). 
825 mg/m2C 
PO 
BID 
Monday morning 
through Friday evening 
on RT days B,C 
RT 
 
1.8 Gy/fraction/day × 28 
doses (50.4 Gy total dose) 
5 doses per week until 
week 5 and 3 doses 
during Week 6D 
AOn the days of radiation therapy, the daily dose of IPdR will be administered within 30 min - 2 hours prior to 
radiation.Patients may take dose at home if the timing allows. 
BCapecitabine will be taken Monday morning through Friday evening each week of RT. 
CDosing will be with 150 mg and 500 mg tablets 
DRT will be given only Monday through Friday 
QD – Once Daily, BID – Twice Daily, PO – Oral, RT – Radiation therapy 
 
6.1.2 IPdR administration 
 
• Method of delivery is by oral administration in capsule form BID × 38 days for Part IA and 
once daily for Part IB (Week 6). 
• Dosing will be based on the patient’s assigned dose level. 
• The initial drug dose is 75 mg BID. 
• The capsules will be taken on an empty stomach (i.e. either 1 hour before or 2 hours after 
meals). 
• On the days of radiation therapy, the daily dose will be administered within 30 min - 2 hours 
prior to radiation and can be taken at home if timing allows. 
• Assessment of compliance with treatment:  Patients will be instructed to keep a medication 
log, recording the date, time and numbers of capsules of each dose (See Appendix D) 
 
6.1.3 Capecitabine 
 
6.1.3.1 
Dose and Schedule 
 
Capecitabine should be dosed at 825 mg/m2 PO BID on days of radiation only.  The usual 
radiation schedule will be Monday through Friday, and in that case, the first capecitabine dose of 
the week will be taken on Monday morning, and the last dose of the week will be taken on 


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49 
Friday evening.  Dosing will be with 150 mg and 500 mg tablets to achieve a dose as close as 
possible to 825 mg/m2.  Additional dose adjustments will be made as needed.  At the discretion 
of the treating physician, the body surface area (BSA) may be capped at 2.20 – 2.25 for 
calculating capecitabine dosage (optional).  Please refer to package insert for exact dose 
calculation details. 
 
6.1.3.2 
Guidance for Administration: 
 
Capecitabine is to be taken roughly 12 hours apart at approximately the same times each day 
with about 200 ml of water within 30 minutes after a meal.  Capecitabine tablets should be 
swallowed as whole and should not be crushed or cut.  Capecitabine tablets should be stored at 
room temperature (15° to 30° C) in the container in which they are provided. 
 
6.1.4 Radiation therapy 
 
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. 
 
Phase  
Target  
Dose (Gy)  Number 
of 
Fractions  
Fraction 
Size  
Rx Length  Rx Days  
Initial  
PTV_4500  45  
25  
 
 
1.8 Gy  
5 weeks  
Monday through 
Friday  
Boost 
PTV_5040  
 
5.4  
 
3  
 
 
3 days 
Total 
 
50.4 
28 
 
6.1.4.1 
Treatment technology 
 
This protocol allows, but does not require, the use of Intensity Modulated Radiation Therapy 
(IMRT).  This protocol requires treatment with photons with minimum nominal energy 
specification of 6 MV.  IMRT is allowed and can be used either with static gantry or arcs 
(VMAT).  Tomotherapy delivery is allowed.  
 
6.1.4.2 
Immobilization and simulation 
 
Immobilization 
  
Proper immobilization is important for this protocol.  Patient setup reproducibility must be 
achieved using appropriate clinical devices.  A custom immobilization device (such as Alpha 
Cradle or Vac-Loc for supine patients and an Alpha Cradle with bowel displacement device for 
prone patients) is suggested to minimize set-up variability.  Simulation may be done with the 
patient in the supine "arms up" position for patients with very thin body habitus or the prone 


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50 
"arms up" position for patients of moderate or large body habitus.  
 
Simulation imaging 
  
CT Simulation is required, and the images must be acquired using a CT-simulator with a slice 
thickness ≤3 mm.  Care should be taken to use the smallest possible FOV that contains the entire 
surface of the patient with a 512×512 image matrix.  Oral CT contrast is strongly suggested.  An 
anal marker at the verge is required.  The CT simulation must be performed with the patient in 
the treatment position.  
 
Typical CT scan limits are mid-femur inferiorly to include the L2 vertebral body superiorly.  The 
CT scan needs to include the following structures in their entirety:  Treatment volumes (PTVs), 
bladder, and femoral heads.  
 
6.1.4.3 
Definition of target volumes and margins  
 
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. 
  
The volumes are to be defined by planning CT/MRI techniques as well as PET scans when 
clinically appropriate.  While PET scans are not mandated as part of the protocol, for those 
patients who have PET scans available, the information may be used to aid in treatment 
planning.  The inferior extent of palpable tumors should be determined by physical examination.  
 
Examples of contoured patients (anorectal atlas) are available for review on the NRG Oncology 
website (https://www.nrgoncology.org/Resources/Contouring-Atlases).  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  
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 
CTV to receive 45 Gy 
Required 
 
Detailed specification:  


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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 (CTV_4500) = 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 (CTV_4500) = 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.  
− External iliac LNs are to be included in CTV_4500. 
− Inguinal LN basins will not be included in the CTV_4500 or CTV_5040 volume 
in low-lying rectal cancer except in patients with high likelihood of pathologic 
involvement by MRI or PET/CT imaging.  A LN biopsy of inguinal LNs is not 
recommended. 
• 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 (CTV_4500) = 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  
− Anterior Border:  should include the interface with the bladder, vagina, uterus or 
prostate  
− Inferior Border:  the levators.  The caudal extent of CTV_4500 is the pelvic 
floor/levators.  If there is radiographic evidence of extension into the ischiorectal 
fossa, the CTV_4500 will extend to 2-3 mm beyond the levator muscles.  For very 


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advanced cT4 tumors extending through the levators, a 2-cm margin up to bone is 
recommended. 
• 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.  
 
6.1.4.4 
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. 
 
Large bowel constraint: 
There is no large bowel constraint.  However, “uninvolved colon” defined as part of the large 
bowel that lies outside of the CTVs (rectum and part of the rectosigmoid) should be contoured 
separately from the rectum. 
 
6.1.4.5 
Dose Prescription 
 


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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  
 
6.1.4.6 
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 Section 6.1.4.7 on compliance criteria must be used.  
 
3-D treatment planning guidelines for rectal cancer for this protocol are detailed in:  
http://econtour.org/training/rectal_cancer_module.pdf 
 
6.1.4.7 
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  
Dmax(Gy) or Dmax(%): 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 6.1.4.5), 
V95%= 100%.  A combination (plan sum) is required to evaluate the dosimetric compliance 
criteria for critical structures.  
 
Heterogeneities will be taken into account in the radiation dose calculation, in accordance with 
the guidelines provided on the IROC website:  http://rpc.mdanderson.org/RPC/home.htm. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 


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met. 
 
6.1.4.8 
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. 
 
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 
 
Dmax(Gy) 
≤50 
≤55 
Femur_L&Femur_R 
D50%(Gy) 
≤30 
≤33 
 
D40%(Gy) 
≤40 
≤44 
 
D5%(Gy) 
≤45 
≤49.5 
 
Dmax(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. 
 
6.1.4.9 
Patient specific QA  
 
Any patient-specific QA that needs to be acquired should follow institutional guidelines.  Only 
sites credentialed for NRG-GI002 can administer pelvic radiation therapy to patients enrolled in 
this trial.  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.  
 


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6.1.4.10 
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  
 
Due to concern about the estimated doses given from IGRT, efforts will be made to limit the 
imaging dose when IGRT is used.  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. 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
Management and dose modifications associated with the above AEs are outlined in Section 7. 
 
DLTs will be captured until 4 weeks after completion of IPdR therapy and will be graded 
according to the CTCAE v5.0.  DLTs will be defined as clinically significant grade 3 or 4 
toxicities possibly or probably related to study treatment.   
 
• Grade 4 neutropenia (ANC < 500/mm3) 
• Grade 4 electrolyte toxicities 
• ANC <1000/mm3 with fever (temp >101 F) or infection 
• Grade 4 thrombocytopenia:  Platelets <25,000/mm3  
• Platelets <50,000/mm3 requiring transfusion  
• Grade 3 or 4 treatment related non-hematologic toxicities excluding alopecia.  
• Patients who receive <67% of intended IPdR secondary to treatment related toxicities 
will also be considered as having a DLT 
 
In addition, during chemoradiation, DLTs will also include AEs requiring interruptions of 
radiation for >5 consecutive scheduled fractions (and / or ≥9 total scheduled fractions) or for >10 
consecutive scheduled doses of capecitabine (and / or ≥19 total scheduled doses of capecitabine).  
The following AEs will not be considered DLTs: 
 
• Any grade of alopecia, 
• Grade 3 arthralgia or myalgia,  
• Brief (<1 week) grade 3 fatigue,  
• Grade 3 fever, 


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• Grade 3 diarrhea or vomiting responding to supportive care 
o Grade 3 nausea, vomiting or diarrhea will be considered a DLT if it occurs for greater 
than 48 hours despite maximal medical support.   
• Grade 3 radiation dermatitis, 
• Grade 3 or 4 electrolyte abnormalities will not be considered DLTs if the electrolyte 
disorder can be corrected to grade 2 or less within 72 hours. 
 
All patients who have received at least one dose of IPdR are evaluable for toxicities.  
 
For dose escalation decisions, patients should have completed ≥80% of the planned 
chemoradiation doses unless the reason for discontinuation is an AE that qualifies for DLT.  
 
Dose escalation will proceed within each cohort in Part IB according to the following scheme.  
DLT is defined above. 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  
1 out of 3 
Enter 3 more patients at this dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• 
If 1 or more of this group suffer DLT (i.e. 2 of 6 
patients), then dose escalation is stopped, and this 
dose is declared the maximally administered dose.   
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose.  At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
During the MTD dose finding portion, patients who are removed from study for reasons other 
than a DLT will be replaced. 
 
6.3 
Dose Expansion Cohorts: 
 
For the expansion cohort, patients will continue to be monitored for occurrence of DLT.  Three 
additional patients will be treated at the dose level below the dose associated with DLT to 
establish the MTD.  The MTD is defined as the dose below which 2 or more of 3 to 6 patients 
experience DLT.  The MTD will be deemed to be RP2D if ≥80% of the patients are able to 
receive ≥80% of the planned treatment doses.  Monitoring of all safety and toxicity data is done 
by the Principal Investigator and the Corresponding Organization on a real-time basis as data are 
entered into Medidata Rave using the Web Reporting Module.  All participating sites are 
expected to notify the Principal Investigator when a DLT has occurred. 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 


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6.4.1 Hematopoietic growth factors 
 
Hematopoietic growth factors are not permitted on this study. 
 
6.4.2 Management of anemia 
 
Transfusion is acceptable for improving the hemoglobin value to >10 gm/dL 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. 
 
6.4.3 Management of diarrhea 
 
Diarrhea is a commonly occurring toxicity with therapy for rectal cancer.  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 F for clinical management of diarrhea and Appendix G for patient instructions for 
diarrhea management). 
 
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 G for sample patient 
instructions for diarrhea management). 
 
Refer to the ASCO Recommended Guidelines for Treatment of Cancer Treatment-Induced 
Diarrhea for additional recommendations regarding diarrhea (Benson et al., 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.  
 
Aggressive supportive care should be provided for patients with grade 4 ANC and ≥ grade 3 
diarrhea until neutropenia and diarrhea resolve.  See Appendix F for clinical management of 
diarrhea.  Hospitalization for evaluation and management of grade 3 or grade 4 complicated 
diarrhea, as defined in Appendix F, is strongly recommended. 
 
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. 
 
6.4.4 Management of nausea or vomiting 
 
Grade 3 nausea and vomiting has been seen in early phase studies with 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 


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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: 
 
Antiemetic therapy should be administered according to National Comprehensive Cancer 
Network (NCCN) or American Society of Clinical Oncology (ASCO) clinical practice 
guidelines. 
 
6.4.5 Mucocutaneous and Dermatologic Toxicity 
 
Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome 
and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine.  
Capecitabine should be permanently discontinued in patients who experience a severe 
mucocutaneous reaction possibly attributable to capecitabine treatment. 
 
Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral 
erythema) is a cutaneous toxicity.  Median time to onset was 79 days (range from 11 to 360 
days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in 
the metastatic setting.  Grade 1 is characterized by any of the following: numbness, 
dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or 
discomfort which does not disrupt normal activities.  Grade 2 hand-and-foot syndrome is defined 
as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the 
patient’s activities of daily living.  Grade 3 hand-and-foot syndrome is defined as moist 
desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe 
discomfort that causes the patient to be unable to work or perform activities of daily living.  See 
Section 7.3 for details on capecitabine dose modification. 
 
6.4.6 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. 
 
• Targeted therapy 
Administration of targeted therapy for malignancy is prohibited prior to resection of the 
primary rectal cancer. 
 
• Radiation therapy 
Administration of radiation therapy other than the radiation therapy specified in this 


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protocol is prohibited. 
 
• 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. 
 
6.4.7 Drug/drug interactions 
 
• Phenytoin:  Increased phenytoin levels have also been reported in patients taking 
capecitabine concurrently with phenytoin and, therefore, need to be monitored. 
 
Because there is a potential for interaction of IPdR with other concomitantly administered drugs, 
the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions.  The study team 
should check a frequently-updated medical reference for a list of drugs to avoid or minimize use 
of.  Appendix C (Patient Clinical Trial Wallet Card) should be provided to patients if available. 
 
Interaction of IPdR with other drugs was not encountered in a previous trial of IPdR in patients 
with GI malignancies (Kinsella et al., 2019).  However, as stated above, the potential for such 
interactions and overlapping toxicities exists and will be closely monitored. 
 
6.5 
Duration of Therapy 
 
In the absence of treatment delays due to AE(s), treatment may continue until study completion 
or until one of the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable AE(s) 
 
• 
Patient decides to withdraw from the study 


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• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
 
o All women of childbearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.6 
Surgery 
 
Surgery must be performed within 8 to 12 weeks following the completion of study treatment. 
 
6.7 
Adjuvant Therapy 
 
Per protocol, adjuvant therapy is not recommended but allowed at the investigator's discretion.  
 
6.8 
Duration of Follow-Up 
 
Patients will be followed for 4 weeks after completion of study treatment, removal from study, or 
until death, whichever occurs first.  Patients will be assessed at 4 weeks (approximately 30 days) 
following completion of IPdR (Week 10 unless there were delays in therapy).  This will be the 
final assessment for study-related toxicity.  Patients will undergo surgical resection 8-12 weeks 
following completion of study treatment, and study-related response will be assessed at that time.  
Patients removed from study for unacceptable AE(s) will be followed until resolution or 
stabilization of the adverse event. 
 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 


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7.1 
IPdR Treatment Management  
 
IPdR dose modifications are as follows: 
 
Table 5: 
Part IA IPdR dose levels 
Dose Level 
IPdR Dose 
1A (starting dose, Part IA) 
75 mg PO BID 
2A 
150 mg PO BID 
3A 
300 mg PO BID 
4A 
600 mg PO BID 
5A 
1200 mg PO BID 
 
Table 6: 
Part IB IPdR dose levels 
Dose Level 
IPdR Dose1,2 
1B (starting dose, Part IB) 
75mg QD 
2B 
150mg QD 
3B 
225mg QD 
4B 
300mg QD 
5B 
See Part IB dose escalation schema, 
Section 6.1.1 
1 The maximum allowed IPdR dose is 2400 mg QD. 
2 Actual doses will be rounded to account for availability of only 75 
mg and 600 mg IPdR capsules. 
 
7.2 
RT Treatment management 
 
Delays in radiation therapy occur for a variety of reasons (e.g. holidays, equipment issues, 
weather, etc.).  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. 
 
During this study, if chemotherapy is held, radiation therapy will continue.  If radiation is held, 
capecitabine will also be held; however, treatment with IPdR 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 v5.0 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. 
 
7.2.1 Management of capecitabine for delay in radiation therapy 
 
Capecitabine is administered BID on each day that the patient receives radiation treatment.  If 
radiation therapy is held, no capecitabine is administered on that day.  If the patient has taken the 


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AM capecitabine dose prior to arrival for radiation therapy, that is allowed, and the PM dose 
would be held.  The patient should resume the AM capecitabine dose on the morning of the next 
scheduled radiation therapy appointment. 
 
The duration of radiation therapy will be extended so that the total number of delivered fractions 
is 28 (Section 6.1).  The patient should receive a minimum of 56 doses of capecitabine (BID on 
each day of radiation therapy and additional doses if an AM dose was taken prior to cancellation 
of radiation therapy for a given day). 
 
7.2.2 Management of IPdR for delay in radiation therapy 
 
IPdR is administered either once daily or twice daily, 7 days a week, beginning with the first 
dose of capecitabine on Day 1.  IPdR must be taken 7 days/week for the duration of radiation 
therapy (i.e. to be discontinued only following the final dose of radiation therapy).  If radiation 
therapy is held, IPdR continues unless criteria for dose adjustment is met per Section 6.2.  IPdR 
either once daily or twice daily, 7 days a week, will continue through the last dose of radiation 
therapy.  Patients may receive up to 5 additional days (10 doses) of IPdR to accommodate delays 
in radiation therapy. 
 
7.3 
IPdR and Capecitabine treatment management 
 
Capecitabine and IPdR dose modifications are detailed in Table 7 and Table 8. 
 
Additionally, the following dose modification instructions must be followed: 
• 
All dose modifications should be based on the AE requiring the greatest dose 
modification. 
• 
If RT is not administered (holiday, weekend, RT related toxicity, etc.), capecitabine is 
held; however, IPdR and RT continue per protocol unless otherwise contraindicated. 
• 
If capecitabine and/or IPdR are held or discontinued, RT continues per protocol unless 
otherwise contraindicated. 
• 
Capecitabine doses that have been reduced may not be escalated. 
• 
IPdR doses that have been reduced may not be escalated. 
 
Table 7: 
Capecitabine and IPdR 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 
Dose Level -1 
Dose Level -2 
 
Dose Level -3 


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Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Dose Level -3 
IPdR 
Part IA: Assigned 
dose level 
 
Part IB: see Table 6 
 
Decrease one 
dose level 
(minimum dose 
is 75 mg QD; 
subjects 
requiring further 
dose reduction 
must have IPdR 
discontinued) 
 
See Tables 5 and 
6 for Parts IA 
and IB dose 
levels 
Decrease one 
dose level 
(minimum dose 
is 75 mg QD; 
subjects 
requiring further 
dose reduction 
must have IPdR 
discontinued) 
See Tables 5 and 
6 for Parts IA 
and IB dose 
levels 
Decrease one 
dose level 
(minimum dose 
is 75 mg QD; 
subjects 
requiring further 
dose reduction 
must have IPdR 
discontinued) 
See Tables 5 and 
6 for Parts IA 
and IB dose 
levels 
 
 
Table 8: Treatment management for capecitabine and IPdR 
 
Important table instructions: 
• Hold capecitabine and IPdR 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 IPdR unless otherwise 
noted. 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that REQUIRED DELAY IN 
TREATMENT 
Neutrophil count 
Hold capecitabine until ≥1200/mm3.  If recovery takes: 
1 wk – maintain dose;  
2-3 wks – ↓ one dose level 
decreased: 
Grade 2 (1000- 
1199/mm3), 3, and 4 
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 


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Important table instructions: 
• Hold capecitabine and IPdR 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 IPdR unless otherwise 
noted. 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that REQUIRED DELAY IN 
TREATMENT 
GI : 
Diarrhea (despite 
optimal antidiarrheal 
management) 
Grades 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) 
Grades 2, 3 
 
 
Hold and delay until ≤ grade 1, then ↓ one dose level 
Grade 4 
↓ one dose level  
Investigations (hepatic): 
Bilirubin, AST, alk phos 
Grades 2, 3 
Hold until bilirubin returns to the baseline grade and AST and alk 
phos have returned to < grade 1;  
then ↓ one dose level 
Grade 4 
Discontinue chemotherapy 
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 
Any event of seizure, regardless of grade or attribution, requires 
discontinuation of IPdR and discussion with the PI regarding the 
decision to resume treatment. 
disorders: 
Seizure 
Grades 1, 2, 3, 4 


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Important table instructions: 
• Hold capecitabine and IPdR 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 IPdR unless otherwise 
noted. 
CTCAE v5.0 
Adverse Event/Grade 
Modifications for AEs that REQUIRED DELAY IN 
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 PI 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent 
 
8.1.1 IPdR (NSC 726188) 
 
Chemical Name: 
5-iodo-2-pyrimidinone-2′-deoxyribose 
 
Classification: 
Pyrimidinone nucleoside analog 
 
Molecular Formula:  
C9H11IN2O4 
 
 
M.W.:  
338 
 
Mode of Action: 
 
 
Oral pro-drug hepatically converted by aldehyde oxidase to IUdR, for IUdR-mediated radio-
sensitization. 
 
Description:  


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IPdR drug substance is a light-yellow powder. 
 
How Supplied: 
 
 
IPdR is supplied by the DCTD, NCI and distributed by the Pharmaceutical Management Branch, 
CTEP, DCTD, NCI as 75 mg and 600 mg capsules. 
 
• The 600 mg capsules are dark green, opaque, hard gelatin capsules, size 0 and contain the 
inactive ingredients:  microcrystalline cellulose, sodium starch glycolate and magnesium 
stearate.  Capsules are packaged in 60 cc white, high-density polyethylene (HDPE) bottles 
with induction seals and white child-resistant polypropylene plastic caps.  Each bottle 
contains 30 capsules with a polystyrene coil and a silica gel desiccant. 
• The 75 mg capsules are white, opaque, hard gelatin capsules, size 1 and contain the inactive 
ingredients:  microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.  
Capsules are packaged in 60 cc white, high-density polyethylene (HDPE) bottles with induction 
seals and white child-resistant polypropylene plastic caps.  Each bottle contains 30 capsules with 
a polystyrene coil and a silica gel desiccant. 
 
Storage: 
 
 
Store bottles refrigerated at 2°-8°C in the original manufacturer’s container. Do not re-package 
capsules or remove the desiccant.  
 
If a storage temperature excursion is identified, promptly return IPdR capsules to 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: 
 
 
Shelf life stability testing of the intact bottles is on-going. 
 
Route and Method of Administration: 
 
 
Oral. Take by mouth on an empty stomach, either 1 hour before or 2 hours after meals. 
 
Availability 
 
IPdR is an investigational agent supplied to investigators by the Division of Cancer Treatment 
and Diagnosis (DCTD), NCI. 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 


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67 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI 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 participating investigator at that institution. 
 
Subjects must be enrolled prior to submission of a Clinical Drug Request via the 
PMB Online Agent Order Processing (OAOP) application.  No starter supplies of 
IPdR are available. 
 
Submit agent requests through the PMB 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, a “current” password, and 
active person registration status.  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.   
 
8.1.2.2 
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. 
 
8.1.3 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, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 


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• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
8.2 
Capecitabine 
 
Product description:  Capecitabine is commercially available as 150 mg or 500 mg tablets.  
Capecitabine tablets should be stored at room temperature (15° to 30°C) in the container in 
which they are provided.  Capecitabine is a white to off-white crystalline powder with an 
aqueous solubility of 26 mg/mL at 20ºC.  Capecitabine is supplied as biconvex, oblong film-
coated tablets for oral administration.  Each light peach-colored tablet contains 150 mg 
capecitabine and each peach-colored tablet contains 500 mg capecitabine. 
 
Solution preparation: Capecitabine is an oral medication 
 
Route of administration:  Capecitabine should be taken by mouth twice daily on days of 
radiation approximately 12 hours apart, within 30 minutes of a meal with about 200 ml of water 
 
Agent Ordering:  Capecitabine is commercially available 
 
Please refer to Capecitabine FDA package insert for complete product information 
 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This is a phase 1 study using an accelerated titration design according to Simon et al. (Simon et 
al., 1997).  A 100% dose increment will be used in Part IA (single-patient cohorts), and a more 
conservative dose increment (dose increment adjusted to accommodate availability of 75mg and 
600mg IPdR capsules) will be used in Part IB (3+3 cohort).  The doses of RT and capecitabine 
will be identical in Part IA and Part IB.  Part IA and Part IB are designed with a stopping rule 
rather than a pre-specified statistical model (Le Tourneau et al., 2009).  As a phase 1 study, the 
primary objective is to determine the MTD and document the toxicities of once daily PO IPdR 
when administered with capecitabine (825 mg/m2 BID) and RT (50.4 Gy in 28 fractions). 
 
DLT in Part IB will be reached when each of at least two of six patients enrolled at a dose level 
experience: 
• any two grade 3 treatment-related non-hematologic toxicities, OR 
• any one grade 4 treatment-related hematologic and/or GI toxicity. 
 
Three additional patients will be treated at the dose level below the dose associated with DLT to 
establish the MTD.  The MTD is defined as the dose below which 2 or more of 6 patients 
experience DLT attributable to IPdR. 
 
The total of six patients treated at the MTD will suffice to recognize common toxicities; common 
toxicities at MTD (those occurring in 30% of patients to be treated at the MTD) will rarely be 


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unobserved (p=0.117=0.76) and very common toxicities (those occurring in 50% of patients) will 
almost never be missed (p=0.016=.56). 
 
9.2 
Sample Size/Accrual Rate 
 
Planned sample size: 10-30 patients 
 
As this is a phase 1 study, the sample size will be determined by the number of patients required 
to establish the MTD of IPdR given with capecitabine and RT.  The statistical power of the 
correlative analyses with samples sizes of up to 30 patients is presented in Section 9.4.1. 
 
Estimated patient accrual rate: 
• Part IA:  The accelerated titration design with single-patient cohorts will allow for an 
estimated patient accrual rate of 1 patient every 3 months. 
• Part IB:  Up to 3 patients at a time may be treated at a given dose level, allowing for an 
estimated patient accrual rate of 2-3 patients every 3 months. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
3 
3 
0 
0 
6 
White 
5 
5 
3 
3 
16 
More Than One Race 
2 
2 
1 
1 
6 
Total 
11 
11 
4 
4 
30 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
 
OMB No. 0925-0001/0002 
 
 


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70 
9.3 
Stratification Factors 
 
N/A 
 
9.4 
Analysis of Secondary Endpoints 
 
9.4.1 Correlative and exploratory biomarker analyses 
 
Pre- to post-treatment changes in tissue biomarker levels measured on continuous and binary 
scales will be assessed using Wilcoxon signed rank or McNemar’s tests, respectively (two-sided; 
α=0.05).  Associations between therapeutic response and baseline biomarker values or temporal 
changes in biomarkers will be explored using Fisher’s exact tests or Wilcoxon rank sum tests.  
For the correlations between %IUdR-DNA incorporation and plasma PK, a two-sided Fisher’s z-
test with significance level of 0.05 and power of 80% will be used and the study will reject the 
null hypothesis (lack of correlation or r0=0) if we observe a correlation with r ranging from 0.79 
for N=10 subjects to 0.49 for N=30 subjects.  For the correlation of %IUdR DNA incorporation 
in circulating granulocytes and peripheral blood counts and toxicities, assuming the target 
prevalence of grade 3/4 toxicity of 30%, the study will have a power of 80% with significance 
level of 0.05 on a two-sample means test to rule out the null hypothesis (equal means in groups 
with/ without grade 3/4 toxicity, m0=m1) if the observed mean %IUdR-DNA incorporation for 
patients with grade 3/4 toxicity is m1=3.3 times the mean m0 in the other group for N=10 enrolled 
subjects, and m1=2.1 times the mean m0 for N=30. 
 
9.4.2 Determination of the pCR rate of IPdR + capecitabine + RT at the MTD 
 
In rectal cancer, the absence of viable tumor cells in the resection specimen (primary tumor 
mass, surrounding tissue and lymph nodes, T0 N0 M0) at the time of surgery, termed pathologic 
complete response (pCR) (Ryan et al., 2005; Martin et al., 2012).  pCR determination will be 
made by the pathologist at the treating institution. 
 
9.4.3 Determination of the Neoadjuvant Rectal Score 
 
NAR is calculated based on the clinical T stage (cT), pathological T (pT) and pN stages as 
(Valentini et al., 2011; George et al., 2015): 
 
                           NAR = [5pN- 3 (cT- pT) + 12]2 / 9.61 
 
9.5 
Analysis of Exploratory Endpoints 
 
9.5.1 To explore the relationship between extent of exposure to RT and the incidence and 
severity of adverse events 
 
9.5.2 To explore the interactions of capecitabine, IPdR and their metabolites 
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 


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Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
10.1.1 CAEPR for IPdR (NSC 726188) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For IPdR (NSC 726188) 
 
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.  
 
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. 
 
Version 1.2, April 12, 20191 
 
Adverse Events with Possible 
Relationship to IPdR  
(CTCAE 5.0 Term) 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
A Phase 1 safety study of single dose IPdR in 10 subjects 
resulted in no treatment-related adverse events.2, 3 
 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2We expect the safety profile for oral IPdR to vary somewhat from the safety profile of 
iododeoxyuridine (IUdR), administered via continuous intravenous infusion in conjunction with 
localized radiation.  Since oral IPdR is converted in the body to IUdR, the side effects of oral 
IPdR therefore may be similar to those adverse events observed in clinical trials of intravenous 
IUdR. The adverse events observed in IUdR clinical trials include: acute bowel obstruction, 
acute gastrointestinal hemorrhage, alanine aminotransferase increased, alkaline phosphatase 


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72 
increased, anemia, aspartate aminotransferase, blood bilirubin increased, diarrhea, nausea, 
neutrophil count decreased, platelet count decreased, and weight loss.  
 
3One early phase 1 single-dose safety clinical trial of IPdR (5-iodo-2-pyrimidinone-2’-
deoxyribose) was conducted that treated 10 subjects resulting in no toxicities associated with 
IPdR. The safety profile may be revised during and after clinical trials are conducted using 
repeated dosing. 
 
There is minimal (i.e., 10 subjects in a single-dose study) human data for IPdR to date, 
however no adverse events were noted in the study. The following toxicities have been 
observed during pre-clinical animal studies with IPdR: 
 
Ferrets Only 
Gastrointestinal disorders - Diarrhea; Nausea; Vomiting 
HEPATOBILIARY DISORDERS - Increased liver weights  
INVESTIGATIONS - Alkaline phosphatase increased  
Metabolism and nutrition disorders - Anorexia 
Nervous system disorders - Decreased motor activity 
RENAL AND URINARY DISORDERS - Decreased kidney weights 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Decreased uterus weights 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bradypnea 
 
Monkeys Only 
Nervous system disorders - Lethargy 
 
Rats Only 
Blood and lymphatic system disorders - Anemia; Bone marrow (hyperplasia) 
Investigations - Decrease alkaline phosphatase; Decreased hematocrit (Hct); Decrease in serum 
globulin; Decrease in total protein; Decreased RBC; Increased percentage of reticulocytes; 
Lobular atrophy in mandibular salivary glands; Lymphocyte count decreased 
 
Ferrets, Rats, and Mice (events seen in all three species) 
GASTROINTESTINAL DISORDERS - Acute bowel obstruction; Acute GI bleed 
HEPATOBILIARY DISORDERS - Increased hepatic cytoplasmic vacuolization 
Investigations - Alanine aminotransferase increased; Aspartate aminotransferase increased; 
Weight loss 
 
Note: IPdR 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. 
 
10.1.2 Adverse Event List for Capecitabine 
 
• Gastrointestinal Disorders:  Diarrhea, nausea, stomatitis, vomiting, abdominal pain, 
constipation, dyspepsia, elevated liver function tests 
 


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• Skin and Subcutaneous Tissue Disorders:  Hand-foot syndrome, alopecia, rash, erythema, 
skin discoloration 
 
• General Disorders:  Fatigue, Pyrexia, asthenia, lethargy, anorexia 
 
• Nervous System Disorders:  Dizziness, headache, dysgeusia 
 
• Blood and Lymphatic Disorders:  Anemia, thrombocytopenia and neutropenia 
 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• 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, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of Adverse Events (AEs) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting.  Sites must initiate all AEs for this study in 
Medidata Rave. 
 
Include the following (highlighted) paragraphs about pre-treatment AEs only if the 
study requires reporting of pre-treatment AEs. Pre-existing medical conditions are not 
considered adverse events and therefore should not be reported on an Adverse Event 
form. 


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74 
 
Pre-treatment AEs:  AEs that occur after informed consent is signed and prior to start of 
treatment are collected in Medidata Rave using the Pre-treatment Adverse Event form.  
 
Pre-existing medical conditions (formerly referred to as baseline AEs) identified during 
baseline assessment are not considered AEs and therefore should not be reported on the 
Pre-treatment Adverse Event form. If these pre-existing conditions worsen in severity, 
the investigator must reassess the event to determine if an expedited report is required. 
Whether or not an expedited report is required, the worsened event should be reported as 
a routine AE. 
 
Treatment-emergent AEs:  All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period and is used to collect AEs that start during the period 
or persist from the previous reporting period.  AEs that occur 30 Days after the Last 
Administration of the Investigational Agent/Intervention are collected using the Late 
Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form.  
Contact the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com 
if you have any issues submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 


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using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
 
• Study specific documents:   Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting, and   
• Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred less than 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 


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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
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 


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77 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  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 routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and X-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 


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78 
initiation of the next cycle of therapy. 
 


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79 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 10 
(4 wks following 
chemoRT)  
End of study for 
toxicity assessment  
Wk 14-18 
(8-12 wks following 
chemoRT) 
End of study for 
response assessment 
IPdR 
 
A 
A 
A 
A 
A 
A 
 
 
Capecitabine 
 
B 
B 
B 
B 
B 
B 
 
 
Radiation therapy 
 
C 
C 
C 
C 
C 
C 
 
 
Surgical resection 
 
 
 
 
 
 
 
 
X 
mFOLFOX6 × 8 cycles 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance statusa 
X 
X 
 
 
 
X 
 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carcinoembryonic Antigen 
(CEA) 
X 
 
 
 
 
 
 
X 
X 
Comprehensive Chemistry 
Panelb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
Blood draws for PK and 
IUdR incorporation in 
granulocyte assays 
(mandatory) 
 
 
Xc,d 
Xc,d 
 
Xc,d 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
 
Radiologic evaluation 
X 
 
 
 
 
 
 
 
Xe 
Digital rectal exam and 
proctoscopic or 
sigmoidoscopic exam 
 
 
 
 
 
 
 
 
Xe 
Pregnancy testf 
X 
 
 
 
 
 
 
 
 
A: 
IPdR:  Dose as assigned; PO QD administered throughout radiation (38 days, 6 weeks) 
B: 
Capecitabine:  825 mg/m2 PO BID on days of radiation therapy (taken Monday morning through Friday evening each week 
of RT) 
C:     Radiation therapy:  1.8 Gy/day × 28 doses (50.4 Gy total dose), M-F Days 1-5, 8-12, 15-19, 22-26, 29-33, 36-38 
a: 
Performance status evaluations are to be conducted every 4 weeks. 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
c: 
10 mL Blood for PK studies in sodium heparin tubes will be drawn on Day 8, prior to IPdR dose; and then after IPdR dose at 
30 min, 60 min, 120 min and 240 min.  On Day 21 and Day 35, blood will be drawn at 1-2 hours after the IPdR dose. 
d: 
5 mL blood for measuring IUdR incorporation in granulocytes will be drawn in EDTA tubes prior to IPdR dose on Day 8, 
and at 1-2 hours after the IPdR dose on Day 21 and Day 35. 
e: 
Scans, digital rectal exam, and proctoscopic or sigmoidoscopic exam will be obtained at 6-10 weeks following completion of 
therapy (pre-operatively within 2 weeks of surgery) 
f: 
Pregnancy test for women of childbearing potential. 


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80 
12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of this drug has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. 
 
12.1 
Antitumor Effect – Solid Tumors 
 
Disease response in this study will be measured by achievement of pathologic complete response 
at the time of surgical resection and determination of the NAR score.  The NAR score requires 
determination of clinical complete response by digital rectal examination and either proctoscopic 
or sigmoidoscopic examination.  Radiologic assessment of response is not used in this study, 
except to confirm that no metastatic disease has developed after chemoradiotherapy (assessment 
performed within 2 weeks of surgical resection). 
  
12.1.1 Clinical Complete Response (CCR) 
 
12.1.1.1 
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. 
 
12.1.1.2 
Definition of CCR 
 
No visible or palpable rectal tumor on direct examination.  Nodes are not included in this 
definition. 
 
12.1.2 Pathologic complete response (pCR) 
 
In rectal cancer, the absence of viable tumor cells in the resection specimen (primary tumor 
mass, surrounding tissue and lymph nodes, T0 N0 M0) at the time of surgery, termed pathologic 
complete response (pCR) (Ryan et al., 2005; Martin et al., 2012).  pCR determination will be 
made by the pathologist at the treating institution. 
 
12.1.3 Neoadjuvant Rectal Score (NAR) 
 
NAR is calculated based on the clinical T stage (cT), pathological T (pT) and pN stages as 
(Valentini et al., 2011, George et al., 2015): 
 
                           NAR = [5pN- 3 (cT- pT) + 12]2 / 9.61 
 
 


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81 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
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. 
 
Rave role requirements: 
 
• Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an Associate Plus 
(AP) registration type, 
• Rave Investigator role, must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR), and 
• Rave Read Only role, site staff must have at a minimum an Associates (A) registration 
type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 


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82 
 
If the study has a 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 email 
from iMedidata.  To accept the invitation, site staff must either click on the link in the email or 
log in to iMedidata via the CTSU members’ website  under Data Management > Rave Home and 
click to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen.  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 eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen.  If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; 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 replace 
the eLearning link 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.   
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 


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83 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
 
13.3 
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, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports.  Review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
 


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84 
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, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 
 
 
 
 
 


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85 
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Kummar, S., L. Anderson, K. Hill, et al.  (2013).  First-in-human phase 0 trial of oral 5-iodo-2-
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19:1852-1857. 
 
Lawrence, T.S., M.A. Davis, J. Maybaum, P.L. Stetson, and W.D. Ensminger. (1992).  
Modulation of iododeoxyuridine-mediated radiosensitization by 5-fluorouracil in human colon 
cancer cells.  Int J Radiat Oncol Biol Phys.  22:499-503.  
 
Lawrence, T.S., M.A. Davis, J. Maybaum, P.L. Stetson, W.D. Ensminger.  (1990).  The effect of 


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single versus double-strand substitution on halogenated pyrimidine-induced radiosensitization 
and DNA strand breakage in human tumor cells.  Radiat Res.  123:192-198. 
 
Le Tourneau, C., J.J. Lee, and L.L. Siu.  (2009).  Dose escalation methods in phase I cancer 
clinical trials.  J Natl Cancer Inst.  101:708-720. 
 
Martin, S.T., H.M. Heneghan, and D.C. Winter.  (2012).  Systematic review and meta-analysis of 
outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal 
cancer.  Br J Surg.  99:918-928. 
 
McGinn, C.J., K.A. Kunugi, K.D. Tutsch, et al.  (1996). Leucovorin modulation of 5-
iododeoxyuridine radiosensitization: a phase I study.  Clin Cancer Res.  2:1299-1305. 
 
McGinn, C.J., D.S. Shewach, and T.S. Lawrence.  (1996b).  Radiosensitizing nucleosides.  J Natl 
Cancer Inst.  88:1193-1203. 
 
Miller, E.M. and T.J. Kinsella.  (1992).  Radiosensitization by fluorodeoxyuridine: effects of 
thymidylate synthase inhibition and cell synchronization.  Cancer Res.  52:1687-1694. 
 
Miller, E.M., K.A. Kunugi, and T.J. Kinsella.  (1995).  Effects of 5'-aminothymidine and 
leucovorin on radiosensitization by iododeoxyuridine in human colon cancer cells.  Clin Cancer 
Res. 1:407-416. 
 
O'Connell, M.J., L.H. Colangelo, R.W. Beart, et al.  (2014).  Capecitabine and oxaliplatin in the 
preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical 
Adjuvant Breast and Bowel Project trial R-04.  J Clin Oncol.  32:1927-1934. 
 
O'Connell, M.J., J.A. Martenson, H.S. Wieand, et al.  (1994).  Improving adjuvant therapy for 
rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative 
surgery.  N Engl J Med.  331:502-507. 
 
Reigner, B., K. Blesch, and E. Weidekamm.  (2001).  Clinical Pharmacokinetics of Capecitabine.  
Clin Pharmacokinet.  40:85-104 
 
Rieber, M. and M.S. Rieber.  (2008).  Sensitization to radiation-induced DNA damage 
accelerates loss of bcl-2 and increases apoptosis and autophagy.  Cancer Biol Ther.  7:1561-
1576. 
 
Robertson, J.M., V.K. Sondak, S.A. Weiss, et al.  (1995).  Preoperative radiation therapy and 
iododeoxyuridine for large retroperitoneal sarcomas.  Int J Radiat Oncol Biol Phys.  31:87-92. 
 
Rodel, C., U. Graeven, R. Fietkau, et al.  (2015).  Oxaliplatin added to fluorouracil-based 
preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal 
cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, 
randomised, phase 3 trial.  Lancet Oncol.  16:979-989. 
 


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89 
Rodel, C., T. Liersch, H. Becker, et al.  (2012).  Preoperative chemoradiotherapy and 
postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally 
advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 
trial.  Lancet Oncol.  13:679-87. 
 
Rodriguez, R., M.A. Ritter, J.F. Fowler, and T.J. Kinsella.  (1994).  Kinetics of cell labeling and 
thymidine replacement after continuous infusion of halogenated pyrimidines in vivo. Int J Radiat 
Oncol Biol Phys.  29:105-113. 
 
Roh, M.S., L.H. Colangelo, M.J. O'Connell, et al.  (2009).  Preoperative multimodality therapy 
improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03.  J Clin 
Oncol.  27:5124-5130. 
 
Ryan, R., D. Gibbons, J.M. Hyland, et al.  (2005).  Pathological response following long-course 
neoadjuvant chemoradiotherapy for locally advanced rectal cancer.  Histopathology.  47:141-
146. 
  
Sauer, R., H. Becker, W. Hohenberger, et al.  (2004).  Preoperative versus postoperative 
chemoradiotherapy for rectal cancer.  N Engl J Med.  351:1731-1740. 
 
Schmoll, H.J., K. Haustermans, T.J. Price, et al.  (2018).  Preoperative chemoradiotherapy and 
postoperative chemotherapy with capecitabine +/- oxaliplatin in locally advanced rectal cancer: 
Final results of PETACC-6.  J Clin Oncol.  36:3500. 
 
Schulz, C.A., M.P. Mehta, B. Badie, et al.  (2004).  Continuous 28-day iododeoxyuridine 
infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical 
study.  Int J Radiat Oncol Biol Phys.  59:1107-1115. 
 
Seo, Y., T. Yan, J.E. Schupp, et al.  (2004).  Differential radiosensitization in DNA mismatch 
repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-
deoxyribose.  Clin Cancer Res.  10:7520-7528. 
 
Seo, Y., T. Yan, J.E. Schupp, T. Radivoyevitch, and T.J. Kinsella.  (2005).  Schedule-dependent 
drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 
human glioblastoma xenografts.  Clin Cancer Res.  11:7499-7507. 
 
Siegel, R., K.D. Miller, and A. Jemal.  (2020).  Cancer statistics, 2020.  CA Cancer J Clin.  70:7-
30. 
 
Simon, R., B. Freidlin, L. Rubinstein, et al.  (1997).  Accelerated titration designs for phase I 
clinical trials in oncology. J Natl Cancer Inst.  89:1138-1147. 
 
Speth, P.A., T.J. Kinsella, K. Belanger, et al.  (1988).  Fluorodeoxyuridine modulation of the 
incorporation of iododeoxyuridine into DNA of granulocytes: a phase I and clinical 
pharmacological study.  Cancer Res.  48:2933-2937. 
 


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90 
Speth, P.A., T.J. Kinsella, A.E. Chang, et al.  (1988b).  Selective incorporation of 
iododeoxyuridine into DNA of hepatic metastases versus normal human liver.  Clin Pharmacol 
Ther.  44:369-375. 
 
Sullivan, F.J., L.L. Herscher, J.A. Cook, et al.  (1994).  National Cancer Institute (phase II) study 
of high-grade glioma treated with accelerated hyperfractionated radiation and iododeoxyuridine: 
results in anaplastic astrocytoma.  Int J Radiat Oncol Biol Phys.  30:583-590. 
 
Urtasun, R.C., T.J. Kinsella, N. Farnan, et al.  (1996). Survival improvement in anaplastic 
astrocytoma, combining external radiation with halogenated pyrimidines: final report of RTOG 
86-12, Phase I-II study.  Int J Radiat Oncol Biol Phys.  36:1163-1167.  
 
Valentini, V., R.G. van Stiphout, G. Lammering, et al.  (2012).  Nomograms for predicting local 
recurrence, distant metastases, and overall survival for patients with locally advanced rectal 
cancer on the basis of European randomized clinical trials.  J Clin Oncol.  29:3163-3172. 
 
 
 
 


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91 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE 
 
Formulas to estimate renal function using serum creatinine provided by the NCI’s Investigational 
Drug Steering Committee (IDSC) Pharmacological Task Force in table below. 
 
1. Estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) (Levey et al., 2009). 
 
Formulae: 
 
Race and 
Sex 
Serum Creatinine (SCr), 
µmol/L (mg/dL) 
Equation 
Black 
 
 
Female 
≤62 (≤0.7) 
GFR = 166 × (SCr/0.7)−0.329 × (0.993)Age 
 
>62 (>0.7) 
GFR = 166 × (SCr/0.7)−1.209 × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 163 × (SCr/0.9)−0.411 × (0.993)Age 
 
>80 (>0.9) 
GFR = 163 × (SCr/0.9)−1.209 × (0.993)Age 
 
 
 
White or 
other 
 
 
Female 
≤62 (≤0.7) 
GFR = 144 × (SCr/0.7)−0.329 × (0.993)Age 
 
>62 (>0.7) 
GFR = 144 × (SCr/0.7)−1.209 × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 141 × (SCr/0.9)−0.411 × (0.993)Age 
 
>80 (>0.9) 
GFR = 141 × (SCr/0.9)−1.209 × (0.993)Age 
 
SCr in mg/dL; Output is in mL/min/1.73 m2 and needs no further conversions. 
 
2. eGFR using the Modification of Diet in Renal Disease (MDRD) Study (Levey et al., 2006). 
 
175 x SCr–1.154 × age–0.203 × 0.742 (if female) × 1.212 (if black) 
Output is in mL/min/1.73 m2 and needs no further conversions. 
3. Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft and 
Gault, 1976). 
 
 
Followed by conversion to a value normalized to 1.73 m2 with the patient’s body surface area 
(BSA). 
 
References 
1. Levey, A.S., L.A. Stevens, C.H. Schmid, et al.  (2009).  A new equation to estimate 
glomerular filtration rate.  Ann Inter Med.  150:604-612. 
2. Levey, A.S., J. Coresh, T. Greene, et al.  (2006).  Using standardized serum creatinine 
values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate.  Ann Intern Med.  145:247-254. 
3. Cockcroft, D.W. and M.H. Gault.  (1976).  Prediction of creatinine clearance from serum 
creatinine.  Nephron.  16:31-41. 
 


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APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  10410 
Study Drug(S):   
5-iodo-2-pyrimidinone-2’-deoxyribose 
(IPdR) 
Capecitabine 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 


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94 
 
APPENDIX D 
PATIENT MEDICATION DIARY 
 
 
PATIENT’S MEDICATION DIARY – IPdR 
Today’s date:   
 
Agent:  IPdR 
Patient Name:   
(initials acceptable) Patient Study ID:   _________________  
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for the study. 
2. You will take your dose of IPdR at the same time, once a day each day, 7 days a week, until your radiation therapy is complete.  
 
        75 mg capsule(s); (and)         600 mg capsule(s) 
You should take IPdR on an empty stomach, either 1 hour before or 2 hours after meals. 
On Days 8, 21, and 35, you will receive instructions about the time you should take your IPdR, depending on the schedule of your radiation. 
3. On the days of radiation therapy, the dose of IPdR should be taken within 30 min - 2 hours prior to radiation.  You can take this at home as 
time allows. 
4. Store IPdR capsules in the original bottle in the refrigerator.  Record the date, the number of capsules you took, and when you took them. 
5. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 4 hours of the scheduled time. If not within 
4 hours, take your next dose at the regularly scheduled time. 
6. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
7. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
8. If you have any comments or notice any side effects, please record them in the Comments column. 
9. Please remember to bring this diary (all pages) and your IPdR containers (even if they are empty) to each visit with your study team. 
Day 
Date 
What time was 
dose taken? 
# of Capsules 
taken 
Comments 
75mg 
600mg 
1. 
 
 
 
 
 
2. 
 
 
 
 
 
3. 
 
 
 
 
 
4. 
 
 
 
 
 
5. 
 
 
 
 
 
6. 
 
 
 
 
 
7. 
 
 
 
 
 
8. 
 
 
 
 
 
9. 
 
 
 
 
 
10.  
 
 
 
 
11.  
 
 
 
 
12.  
 
 
 
 
13.  
 
 
 
 
14.  
 
 
 
 
15.  
 
 
 
 
16.  
 
 
 
 
17.  
 
 
 
 
18.  
 
 
 
 
19.  
 
 
 
 
20.  
 
 
 
 
21.  
 
 
 
 
22.  
 
 
 
 
23.  
 
 
 
 
24.  
 
 
 
 
25.  
 
 
 
 
26.  
 
 
 
 
27.  
 
 
 
 
28.  
 
 
 
 
CTEP-assigned Protocol # 10410 
Local Protocol # TBD 


NCI Protocol #: 10410 
Version Date: June 2, 2022 
 
95 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for the study. 
2. You will take your dose of IPdR at the same time, once a day each day, 7 days a week, until your radiation therapy is complete.  
 
        75 mg capsule(s); (and)         600 mg capsule(s) 
You should take IPdR on an empty stomach, either 1 hour before or 2 hours after meals. 
On Days 8, 21, and 35, you will receive instructions about the time you should take your IPdR, depending on the schedule of your radiation. 
3. On the days of radiation therapy, the dose of IPdR should be taken within 30 min - 2 hours prior to radiation.  You can take this at home as 
time allows. 
4. Store IPdR capsules in the original bottle in the refrigerator.  Record the date, the number of capsules you took, and when you took them. 
5. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 4 hours of the scheduled time. If not within 
4 hours, take your next dose at the regularly scheduled time. 
6. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
7. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
8. If you have any comments or notice any side effects, please record them in the Comments column. 
9. Please remember to bring this diary (all pages) and your IPdR containers (even if they are empty) to each visit with your study team. 
Day 
Date 
What time was 
dose taken? 
# of Capsules 
taken 
Comments 
75mg 
600mg 
29.  
 
 
 
 
30.  
 
 
 
 
31.  
 
 
 
 
32.  
 
 
 
 
33.  
 
 
 
 
34.  
 
 
 
 
35.  
 
 
 
 
36.  
 
 
 
 
37.  
 
 
 
 
38.  
 
 
 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
 ________________________________________________ 
2. Date patient was removed from study 
 ________________________________________________ 
3. Patient’s planned total daily dose 
 ________________________________________________ 
4. Total number of capsules taken during the study (each size) _________________________________________ 
 
5. Physician/Nurse/Data Manager’s Signature 
 ________________________________________________ 
 
Patient’s signature:   
 
 
 


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96 
 
 
PATIENT’S MEDICATION DIARY – Capecitabine 
Today’s date:   
 
Agent:  Capecitabine 
Dose: 
 
 
Patient Name:   
(initials acceptable) Patient Study ID:   _________________  
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for the study. 
2. You will take your dose of capecitabine at the same time twice a day, about 12 hours apart, on Monday morning through Friday evening each 
week during the time you receive radiation therapy. 
        150 mg tablets and         500 mg tablets 
You should take capecitabine within 30 minutes after eating breakfast and dinner. 
3. Store capecitabine tablets in the original bottle at room temperature.  Record the date, the number of tablets you took, and when you took them. 
4. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 4 hours of the scheduled time.  You should not 
take the missed dose if it is within 8 hours of your next scheduled dose.  Take your next dose at the regularly scheduled time. 
5. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
6. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
7. If you have any comments or notice any side effects, please record them in the Comments column. 
8. Please remember to bring this diary (all pages) and your capecitabine containers (even if they are empty) to each visit with your study team. 
Day 
Date 
What time was dose 
taken? 
# of tablets taken 
(morning) 
# of tablets taken 
(evening) 
Comments 
AM 
PM 
150 mg 
500 mg 
150 mg 
500 mg  
1. 
 
 
 
 
 
 
 
 
 
2. 
  
 
 
 
 
 
 
 
3. 
  
 
 
 
 
 
 
 
4. 
  
 
 
 
 
 
 
 
5. 
  
 
 
 
 
 
 
 
6. 
  
 
 
 
 
 
 
 
7. 
  
 
 
 
 
 
 
 
8. 
  
 
 
 
 
 
 
 
9. 
  
 
 
 
 
 
 
 
10. 
  
 
 
 
 
 
 
 
11. 
  
 
 
 
 
 
 
 
12. 
  
 
 
 
 
 
 
 
13. 
  
 
 
 
 
 
 
 
14. 
  
 
 
 
 
 
 
 
15. 
  
 
 
 
 
 
 
 
16. 
  
 
 
 
 
 
 
 
17. 
  
 
 
 
 
 
 
 
18. 
  
 
 
 
 
 
 
 
19. 
  
 
 
 
 
 
 
 
20. 
  
 
 
 
 
 
 
 
21. 
  
 
 
 
 
 
 
 
22. 
  
 
 
 
 
 
 
 
23. 
  
 
 
 
 
 
 
 
24. 
  
 
 
 
 
 
 
 
25. 
  
 
 
 
 
 
 
 
26. 
  
 
 
 
 
 
 
 
27. 
  
 
 
 
 
 
 
 
28. 
  
 
 
 
 
 
 
 
29. 
  
 
 
 
 
 
 
 
30. 
  
 
 
 
 
 
 
 
31. 
  
 
 
 
 
 
 
 
32. 
  
 
 
 
 
 
 
 
33. 
  
 
 
 
 
 
 
 
CTEP-assigned Protocol # 10410 
Local Protocol # TBD 


NCI Protocol #: 10410 
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97 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for the study. 
2. You will take your dose of capecitabine at the same time twice a day, about 12 hours apart, on Monday morning through Friday evening each 
week during the time you receive radiation therapy. 
        150 mg tablets and         500 mg tablets 
You should take capecitabine within 30 minutes after eating breakfast and dinner. 
3. Store capecitabine tablets in the original bottle at room temperature.  Record the date, the number of tablets you took, and when you took them. 
4. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 4 hours of the scheduled time.  You should not 
take the missed dose if it is within 8 hours of your next scheduled dose.  Take your next dose at the regularly scheduled time. 
5. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
6. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
7. If you have any comments or notice any side effects, please record them in the Comments column. 
8. Please remember to bring this diary (all pages) and your capecitabine containers (even if they are empty) to each visit with your study team. 
Day 
Date 
What time was dose 
taken? 
# of tablets taken 
(morning) 
# of tablets taken 
(evening) 
Comments 
AM 
PM 
150 mg 
500 mg 
150 mg 
500 mg  
34. 
  
 
 
 
 
 
 
 
35. 
  
 
 
 
 
 
 
 
36. 
  
 
 
 
 
 
 
 
37. 
  
 
 
 
 
 
 
 
38. 
  
 
 
 
 
 
 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
 ________________________________________________  
2. Date patient was removed from study 
 ________________________________________________  
3. Patient’s planned total daily dose 
 ________________________________________________  
4. Total number of capsules taken during the study (each size) _________________________________________  
 
5. Physician/Nurse/Data Manager’s Signature 
 ________________________________________________  
 
Patient’s signature:   
 


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98 
 
APPENDIX E 
MODIFIED FOLFOX6 
 
Drug 
Dose 
Administration 
Dosing 
Interval 
Planned 
Duration 
Oxaliplatin 
85 mg/m2 
IV diluted in separate infusion 
bags of 250 mL D5W, given 
concurrently through separate 
lines connected by 
Y-line tubing, over approximately 
2 hours. Flush infusion line. 
 
 
 
 
Day 1 
every 2 
weeks 
 
 
 
 
 
8 cycles 
 
 
Leucovorin 
 
 
400 mg/m2 
 
 
5-Fluorouracil (5-FU) 
 
400 mg/m2 
IV bolus recommended over 2 – 4 
minutes immediately following 
oxaliplatin/leucovorin infusion 
2400 mg/m2 
IV continuous infusion over 46- 
48 hours (total dose) 


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APPENDIX F 
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. 


NCI Protocol #: 10410 
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100 
 
• Eat frequent small meals. 
• Maintain a low fat diet enriched with rice, bananas, and applesauce, and/or toast. 


NCI Protocol #: 10410 
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101 
 
APPENDIX G PATIENT-FRIENDLY DIARRHEA MANAGEMENT GUIDE 
 
You will likely experience diarrhea while getting the therapy in this study, and possibly for 
several weeks after the study therapy has stopped.  Below are guidelines for how to best manage 
diarrhea, both with medications and by adjusting your diet. 
 
1. Be sure to have ready access to antidiarrheal medication (for example, loperamide) 
starting on Day 1 of the study treatment. 
2. Start antidiarrheal medication at the very first sign of loose or more frequent stools, and 
continue taking it as directed. 
3. Promptly report diarrhea symptoms to your doctors. 
4. Record your usual number of daily bowel movements before starting the study treatment, 
as well as each occurrence of loose stools and all use of antidiarrheal medication while 
you receive the study treatment.  Bring all pages of this record with you to each treatment 
visit so you and your doctors can review it together. 
5. Stop eating and drinking all lactose-containing foods (milk, yogurt, cheese, etc.). 
6. Drink 8-10 large glasses (64-80 ounces) of clear liquids every day. 
7. Eat frequent small meals. 
8. Maintain a low-fat diet enriched with rice, bananas, applesauce, and toast. 
9. If you experience constipation, report this to your doctors before taking any laxatives or 
stopping any antidiarrheal medication. 

ICF_001.pdf: 
Protocol Version Date: June 2, 2022 
 
Page 1 of 14 
10410 
Research Study Informed Consent Document 
 
Study Title for Participants: Testing the addition of a radiation sensitizing drug, IPdR, to 
the usual chemotherapy treatment (capecitabine) during radiation therapy for rectal cancer 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  Protocol 
10410, “Phase I study of IPdR in Combination with Capecitabine and Radiotherapy for 
Rectal Cancer” (NCT# 04406857) 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study.  This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this research study because you have rectal cancer that is 
considered locally advanced (has grown outside the rectum but has not yet spread to distant parts 
of the body) and you have not yet been treated with surgery. 
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this study being done? 
 
This study is being done to answer the following question:  
 
What is the highest dose of IPdR that can be given safely and tolerably (with manageable side 
effects) with the usual drug capecitabine, and radiation therapy (RT) for patients with locally 
advanced rectal cancer? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your rectal cancer.  The usual approach is defined as care most people get for 
rectal cancer. 


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What is the usual approach to my rectal cancer? 
 
The usual approach for patients who are not in a study is treatment with chemotherapy, 
chemotherapy in combination with RT, and then surgery.   
 
You have already received the usual chemotherapy phase of treatment.  There are several 
chemotherapy drugs like capecitabine approved by the Food and Drug Administration (FDA) 
that are commonly used with RT (chemoRT).  Patients then usually have surgery 2-3 months 
after finishing the chemoRT phase to remove any remaining rectal cancer.  For patients who get 
the usual approach for this cancer, about 70 out of 100 are free of cancer after 5 years.   
 
What are my choices if I decide not to take part in this study? 
 
x You may choose to have the usual approach described above. 
x You may choose to take part in a different research study, if one is available. 
x You may choose not to be treated for cancer. 
x You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will get capecitabine with the study drug IPdR, and 
you will get RT.  IPdR capsules are taken by mouth once a day. IPdR capsules are taken on an 
empty stomach, either 1 hour before or 2 hours after meals, 7 days per week, until your radiation 
therapy is complete.  On days when you will also get radiation treatment, your IPdR dose should 
be taken between 30 minutes and 2 hours before radiation begins. These doses can be taken at 
home.  Capecitabine tablets are taken by mouth with a glass of water twice a day, about 12 hours 
apart and within 30 minutes of a meal, on days when you get RT.  You will take capecitabine 
tablets on Monday morning through Friday evening only, each week until your radiation therapy 
is complete.  This combination is called chemoRT and will take about 6 weeks.  After you finish 
chemoRT, your doctor will watch you for side effects for 4 weeks.  You will have an 
appointment at that time for your doctor to talk with you, examine you, and obtain some follow-
up blood tests. 
 
About 8 to 12 weeks after you finish the study treatment, you will have surgery.  As is usual, the 
specimen removed by the surgeon during this surgery will be examined by a pathologist, and the 
pathologist will check if there are any rectal cancer cells still left in the specimen or if all of the 
rectal cancer cells have been killed by the chemotherapy and chemoRT. 


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What are the risks and benefits of taking part in this study?
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.    
Risks
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section.
If you choose to take part in this study, there is a risk that adding IPdR to the usual treatment 
may not be as good as the usual approach alone at shrinking or stabilizing your cancer.  
There is also a risk that you could have side effects from the study drug, IPdR.  These side 
effects may be worse and may be different than you would get with the usual approach for your 
cancer.  
Some of the most common side effects that the study doctors know about are:
x
Diarrhea
x
Dehydration
Usual ChemoRT
Radiation therapy (RT)
28 doses – (Monday through Friday, Weeks 1- 6)
Capecitabine
Tablet by mouth twice a day (Mon AM-Fri 
PM) during RT
Study treatment adds
IPdR
Capsule by mouth once a day (7 days/week) 
during RT


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There may be some risks that the study doctors do not yet know about.  Other side effects may be 
very serious and even result in death. 
 
Benefits 
 
There is some evidence in animals implanted with human colorectal cancer tumors that adding 
IPdR to the usual approach can shrink and/or stabilize the cancer for longer than the usual 
approach alone.  However, we do not know if this will happen in people with rectal cancer.  It is 
unlikely that adding IPdR to the usual approach will help you live longer than the usual approach 
alone.  This study may help the study doctors learn things that may help other people in the 
future. 
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
x Your health changes and the study is no longer in your best interest. 
x New information becomes available and the study is no longer in your best interest. 
x You do not follow the study rules. 
x For women: You become pregnant while on the study. 
x The study is stopped by the, Institutional Review Board (IRB), FDA, or study sponsor 
(NCI).  The study sponsor is the organization who oversees the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
 
The purpose of this study is to test the safety and tolerability of the study drug called IPdR when 
added to a usual treatment for rectal cancer, capecitabine along with radiation therapy.  We are 
also trying to determine the highest dose that has manageable side effects.  This drug has been 
tested in animals and in people with radiation therapy, but has not been tested in combination 
with capecitabine plus radiation therapy or in subjects with rectal cancer.  This study tests 


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different doses of the drug to see which dose is safe to give along with capecitabine and radiation 
therapy for people.  There will be about 20-30 people taking part in this study. 
 
What are the study groups? 
 
Different people taking part in this study will get different doses of the study drug, IPdR.   
 
Treatment schedule:  You will take IPdR capsules by mouth once a day.  You will take IPdR 
capsules on an empty stomach, either 1 hour before or 2 hours after meals, for about 6 weeks.  
On days when you will also get radiation treatment, your IPdR dose should be taken between 30 
minutes and 2 hours before radiation begins.  These doses can be taken at home.  You will start 
taking IPdR capsules on the first morning of radiation treatment every day (7 days a week), and 
will stop after the last radiation treatment.  You will also take capecitabine tablets twice daily 
(morning and evening) on days that you receive RT.  Radiation treatment consists of 28 doses of 
radiation, which will be given to you over a period of about 6 weeks.  Because radiation 
treatments are usually given Monday through Friday, you will take capecitabine Monday 
morning through Friday evening each week of RT.  Capecitabine should be taken within 30 
minutes after a meal (breakfast and dinner).  See the study calendar at the end of this document 
for more information. 
 
The first person taking part in this study will get the lowest dose.  If the drug does not cause 
serious side effects, which will be observed for a period of 4 weeks following chemoRT, the 
second person in the study will get double the dose that the first person received.  The study 
doctor will watch each participant carefully as they increase the dose.  The doses will continue to 
double for every new participant until someone has serious side effects.  When this happens, if 
the side effect is severe, the dose doubling stops. If the side effect is serious but not severe, two 
new participants will get the same dose as this person.  If neither of these two people also has 
serious side effects, the dose will continue to double for each new participant. 
 
When one participant has a severe side effect or at least two participants have serious but not 
severe side effects at a given dose, dose doubling stops.  Three new participants will get this dose 
and be watched for side effects.  If none of these people have serious side effects, the next group 
of three participants will receive a slightly higher dose.  If only one participant has serious side 
effects at a given dose, three more participants will get this dose.  If none of these new 
participants has serious side effects, the dose will increase slightly for a group of three new 
participants.  When at least two participants getting the same dose experience serious side 
effects, dose increases stop.  Once the highest dose with manageable side effects is found, the 
study is stopped.   
 
You will not be able to get additional doses of the study drug IPdR.  This drug is not approved 
by the FDA for treatment of your disease. 
 
What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 


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join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study.  
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
You will need to have blood samples taken for the study.  Blood samples will be collected on 
Days 8, 21, and 35 during study treatment at multiple time points before and after taking the 
IPdR capsules to check the level of IPdR in your blood and also to check the effect of IPdR on 
your blood cells. On these days (Days 8, 21, and 35), you will be instructed about the specific 
time to take your IPdR dose. 
x On Day 8- Three teaspoons of blood will be drawn prior to taking IPdR morning dose, 
and then another two teaspoons at 30 min, 1 hour, 2 hours, and 4 hours after taking IPdR 
x On Days 21 and 35- Three teaspoons of blood will be drawn at 1-2 hours following IPdR 
morning dose 
 
The timing (about 8-12 weeks following completion of chemoRT) and procedure for your 
surgery to remove any remaining tumor is the same as if you were not on this study. 
 
If you are on this study, some of the tissue from your surgery will be tested to see if there are any 
remaining tumor cells, and if so, if there is any IPdR in them.  This testing uses some of the 
tissue from your surgery, but no extra tissue will be removed at the time of surgery for this test.  
This testing is a required part of the study.  You and your study doctor will not get the results of 
this testing. 
 
A patient study calendar is attached at the end of this document.  It shows how often these 
procedures will be done. 
 
What risks can I expect from taking part in this study? 
 
General Risks 
 
If you choose to take part in this study, there is a risk that the addition of the study drug, IPdR, to 
the usual approach may not be as good as the usual approach alone for your rectal cancer at 
shrinking or stabilizing your cancer. 
 
You also may have the following discomforts: 
 
x Spend more time in the hospital or doctor’s office. 
x Be asked sensitive or private questions about things you normally do not discuss. 
x May not be able to take part in future studies.  
 
The study drug, IPdR used in this study could be very harmful to an unborn or newborn baby.  
There may be some risks that doctors do not yet know about.  It is very important that you check 


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with your study doctor about what types of birth control or pregnancy prevention to use during 
the study and for 4 months after you have completed the study. 
 
This study will use a sample of your tissue.  Generally, your hospital will keep some of your 
tissue.  This tissue may be used to help treat your cancer in the future.  Because this study will 
need to use some of this tissue, there is a small risk that it could be used up.   
 
Blood Draw Risks 
 
Some of the risks from drawing blood from your arm may include pain, bruising, light-
headedness, and rarely, infection.  For most people, needle punctures to get blood samples do not 
cause any serious harm.  The multiple, and frequent blood draws for research testing may be 
burdensome and inconvenient given the time you need to stay in the clinic.  In addition, the 
frequent needle sticks in your arm may be uncomfortable if you do not have an infusion line or it 
cannot be used.  Let your study doctor know of any questions you have about possible side 
effects.  You can ask the study doctor questions about side effects at any time. 
 
Side Effect Risks 
 
The study drug used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood.  The study doctor will test your blood and let you know if 
changes occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study drug. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
x If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
x Your study doctor will work with you to treat your side effects. 
x Your study doctor may adjust the study drugs to try to reduce side effects. 
 
This study is looking at a combination of the usual drugs used to treat this type of cancer plus a 
study drug.  This different combination of drugs may increase your side effects or may cause 
new side effects.   
 


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You should notify your doctor immediately at the first sign of poorly formed or loose stools or 
an increased frequency of bowel movements.  Loperamide (Imodium) should be kept on hand 
and should be taken as recommended by your doctor.  
 
Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of IPdR (Table Version Date:  April 12, 2019) 
 
POSSIBLE, SOME MAY BE SERIOUS 
Please Note:  A safety study of single dose IPdR in 10 study participants resulted in no 
treatment-related side effects. However, some side effect data is available for 
iododeoxyuridine (IUdR) administered by continuous intravenous infusion in 
combination with localized radiation.  Since oral IPdR is converted in the body to 
IUdR, the side effects of oral IPdR may be similar to those side effects observed in 
clinical trials of intravenous IUdR. The side effects observed in IUdR clinical trials are 
presented in this condensed risk list: 
x Blockage of the bowel which may cause belly pain, vomiting 
x Internal bleeding which may cause black tarry stool, belly pain 
x Anemia which may cause tiredness, or may require blood transfusion  
x Diarrhea, nausea  
x Bruising, bleeding  
x Weight loss 
Additional side effects observed only in animal studies using IPdR:   
x Loss of appetite 
x Muscle weakness 
x Shortness of breath 
x Tiredness 
 
Possible Side Effects of Capecitabine (Table Version Date: October 17, 2019) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Capecitabine, more than 20 and up to 100 may have: 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Capecitabine, more than 20 and up to 100 may have: 
x Infection, especially when white blood cell count is low 
x Bruising, bleeding 
x Anemia which may require blood transfusions 
x Diarrhea, loss of appetite, nausea, vomiting 
x Sores in mouth which may cause difficulty swallowing 
x Swelling of the body 
x Pain 
x Feeling of "pins and needles" in arms and legs 
x Tiredness 
x Fever 
x Blisters on the skin 
x Redness, pain or peeling of palms and soles 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Capecitabine, from 4 to 20 may have: 
x Abnormal heartbeat 
x Constipation 
x Blurred vision, dry or itchy eyes 
x Muscle spasms, body aches 
x Restlessness, irritability 
x Swelling of face, fingers and lower legs 
x Difficulty with balancing 
 
RARE, AND SERIOUS 
In 100 people receiving Capecitabine, 3 or fewer may have: 
x Damage to the heart 
x Internal bleeding which may cause blood in vomit or black tarry stools 
x Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
x Difficulty speaking, walking or seeing 
 
Additional Drug Risks 
 
The study drug, IPdR, could interact with other drugs.  There are no known interactions of IPdR 
with other drugs, but always tell your doctor about any drugs (prescription or over the counter) 
that you are taking.  Your study doctor will give you a clinical trial wallet card that lists the drugs 
you are taking.  Share this information with your family members, caregivers, other health care 
providers, and pharmacists. 
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
Possible Side Effects of Radiation Therapy 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, 20 to 100 may have: 
x Reddening, tanning, or peeling of the skin 
x Mild pain 
x Hair loss 
x Tiredness 
x Diarrhea, nausea 
x Anemia, which may require transfusion 
x Infection, especially when white blood cell count is low 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, 4 to 20 may have: 
x Thickening and numbness of the skin 
x Sores or ulcers on the skin or near the cancer location 
x Permanent hair loss 
x Bleeding from the skin 
x Sores in mouth which may cause difficulty swallowing 
 
RARE, AND SERIOUS 
In 100 people receiving radiation therapy, 3 or fewer may have: 
x Damage to internal organs 
x Abnormal opening in internal organs which may cause pain and bleeding 
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
x Keep your study appointments. 
x Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
x Write down in your medication diary when you take the study drug at home.   
x Bring your medication diary and the IPdR and capecitabine containers (even if they are 
empty) with you to each visit with your study team. 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  Tell your study doctor right away if you 
think that you or your partner have become pregnant during the study or within 4 months after 
your last dose of study drug. 
 
What are the costs of taking part in this study? 
 


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You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your cancer.  This includes: 
 
x the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
x the costs of capecitabine and radiation therapy. 
x the costs of the digital rectal exam and either a proctoscopy or sigmoidoscopy done as 
part of your pre-operative examination.  Proctoscopy is a procedure that uses a 
proctoscope to look inside the anus and rectum.  Sigmoidoscopy is the examination of the 
lower colon using a sigmoidoscope, inserted into the rectum.  A proctoscope and a 
sigmoidoscope are thin, tube-like instruments with a light and a lens for viewing.  They 
may also have a tool to remove tissue to be checked under a microscope for signs of 
disease.   
x the costs of the surgery at about 8 to 12 weeks after you finish the study treatment. 
x your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
 
x The blood tests on the Day 8 to check the level of IPdR in the blood 
x The blood tests on the Days 21 and 31 to check the level of IPdR in the blood and 
examine the effect of IPdR on your blood cells 
 
You or your insurance provider will not have to pay for the IPdR while you take part in this 
study.  As mentioned above, you or your insurance provider will be responsible for the costs of 
the capecitabine and radiation therapy. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment. 
 
What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 


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If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records.  Your health information in the research database also may be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group.   
 
Some of these organizations are: 
 
x The study sponsor and any company supporting the study in the future.  This would 
include any organization helping the sponsor/company with the study. 
x The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study.  
x The FDA and the groups it works with to review research. 
x The NCI and the groups it works with to review research. 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy.  The goal of this 
data sharing is to make more research possible that may improve people’s health.  Your study 
records may be stored and shared for future use in public databases.  However, your name and 
other personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
x You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
x You and your study doctor will not be told when or what type of research will be done. 


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x You will not get reports or other information about any research that is done using your 
information.  
 
 
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor (*insert name of study doctor[s]*) at 
(*insert telephone number, and email address if appropriate*). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 
 
My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  
 
 
Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature 
  
 
 


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10410 – Patient Study Calendar 
 
 
Pre- 
Study 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
4 weeks after the 
completion of study 
treatment (Week 10) 
Surgery at 8-12 weeks 
following completion 
of study treatment 
(Week 14-18) 
IPdRA 
 
X-----------------------------------------------------X 
 
 
CapecitabineB 
 
X-----------------------------------------------------X 
 
 
Radiation therapy (RT)C 
 
X-----------------------------------------------------X 
 
 
Pre-study procedures 
including Informed consent, 
Demographics, Medical 
history, and Height 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-----------------------------------------------------X 
X 
X 
Physical exam, Vital signs, 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
An assessment of how you 
perform everyday tasks and 
activities 
X 
X 
 
 
 
X 
 
X 
X 
Blood draws for complete 
blood count and general 
health status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
Blood draws for research 
study (mandatory) 
 
 
Xb 
Xb 
 
Xb 
 
 
 
Side effects evaluation 
 
X-----------------------------------------------------X 
X 
 
Mandatory collection of a 
sample from your surgery 
 
 
 
Xa 
Medical imaging scans to 
look at your tumor 
X 
 
 
 
 
 
 
 
Xc 
Digital rectal exam and 
proctoscopic or 
sigmoidoscopic exam 
 
 
 
 
 
 
 
 
Xd 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
A: 
IPdR:  Dose as assigned; take by mouth once a day everyday throughout the duration of RT (Weeks 1-6).  On days when you 
will also get radiation treatment, the  IPdR dose should be taken between 30 minutes and 2 hours before radiation begins.  
These doses can be taken at home.   
B: 
Capecitabine:  Dose as assigned; take by mouth twice a day on days of RT (taken Monday morning through Friday evening 
each week of RT) 
C:     You will receive RT on Monday to Friday for 6 weeks (Weeks 1-6) and will receive a total of  28 doses 
 
a:      Specimen removed by the surgeon during this surgery will be examined by a pathologist, and the pathologist will check if 
there are any rectal cancer cells still left. 
b:      Blood for research studies will be drawn on Day 8, prior to taking your IPdR dose; and then at 30 min, 1 hour, 2 hour, and 4 
hours after taking your IPdR dose.  On Day 21 and Day 35, blood will be drawn at 1-2 hours after taking your IPdR dose. 
c: 
You will need to come in for this scan at 6-10 weeks following completion of therapy (within the 2 weeks before you have 
surgery). 
d:      Your surgeon will perform a digital rectal exam and either a proctoscopy or sigmoidoscopy as part of your pre-operative 
examination (within the 2 weeks before you have surgery)