Phase 1 and Pharmacology Study of Oral 5-Iodo-2-Pyrimidinone-2-Deoxyribose (IPdR) as a Prodrug for IUdR-Mediated Tumor Radiosensitization in Brain Metastases
Phase: PHASE1
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Metastatic Malignant Neoplasm in the Brain
Sponsor: National Cancer Institute (NCI)

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Date: 
September 4, 2020 
 
To: 
CTEP Protocol and Information Office 
 
From: 
Pranshu Mohindra, MD, MBBS, DABR 
 
Re: 
Amendment #9 in response to the Dr. Gore’s request for amendment dated 
8/24/2020 
 
 
SUMMARY OF CHANGES - Protocol  
 
I. 
Response to request for amendment: 
 
# 
Section 
Comments 
1. 
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Add CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved 
Populations as a Participating Organization. 
 
II. 
Changes requested by the PI: 
 
# 
Section 
Comments 
2. 
General 
General formatting throughout the document. 
 
 
SUMMARY OF CHANGES – Consent Forms 
 
III. 
Consent Form Part 1 
 
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Comments 
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Updated protocol version date. 
 
IV. 
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Updated protocol version date. 
 
 
 
 
 

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Phase 1 and Pharmacology Study of Oral 5-iodo-2-pyrimidinone-2-deoxyribose (IPdR) as a 
Prodrug for IUdR-Mediated Tumor Radiosensitization in Brain Metastases 
 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
 
Principal Investigator: 
Pranshu Mohindra, M.D., M.B.B.S., D.A.B.R. ® 
University of Maryland School of Medicine 
Department of Radiation Oncology 
22 South Greene Street, Room GGJ-35 
Baltimore, MD 21201 
Telephone: (410) 328-9155 
Telefax: (410) 328-5279 
Email: pmohindra@som.umaryland.edu 
 
 
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-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 

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Co-Investigators: 
 
Medical Oncology 
Aaron Mansfield, M.D. 
Mayo Clinic 
Email: mansfield.aaron@mayo.edu 
 
Radiology 
Rao Gullapalli, M.D.  
 
Prashant Raghavan, M.D. 
University of Maryland 
 
University of Maryland 
Email: rpg@umm.edu 
 
Email: praghavan@umm.edu 
 
Timothy Kaufmann, M.D. 
Mayo Clinic 
Email: kaufmann.timothy@mayo.edu 
 
Statistician 
 
 
 
 
 
Jacob Allred, M.S. 
 
 
 
 
 
Mayo Clinic 
 
 
 
 
 
Rochester, MN 55905  
 
 
 
 
Telephone: (507) 266-2874 
 
 
 
 
Email: allred.jacob@mayo.edu 
 
 
 
 
Protocol Manager:  
Judy Murray 
JHU Sidney Kimmel Comprehensive Cancer Center  
Telephone: 410-955-4044  
Email: jmurra33@jhmi.edu 
NCI-Supplied Agent:  5-iodo-2-pyrimidinone-2-deoxyribose (IPdR; NSC # 726188) 
 
IND Sponsor:  DCTD, NCI.  
 
 
 

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Protocol Type / Version # / Version Date: 
 
Original / Version 1 / December 15, 2015 
Resubmission / Version 2 / February 11, 2016 
Resubmission / Version 3 / March 22, 2016 
Resubmission / Version 4 / April 1, 2016 
Resubmission / Version 5 / April 19, 2016 
Resubmission / Version 6 / June 27, 2016 
Resubmission / Version 7 / September 21, 2016 
Resubmission / Version 8 / October 26, 2016 
Resubmission / Version 9 / November 3, 2016 
CTSU Activation on December 7, 2016 
Amendment 1 / FDA Response / Version 10 / January 6, 2017 
Amendment 2 / Version 11 / January 19, 2017 
Amendment 3 / Version 12 / July 26, 2017 
Amendment 4 / Version 13 / October 2, 2017 
Amendment 5/ Version 14/ October 23, 2017 
Amendment 6/ Version 15/ December 12, 2017 
Amendment 6 / Version 15 / April 3, 2018 
Amendment 6 / Version 16 / May 3, 2018 
Amendment 7 / Version 17 / February 5, 2020 
Amendment 8 / Version 18 / July 7, 2020 
Amendment 9 / Version 19 / September 4, 2020 
 
 

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SCHEMA 
 
 
Pre-
study 
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 
 
IPdR 
 
po qd dose x 28 days, days 1-28 
 
 
RT 
 
 
2.5 Gy/fraction x 15 fractions 
days 8-12, 15-19, 22-26 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
Title 
Phase 1 and Pharmacology Study of Oral 5-iodo-2-pyrimidinone-2-deoxyribose 
(IPdR) as a Prodrug for IUdR-Mediated Tumor Radiosensitization in Brain 
Metastases 
Study 
Objectives 
Primary Objective 
• To conduct a phase 1 dose escalation trial in patients with brain metastases to 
determine the recommended Phase II dose (RP2D) of daily oral IPdR 
administered alone for 7 days then concurrently with conventionally fractionated 
whole brain radiation therapy (WBRT) for 3 weeks. 
 
Secondary Objectives 
• To evaluate radiographic overall response rates (ORR) using RECIST 1.1.  Only 
patients in Part 2 of the study will be included in this evaluation. 
• To estimate 6-month intracranial progression-free survival (PFS). 
• To establish the pharmacokinetics of daily oral dosing of IPdR times 8 days. 
• To evaluate safety and tolerability of oral IPdR x 28 days and WBRT.  
• To estimate the incidence of delayed neurological toxicity at 2, 4,  6-months (± 1 
week) post-completion of WBRT (for patients without intracranial progression) 
including:  
a. Delayed-recall through HVLT-R  
b. Quality of life as measured by the FACT-BR.  
 
Correlative Objectives (in 6 additional patients accrued at RP2D) 
• To evaluate %IUDR-DNA incorporation into normal tissues. 
• To evaluate %IUDR-DNA incorporation in tumor only in patients with easily 
accessible tumor outside of the brain 
Study 
Design 
This is a phase 1 study to determine the RP2D of IPdR when delivered with WBRT 
using a 2-part accelerated titration design. 

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Treatment 
Interventions 
IPdR: 
Eligible patients with brain metastases (BM) will receive daily oral IPdR for 28 consecutive 
days.   
 
An initial single patient dose escalation of IPdR will be conducted in Part 1.  The starting dose is 
150 mg (dose level 1A).  A 100% dose escalation was used until dose level 1B of 300 mg.  
 
Part 1 IPdR Dose  Increment Schedule 
Dose 
Level 
Dose 
(mg) 
Multiple of 
starting 
dose 
% increase 
above previous 
dose level 
1A 
150 
1x 
 
1B 
300 
2x 
100 
 
In Part 2 of this Phase 1 protocol, a modified cohort 3+3 design (see table below) was planned 
where up to three patients were planned to be accrued to a given dose level (starting with 1200 
mg IPdR dose).  
Part 2 IPdR Dose Increment Schedule  
Dose level 
Dose (mg) 
2A 
1200 
2B 
1800 
2C 
2400 
 
 
Design Amendment #2: 
The study accrued per plan with three patients accrued to the dose-level 2A (1200 mg) 
showing no DLTs. Dose-level 2B (1200 mg) was opened with 1st pt demonstrating a 
serious DLT. In the meantime, a previously ongoing study with IPdR and palliative 
radiation for gastrointestinal cancers completed accrual establishing 1200 mg as RP2D. 
As described in section 2.5.2, after accruing one patient at the dose-level 2B of table 5, 
the study is being amended to close the dose-level 2B and re-open 2A (1200 mg) to 
enroll 3 additional patients. The results of 6 total patients at dose-level 2A (1200 mg) 
will be evaluated per the table below 
 
Table: Part 2 Dose Escalation Decision Rules  
 
Number of Patients with DLT  
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3  
(0 out of 6 patients) 
This dose-level is declared the recommended phase 2 
dose (RP2D). The study will proceed to the expansion 
phase. 

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1 or 2 out of 3  
(total 1 or 2 out of 6 patients) 
This dose level is declared the RP2D. The study will 
proceed to the expansion phase. 
3 out of 3 
(total 3 out of 6 patients) 
MTD is exceeded and the dose level will be declared the 
maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level such that a total of 
6 patients are treated to more fully assess the toxicities 
(unless there have already been 6 accrued to that lower 
level which will then be labeled as the RP2D and the 
study will proceed to the expansion cohort). 
 
Whole brain radiation therapy (WBRT): 
WBRT will be delivered concurrently once daily Monday through Friday for 3 consecutive 
weeks starting during the second week of IPdR (Day 8).  The prescribed dose will be 37.5 Gy in 
15 fractions of 2.5 Gy each.   IPdR will be administered 0.5-2 hours prior to WBRT.   
 
Sample Size 
A sample size estimate is quite cumbersome in this situation, as the study team does not know at 
what level Part 1 will end or how many dose levels will be required in Part 2.  In the proposed 
amendment #6 (Dec. 2017), to accelerate accrual, the dose-escalation design was changed such 
that part -1 was truncated at dose level IB, with one patient accrued at each dose-level (total 2). 
The study  opened part-2 as a modified 3+3 design with three dose-levels accruing up to 6 
patients each depending on the occurrence of DLT. Thereby, the number of patients accrued in 
part 1 and 2 were expected to range from 8 (2+6) to 20 (2+6+6+6). Till date (December 2019), 2 
patients have been accrued in part 1 (1+1), 3 patients at dose-level 2A and 1 patient at dose-level 
2B. In the current proposed design amendment #2, since dose-level 2B is being stopped with one 
patient and dose level 2A will be reopend for additional 3 patients, the expected accrual in the 
two parts will range from 9 (2+7) to 15 (2+7+6) patients. Ten patients will be accrued at the 
RP2D in the expansion cohort to help narrow the confidence interval on the estimate of incidence 
of toxicity at the MTD which makes the range of accrual between 19 and25. The maximum 
accrual will be 25 patients. Up to a total of six patients in the expansion cohort will be analyzed 
for the %IUdR-DNA cellular incorporation in circulating granulocytes and tumor once RP2D has 
been determined.     
 
Sponsor 
DCTD, NCI. 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.................................................................................................................6 
TABLE OF CONTENTS .................................................................................................................9 
1. 
OBJECTIVES ....................................................................................................................11 
1.1 
Primary Objectives .................................................................................................11 
1.2 
Secondary Objectives .............................................................................................11 
1.3 
Correlative Objectives (in 6 additional patients accrued at RP2D) .......................11 
2. 
BACKGROUND ...............................................................................................................12 
2.1 
Brain Metastases ....................................................................................................12 
2.2 
Radiosensitization ..................................................................................................13 
2.3 
5-iododeoxyuridine (IUdR) ...................................................................................13 
2.4 
5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) .....................................................14 
2.5 
Rationale ................................................................................................................18 
2.6 
Correlative Studies Background ............................................................................21 
3. 
PATIENT SELECTION ....................................................................................................25 
3.1 
Eligibility Criteria ..................................................................................................25 
3.2 
Exclusion Criteria ..................................................................................................26 
3.3 
Inclusion of Women and Minorities ......................................................................27 
4. 
REGISTRATION PROCEDURES ...................................................................................28 
4.1 
Investigator and Research Associate Registration with CTEP ..............................28 
4.1 
Investigator and Research Associate Registration with CTEP ..............................28 
4.2 
Site Registration .....................................................................................................29 
4.3 
Patient Registration ................................................................................................31 
4.4 
General Guidelines .................................................................................................32 
5. 
TREATMENT PLAN ........................................................................................................33 
5.1 
Agent Administration .............................................................................................33 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................43 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................44 
5.4 
Duration of Therapy ...............................................................................................46 
5.5 
Duration of Follow Up ...........................................................................................46 
5.6 
Criteria for Removal from Study ...........................................................................47 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................48 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................49 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................49 
7.2 
Adverse Event Characteristics ...............................................................................50 
7.3 
Expedited Adverse Event Reporting ......................................................................51 
7.4 
Routine Adverse Event Reporting .........................................................................53 

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7.5 
Secondary Malignancy ...........................................................................................53 
7.6 
Second Malignancy ................................................................................................54 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................55 
8.1 
IPdR (NSC 726188) ...............................................................................................55 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................58 
9.1 
Pharmacokinetics of IPdR ......................................................................................58 
9.2 
Measurement of %IUdR-DNA Incorporation in Peripheral Granulocytes 
and Tumor Tissues as an Exploratory Biomarker for IPdR Effects at the 
MTD. ......................................................................................................................59 
10. 
STUDY CALENDAR .......................................................................................................62 
10.1 
Neurocognitive Evaluation ....................................................................................64 
10.2 
Functional Assessment of Cancer Therapy with Brain Subscale (FACT-
BR) for Quality of Life (QOL) ..............................................................................65 
11. 
MEASUREMENT OF EFFECT........................................................................................66 
11.1 
Antitumor Effect – Intracranial Metastases ...........................................................66 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................71 
12.1 
Study Oversight .....................................................................................................71 
12.2  Data Reporting .......................................................................................................71 
12.3 
CTEP Multicenter Guidelines ................................................................................73 
12.4 
Collaborative Agreements Language .....................................................................73 
13. 
STATISTICAL CONSIDERATIONS...............................................................................76 
13.1 
Study Design/Endpoints – Determination of the Maximum Tolerated Dose ........76 
13.2 
Sample Size/Accrual Rate ......................................................................................76 
13.3 
Stratification Factors ..............................................................................................77 
13.4 
Analysis of Secondary Endpoints ..........................................................................78 
REFERENCES ..............................................................................................................................79 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................85 
APPENDIX B: IPdR MEDICATION DIARY..............................................................................86 
APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ........89 
 
 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To conduct a Phase 1 dose escalation trial in patients with brain metastases to determine 
the recommended phase -2 dose of IPdR when administered alone orally once daily for 7 
consecutive days and then concurrently with conventionally fractionated whole brain 
radiation therapy (WBRT) for additional 21 days.   
 
1.2 
Secondary Objectives 
 
1.2.1 To observe and record anti-tumor activity to IPdR-mediated radiosensitization.  Although 
the clinical benefit of this drug used before and during radiation therapy 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 at 6 months 
using RECIST criteria in addition to safety and tolerability.  Only patients in Part 2 of the 
study will be included in this evaluation. 
 
1.2.2 To estimate 6 month intracranial progression-free survival (PFS) in brain metastasis 
cancer patients who receive daily oral IPdR x 28 days and WBRT. 
 
1.2.3 To establish the pharmacokinetics of daily oral dosing of IPdR times 8 days. 
 
1.2.4 To evaluate safety and tolerability of oral IPdR x 28 days and WBRT. 
 
1.2.5 To estimate the incidence of delayed neurological toxicity at  2, 4 and 6 months (± 1 
week) post-completion of WBRT (for patients without intracranial progression) 
including:  
a. Delayed-recall through HVLT-R  
b. Quality of life as measured by the FACT-BR. 
 
1.3 
Correlative Objectives (in 6 additional patients accrued at RP2D) 
 
1.3.1 To assess for biochemical evidence of IPdR effect in normal tissues (circulating 
granulocytes) by measuring %IUdR-DNA cellular incorporation by flow cytometry and 
high-pressure liquid chromatography (HPLC) analyses as an exploratory biomarker for 
the following effects: 
 
a.   The %IUdR-DNA tumor cell incorporation from Day 8 extracranial tumor 
biopsies in brain metastasis cancer patients receiving RP2D doses of IPdR as an 
exploratory biomarker of tumor radiosensitization using RECIST criteria. 
 
b.   The %IUdR-DNA cellular incorporation in patients’ circulating granulocytes 
taken weekly during the 28-day IPdR RP2D dose, on Day 29, and Week 8 as an 
exploratory biomarker of IPdR systemic toxicities to bone marrow as measured 
by serial CBC/differential values 

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2. 
BACKGROUND 
 
2.1 
Brain Metastases 
 
Brain metastases (BMs) are the most common type of intracranial malignancy, occurring 
in 10-30% of adults with cancer; in fact, BMs are 10 times more common than primary 
brain tumors.[1, 2]  The prognosis for patients with BMs is very poor with median 
survivals typically measured in months rather than years.  Even BM patients with the best 
prognostic score according to the Radiation Therapy Oncology Group (RTOG) recursive 
partitioning analysis (RPA) have estimated median survival of only 7.1 months; that 
number drops dramatically to 2.3 months for those with the worse RPA score.[3]  The 
RTOG index notably is not disease-specific and while any extracranial malignancy 
cancer can spread to the brain, certain cancers have a higher predilection for brain 
involvement including those starting in the lung and breast.[4]  A newer prognostic 
index, the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score, accounts 
for primary tumor type with median survival being shorter for certain tumors (e.g. 
melanoma: 3.38-13.23 months) compared to others (e.g. breast: 3.35-25.30 months).[5]   
 
The treatment options for patients with BMs is influenced by various factors including 
the primary tumor type, extent and control of extracranial disease, performance status, 
symptoms from BMs, and also important the number, size, and location of the 
intracranial lesion(s).  The most commonly used treatments are surgery and/or radiation 
therapy (RT).   
 
Whole brain radiation therapy (WBRT) has played an integral role in the treatment of 
BMs for decades.  The most commonly used WBRT dose fractionation schedules are 30-
40 Gy in 10-20 daily fractions.  There is no clear evidence that treatment efficacy differs 
based on the particular dose fractionation schedule used, but higher dose per fraction 
(especially >3 Gy per fraction) may be associated with a higher rate of neurotoxicity.[6-
8] The benefits of WBRT include improved neurologic symptoms from BMs, [9] 
improved local control of macroscopic intracranial disease,[10-13] and lower incidence 
of intracranial relapse.[11, 14, 15]  Overall survival may also be extended with WBRT, 
particularly in patients with control of limited extracranial disease.[16, 17]  Although 
WBRT can provide significant clinical benefit, there is a need to improve outcomes after 
WBRT.  In a European randomized trial of patients with 1-3 BMs, 28% of patients who 
received adjuvant WBRT after either surgery or stereotactic radiosurgery (SRS) for BM 
died due to intracranial progression (compared to 44% who did not received adjuvant 
WBRT).[13] In a recently reported U.S. cooperative group trial, 12-month intracranial 
tumor control was 85% with the addition of WBRT (compared to 51% without, p<0.001); 
no difference in overall survival was reported.[18]  
 
Attempts to improve survival and intracranial response rates by adding radiosensitizing 
drugs including lonidamine, metronidazole, misonidazole, motexafin gadolinium, 
bromodeoxyuridine, and efproxiral to WBRT have been unsuccessful.[19-24]  Subgroup 
analyses suggested that efproxiral improved response and survival in breast cancer 
patients [21] while motexafin gadolinium improved neurocognitive function in lung 

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cancer patients [24] although these trials were not powered for these subgroup analyses.  
Because intracranial disease progression is a significant cause of morbidity and mortality 
despite WBRT, there is a significant clinical need to identify an effective radiosensitizer 
that is well tolerated and enhances the effect of WBRT. 
 
2.2 
Radiosensitization  
 
It is estimated that 1,658,370 men and women will be diagnosed with cancer in 2015 
(http://seer.cancer.gov/statfacts/html/all.html) and approximately two-thirds of patients 
will receive radiation at some time during the course of their cancer treatment 
(http://www.rtanswers.org/statistics/aboutradiationtherapy/). Therefore, any intervention 
to improve the efficacy and/or toxicity profile of radiation therapy (RT) will have a 
profound impact on the field of oncology.  
 
A strategy to improve the efficacy/toxicity profile of RT is to use a drug(s) that 
specifically target(s) mechanisms of tumor cell resistance to RT, thereby making the 
tumor more susceptible to the damaging effects of RT relative to the normal tissues. 
While it is an appealing strategy, there are currently no drugs with a specific FDA 
approved indication of radiosensitization. However, it is well recognized that the primary 
cellular target of RT is DNA. RT kills cells by causing irreversible DNA strand breaks, 
making them unable to divide and proliferate. Well over 50 years ago it was recognized 
that certain drugs called nucleoside analogs are falsely incorporated into DNA and when 
these cells with defective DNA are exposed to RT tumor cell killing is increased by up to 
two-three fold compared to cells without the defective DNA.[25] 
 
2.3 
5-iododeoxyuridine (IUdR) 
 
To date, the nucleoside analog that has been found to be the most effective as a specific 
radiosensitizing drug is 5-iododeoxyuridine (IUdR).[26, 27]  IUdR, a halogenated 
thymidine (TdR) analog, has been recognized as a potential radiosensitizing agent since 
the early 1960s and clinical trials during the 1980’s-1990’s showed that IUdR enhanced 
the effectiveness of RT in the treatment of RT-resistant brain and soft tissue/bone cancers 
(Tables 1 and 2).[28-30]  However, IUdR is rapidly dehalogenated by both hepatic and 
extrahepatic metabolism with plasma half-life of < 5 minutes after bolus infusion.  
Therefore, the clinical use of IUdR is impractical because it needs to be administered as a 
continuous intravenous (CIV) infusion, 24 hours/day for 5-6 weeks during RT to 
maintain steady-state plasma concentration.[31]  A consequence of this is that IUdR 
accumulates in rapidly proliferating normal tissues and has dose limiting systemic 
toxicity to bone marrow and bowel, limiting the tolerated doses and the potential for 
further clinical radiosensitization.[32, 33]  Consequently, NCI did not pursue further 
development of IUdR.  
 
 
 
 
 

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Table 1.  NCI sponsored clinical efficacy studies of IUdR (compared to historical RT-alone 
controls) for treatment of high grade primary brain tumors (RTOG*, NCI** trials) [28-30] 
Tumor 
Treatment 
Median survival (Months) 
Anaplastic astrocytomas  
(Grade 3 of 4)*, ** 
RT alone 
24 
 
RT + IUdR 
39 
Glioblastoma Multiforme  
(Grade 4 of 4)** 
RT alone 
9 
 
RT + IUdR 
14 
 
Table 2.  Clinical efficacy studies of IUdR (compared to historical RT-alone controls) for 
treatment of high grade retroperitoneal (RP) sarcomas (NCI**; University of Michigan*** 
trials) [34-36] 
Tumor 
Treatment 
Local Control at 2 years 
High grade RP sarcomas (resectable)*** 
RT + Surgery 
25% 
 
RT + IUdR + 
Surgery 
45% 
High grade RP sarcomas (un-resectable)** 
RT alone 
<10% 
 
RT + IUdR 
60% 
                *RTOG: Radiation Therapy Oncology Group, **NCI, *** University of Michigan 
 
 
2.4 
5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) 
 
2.4.1 Mechanism of Action 
More recently a newer nucleoside analog, 5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR), 
has been developed.[37]  IPdR is taken by mouth (PO) and is a prodrug of IUdR.  That is, 
when IPdR is ingested, the body converts it into IUdR via an aldehyde oxidase 
principally in liver.  IPdR is essentially a way to conveniently administer IUdR that is 
known to enhance the effectiveness of RT.[38]  IUdR is then phosphorylated by 
thymidine kinase (TK), and subsequently sequentially phosphorylated into a triphosphate, 
which is incorporated into replicating DNA in competition with deoxythymidine 
triphosphate (dTTP).  The incorporation of the thymidine analog leads to the generation 
of highly reactive uracil-based free radicals by ionizing radiation (IR), which could also 
damage unsubstituted complementary-strand DNA by creating double-strand breaks 
(DSB).  
 
2.4.2 Non-Clinical Studies 
 
IPdR has been specifically developed as a radiosensitizing drug, this development having 

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been sponsored by the NCI through a series of extramural and intramural grants over the 
last two decades.  As summarized in Table 3, the extensive preclinical studies of IPdR 
passed the rigid guidelines from the FDA, leading to an investigator initiated IND (T. 
Kinsella, PI, # 70,333).  The IND was subsequently transferred to CTEP.  Importantly, 
IPdR was found to be more effective as a tumor radiosensitizing drug with minimal 
normal tissue toxicity when directly compared to continuous infusions of IUdR.  
 
2.4.2.1 In Vitro Antitumor Studies 
 
There are no in vitro data published to date. 
 
 
2.4.2.2 In Vivo Antitumor Studies 
 
In preclinical studies, PO IPdR was found to be a more effective radiosensitizer versus 
CIV IUdR infusions, due in part to the 2-3 times greater percentage of IUdR-DNA 
incorporation in tumors treated with PO IPdR compared to IUdR.  Therefore, PO IPdR 
in combination with radiation therapy (RT) may be an effective regimen for drug-
resistant tumors.  Studies in athymic mice using two different human colorectal cancer 
cell lines (HT-29 and HCT116) and one human glioblastoma cell line (U251) grown as 
subcutaneous xenografts found > 2-fold increases in %IUdR-DNA tumor cell 
incorporation and > 2-fold decreases in %IUdR-DNA incorporation in proliferating 
dose-limiting normal tissues (bone marrow and intestine) with IPdR (up to 1.5 
gm/kg/day x 6 or 14 days) compared to IUdR (MTD: 100 mg/kg/day x 6 days).[39-41]  
Additionally, a 1.3-1.5 fold enhancement in radiosensitization was reported, as 
measured by a standard xenograft tumor regrowth delay assay, with IPdR (given daily 
for 6-14 days) plus fractionated RT (2 Gy/d for 4 days) in the same human tumor 
xenografts compared to fractionated RT alone.[40-42]  Based on prior studies, the 
calculated radiosensitizer enhancement for IPdR of 1.3-1.5 would be predicted to result 
in clinically relevant radiosensitization in human cancers.  
 
2.4.2.3 Pharmacokinetics and Product Metabolism in Animals 
 
Extensive pharmacokinetic studies were performed in mice, rats, ferrets and rhesus 
monkeys, showing rapid and efficient clearance of IPdR from the plasma following 
single and multiple once daily oral dosing (gastric gavage) with plasma IUdR levels 
peaking within 30 minutes of IPdR dosing and persisting for up to 4 hours at >1 mol/L 
(plasma level associated with radiosensitization)[43-45].  The absorption and 
elimination kinetics of IPdR were found to be linear over the dose range studied 
although repeated PO IPdR administration enhanced its elimination.  Finally, in all 
models there was little incorporation of IUdR-DNA into bone marrow or intestinal 
tissue.   
 
2.4.2.4 Toxicology 
 
A series of IPdR-related toxicology studies were performed under a NCI RAID grant 
(#197), using escalating daily doses of IPdR for 14 or 28 days in mice, rats, and ferrets, 

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showing a 10-15% reversible weight loss at 1500-2000 mg/kg/d for 14 or 28 days in 
ferrets and rats, respectively, but no clinical toxicities (CBC, LFTs, BUN, Cr) or 
histopathologic changes at full necropsy.[44, 45]  In ferrets, the most sensitive species, 
the MTD for PO IPdR administration was found to be ≤1.5 g/kg/day for 14 days.  There 
were no systemic toxicities.  Dose-limiting toxicities (DLTs) included hepatic toxicities 
(increase in liver weight and cytoplasmic vacuolation of hepatocytes) and 
gastrointestinal toxicities (vomiting, diarrhea, decreased food intake).  Based on these 
data, the recommended phase I dose was 85 mg/m2 once-daily for 14 days, which is 
1/10th of the MTD in ferrets.  The results of these preclinical studies documented the 
feasibility of repeated daily dosing, reproducible pharmacokinetics, modest (tolerable) 
systemic toxicities, and efficacy of IPdR as a radiosensitizer. 
 
2.4.3 Clinical Studies 
 
2.4.3.1 First In-Human Phase 0 Study 
 
Protocol 8866, “An Early Phase 0 Study of IPdR Absorption, Metabolism, and Safety 
in Patients with Advanced Solid Tumors and Lymphomas” was conducted at the 
Developmental Therapeutics Clinic (DTC), NCI and completed February 19, 2013; Dr. 
Shivaani Kummar was the principal investigator.  This was a first-in-human study and 
the initial dose was selected based on 1/10th of the MTD in ferrets, the most sensitive 
preclinical species tested.  As an additional safety factor, only a single dose of the agent 
was administered, rather than repeated dosing.  
The primary objectives were to determine the safety of administering a single PO dose 
of IPdR, and to measure the plasma concentrations of IPdR, the active metabolite 
IUdR, and IUdR metabolites.  The study was to be closed for futility if IUdR could not 
be detected in patient plasma samples.  
The patients received a single PO dose of IPdR on Day 1.  Blood and urine samples for 
PK analyses were collected over a 24-hour period after IPdR dosing to measure 
concentrations of IPdR, IUdR, and IUdR metabolites.  The total duration of study 
participation was 14 days for each patient.  All patients were carefully monitored for 
side effects while on study.  The trial was conducted using five dose levels (DL) of 
IPdR: 150 mg (DL 1), 300 mg (DL 2), 600 mg (DL 3), 1200 mg (DL 4), 2400 mg (DL 
5).  One evaluable patient was enrolled successively in each cohort starting at DL 1. 
Patients were followed for a total of 14 days on study.  Once each patient completed the 
14-day course and there were no significant AEs, the next patient was enrolled at the 
next dose level, until the highest level (DL 5) was reached.  A total of six patients were 
to be enrolled at DL 5. In May 2011, the protocol was amended to allow multiple 
patients to be concurrently enrolled at DL 5 (patients were still followed for 14 days, 
but additional patients could be enrolled during this period).  
As of May 2011, one patient had been treated at each DL, up to and including DL 5 
(2400 mg), with no AEs reported as at least possibly drug-related (Protocol 
Amendment, May 2011). The protocol was amended in order to accelerate the accrual 
rate at DL 5 (see above). Dose escalation was halted at DL 5, as the objectives of this 
trial were solely to determine the PK and safety of single-dose IPdR, not to establish 
the MTD. A total of 10 patients were enrolled on the trial, including 6 patients at DL 

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5.[46] All patients tolerated the drug well, with no treatment-related AEs. The trial was 
closed to accrual and treatment in May 2012 and completed in February 2013. 
 
The final published results (Kummar et al., Clin Cancer Res. 2013 Apr 1;19(7):1852-7. 
doi: 10.1158/1078-0432), confirmed no drug related AE. The authors noted that the 
plasma concentrations remained above 1 μM for 3–4 hours and declined with a half-life 
of 1.5 hours. Per trial eligibility, prior anti-neoplastic therapy must have been 
completed at least 2 weeks prior to enrollment. 
 
Table 3: IPdR pre-clinical studies leading to IND application and initial clinical Phase 0 
trial 
Study 
Description 
Summary of Findings 
A. IPdR Metabolism by hepatic aldehyde oxidase 
Chang, 1992 [38] 
Metabolism of IPdR vs 
IUdR 
Elucidated IPdR metabolism by aldehyde 
oxidase 
Characterized properties of aldehyde 
oxidase 
Kinsella, 2000, 2008 
[41, 44] 
IPdR Metabolism in rats and 
ferrets 
Characterized kinetics of IPdR 
metabolism  
B. Pharmacokinetic and toxicology studies 
Kinsella, 1994,1998, 
2000 [39-41] 
Pharmacokinetics of PO 
IPdR in mice 
Established absorption, distribution, 
metabolism, and elimination kinetics of 
PO IPdR in mice 
Kinsella, 2000 [45] 
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 
Kinsella, 2008 [44] 
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. 
Kummar, 2013 [46] 
Pharmacokinetics of single-
dose PO IPdR in humans 
Phase 1 study of PO IPdR, 150mg-
2400mg in humans: No toxicities.  
C. Pre-clinical efficacy studies of IPdR-mediated radiosensitization 
Kinsella, 1998, 2000 
[40, 41] 
Seo, 2004, 2005 [43, 
47] 
Efficacy/toxicity studies of 
PO IPdR vs 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, 1994 [39] 
Efficacy, PK, toxicity, and 
DNA incorporation of PO 
Demonstrated improved therapeutic 
index of PO IPdR vs PO IUdR for IUdR-

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IPdR vs PO IUdR in human 
colon cancer xenografts.  
mediated radiosensitization 
 
2.4.3.2 Completed Phase-1 study:  
 
In the current ongoing study, NCI 9882/ NCT02381561: Phase I and Pharmacology Study of 
Oral 5-Iodo-2-Pyrimidinone-2'- Deoxyribose (IPdR) as a Prodrug for IUdR-Mediated Tumor 
Radiosensitization in Gastrointestinal Cancers, is a phase I dose escalation trial to determine the 
safety and the maximum tolerated dose (MTD), of oral (po) IPdR (ropidoxuridine) given daily 
for 28 consecutive days starting 7 days prior to the initiation of RT with concurrent intensity-
modulated radiation therapy (IMRT) to a dose of 37.5 Gy in 15 fractions in patients with 
advanced gastrointestinal cancers treated with palliative radiation. Beginning on day 8, patients 
undergo IMRT 5 days a week for 3 weeks in the absence of disease progression or unacceptable 
toxicity. IPdR starts on Day 1 and is taken 30 minutes to 2 hours prior to radiation therapy. After 
completion of study treatment, patients are followed up for 4 weeks. The study has completed 
accrual with final results published (https://www.ncbi.nlm.nih.gov/m/pubmed/31337643/). 
Nineteen patients were entered on study. Dose limiting toxicity was encountered at 1,800 mg 
every day, and the recommended phase II dose is 1,200 mg every day. Patients each for dose 
levels 600, 900, and 1,200 mg received therapy without evidence of IPdR-related grade 2 or 
higher clinical or laboratory toxicity. At 1,800 mg orally every day, 2 of 3 patients experienced 
grade 3 toxicity deemed probably or definitely related to IPdR. These were related to 
development of a community acquired pneumonia and peri-anal abscess respectively. Neither 
patient demonstrated leukopenia or neutropenia at any time. Both patients had resolution of their 
toxicity without sequelae. The plasma PK data shows good intra- and interpatient levels of IPdR 
and IUdR on days 1,1 and 22-above 1uM at 900 and 1200 mg dosing. 
 
2.5 
Rationale 
 
Preclinical and early Phase 0 data demonstrated that IPdR was well tolerated and 
effective as a radiosensitizer.  These data provide justification for further clinical 
evaluation since there are no clinical data of IPdR and WBRT.   
 
BMs are the most common intracranial malignancy, and a cause of significant neurologic 
morbidity and mortality.  While there is a higher likelihood for development of BMs 
based on tumor type, any malignancy may metastasize to the brain.  Therefore, all tumor 
types will be evaluated with the exception of traditionally radiosensitive tumors (germ 
cell, lymphoma, leukemia).   
 
The starting dose for po IPdR for Phase 1 testing is based on the most sensitive (lower 
MTD) of the two animal species tested, i.e. ferrets and rats.[44, 45]  The MTD for po 
IPdR in ferrets, the most sensitive species, was determined to be  150 mg/kg/d x 14 days 
[45], which is equivalent to 850mg/M2/day x 14 days.  The human equivalent dose 
(HED) is also 850 mg/M2/day, the same as the ferret dose, based on body surface area 
(BSA).[48]  Based on these calculations and pre-clinical animal data, 1/10th of the MTD 
is 85mg/M2/day (150mg), the proposed starting dose for our proposed Phase 1 trial. 

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This Phase 1 study will determine the maximum tolerated dose of single agent IPdR 
when given in conjunction with WBRT for palliation in patients with brain metastases. 
Once the MTD of single agent IPdR and WBRT is determined, future studies will 
evaluate the efficacy of IPdR and WBRT in controlling intracranial metastatic disease. 
 
2.5.1 Rationale for study modification (Amendment #06 including revised submissions) 
 
Multiple amendments were requested in the study protocol to boost accrual. These are 
detailed below: 
a. Change in two part dose-escalation design: Based on the published results from the study 
8866 (phase-0) and updated results from the NCI 9882/ NCT02381561 noted in sections 
above along with recommendations from the CTEP medical officer, it was elected to stop 
accrual to part 1 at dose-level 1B (300 mg) and directly activate part 2 of the study at 1200 
mg dosing.  
 
At the time of submission of amendment #6 (Dt 12/12/2017), #6 rev (02/26/2018) and the 
current version, one patient each was accrued at dose levels of 150 and 300 mg with no 
DLT.   
 
Based on the recommendations noted in the amendment #6rev disapproval letter, the study 
accrual will be suspended at dose level 1B with the plan to open the study directly at 1200 
mg dose level of part 2, once the amendment has been approved.   
 
b. Change in dose-escalation schedule: The dose-escalation schedule was also amended. The 
original modified accelerated design was found to restrict speed of accrual, since once a 
patient was registered, for the duration of pre-study work-up, study treatment and post-
study DLT assessment, no other patient could be accrued on the study. This lead to non-
availability of slots for any other eligible patient and was felt to be a barrier in accrual. 
Hence, per the communication received from the CTEP medical officer, a change to a 3+3 
design was recommended. 
 
A conservative 3+3 phase-1 study design poses unique challenges for the brain metastases 
population to be treated with WBRT + study drug related to high baseline incidence of 
adverse events in this population and due to inherent limitations of a conservative 3+3 
design. The most recent large-scale multi-institutional randomized trial of post-operative 
SRS to the surgical cavity versus WBRT (NCCTG N107C/CEC.3, Brown et al., Lancet 
Oncol 2017), showed grade 3 or worse adverse events (irrespective of attribution) in 36 
(39%) patients in the SRS group and 37 (40%) patients in the WBRT group. Corresponding 
grade 3 or more events that were possibly related to treatment were 11 (12%) patients in 
the SRS group compared with 17 (18%) patients in the WBRT group. Despite, 77% of 
patients having only one lesion which was surgical resected and an ECOG PS of 1 or less 
in 90% patients, only about 50% patients survived one year in both the arms. In patients 
with 1-3 brain metastases (SRS alone candidates), another multi-institutional randomized 
trial of SRS alone or SRS + WBRT (NCCTG N0574 study, Brown et al, JAMA 2016), at 
least one grade 3 or more AE was seen in 41.4-43.1% of patients. Median overall survival 

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was only 10.4 months in SRS alone and 7.4 months in SRS + WBRT patients. The rates of 
adverse events are expected to be higher and survival outcomes lower in non-surgical 
patients with multiple brain metastases, which form the patient population in this study. 
Indeed, in the phase 3 randomized trial of WBRT plus motexafin gadolinium for patients 
with brain metastases from non-small cell lung cancer (Mehta et al, Int J Radiat Oncol Biol 
Phys 2009) or with WBRT + efaproxiral for breast cancer (Suh t al., J Clin Oncol 2006), 
the incidence of ≥ Grade 3 toxicity with WBRT alone was approximately 10%, while with 
WBRT + drug combination was approximately 25-30%. 
 
As such, in the setting of poor overall prognosis, high baseline incidence of adverse events 
(related to the presence of brain metastases or WBRT) and since the study design is 
changed to a more conservative 3+3 design which may be at risk of falsely under-predicting 
MTD due to random occurrence of an AE at a lower dose level, it is justified to explore 
treatments with higher incidence of adverse events if it can help improve the dismal 
survival outcomes.  
 
In the current proposed revision, a modified 3+3 design was proposed that includes a 10 
patient expansion cohort in addition to 3-6 patients accrued at each dose-level. Based on 
the design proposed, the highest acceptable probability of DLT is 31.25% (5 or less events 
in 16 patients), with the target expected probability of DLT of 20-30% (of which 18-20% 
is expected from WBRT alone). The operating characteristics are described in section 5.1. 
 
Finally, per the first-in-human phase 0 trial eligibility, prior anti-neoplastic therapy must 
have been completed at least 2 weeks prior to enrollment. Hence, to boost further accrual 
and increase clinical applicability, the time-period of prior chemotherapy or 
immunotherapy was reduced to 2 weeks from the start of study therapy, keeping 3 weeks 
for investigational agents, or radiotherapy to a non-brain site for 2 weeks before initiation of 
IPdR therapy. With regards to any standard of care, oral targeted agent, based on the 
comments from amendment #6rev disapproval letter and recognizing the variation in 
half-lives of different drugs, the study investigators have standardized pre-study treatment 
time to 2 weeks irrespective of whether oral administration or not. For oral 
investigational agents, however, a time of 4 half-life and for other investigational agents a 
time interval of 3 weeks is retained.  
 
2.5.2 To date, the current study has completed accrual to dose-level 1A, 1B and 2A. No DLTs 
were noted at these dose-levels. Hence, per the study design, decision was taken to 
continue dose-escalation opening dose-level 2B (1800 mg). However, the 1st patient 
enrolled to dose level 1800mg had multiple concerning adverse events: acute kidney 
injury grade 3, acute oral mucositis grade 3 and acute vomiting grade 3. Per local study 
team, these were attributed to study drug as ‘Probable’ to ‘Definite’. 
 
In discussion with the CTEP Medical Officer, Dr Charles Kunos, based on the review of 
results of the completed phase 1 study detailed in 2.4.2 and recognizing the challenges 
with study accrual, a recommendation was received from CTEP to close dose-level 2B 
(1800 mg). Instead, dose-level 2A (1200 mg) is being re-opened to enroll 3 additional 
patients at the 1200mg dose level. Enrollment of 6 total patients at 1200 mg dose would 

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allow more robust assessment of safety of the 1200 mg level and could allow to complete 
the trial labeling 1200 mg daily IPdR x 28 days as the RP2D.     
 
2.6 
Correlative Studies Background 
 
As the %IUdR-DNA cellular incorporation in human tumor xenografts in athymic mice 
was linearly related to the IPdR dose when given po qd x 6-14 days [39, 41, 47], we will 
correlate %IUdR-DNA cellular incorporation in human tumor biopsies as an exploratory 
biomarker of tumor radiosensitization in a cohort of 6 brain metastases cancer patients 
receiving the RP2D by linear regression.  Dr. Jerry Collins, Associate Director for 
Developmental Therapeutics, DCTP, NCI will actively participate in the PK and %IUdR-
DNA cellular incorporation analyses. 
 
 
2.6.1 Pharmacokinetics of IPdR 
 
The clinical pharmacology of PO IPdR was characterized in the initial, DCTD-sponsored 
phase 1 trial 8866. Patients received a single PO dose of IPdR.[46]  Plasma 
concentrations of the active metabolite IUdR generally increased with increasing dose.  
At dose level (DL) 5 (2400 mg IPdR), plasma IUdR levels reached a peak of 4.0 ± 1.02 
mcM after 1.67 ± 1.21 hours, remained above 1 mcM for 3 to 4 hours, and declined with 
a half-life of 1.5 hours.  Plasma exposure values of the major secondary metabolite IU 
increased more than proportionally as doses were doubled, and remained at a sustained 
high level (near 100 mcM) for 10 hours in four of the 6 patients treated at DL 5, 
indicating disproportionate accumulation due to saturation of metabolic elimination.  
IPdR and its metabolites, IUdR, IP, and IU, were detectable in urine samples from 
patients receiving 2400 mg of IPdR.  Twelve percent (± 8%) of the dose was recovered 
over 24 hours; of the metabolites measured in urine, 90 ± 13% consisted of IU.  Previous 
clinical trials had defined 1 mcM as the minimum IUdR plasma concentration for 
efficacy[31, 49]; since DL 5 of this trial had achieved a mean peak IUdR plasma 
concentration of around 4 mcM, investigators concluded that PO IPdR may prove to 
show clinical antitumor activity, and future trials may focus on determining the optimal 
dosing schedule in sequence with RT. 
 
2.6.2 %IUdR-DNA Incorporation into Tumor 
 
Athymic nude mice bearing HCT-116 human colon cancer xenografts, either as liver 
metastases, subcutaneous (SC) flank tumors, or both, were administered IPdR PO for 6 
days at its RP2D (1 g/kg/day).[39]  This treatment resulted in a 2-to 3-fold greater 
incorporation of IUdR into tumor DNA than IUdR administered at its RP2D (250 
mg/kg/day), indicating a greater potential for radiosensitization.  
In a second study, athymic mice with HT29 human colon cancer xenografts were treated 
up to 2 g/kg PO IPdR for 6 days and the investigators found < 1.5 times increase in the 
percentage of IUdR-DNA in the tumor xenografts.[40]  A subset of the mice with SC 
xenografts measuring 0.25-0.3 cm2 were treated with RT (2 Gray [Gy]/day for 4 days) 
with or without PO doses of IPdR at the RP2D of 1000 mg/kg/day for 6 days.  A tumor 

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regrowth assay demonstrated a 1.5-fold improvement in outcome (time to regrowth of 
tumor to 300% of pre- treatment volume) of the IPdR + RT group versus RT alone.  
Mice with U251 human glioblastoma xenografts were treated with 750 or 1500 
mg/kg/day IPdR over 14 days.[41]  A significant sensitizer enhancement ratio (SER), 
calculated as the ratio of growth delay [time to 300% original tumor volume] after agent 
+ RT to the delay after RT alone) was found for PO IPdR + RT (SER=1.31, P=0.05) but 
not for 14-day CIV IUdR + RT (SER=1.07, P=0.57), indicating that IPdR could be a 
useful clinical radiosensitizing agent.  
 
Deficiencies in the mismatch repair (MMR) system have been implicated in the genesis 
of hereditary nonpolyposis colon cancer and an increasing number of sporadic cancers 
(Peltomaki, 2003).  Athymic nude mice with an isogenic pair of human colon cancer 
xenografts HCT116 (MMR-, hMLH1-) and HCT116/3-6 (MMR+, hMLH1+), were treated 
with PO IPdR (1g/kg/d) every day for 14 days.[47] On Days 11 to 14, RT was delivered 
to the tumor xenografts with 2 Gy or 4 Gy per fraction for 4 days.  The tumor size and the 
body weight were monitored daily until the tumors grew to ≤ 300% of their pre-
irradiation volume.  The tumor volumes were estimated by the formula: R1x R2 x R2/2, 
where R1 is the maximum diameter and R2 is the rectangular diameter.  Tumor regrowth 
delay was calculated as the area between the 300% volume line and the growth curves for 
the various control and treatment groups.  Substantial increases in regrowth delay were 
found in both HCT116 and HCT116/3-6 tumor xenografts and there was substantial 
radiosensitization in both HCT116 and HCT116/3-6 tumor xenografts.  
 
Athymic nude mice with human glioblastoma (U251) SC xenografts were treated with 
IPdR: 1) 500 mg/kg of every other day (QOD); 2) 500 mg/kg QD; 3) 166 mg/kg three 
times a day (TID); or 4) vehicle alone (control).[43]  On the IPdR treatment Days 11 to 
14 (for the QD, TID, and control groups) and Days 25 to 29 (for the QOD group), RT 
was delivered using 2 Gy/fraction for 4 days to the tumor xenografts.  The tumor 
regrowth assay showed in all three IPdR treatment groups enhanced tumor growth delay 
compared to control (QOD, 29.4 days; QD, 29.7 days; TID, 34.7 days; radiotherapy alone 
15.7 days).  The SER of each schedule was calculated: QOD 2.17; QD, 2.20; and TID, 
2.56.  The QOD schedule also resulted in reduced systemic toxicity.  
 
In the most recent study in mice, athymic male nude mice (6–8 weeks old) were 
implanted with SC U87 xenograft tumors (4 × 106 cells) and then randomized to 10 
treatment groups receiving increasing doses of PO IPdR (0, 100, 250, 500, and 1000 
mg/kg/d) administered QD for 14 days with or without RT (0 or 2 Gy/d for 4 d) on Days 
11–14 of IPdR treatment.[42]   At Day 31, the mean tumor volume reduced from 1609 ± 
285 mm3 to 821 ± 113 mm3 with RT alone.  IPdR treatment with or without RT caused a 
dose-dependent reduction in tumor volume: 250 mg/kg/d for 14 days (IPdR alone, 1040 ± 
105 mm3; IPdR + RT, 551 ± 86 mm3); 500 mg/kg/d for 14 days (IPdR alone, 960 ± 131 
mm3; IPdR + RT, 268 ± 69 mm3); 1000 mg/kg/d for 14 days (IPdR alone, 718 ± 99 mm3; 
IPdR + RT, 309 ± 60 mm3).  The SER was approximately 2–3 for the two lower IPdR 
dose groups and 5–6 for the two higher IPdR dose groups.  These results indicated that 
the efficacy of PO IPdR plateaus around ≥ 500 mg/kg/day.  
 

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Correlation of tumor response using RECIST Criteria with the %IUdR-DNA cellular 
incorporation in tumor from biopsies of tumors in patients with brain metastases at the 
RP2D will be analyzed to determine the tumor response relationship to the %IUdR-DNA 
cellular incorporation in tumor on Day 8 of the 28-day IPdR treatment based on HPLC 
and flow cytometry measurements.  A tumor biopsy on Day 8 of IPdR treatment was 
selected to provide for measurable IUdR-DNA incorporation in tumor and to eliminate 
the effect of RT on tumor tissue as the tumor biopsy will be performed prior to the 
initiation of RT.  Tumor biopsy is not required for participation in this study.  Tumor 
biopsy should only be considered for tumors that are easily accessible and would not 
subject that patient to a high risk of morbidity as a result of a tumor biopsy.  Otherwise, if 
tumor is easily accessible and biopsy would pose minimal risk to the patient, then tumor 
biopsy should be performed.  A biopsy may be taken of the primary tumor or any 
extracranial metastasis.  A biopsy of the brain metastasis is not permitted.  In this 
analysis, tumor response is the dependent variable and can be binomial (i.e. response vs. 
no response) or multinomial (i.e. complete response, partial response, stable disease or 
progressive disease) and the %IUdR-DNA cellular incorporation is the independent 
variable. 
 
The survival times will also be obtained from the brain metastases cancer patients and, if 
data allow, will be analyzed using a Cox proportional hazards model with %IUdR-DNA 
cellular incorporation in tumor as the covariate.  However, given the variable tumor types 
and extent of disease, according to the eligibility criteria, a valid survival analysis is 
unlikely. 
 
2.6.3 %IUdR-DNA Incorporation into Normal tissues 
 
In the pre-clinical in vivo testing of po IPdR as a prodrug for IUdR-mediated 
radiosensitization,  2-fold decreases in %IUdR-DNA incorporation in proliferating 
dose-limiting normal tissues (bone marrow and intestine) following PO IPdR were 
consistently found compared to PO or CIV infusions of IUdR (using RP2D schedules) in 
4 different human tumor xenografts in athymic mice.[39-42]  In prior clinical Phase 1 
trials of CIV infusions of IUdR ( biochemical modulators), the %IUdR-DNA 
incorporation in circulating granulocytes during and following the IUdR infusion as a 
surrogate for a proliferating normal human tissue (bone marrow) has been measured.[32, 
50-54]  In general, the %IUdR-DNA incorporation in circulating granulocytes increased 
linearly with a linear increase in steady-state plasma levels of IUdR.  Additionally, high 
( 6%) %IUdR-DNA levels in peripheral granulocytes predicted for systemic bone 
marrow toxicity to CIV IUdR.  In the pre-clinical studies of po IPdR daily for 14 days in 
athymic mice and ferrets,[39, 41, 47] the %IUdR-DNA incorporation was  2% in 
circulating granulocytes following treatment and no changes in blood counts were found 
in ferrets and rats,[44, 45] suggesting that bone marrow toxicity may not be dose-limiting 
for PO IPdR in humans.  Additionally, no myelosuppression or bone marrow 
abnormalities were seen in the IPdR toxicology studies, where IPdR was given once daily 
for 14 days in ferrets and for 28 days in rats.[44, 45] 
 

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Correlation will be performed of the %IUdR-DNA cellular incorporation in peripheral 
(circulating) granulocytes as an exploratory biomarker of bone marrow acute normal 
tissue toxicity with the po IPdR RP2D and RP2D pharmacokinetics.  This exploratory 
assay was originally developed in Dr. Jerry Collins’ laboratory at NCI.[55]  Additionally, 
we do not expect a linear relationship between the %IUdR-DNA cellular incorporation in 
circulating granulocytes and peripheral blood counts measured weekly during RP2D drug 
exposures and at Day 29 and Week 8 follow-up.  Nevertheless, we will test the 
hypothesis that IPdR drug dose and drug plasma pharmacokinetics will be linearly related 
to the %IUdR-DNA cellular incorporation in circulating granulocytes. 
 
 
 
 

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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically confirmed malignancy with brain metastases and are 
recommended palliative WBRT. 
 
3.1.2 Life expectancy of greater than 2 months to allow completion of study treatment and 
assessment of dose-limiting toxicity. 
 
3.1.3 Age ≥ 18 years.  Because no dosing or adverse event data are currently available on the 
use of IPdR in patients < 18 years of age, children are excluded from this study, but will 
be eligible for future pediatric trials. 
 
3.1.4 ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A). 
 
3.1.5 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
 
≥ 3,000/mcL 
− 
absolute neutrophil count 
 
≥ 1,000/mcL 
− 
platelets 
 
≥ 100,000/mcL 
- 
calculated creatinine clearance ≥ 45 mL/min/1.73 m2  
 
− 
Total bilirubin, AST (SGOT) and ALT (SGPT): 
 If no known liver metastases: 
 Total bilirubin < 1.5 x institutional upper limit of normal (ULN), AST/SGOT 
and ALT/SGPT both < 2 x ULN.  
 
If known liver metastases, then: 
Total bilirubin < 2.5 x ULN, AST/SGOT and ALT/SGPT both < 5 x ULN. 
 
3.1.6 HIV+ patients with CD4 counts ≥ 250 cells/mm3 on anti-viral therapy are eligible for the 
study. 
 
3.1.7 Negative urine or serum pregnancy test result for females of child bearing potential only. 
Note: The effects of IPdR on the developing human fetus are unknown.  For this reason 
and because radiation therapy is known to be teratogenic, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men and women 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. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 

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3.2 
Exclusion Criteria 
 
3.2.1 Presence of diffuse lepto or pachy meningeal carcinomatosis (focal/localized 
involvement from limited meningeal based metastases are acceptable), greater than 1 cm 
mid-line shift, uncal herniation, or severe hemorrhage/hydrocephalous (small intra-
lesional or anticipated surgical cavity hemorrhage is acceptable).  Patients with seizure at 
presentation who have been started on Levetiracetam and have been stable for 48 hours 
prior to study registration are eligible at the discretion of treating physician.   
 
3.2.2 Patients who have received systemic cytotoxic chemotherapy or approved oral targeted therapy or 
immunotherapy for 2 weeks, or other investigational agents for 3 weeks (4 half-lives for any oral 
targeted agents), or radiotherapy to a non-brain site for 2 weeks before initiation of IPdR therapy. 
Patients who have recovered from serious (CTCAE grade 3 or more higher) to grade 1 or 
less adverse events from the previous therapies are eligible.  Prior/current/future 
hormonal therapy and/or bisphosphonates are permitted with no minimum interval to 
initiation of study therapy. If indicated, patients can receive palliative radiation therapy to 
a non-brain site concurrent or immediately post-study treatment with no minimum 
interval to initiation of study therapy. 
 
3.2.3 Patients must not have received prior whole brain radiation therapy. Previous SRS/SRT 
done at least 3 weeks from the planned start of IPdR therapy is acceptable. 
SRS/SRT/fractionated boosts or neurosurgery can be performed once the DLT 
assessment has been completed, if felt clinically necessary. 
 
3.2.4 Patients with primary tumors including germ cell tumor, or lymphoma/leukemia. 
 
3.2.5 Patients who are receiving any other investigational agent. 
 
3.2.6 Patients needing more than 8 mg dexamethasone per day at the time of start of WBRT 
will not be eligible to participate in the study.  However, patients will be allowed entry 
into the study if it is medically safe to reduce the daily dose of dexamethasone to 8 mg or 
less from the day of the start of WBRT.  The dexamethasone dose for such patients may 
be increased beyond 8 mg per day during the course of treatment if medically necessary.  
This increased need for dose should be communicated to the study’s Principal 
Investigator, Dr Mohindra at the University of Maryland. 
 
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to IPdR. 
 
3.2.8 Uncontrolled intercurrent illness if itwould increase the risk of toxicity or limit 
compliance with study requirements.  This includes, but is not limited to, ongoing 
uncontrolled serious infection requiring i.v. antibiotics, progressive congestive heart 
failure, unstable angina pectoris, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 

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3.2.9 Pregnant women are excluded from this study because IPdR is an agent with 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. 
 
3.3 
Inclusion of Women and Minorities 
 
Patients are eligible for this trial regardless of sex/gender, race, or ethnicity.  Subject 
selection is equitable if they meet the inclusion and exclusion criteria.  In conformance 
with the National Institutes of Health (NIH) Revitalization Act of 1993 (amended in 
October, 2001) with regard to inclusion of women and minorities in clinical research, 
possible interaction between race/ethnicity and treatment have been considered. 
 
 
 
 
 

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4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
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 (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site 
staff requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the 
table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/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 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list 
all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
For questions, please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. 
 
 
 

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4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the CTSU 
Regulatory Support System (RSS) uses extensive data to make a determination of whether a site 
has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
A valid IRB approval 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the  CIRB are not 
required to submit separate IRB approval documentation to the CTSU Regulatory Office.  
For sites using the CIRB, IRB approval information is received from the CIRB and 
applied to the RSS in an automated process.  Signatory institutions  must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate 
their intention to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study.  
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9979 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree or 
Click on the By Lead Organization folder to expand, then select LAO-MN026 
and protocol # 9979. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 

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initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Submitting Regulatory Documents 
 
Requirements For 9979 Site Registration 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted)  
• Credentialing for performing neurocognitive testing through existing mechanisms 
within cooperative groups including but not limited to participation in a prior NRG 
or Alliance or any other cooperative group study or other PI approved measures 
including but not limited to credentialing through training arranged by the stud PI 
(or representative) or participating site’s internal training. Each participating site 
should review the credentialing process with the study PI (or representative) prior 
to site activation. 
• Completion of a Site Initiation Visit teleconference (SIV TC) with the lead site 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite  3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU Web 
site.   
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration subtab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 

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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 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar.  Registrars must hold a 
minimum of an AP registration type. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab 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.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 

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is available on the Theradex website: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  This 
link to the Theradex website is also on the CTSU website OPEN tab.  For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment as rapidly as possible.  
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. 
 
 
 
 

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5. 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described 
in Section 6.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
5-iodo-2-pyrimidinone-2’-deoxyribose (IPdR) (NSC 726188) will be delivered by oral 
(po) administration in capsule form once daily x 28 days.  The capsules will be taken on 
an empty stomach (either 1 hour before or 2 hours after meals). 
 
IPdR will be administered alone without WBRT during Week 1 (7 calendar days) and 
with WBRT during Weeks 2-4.  On days when IPdR and WBRT are given concurrently, 
IPdR should be administered within 30 minutes to 2 hours prior to WBRT. 
 
Because IPdR is an orally administered agent patients will be requested to maintain a 
medication diary of each dose of medication.  The medication diary will be returned to 
clinic staff at the end of each course. 
 
Since the IPdR half-life is <1 day, 5 half-lives will be less than 1 week. Hence, an 
observation period up to D35 (D1 being 1st day of IPdR) is required to assess toxicity 
before enrolling a patient at the next IPdR dose level.  Patients will be allowed to initiate 
systemic therapy per clinician preference after the D35 assessment. 
 
 
 
The starting dose for IPdR for Phase 1 testing is based on the most sensitive (lower 
MTD) of the two animal species tested, i.e. ferrets and rats [44, 45]. The MTD for IPdR 
in ferrets, the most sensitive species, was determined to be  150 mg/kg/d for 14 
days[45], which is equivalent to 850 mg/M2/day for 14 days.  The human equivalent dose 
(HED) is also 850 mg/M2/day, the same as the ferret dose, based on body surface area 
(BSA).[48]   Based on these calculations and pre-clinical animal data, 1/10th of the MTD 
is 85 mg/M2/day (150 mg), the starting dose for this trial. 
 
 
 

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5.1.1 Part 1 IPdR Dose Escalation Schedule 
 
Original Design (no longer active, reference only): An initial single patient dose 
escalation of IPdR will be conducted in Part 1.  The starting dose is 150 mg (dose level 
1A).  A 100% dose escalation will be used until a treatment-related Grade 2+ toxicity or 
otherwise a DLT (as defined in Section 5.2) is observed.  If a grade 2+ toxicity or DLT is 
observed in a patient, two additional patients will then be entered at this dose level.  
Subsequent steps would be guided by the occurrence of any grade 2+ toxicity or DLT in 
the cohort of 3 patients (including the initial single patient) with rules as states below: 
 
a. If only 1 of the 3 patients experiences Grade 2+ toxicity and this is not a DLT, then 
the design will stay with Part 1.  
 
b. If any of the 3 patients experience a DLT or 2+ patients experience Grade 2+ toxicity, 
then the design will switch to Part 2. 
 
i. 
If only 1 of 3 patients has experienced a DLT or 2+ patients experience Grade 2+ 
toxicity, the dose level in Part 2 will be the same and that dose level will be 
expanded to 6 patients (3 more patients)  
ii. 
If 2+ patients have experienced a DLT, then the dose will be de-escalated on Part 
2 to half of the current dose (same as one level lower dose of part 1).   
 
If dose level 1A results in 2 DLTs, then the trial will be closed as no maximum tolerated 
dose will have been identified.  Dose Increment Schedule will be as shown in table 4 
after 4 weeks of follow up of the prior cohort to assess acute, but delayed, toxicity).  
 
Design Amendment: 
 
The above text in section 5.1.1 is how the study was originally designed.  However, to 
speed up accrual at the recommendation of CTEP medical officer and based on updated 
results of study 8866 and 9882 demonstrating safety of the drug IPdR at higher doses 
both alone and in combination with radiation (section 2.4) it was recommended to stop 
accrual to part 1 of the study at dose level IB and open Part 2 at dose level 2A (1200mg), 
following the modified 3+3 design outlined in the Part 2 below.  
 
Table 4: Part 1 IPdR Dose Increment Schedule 
Dose 
Level 
Dose (mg) 
Multiple of 
starting dose 
% increase 
above 
previous dose 
level 
1A 
150  
1x 
N/A 
1B 
300  
2x 
100 
 
 

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5.1.2 Part 2 IPdR Dose Escalation Schedule 
 
Original Design (no longer active, reference only): In Part 2 of this Phase 1 protocol, a 
standard cohort 3+3 design (see table 5) will be used where up to three patients will be 
accrued to a given dose level (starting with no increase of the final Part 1 dose and 
escalating per table 6).  After each cohort has been accrued the study will temporarily 
close to assess DLT status of each patient.  The decisions to re-open, and at what level to 
re-open, are on the following: 
• If DLT is not seen in any of the 3 patients, 3 new patients will be accrued and 
treated at the next higher dose level.  If DLT is seen in 2 or 3 of 3 patients 
treated at a given dose level, then the MTD has been exceeded and the next 3 
patients will be treated at the next lower dose level (unless there have already 
been 6 accrued to that lower level). 
• If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level.  If  DLT 
is seen in at least one of these additional patients (at least 2 of 6), the MTD 
will have been exceeded.  If DLT is not seen in any of the three additional 
patients, 3 new patients will be accrued and treated at the next higher dose 
level. 
• After enrolling 6 patients on a specific dose level, if DLT is observed in at 
least 2 of 6 patients, then the MTD will have been exceeded and defined as the 
previous dose level unless only 3 patients were treated at the lower dose level.  
In that case, 3 additional patients will be treated at this lower dose level such 
that a total of 6 patients are treated at the MTD to more fully assess the 
toxicities associated with the MTD. 
• If a patient fails to complete the initial course of therapy (cycle 1) for reasons 
other than dose-limiting toxicity defined adverse events, the patient will be 
regarded as uninformative in regard to the MTD goal and an additional patient 
will be treated at the current dose level; however, all toxicity information will 
be utilized in the analysis. 
 
The MTD is defined as the dose below which 2 or more of 6 patients experience dose-
limiting toxicity. 
 
Design Amendment #1 (to be superceded by Design amendment #2 below): 
In Part 2 of this Phase 1 protocol, a modified cohort 3+3 design (see table 5) will be used 
where up to three patients will be accrued to a given dose level (starting with 1200 mg 
IPdR dose and escalating per table 6).  After each cohort has been accrued the study will 
temporarily close to assess DLT status of each patient.  The decisions to re-open, and at 
what level to re-open, are on the following: 
• If DLT is not seen in any of the 3 patients, 3 new patients will be accrued and 
treated at the next higher dose level.   
• If DLT is seen in 3 of 3 patients treated at a given dose level, then the 
maximally tolerated dose (MTD) has been exceeded and the next 3 patients 
will be treated at the next lower dose level such that a total of 6 patients are 

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treated to more fully assess the toxicities (unless there have already been 6 
accrued to that lower level which will then be labeled as the MTD and the 
study will proceed to the expansion cohort). 
• If DLT is seen in 1 or 2 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level.  
Including the three additional patients, following rule will be applied:  
o DLT is seen in 1 of the total 6 patients, proceed to the next higher dose 
level.  
o DLT is seen in 2 of the total 6 patients, then dose escalation is stopped, 
and this dose level is declared the MTD. The study will proceed to the 
expansion phase.  
o DLT is seen in 3 or more of the 6 patients have DLT, the MTD will 
have been exceeded and the next 3 patients will be treated at the next 
lower dose level such that a total of 6 patients are treated to more fully 
assess the toxicities (unless there have already been 6 accrued to that 
lower level which will then be labeled as the MTD and the study will 
proceed to the expansion cohort).   
• If a patient fails to complete the initial course of therapy (cycle 1) for reasons 
other than dose-limiting toxicity defined adverse events, the patient will be 
regarded as uninformative in regard to the MTD goal and an additional patient 
will be treated at the current dose level; however, all toxicity information will 
be utilized in the analysis. 
• In the event MTD is exceeded in part 2 at the first dose level (1200mg), the 
next lower dose of IPdR will be 900 mg. If MTD is exceeded even at 900 mg, 
then a dose level of 600 mg will be tested. At both these levels, a minimum of 
6 patients will be evaluated. 
 
The MTD is defined as the highest dose that has fewer than 3 (out of 6) patients 
experiencing dose-limiting toxicity. 
 
Table 5: Part 2 IPdR Dose Increment Schedule 
Dose level 
Dose (mg) 
2A* 
1200 
2B 
1800 
2C 
2400 
* See text in 5.1.2 for the scenario MTD is exceeded at 1200 mg dose. 
 
 
 
 
 
 

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Table 6: Part 2 Dose Escalation Decision Rules  
 
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. If this is the 
highest dose-level, then accrue additional 3 patients at 
the dose-level. 
3 out of 3 
MTD is exceeded and the dose escalation will be 
stopped.  This dose level will be declared the maximally 
administered dose (highest dose administered).  Three 
(3) additional patients will be entered at the next lowest 
dose level such that a total of 6 patients are treated to 
more fully assess the toxicities (unless there have 
already been 6 accrued to that lower level which will 
then be labeled as the MTD and the study will proceed 
to the expansion cohort). 
1 or 2 out of 3 
Enter 3 more patients at this dose level. 
• DLT is seen in 1 of the total 6 patients, proceed to the 
next higher dose level. 
• DLT is seen in 2 of the total 6 patients, then dose 
escalation is stopped, and this dose level is declared 
the maximally tolerated dose (MTD). The study will 
proceed to the expansion phase. 
• DLT is seen in 3 or more of the total 6 patients, then 
MTD is exceeded and the dose escalation is stopped. 
This dose level is declared maximally administered 
dose (highest dose administered). Three (3) 
additional patients will be entered at the next lowest 
dose level such that a total of 6 patients are treated 
to more fully assess the toxicities (unless there have 
already been 6 accrued to that lower level which will 
then be labeled as the MTD and the study will 
proceed to the expansion cohort). 
≤ 2 out of 6 at highest  
dose level below the  
maximally administered dose 
This is the maximally tolerated dose, MTD. 
 
Design Amendment #2: 
As described in section 2.5.2, after accruing one patient at the dose-level 2B of table 5, 
the study is being amended to close the dose-level 2B and re-open 2A (1200 mg) to 
enroll 3 additional patients. The results of 6 total patients at dose-level 2A (1200 mg) 
will be evaluated per the table 7 below 
 
 
 

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Table 7: Part 2 Dose Escalation Decision Rules  
 
Number of Patients with DLT  
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3  
(0 out of 6 patients) 
This dose-level is declared the recommended phase 2 
dose (RP2D). The study will proceed to the expansion 
phase. 
1 or 2 out of 3  
(total 1 or 2 out of 6 patients) 
This dose level is declared the RP2D. The study will 
proceed to the expansion phase. 
3 out of 3 
(total 3 out of 6 patients) 
MTD is exceeded and the dose level will be declared the 
maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level such that a total of 
6 patients are treated to more fully assess the toxicities 
(unless there have already been 6 accrued to that lower 
level which will then be labeled as the RP2D and the 
study will proceed to the expansion cohort). 
 
5.1.3 Expansion Cohort  
 
An expansion cohort of 10 additional patients will be treated at the RP2D to confirm 
safety and further test the exploratory biomarkers.   If after 16 patients have been treated 
at the RP2D (6 in part 2 and 10 in the expansion cohort), there are at most 5 patients with 
a DLT (31.25%) then this dose will remain as the RP2D.  If there are more than 5, then 
the next lower dose will be RP2D.   
Based on the design proposed, the highest acceptable probability of DLT is 31.25% (5 or 
less events in 16 patients), with the target expected probability of DLT of 20-30% (of 
which 18-20% is expected from WBRT alone).  
 
The following table shows some of the operating characteristics for the current design 
under a number of possible DLT rates.  For each given dose, the table displays the 
likelihood of increasing to the next dose and the probability of having at most 5 patients 
with DLTs (out of 16). For example, if the true DLT rate is 0.4 for a given dose level, 
there is only a 31% chance of accruing above that dose level.  If on the other hand, the 
true DLT rate for a given dose is 0.3 (close to target acceptable rate) and if this dose level 
is determined to be the MTD during the dose finding stage, then there is a 66.6% chance 
of having 5 or fewer patients with DLT (out of 16). 
 
DLT 
Rate 
Probability of dose 
escalation 
Probability of having at most 
5 Patients with DLT (out of 
16) 
0.1 
0.906 
0.997 
0.2 
0.709 
0.918 

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0.3 
0.494 
0.660 
0.4 
0.309 
0.329 
0.5 
0.172 
0.105 
0.6 
0.082 
0.019 
 
When a patient at any site is undergoing the study treatment or is pending DLT 
assessment, the PI of the study (or representative) will regularly meet (in person, by 
teleconference or by email) with the study statistician and the participating site’s study 
team to review any updates regarding potential adverse events being experiences by the 
study subject from the WBRT (or any other extracranial RT, if applicable).  If necessary, 
clinical inputs from the treating physician and the participating site PI will be obtained to 
assist in the decision regarding the adverse event being labeled as a DLT.  
 
Unexpected severe late neurologic radiation toxicity or extra-cranial radiation toxicity 
will be recorded as a secondary end-point. These events will be reviewed by the 
independent DSMB who will be charged with considering cessation of the trial if the long 
term/delayed (6 months) ≥ grade 3 symptomatic neurotoxicity or other extra-cranial 
radiation toxicity is > 20%.   
 
Use of other therapies post-DLT assessments which might impact neurological 
functioning (including but not limited to immunotherapy, for which safety data of 
immune-related neurological adverse events after WBRT is relatively limited) will be 
considered for this decision. 
 
5.1.4 Whole Brain Radiation Therapy 
 
5.1.4.1 
Dose Specifications 
 
Protocol whole brain radiation therapy (WBRT) will begin on Day 8 (7 days after the 
start of PO IPdR administration).  One treatment (fraction) of 2.5 Gy will be given 
daily for not more than 5 days per week (15 fractions), once daily fractionation, 
Monday through Friday, without any planned interruptions for a total of 37.5 Gy over 
3 weeks.  Therefore, WBRT will be delivered from days 8 onward (Week 2 through 
4).  All portals shall be treated during each treatment session.  Doses are specified as 
the target dose, which will be the dose on the central ray at mid-separation for two 
opposed coaxial equally weighted beams. “Compensating beams” that minimize hot 
spots (these hot spots are typically present along the midline due to less tissue present 
in these regions compared to mid-brain) are allowed to achieve optimal dose 
homogeneity. 
 
5.1.4.2 
Technical Factors 
 
Treatment will be delivered with megavoltage (MV) machines of energy ranging 
from 4 MV to 6 MV photons.  Patients will be planned and treated using three-
dimensional conformal radiation technique (3D-CRT). Field-in-field approaches to 

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3DCRT to optimize homogeneity are permitted. Intensity Modulated Radiotherapy 
(IMRT) with or without hippocampal avoidance (Fixed-gantry IMRT, helical 
tomotherapy or VMAT) will be allowed per institutional protocols.  Partial brain cone 
down, stereotactic radiosurgery boost, electron therapy, particle therapy, or 
brachytherapy boost are not permissible during the course of the study treatment and 
until the DLT assessments are complete. However, patients will be eligible to 
undergo SRS/SRT/fractionated boosts or neurosurgery, once the DLT assessment has 
been completed, if felt clinically necessary. 
  
5.1.4.3 
Localization, Simulation,Immobilization and Dose prescription. 
 
The patient will be treated in the supine position to allow planning and delivery of 
WBRT.  A head-holding device that is transparent to x-rays must ensure adequate 
immobilization during therapy and ensure daily treatment reproducibility.  A non-
contrast treatment-planning CT scan of the entire head region extending into neck 
should be obtained. When using hippocampal avoidance WBRT, it is recommended 
he axial slice thickness should match the MRI axial slice thickness as much as 
possible (preferred 1.5 mm). The treatment-planning CT scan must be acquired with 
the patient in the same position and immobilization device as for treatment.  
 
For 3D-CRT, the target volume will include the entire cranial contents, with flashing 
beyond skin and adequate margin on the skull base as visualized on the simulator or 
portal films to account for beam penumbra and day-to-day set-up variation.  Attempts 
will be made to exclude the lenses and the anterior globe from the beam either by 
field arrangement or shielding.  ‘Helmet’ portals with customized immobilization and 
shielding are permitted. The dose is specified as the target dose, which shall be the 
dose on the central x-ray at mid-separation for two opposed coaxial equally weighted 
beams. “Compensating beams” that block hot spots (these hot spots are typically 
present along midline due to less tissue present in these regions compared to mid-
brain) are allowed to achieve better dose homogeneity. All portals shall be treated 
during each treatment session. 
 
5.1.4.4 
Hippocampal avoidance WBRT should be planned in accordance with the ongoing 
(or most recently completed, if no ongoing study) cooperative group protocol. The 
target volume will include the entire cranial contents to the foramen magnum (labeled 
as CTV). Care should be taken to delineate cribriform plate in the CTV. The PTV is 
equal to CTV without the hippocampal avoidance region. IMRT plan should be 
normalized such that 95% of the PTV volume receives prescription dose of 37.5 Gy 
(V37.5 Gy ≥ 95%), D2% (Dose to hottest 2% of PTV) is ≤ 40 Gy, D98% (Dose to 
2% of PTV) is ≥ 32.5 Gy. Variation Acceptable include, V37.5 Gy ≥ 90%, D2% is ≤ 
43 Gy and D98% is ≥ 30 Gy. QA for the physician-approved plan should be 
performed per institutional policies.Critical Structures 
 
For both 3DCRT and hippocampal avoidance WBRT, the left (Lens_L) and right 
(Lens_R) lens should be contoured using the CT dataset only. For patients post-
cataract surgery, a surrogate lens structure should be created.  

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For hippocampal avoidance WBRT, bilateral hippocampal contours (Hippocampi) 
will be manually generated on the fused planning MRI/CT image set by the treating 
physician according to contouring instructions specified on 
http://www.rtog.org//corelab/contouringatlases/hippocampalsparing.aspx . 
Hippocampal avoidance region (Hippocampi_05) will be generated by three-
dimensionally expanding the hippocampal contours by 5 mm. Bilateral hippocampal 
contours will be subdivided into Left (Hippo_L) and Right (Hippo_R) hippocampi. 
Due to variance in eye position between the CT and MRI, if possible, the left 
(OpticNerve_L) and right (OpticNerve_R) optic nerve should be contoured using the 
CT dataset only. Located above the pituitary fossa, the optic chiasm (OpticChiasm) 
includes both anterior and posterior limbs. It is best visualized on SPGR/MPR/TFE 
T1 MRI sequence, but should be confirmed on CT dataset due to potential variation 
in CT/MRI fusion.  
 
OAR constraints for hippocampal avoidance WBRT are shown below: 
 
Name of 
Structure  
Dosimetric 
parameter  
Per Protocol  
Variation 
Acceptable  
Notes  
 
D100%(Gy)  
≤ 11  
11 to 13  
Dose to 100% of 
Hippocampus  
 
Dmax(Gy)  
≤ 16  
16 to 20  
Dose to hottest 0.03 
cc volume of 
Hippocampus  
OpticNerve_L  
Dmax(Gy)  
≤ 37.5 
37.5 to 40 Gy 
Dose to hottest 0.03 
cc volume of 
OpticNerve_L  
OpticNerve_R  
Dmax(Gy)  
≤ 37.5  
37.5 to 40 Gy 
Dose to hottest 0.03 
cc volume of 
OpticNerve_R  
OpticChiasm  
Dmax(Gy)  
≤ 37.5  
37.5 to 40 Gy 
Dose to hottest 0.03 
cc volume of 
OpticChiasm  
  
In optimizing planning, the following treatment-planning priorities should be 
followed: 
1. OpticChiasm 
2. OpticNerve_L or OpticNerve_R 
3. Hippocampus 
4. PTV_3000 
5. Lens_L or Lens_R 
In the event that an OAR with higher priority than PTV cannot be constrained within 
Unacceptable Deviation limits, then D98% and/or V30Gy for PTV should be lowered 
to Variation Acceptable range to ensure that the OAR with higher priority does not 
exceed Unacceptable Deviation limits. Please contact the study PI (or representative) 
if there are challenges meeting above. 
 

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5.1.4.5 
Documentation Requirements 
 
The following documents should be submitted to the PI at the University of Maryland 
• 
Radiation Total Dose  
• 
Radiation Dose per Fraction 
• 
Radiation Number of fractions 
• 
Radiation Technique: 3D-CRT or IMRT/VMAT/Tomotherapy 
• 
Use of Hippocampal avoidance: Yes or No 
• 
Radiation Start Date 
• 
Radiation Completion Date 
• 
Treatment Interruptions/Delays 
• 
Acute on-treatment toxicity with grades 
• 
RT plan report with dose to organs at risk, if applicable. 
• 
Dexamethasone pill diary during WBRT and for three weeks post-WBRT 
(DLT assessment period) 
 
Copies of simulation and port films and the complete WBRT daily treatment record 
and calculations will be submitted to the University of Maryland, Baltimore, 
Department of Radiation Oncology ONLY if specifically requested. 
 
5.1.4.6 
Compliance Criteria 
 
The planned protocol treatment should be completed without any unplanned breaks/ 
interruptions.  Dose delay/modification table has been noted in section 7.  
 
5.1.4.7 
Radiation Adverse Events 
 
A focused history and physical examination should be performed at least once weekly 
during Weeks 1 through 4 (study treatment) and then towards the end of week 6 and  
8 (observation period) to assess for acute treatment-related toxicity. 
 
Acute (≤ 90 days from treatment start): Expected adverse events include hair loss, 
erythema of the scalp, headache, nausea and vomiting, eye/ear irritation, mucositis, 
taste/salivary changes, loss of appetite, fatigue, lethargy, and transient worsening of 
neurological deficits.   
 
Late (> 90 days from treatment start): Possible adverse events include radiation 
necrosis, cognitive dysfunction, visual difficulties, accelerated atherosclerosis, and 
radiation-induced neoplasms.  
 
5.1.4.8 
Radiation Adverse Event Reporting 
 
See Section 8 for Adverse Event Reporting 
 
 
 

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5.2 
Definition of Dose-Limiting Toxicity 
 
Patients who are removed from protocol treatment due to non-treatment related toxicities 
requiring treatment delay of > 14 days are not assessable for determination of the MTD 
and will be replaced.  
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6. 
 
Toxicities will be recorded as adverse events on the Adverse Event case report form and 
must be graded using The National Cancer Institute’s Common Toxicity Criteria 
(CTCAE) version 5. 
 
Dose-limiting toxicity (DLT) in Parts 1 and 2 includes toxicity that is attributable to the 
IPdR and/or whole brain radiotherapy per the following:  
 
• Any Grade 4+ neurologic adverse event, of any duration.  
 
• Any Grade 3 neurologic adverse event that does not improve to baseline or Grade 
1 within 7 days of onset. 
 
• Any Grade 3 symptomatic CNS hemorrhage or ischemia 
 
• Any Grade 4+ non-neurologic toxicity 
o An exception is Grade 4 cytopenia or metabolic abnormality without 
associated serious clinical symptoms (grade 4+)  that improves to < Grade 
4 within ≤ 7 days of onset  
 
Patients with brain metastases are likely to have other sites of symptomatic extra-cranial disease 
in need of palliative radiation. Hence, per standard clinical practice, patients in this study 
protocol will be allowed to receive palliative extra-cranial irradiation, concurrently or 
sequentially, as indicated. This reflects best clinical practice. 
 
However, such a procedure, may pose a possible risk of exaggerated radiation toxicity at the 
extra-cranial site, due to ongoing IPdR therapy. Since the use of palliative extra-cranial 
irradiation may be for a variety of extra-cranial indications, it is not feasible to account for all 
possible scenarios in the DLT definition. Further, for a more focused assessment of safe dose of 
IPdR in combination with WBRT, it is important to keep the DLT focused on neurological 
toxicity. Nevertheless, it will important to monitor patients for toxicity from extra-cranial 
palliative radiotherapy. Hence, to note that “Any grade 3+ adverse event that might occur from 
palliative radiation therapy to a non-brain site concurrent or immediately post-study treatment 
will not be considered as DLT for the study. But such events will be recorded by the local study 
team and communicated to the study PI. A final decision regarding RP2D will take these events 
into account. Further, the local site should update the study PI (or representative) of the plan for 
palliative radiation, including location, dose and fractionation. No such treatment should be 

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started without the study PI’s approval.” 
 
Any grade 3+ adverse event that might occur from SRS/SRT/fractionated boosts or 
neurosurgery, once the DLT assessment has been completed will be accounted for as unexpected 
severe late radiation toxicity and noted as secondary end-point (See 5.1 above). Use of other 
therapies post-DLT assessments which might impact neurological functioning (including but not 
limited to immunotherapy, for which safety data of immune-related neurological adverse events 
after WBRT is relatively limited) will be considered for this decision. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
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.   
 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) and documented on each site’s source 
documents as concomitant medication.  Hematologic growth factor support is acceptable. 
Prior/current/future hormonal therapy and/or bisphosphonates are permitted with no 
minimum interval to initiation of study therapy. If indicated, patients can receive 
palliative radiation therapy to a non-brain site concurrent or immediately post-study 
treatment with no minimum interval to initiation of study therapy. Any grade 3+ adverse 
event that might occur from this treatment will not be considered as DLT for the study. 
 
Patients with symptoms, neurologic signs or imaging evidence of edema or mass effect 
should be placed on dexamethasone at the time of brain metastasis diagnosis.  Steroids 
will be continued without taper until WBRT is completed.  For this patient population, 
variations in the amount and frequency of steroid usage are anticipated.  Per standard of 
care, the least amount of steroid necessary is used.  Hence, it is not appropriate to define a 
uniform stable dose of steroid for all patients accrued to the clinical study.  Patients will 
be used to record the use of steroid medications using the steroid medication diary in 
Appendix E from time of consent through the DLT assessment period. 
 
Nevertheless, to reduce/limit any potential PK impact of the concurrent use of 
dexamethasone, the maximum dose of dexamethasone for the patients at the time of the 
start of IPdR will be restricted to 8 mg per day or lower (2 mg qid, 4 mg bid or 8 mg once 
a day).  Patients needing more than 8 mg dexamethasone on the day of the start of IPdR 
will not be eligible to participate in the study.  Patients already accrued in the study at a 
dose of 8 mg or less who subsequently need more than 8 mg of dexamethasone per day 
while undergoing study treatment should be reported to the study PI.  This will be 
recorded as an AE.  Steroids will be continued without taper until the whole brain 
radiation therapy is completed.   
 
At the completion of WBRT, a steroid taper should be initiated provided that the patient 

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does not have persistent symptoms related to edema or mass effect from brain metastases.  
Every four days, the dose should be lowered as follows: 
 
Table 8: Dexamethasone Taper Schedule after Completion of WBRT 
8 mg Starting Dose* 
Duration 
2 mg  
four times a day  
4 mg  
two times a day  
2 mg four times a 
day 
4 mg two times a day 
Throughout course of WBRT 
2 mg two times a 
day 
3 mg two times a day 
4 days 
1 mg two times a 
day 
1 mg two times a day 
4 days 
1 mg once daily 
1 mg once daily 
4 days 
1 mg every other 
day 
1 mg every other day 
4 days 
Discontinue 
Discontinue 
 
 
* If the daily dose is < 8 mg per day, then maintain the same dose during WBRT and 
thereafter reduce dose by half every 4 days until 1 mg every other day times 4 days and 
then stop. 
 
 
In patients who cannot tolerate taper and/or cessation of steroids, the steroid dose will be 
maintained at the lowest dose consistent with good medical practice.  Patients on steroids 
are recommended to receive gastritis prophylaxis and monitoring/treatment for 
oropharyngeal candidiasis. 
 
Anticonvulsant usage and dosage should be noted at the time of study entry, at each 
follow-up evaluation and at any changes in medication use.  Please refer to Section 6.4 
for choice of anticonvulsant therapy. 
 
Since, memantine use is increasingly becoming part of routine clinical practice and was 
considered part of the standard of care arm in the recently concluded NRG CC001 study, 
both twice daily memantine and extended release memantine (Namenda XR), including 
generic forms, will be strongly recommended. It is recommended to start memantine with 
the start of WBRT or the earliest feasible thereafter. The target daily dose for memantine 
is 20 mg (10mg divided twice daily). Dose is escalated by 5 mg per week to target of 10 
mg twice daily (i.e., 5 mg a day for week 1, then 5 mg BID for week 2, then 10 mg in 
AM and 5 mg in PM for week 3, then 10 mg in AM and 10 mg in PM by week 4). The 
target dose for extended release memantine is 28 mg. Dose is escalated by 7 mg per week 
to target of 28 mg daily (i.e., 7 mg a day for week 1, then 14 mg a day for week 2, then 
21 mg a day for week 3, then 28 mg a day for by week 4). Patients continue on 
memantine for 24 weeks. 
 
 

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At the same time, variations in practice patterns and insurance coverage for memantine 
exist. Variation in memantine use between patients in this phase-1 study may result in 
potential challenges in interpreting neurocognitive evaluations. Any future phase-II study 
will either require either standard use of memantine (like NRG CC001 study) or 
stratification by its use. However, given that the primary end-point of this phase-1 study is 
serious DLT as defined in section 5.2, to prevent any slow down in accrual, memantine use 
will not be mandatory. 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment will be planned for 4 
weeks followed by 1 week for observation of acute toxicity and 6-months from the 
completion of WBRT for delayed toxicity or until one of the following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• Unacceptable adverse event(s), 
 
• Patient decides to withdraw from the study, or 
 
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.5 
Duration of Follow Up 
 
Patients will be evaluated for up to two years from the study registration or until death, 
whichever occurs first. From the date of completion of WBRT, follow-ups would be done 
through clinic visits every 2 months (± 1 week) for the first 6 months, every 3-4 months 
(± 2 weeks) for the next 6 months and every 6 months (± 3 weeks) for the next one year. 
After the first DLT assessment visit (primary endpoint), these visits in the first 6 months 
can be performed at an outside institution if appropriate research staff (credentialed and 
registered as a study team member) is available to complete adverse event and 
neurocognitive evaluation. After the first 6 months of follow up, clinic visits may be 
replaced by phone calls or visits at an outside institution, if not felt feasible for logistic 
reasons. Follow up notes or documentation of phone calls must be included in the study 
chart.  Patients removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.   
 
Follow-up MRI at 6 months (± 2 weeks) from the completion of WBRT is required to 
assess intracranial treatment response and disease control.  As guided by institutional 
practices, MRIs are also recommended to be performed during follow-up visits every 2 
months ( ± 1 week) for the first 6 months and every 3-4 months ( ± 2 weeks) for the next 
6 months from the completion of WBRT.  

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5.6 
Criteria for Removal from Study 
 
Patients will go off study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
 
 
 

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6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Since treatment for this Phase 1 study includes only 1 cycle of treatment consisting of 4 
weeks of IPdR with 15 fractions of concurrent radiation, treatment with IPdR and WBRT 
will continue as long as there is no DLT as defined above.  There will be no dose 
modifications if a DLT occurs. Patients experiencing a DLT will be removed from IPdR 
protocol treatment and may complete WBRT when toxicities recover to < Grade 3 as per 
institutional standard of care.  
Patients experiencing non-treatment related toxicities may have IPdR and WBRT held 
until toxicities resolve to < Grade 3 for up to 14 days and then they may resume IPdR (at 
the assigned dose level) and WBRT to complete protocol treatment.  Patients who are 
removed from protocol treatment due to non-treatment related toxicities requiring 
treatment delay of > 14 days are not assessable for determination of the MTD and will be 
replaced. 
 
 
 
 

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7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited reporting via the CTEP Adverse 
Event Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
7.1.1 CAEPR for IPdR 
 
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 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 

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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. 
 
7.2 
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 web site 
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 7.1.1) should be reported through 
CTEP-AERS only if the grade is above the grade provided in the SPEER. 
 
- 
Other AEs for the protocol that do not require expedited reporting are 
outlined in section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 

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- 
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. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when 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 phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 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.  
 
7.3.3 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.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  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.  
 
 
 

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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 
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 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
 
 

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CTCAE SOC 
Adverse Event 
Grade 
Injury, Poisoning and  
Procedural Complications 
Radiation Dermatitis 
1 or 2 
Skin and Subcutaneous 
Connective Tissue Disorder 
Scalp Alopecia 
1 or 2 
Respiratory, Thoracic and 
Mediastinal Disorders 
Pharyngeal mucositis 
1 or 2 
Ear and Labyrinth Disorder 
Otitis 
1 or 2 
Hearing Loss 
1 
Tinnitus 
1 
Eye Disorder 
Conjunctivitis 
1 or 2 
Blurred vision 
1 
Nervous System Disorder 
Dysgeusia 
1 or 2 
Gastrointestinal Disorders 
Dry mouth 
1 or 2 
 
7.4 
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 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. 
 
7.5 
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  
 

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Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
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. 
 
 
 
 

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8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
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: IPdR drug substance is a light yellow powder. 
 
How Supplied: IPdR is supplied by the DCTD and distributed by the Pharmaceutical 
Management Branch, NCI as 300 mg and 600 mg capsules.  
 
• The 300 mg capsules are Swedish orange, opaque, hard gelatin capsules, size 2 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 silica gel 
desiccant. 
• 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. 
 
Storage: Store bottles refrigerated at 2-8oC in the original manufacturer’s container.  Do not 
re-package capsules or remove the desiccant.   
 
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. 
 

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8.1.1 Agent Ordering and Agent Accountability 
 
8.1.1.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
8.1.1.2 
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. 
 
8.1.1.3 
Useful Links and Contact 
 
• 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/ 

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• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
8.1.1.4 
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. 
 
 
 

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9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Pharmacokinetics of IPdR 
 
The plasma pharmacokinetics sampling strategy for the human subjects in this Phase 1 
study is based on drug clearance measurements of IPdR in athymic mice,[39-41] Fischer-
344 rats [44] and Rhesus monkeys [45] and the studies of hepatic IPdR-aldehyde oxidase 
activity following IPdR treatment in athymic mice [40], Fischer-344 rats [44] and ferrets 
[45].  In athymic mice, rats and Rhesus monkeys, peak plasma levels of IPdR were noted 
within 15-30 minutes of IPdR administration.[38, 41, 44]  In Rhesus monkeys, the 
measured initial plasma distributive half-life (T1/2 ) was 6.5 min and the elimination half-
life (T1/2) in plasma was 63 min following an iv dose of 50 mg/kg.[45]  In athymic mice, 
the plasma pharmacokinetics at higher po IPdR doses ( 1000 mg/kg) showed longer 
elimination phases suggestive of partial hepatic enzyme saturation.[39]  In a follow-up 
study in athymic mice,[40] we found that a single IPdR dose of 1000 mg/kg resulted in a 
50% reduction in hepatic IPdR-aldehyde oxidase activity at 24 hours following drug 
administration that returned to normal levels at 48-96 hours.  Additionally, measurement 
of hepatic IPdR-aldehyde oxidase activity in ferrets receiving 150 or 1500 mg/kg/d x 14 d 
showed a decrease in enzyme activity to 50% and 30% of controls, respectively, when 
measured at the end of the 14-day treatment period.[45]  In the recently published Phase 
0 clinical trial of single dose oral IPdR, peak plasma levels after 2400 mg reached 4.0 
µmol/L at ~90 minutes with a half-life of elimination of 90 minutes.[46] 
 
Based on these pre-clinical data, we have designed an initial plasma pharmacokinetic 
strategy that will be limited to 16 blood samples per study patient. 
• On Day 1, a pre-study blood will be obtained and then sampling will be done at 
30, 60, 120, 240 minutes and 24 hours (just prior to Day 2 po dose) following the 
initial po drug administration. 
 
•  On Days 15 and 22 of the 28-day dosing schedule, blood will be obtained just 
prior to the po drug administration and then at 30, 60, 120 and 240 minutes 
following po dosing.   
 
• A five minute positive or negative margin on each of the above times on Day 1 
(30 through 240 minutes) and 10 min for the 24 hours timepoint is acceptable. 
 
Five cc of blood in a heparinized tube will be taken on Days 1, 15 and 22 at each time 
point and the plasma separated and frozen in liquid nitrogen or an -80º C freezer and 
stored in a -80º C freezer.  The samples will be shipped under dry ice in individual patient 
batches (Day 1, Day 15 and Day 22 all sent in one shipment) for later processing using 
the LC/MS/MS method in the research laboratory of Dr. Jerry Collins at NCI.  The 
plasma samples from the initial Part I patient group will then be analyzed to determine 
plasma levels of IPdR, IUdR, IP and IU and the data plotted for pharmacokinetics 
observations (modeling).  Adjustments in sampling will then be decided to provide 
appropriate data points in humans for Part 2 of the Phase 1 study.  For measurement of 

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levels of IPdR and its metabolites in plasma, the methods, equipment and personnel are 
the same as utilized in the CTEP protocol for the Phase 0 study of IPdR as published.[46]  
 
If the mouse, ferret, and Rhesus monkey data are not predictive of po IPdR metabolism in 
humans, then the initial sampling strategy should point to the best approach.  All 
pharmacokinetic data will be monitored in collaboration with Jerry Collins, Ph.D. at 
DCTP.  The previously described LC/MS/MS technique will be used, as previously 
published,[44] to measure the extracted nucleoside analogs and metabolites.  The final 
pharmacokinetic sampling protocol will monitor IPdR decay in plasma for at least 2 to 3 
half-lives on Days 1 (including just prior to dosing on Day 2), 15, and 22. 
 
9.2 
Measurement of %IUdR-DNA Incorporation in Peripheral Granulocytes and 
Tumor Tissues as an Exploratory Biomarker for IPdR Effects at the MTD. 
 
9.2.1 Background 
 
%IUdR-DNA incorporation in a cell (in vitro) or tissue (in vivo) has been shown to 
correlate directly with the extent of radiosensitization.[25, 26]  In the pre-clinical in vivo 
testing of po IPdR as a prodrug for IUdR-mediated radiosensitization,  2-fold increases 
in %IUdR-DNA tumor cell incorporation and  2-fold decreases in %IUdR-DNA 
incorporation in proliferating dose-limiting normal tissues (bone marrow and intestine) 
following po IPdR compared to oral or continuous intravenous infusions of IUdR (using 
MTD schedules) have been found in 4 different human tumor xenografts in athymic 
mice.[39-42]  In prior clinical Phase 1 trials of continuous intravenous infusions of IUdR 
( biochemical modulators), the %IUdR-DNA incorporation in circulating granulocytes 
during and following the IUdR infusion has been measured as a surrogate for 
proliferating normal human tissue (bone marrow).[32, 50-54]  In general, the %IUdR-
DNA incorporation in circulating granulocytes increased linearly with a linear increase in 
steady-state plasma levels of IUdR.  Additionally, high ( 6%) %IUdR-DNA levels in 
peripheral granulocytes predicted for systemic bone marrow toxicity to continuous 
infusion IUdR.  In the pre-clinical studies of oral IPdR daily for 14 days in athymic mice 
and ferrets,[39, 41, 47] the %IUdR-DNA incorporation was  2% in circulating 
granulocytes during and following treatment and no changes in blood counts were found 
in ferrets and rats,[44, 45] suggesting that bone marrow toxicity may not be dose-limiting 
for oral IPdR in humans.  Additionally, no myelosuppression or bone marrow 
abnormalities were seen in the IPdR toxicology studies, where IPdR was given once daily 
x 14 days in ferrets and x 28 days in rats.[44, 45] 
 
In some human Phase 1 studies of ci IUdR, tumor biopsies have been obtained at defined 
intervals to correlate %IUdR-DNA incorporation in tumor cells to the duration and/or 
plasma steady state drug levels of CIV IUdR.[59-64]  Again, a linear relationship of the 
%IUdR-DNA incorporation in tumor tissue and the steady-state plasma IUdR level was 
found. 
 
 

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9.2.2 Plan for Measurement of %IUdR-DNA Incorporation in Peripheral Granulocytes and 
Tumor Tissues as an Exploratory Biomarker for IPdR Effects at the MTD 
 
When the MTD of oral IPdR given once daily for 28 days is established, we will measure 
the %IUdR-DNA incorporation in circulating granulocytes as a surrogate of bone marrow 
using MTD dosing in 1st 6 patients accrued in the expansion cohort at the MTD.  For 
these patients, the measurements will be done prior to study (Day 1) and at Days 8, 15, 22 
and 29 of the 28-day treatment and at the first two-month follow-up.  Granulocyte 
isolation will be accomplished using a histopaque (Sigma Chemical Co., St. Louis, MO) 
1077/1119 gradient, based on a previously used technique.[32]  Following digestion of 
DNA to nucleosides, the %IUdR-DNA incorporation will be determined by HPLC using 
a previously published technique by our group.[32]  The % thymidine replacement will 
be calculated using authentic nucleoside standards as: 
 
[mMoles IUdR] X 100 
[mMoles IUdR + mMoles TdR] 
 
We also propose to measure the %IUdR-DNA incorporation in tumor tissue in patients 
with brain metastases receiving the MTD of po IPdR whose tumor(s) can be biopsied by 
direct visualization (i.e. subcutaneous mass or endoscopy) or by CT guidance.  Tumor 
biopsy is not required for participation in this study.  Tumor biopsy is not recommended 
if tumor is not easily accessible for biopsy (i.e. tumor biopsy should not be attempted if it 
is associated with a greater than minimal risk of complications as determined by the 
treating physician).  However, if tumor is easily accessible and biopsy would have a 
minimal risk of complications, then tumor biopsy should be performed.  Tumor biopsies 
may be obtained from the primary tumor or extracranial metastasis, whichever is most 
easily accessible.  Biopsy of the brain metastasis is not permitted.  Tumor biopsies will be 
obtained at Day 8 of the 28-day IPdR treatment.  For cutaneous tumors, a 6 mm punch 
biopsy will be performed.  For subcutaneous tumors or deep-seated tumors, a 14-gauge 
Tru-cut needle biopsy will be performed.  For endoscopy, snare biopsy (ies) of the 
luminal mass will be performed. CT-guidance will be used for needle biopsies or deep-
seated tumors.  The sample will be collected on aluminum foil and flash frozen in liquid 
nitrogen. Both flow cytometry and HPLC analysis will be performed on tumor tissue to 
determine the %IUdR-DNA incorporation in tumor cells.  Sections of the tumor biopsy 
will also be evaluated to confirm the presence of tumor using hematoxylin and eosin 
staining. 
 
For flow cytometry and HPLC analysis, the remainder of the tumor specimen will be 
fixed in 70% ethanol (2 ml Hanks balanced salt solution + 5 ml 95% ethanol) within 1 
hour of tissue acquisition and stored at 4C.  Flow cytometry and HPLC samples will be 
processed in Dr. Collins’ lab at NCI as previously published by Drs. Collins, Kinsella and 
collaborators.[32, 55, 59-64]  Briefly for flow cytometry, nuclei from tumor tissue will be 
isolated with pepsin, partially denatured with 2N HCl, incubated with a mouse anti-
BUdR/IUdR monoclonal antibody (Becton Dickinson, Mountain View, CA) followed by 
incubation with a fluorescein isothiocyanate-labeled goat anti-mouse secondary antibody.   
Finally, the nuclei will be incubated with propidium iodide to label DNA.  Up to 1 x 104 

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nuclei will be analyzed using an EPICS V cell sorter (Coulter, Corp. Inc., Hialeah, FL).  
For HPLC, DNA from isolated nuclei will be enzymatically digested into free 
nucleosides.  A Waters 600 E solvent delivery system on a 3.9 x 300 mm  Bondapak 
reverse-phase column (Waters Corp., Milford, MA) will be used, according to the method 
of Belanger et al.[32, 55] The mobile phase consists of 100 mm of sodium acetate buffer 
(pH 5.45) plus 7% (v/v) acetonitrile.  Peak identification and quantitation of IUdR and 
thymidine (TdR) will again be performed against authentic nucleoside standards and the 
%IUdR-DNA incorporation will be calculated as above. 
 
9.2.3 Specimen submission 
 
Please email Dr. Larry Anderson (larry.anderson@nih.gov) and Ms. Kimberly Hill 
(hillk2@mail.nih.gov ) when the shipment is sent and avoid a Friday delivery. The 
shipping address of Dr. Collins’ laboratory for the plasma PK samples and the 
granulocyte and tumor tissue samples for %IUdR-DNA cellular incorporation is: 
 
Kimberly Hill/Larry Anderson 
FNLCR 
OAD/DTP 
150 Boyles Street; Building 1036/1047 
Frederick, MD 21702 
 
 

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10. 
STUDY CALENDAR 
Pre-treatment laboratory tests and exams must be completed, eligibility confirmed and the patient registered within 6 weeks; baseline 
brain imaging evaluations to be done within 4-6 weeks before start of the study treatment.  Study treatment should begin within 2 
weeks after registration. Vital signs and performance status should be obtained within 1 week before the start of study treatment.  
 
Pre- 
Study 
treatment 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
DLT Assessment 
On D35 
(or ≤ 3 days after D35) 
Follow-
Up i 
Off Study k 
Informed consent 
X 
 
 
 
 
 
 
 
WBRT planning 
Xa 
Xa 
 
 
 
 
 
 
IPdR R 
 
X 
X 
X 
X 
 
 
 
WBRT 
 
 
X 
X 
X 
 
 
 
Urine or serum pregnancy test 
(if indicated) 
X 
 
 
 
 
 
 
 
History and  
physical exam b 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events b 
 
X 
X 
X 
X 
X 
X 
X 
Blood work c 
X 
X 
X 
X 
X 
X 
 
 
PK studies R 
 
Xd 
 
Xe 
Xe 
 
 
 
Up to 6 RP2D/MTD patients 
only (expansion cohort): 
Blood for granulocytes R  
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
Up to 6 RP2D/MTD patients 
only (expansion cohort):  
 Extracranial tumor biopsy 
mandatory l, R 
 
 
Xf 
 
 
 
 
 
MRI brain w/ IV contrast h 
X 
 
 
 
 
 
Xg 
X 
Neurocognitive and Quality 
of life evaluation R 
X 
 
 
 
 
Xj 
Xj 
X 
 
a.   May be performed prior to study registration per standard of care 
b.   Baseline physical examinations are to be conducted within 1 week prior to start of protocol therapy. In the event that the patient’s condition is 

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deteriorating, these evaluations should be repeated within 48 hours prior to the initiation of therapy.  Physical examination includes vital signs 
(pulse, blood pressure, temperature), concomitant medications, performance status, weight and at pre-study only, height. The evaluations are 
recommended to be done towards the end of the respective week. 
c.   Blood work to include CBC with differential count, comprehensive metabolic profile including serum albumin, alkaline phosphatase, total 
bilirubin, BUN, creatinine, total protein, SGOT [AST], SGPT [ALT]. The evaluations are recommended to be done towards the end of the 
respective week. 
d.   On Day 1, a pre-study blood will be obtained and then sampling will be done at 30, 60, 120 and 240 minutes and 24 hours (just prior to Day 2 
dosing) following the initial po drug administration.  A five minute positive or negative margin on each of the above times on Day 1 (30 
through 240 minutes) and 10 min for the 24 hours timepoint is acceptable. 
e.  On Days 15 and 22 of the 28-day dosing schedule, blood will be obtained just prior to the po drug administration and then at 30, 60, 120 and 
240 minutes following po dosing.  A five minute positive or negative margin on each of the above times on Day 1 (30 through 240 minutes) is 
acceptable. 
f:    %IUdR-DNA cellular incorporation. Sample collection will be prior to study (Day 1) and at Days 8, 15, 22 and 29 of the 28-day treatment 
followed by first two-month follow up. 
g:   Follow-up MRI at 6 months (± 2 week) from the completion of WBRT is required. As guided by institutional practices, MRIs are also 
recommended during follow-up visits every 2 months (± 1 week) for the first 6 months and every 3-4 months ( ± 2 weeks) for the next 6 
months from the completion of WBRT. If progressive disease is seen on MRI, subsequent evaluations are not required for study.   
h.   For patients accrued to part 2 of the study, please send anonymized pre- and post-treatment (up to 6 months from the date of completion of 
WBRT) scans via FTP or hard copy CD to the study PI for central review of response. 
i      From the date of completion of WBRT, follow-up visits to be done every 2 months (± 1 week) for the first 6 months, then and are 
recommended every 3-4 months (± 2 weeks) for the next 6 months then every 6 months (± 3 weeks) for the next one year. These visits can be 
performed at an outside institution if appropriate research staff (credentialed and registered as a study team member prior to the evaluations) is 
available to complete adverse event, neurocognitive testing and QOL evaluation. After the first 6 months of follow up, clinic visits may be 
replaced by phone calls or visits at an outside institution. Follow up notes or documentation of phone calls must be included in the study chart. 
 
j. 
Neurocognitive and quality of life evaluation to be performed at the D35 assessment time-point and then during follow-up visits every 2 months 
(± 1 week) for the first 6 months from the date of completion of WBRT (for patients without intracranial progression). A total of 5 neurocognitive 
and quality of life evaluations will be performed: Baseline, D35, 2-, 4- and 6- months from the date of completion of WBRT.   
k.    To be performed only if feasible if the patient is removed from the study. 
l. 
Perform biopsy only if patient has an easily accessible tumor. 
R. Research. 

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10.1 
Neurocognitive Evaluation 
 
10.1.1 Hopkins Verbal Learning Test (HVLT-R) 
  
The HVLT-R incorporates 6 different forms, helping to mitigate practice effects of 
repeated administrations.  Each form includes 12 nouns (targets) for memorization with 4 
words drawn from 3 semantic categories, which differ across the 6 forms.  Patients will 
be asked to recall from the list of 12 targets for 3 consecutive trials (immediate recall), 
identify the 12 targets from a list of semantically related or unrelated items (immediate 
recognition), and recall the 12 targets after a 20-minute delay (delayed recall).  Raw 
scores will be derived for total recall, delayed recall, retention (percentage retained), and 
a recognition discrimination index.  Each patient will serve as his/her own control, as the 
difference in scores obtained at baseline and at pre-specified post-treatment intervals will 
be calculated.  The HVLT-R is owned and copyright protected by Psychological 
Assessment Resources, Inc. (PAR).  Electronic distribution of the HVLT form is not 
currently permitted by PAR; please send an email to the study PI, Dr Mohindra, 
University of Maryland, to request a paper copy of the HVLT prior to enrolling any 
patients (or to get information regarding procuring institutional copies for the study).   
Future updates regarding electronic handling of these forms if allowed will be provided 
directly to the study teams, as and when available.  Based on the copyright agreement 
with PAR, completed HVLT-R forms can be uploaded to NCI’s secure, password 
protected online portal, iMedidata RAVE (“web portal”).  The uploaded forms should 
contain the original copyright notice on the form.  Access to the web portal shall be 
limited to authorized study personnel at the study site.  Completed HVLT-R forms shall 
not be printed or downloaded from the web portal.  Once uploaded to iMedidata RAVE, a 
hard copy of the completed HVLT-R forms should be mailed to the study PI.   
 
Study personnel administering the HVLT must be previously credentialed in performing 
neurocognitive testing through existing mechanisms within cooperative groups including 
but not limited to participation in a prior NRG or Alliance or any other cooperative group 
study.  Email a copy of this certification to the study PI, Dr Mohindra.  The PI may also 
approve other measures as applicable including but not limited to credentialing through 
training arranged by the stud PI (or representative) or participating site’s internal training. 
Each participating site should review the credentialing process with the study PI (or 
representative) prior to site activation. This requirement is necessary before any patients 
can be enrolled into the study at the site; see Site Registration, section 4.2.2.  These 
assessments can be performed at an outside institution if appropriate research staff 
(credentialed and registered as a study team member prior to the evaluations) is available 
to complete adverse event and neurocognitive evaluation. 
 
Scoring of HVLT-R 
1. HVLT-R Delayed Recall 
Patient scores on the HVLT-R delayed recall section have an integer range from 0 
to 12 with lower scores indicating declining cognitive function.  The score is the 
number of words a patient can recall from a list of 12 words.  The change in score 

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from baseline to 2-, 4- and 6- months ranges from - 12 to 12.  Change scores from 
1 to 12 indicate declining cognitive function.  A change score of 0 indicates 
preserved cognitive function.  Change scores from -1 to -12 indicate improved 
cognitive function and are not expected. 
 
2. HVLT-R Free Recall 
Patient scores on the HVLT-R free recall section have an integer range from 0 to 
36 with lower scores indicating declining cognitive function. The score is the 
number of words a patient can recall from a list of 12 words in three trials. 
 
3. HVLT-R Delayed Recognition 
10.1.2 Patient scores on the HVLT-R delayed recognition section have an integer 
range from -12 to 12 with lower scores indicating declining cognitive function. 
The score is the number of correctly identified words from the list of 12 words 
minus the number of incorrectly identified words from the list of 12 words. 
 
10.2 
Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR) for 
Quality of Life (QOL)  
 
The FACT-BR is a multidimensional, self-report QOL instrument specifically designed 
and validated for use with brain malignancy patients.  It is written at the 4th grade 
reading level and can be completed in 5 to 10 minutes with little or no assistance in 
patients who are not neurologically incapacitated.  It measures quality of life related to 
symptoms or problems across 5 scales: physical well-being (7 items); social/family well-
being (7 items); emotional well-being (6 items); functional well-being (7 items); and 
concerns relevant to patients with brain tumors (23 items).  Items are rated on a five-point 
scale: 0-“not at all”, 1- “a little bit”, 2-“somewhat”, 3-“quite a bit” and 4-“very much”. 
The measure yields information about total QOL, as well as information about the 
dimensions of physical well-being, social/family well-being, emotional well-being, 
functional well-being, and disease-specific concerns.  Six additional experimental items 
request information regarding how much each dimension affects QOL, using a "0" (not at 
all) to "10" (very much so) rating scale.  Patient scores on the FACT-Br range from 0 to 
92 with lower scores indicating declining quality of life.  FACT-BR is self-administered 
and does not require precertification.  It has been translated into 26 languages and is 
available free of charge to institutions with the completion of an agreement to share data, 
accessible at: http://www.facit.org/facitorg/questionnaires. 
 
The assessments will be scored centrally by a blinded reviewer to avoid potential bias.  
The self-report of quality of life can be completed by the patient or the examiner and does 
not require pre-certification. 
 
Scoring of FACT-BR Assessments: 
The change scores from pretreatment from baseline to 2, 4 and 6 months will be 
estimated.  A mean difference of 5 points represents a clinically meaningful change 
(CMC).  A difference of less than 5 will not be considered meaningful, even if it has 
statistical significance.   

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11. 
MEASUREMENT OF EFFECT 
 
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 patients in part 2 
of the study (to exclude patients treated at lower doses in part 1 thereby minimizing 
heterogeneity in response) will be carefully monitored for tumor response in addition to 
safety and tolerability.  Patients with measurable disease will be assessed by standard 
criteria noted below.  Each eligible patient must have at least one measurable lesion that 
will be included in the radiation treatment volume.  If the measurable disease is restricted 
to a solitary lesion, the presence of malignancy must be confirmed by cytology/histology. 
Tumor lesion(s) included within the high dose radiation treatment volume ( 95% 
isodose line) will be considered as the target lesions for response evaluation. Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this 
study, patients should be evaluated at baseline at 6 months (± 2 weeks) from the completion 
of WBRT.  As guided by institutional practices, MRIs are also recommended during follow-up 
visits every 2 months (± 1 week) for the first 6 months and every 3-4 months (± 2 weeks) for the 
next 6 months from the completion of WBRT. 
 
11.1 
Antitumor Effect – Intracranial Metastases 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with IPdR. 
 
Evaluable for objective response.  All patients will be evaluable for objective response 
from the time of their first treatment with IPdR.   
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received 
at least 7 daily doses of IPdR and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm (≥1 
cm) with MRI.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 

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Non-measurable disease.  All other lesions including small lesions (longest diameter 
<10 mm [< 1 cm]) are considered non-measurable disease.   
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions in total should be 
identified as target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) and 
should be those that lend themselves to reproducible repeated measurements.  It may be 
the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the longest diameters for all target lesions 
will be calculated and reported as the baseline sum diameters.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout 
follow-up.  
 
11.1.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  
 
Conventional MRI.  MRI-scan based response evaluation is based on the assumption 
that MRI slice thickness is 5 mm (0.5 cm) or less.  If MRI scans have slice thickness 
greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  It is recommended that MRI sequences be followed per the 
consensus recommendations as detailed in the article: “Consensus recommendations for 
standardized brain tumor imaging protocol in clinical trials. Benjamin M. Ellingson et 
al. Neuro Oncol. 2015 Sep; 17(9):1188-98. doi: 10.1093/neuonc/nov095. Epub 2015 
Aug 5.”  
 
Please contact the PI and the Radiology Co-Investigators, Dr. Prashant Raghavan, Dr 
Timothy Kaufmann or Dr Rao Gullapalli, with any questions. 
  
 
 
 

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11.1.4 
Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.   
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.   
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of measurement criteria. 
 
 
 

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For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ 
Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/ 
Non-PD/ 
Not evaluated 
No 
PR 
SD 
Non-CR/ 
Non-PD/ 
Not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 

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until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.1.6 
Intracranial Progression-Free Survival 
 
The date at which intracranial progression is radiographically identified will be used 
to calculate the intracranial PFS.  Intracranial PFS will be measured from the date of 
start of treatment to time of progression or death, whichever occurs first. Intracranial 
PFS will be assessed 2, 4, 6 and 8 months after the initiation of study therapy.  If 
intracranial progressive disease is seen on MRI, any subsequent MRI scans will be 
performed as clinically indicated standard of care.   
 
11.1.7 
Response Review 
 
All responses will be reviewed by the radiology investigator of the study at the 
study’s completion to allow simultaneous review of the patients’ files and 
radiological images.  Raw data from baseline and follow up MRI will be obtained 
from the participating institutions for volumetric, perfusion and diffusion-based 
response assessments.  Sites should send anonymized pre- and post-treatment scans 
via FTP or as a hard copy CD to the study PI, Dr Mohindra at the University of 
Maryland, as listed on the title page.  The scans and data will be stored in HIPAA 
compliant secure servers within the Department of Radiology.  Each patient will be 
identified only with the patient number assigned by the study.   
   
 
 
 
 

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12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
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. 
 
12.2  Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to 
the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles assigned in the Regulatory Support System (RSS).  To access Rave via 
iMedidata, the site user must have an active CTEP IAM account (check at < 
https://ctepcore.nci.nih.gov/iam  >) and the appropriate Rave role (Rave CRA, Read-Only, CRA 
(Lab Admin, SLA or Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type.  To hold the Rave Site Investigator role, the individual must 
be registered as an NPIVR or IVR.  Associates can hold read-only roles in Rave.  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 RSS, all persons with Rave roles 

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assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.  
To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password 
and click on the “accept” link in the upper right-corner of the iMedidata page.  Please 
note, site users will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed.  Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane 
of the iMedidata screen.   
 
Users 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, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave 
is available on the CTSU members’ website under the Rave tab or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
12.2.1 
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) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2.2 
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 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 

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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.ht
m)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI and is to include a summary of 
study endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  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
). 
 
12.3 
CTEP Multicenter Guidelines 
Not Applicable 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 

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clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators.  The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary to 
allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 

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with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 

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13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints – Determination of the Maximum Tolerated Dose 
 
The primary endpoint of this study is to determine the RP2D dose  of daily oral IPdR 
administered alone for 7 days and then concurrently with conventionally fractionated 
whole brain radiation therapy (WBRT) for 3 weeks in patients with brain metastases.  In 
order to determine the RP2D, an expansion cohort will be utilized, which is outlined in 
detail in sections 5.1.3.  Dose limiting toxicity (DLT) is fully defined in section 5.2.   
 
13.2 
 Sample Size/Accrual Rate 
 
Any estimate of accrual in a dose escalation study is difficult because the study team does 
not know when the MTD will be found.  In the original design, assuming both Parts 1 and 
2 require 3 dose escalations to determine the MTD, the sample size was estimated 
between 17 (1 patient at 2 levels and 3 at the third level in Part 1 and 3 patients at the first 
level, 6 at the second level, and 3 at the third in Part 2) and 27 (3 patients at each of the 3 
levels in Part 1 and 6 at each level in Part 2).  Six patients were planned to be accrued at 
the MTD in the expansion cohort to permit the analyses of the %IUdR-DNA cellular 
incorporation in circulating granulocytes and tumor once MTD has been determined.  
This would also help narrow the confidence interval on the estimate of incidence of 
toxicity at the MTD which makes the expected accrual between 23 and 33.  The low 
number of the expansion cohort was chosen considering the logistics of arranging for a 
study screening, consent, registration, biomarker testing and limiting total patient 
numbers/budget.  The maximum accrual will be 47.  This includes 7 in Part 1 (1 patient at 
the first 4 levels followed by 3 at level IE), 30 in Part 2 (6 patients at each of the 5 dose 
levels), 6 additional patients at the MTD, and an additional 4 to account for replacements. 
 
In the proposed amendment #6 (Dec. 2017), to accelerate accrual, the dose-escalation 
design was changed such that part -1 was truncated at dose level IB, with one patient 
accrued at each dose-level (total 2). The study wasopened to part-2 as a modified 3+3 
design with three dose-levels accruing up to 6 patients each depending on the occurrence 
of DLT. Thereby, the number of patients accrued in part 1 and 2 will range from 8 (2+6) 
to 20 (2+6+6+6).  
Till date (December 2019), 2 patients have been accrued in part 1 (1+1), 3 patients at 
dose-level 2A and 1 patient at dose-level 2B. In the current proposed design amendment 
#7, since dose-level 2B is being stopped with one patient and dose level 2A will be re-
opened for additional 3 patients, the expected accrual in the two parts will range from 9 
(2+7) to 15 (2+7+6) patients. Ten patients will be accrued at the RP2D in the expansion 
cohort to help narrow the confidence interval on the estimate of incidence of toxicity at 
the RP2D which makes the range of accrual between 19 and 25. The maximum accrual 
will be 25 patients. Up to a total of six patients in the expansion cohort will be analyzed 
for the %IUdR-DNA cellular incorporation in circulating granulocytes and tumor once 
RP2D has been determined.     
 
Assuming an accrual rate of 1-2 patients per month, for a minimal accrual of 18 patients 

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will require approximately18-24 months.  Additionally the study will close for evaluation 
of DLT leading to atotal estimated study time of 30 months   
 
Both men and women of all races and ethnic groups, when appropriate, will be eligible 
for these studies.  Subject selection is equitable if they meet the inclusion and exclusion 
criteria. In conformance with the National Institutes of Health (NIH) Revitalization Act 
of 1993 (amended in October, 2001) with regard to inclusion of women and minorities in 
clinical research, possible interaction between race/ethnicity and treatment have been 
considered.  Based on the historical number of brain metastases patients who receive 
WBRT per month at the University of Maryland and Mayo Clinic, there are expected to 
be approximately 15% of participants classified as minorities by race and 50% of 
participants to be female.  
 
PLANNED ENROLLMENT REPORT 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
2 
1 
0 
4 
White 
19 
19 
1 
1 
40 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
21 
23 
2 
1 
47 
 
13.3 
Stratification Factors 
None. 
 
 
 
 

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13.4 
Analysis of Secondary Endpoints 
 
13.4.1 
Tumor Response  
 
Best Response is defined to be the best objective status recorded from the start of the 
treatment until disease progression/recurrence.  The patient’s best response assignment 
will depend on the achievement of measurement criteria as described in section 11.0.  
Responses will be summarized by simple descriptive summary statistics delineating 
complete and partial responses as well as stable and progressive disease in this patient 
population (overall and by tumor group). The number of responses may indicate further 
evaluation for specific tumor types in a Phase 2 setting.  Only patients in Part 2 of the 
study will be included in this evaluation. 
 
13.4.2 
Pharmacokinetics 
 
The pharmacokinetics of daily oral dosing of IPdR for 28 days will be explored. 
 
13.4.3 
Biomarkers 
 
Biomarker data will be explored in a simple descriptive manner as data are limited in 
this small phase 1 study. 
 
13.4.4 
Intracranial progression free survival (icPFS) and Overall Survival (OS) 
These will be explored using the Kaplan-Meier method.  For estimation of icPFS, 
patients alive without intracranial progression at last follow-up will be censored at the 
date of the last radiologic assessment whereas intracranial progression or death will be 
scored as events. The icPFS estimates at 6 months with their standard error of the 
estimate will be reported.  For calculation of OS, patients alive at last follow-up will be 
censored. 
 
13.4.5 
Incidence of delayed neurological toxicity at 2, 4 and 6-months (± 1 week) post-
completion of WBRT (for patients without intracranial progression) including: 
a. Delayed-recall through HVLT-R 
b. Quality of life as measured by the FACT-BR 
 
 
 
 

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26. Kinsella, T.J., An approach to the radiosensitization of human tumors. Cancer J Sci Am, 
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27. Shewach, D.S. and T.S. Lawrence, Antimetabolite radiosensitizers. Journal of clinical 
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29. Urtasun, R.C., et al., Survival improvement in anaplastic astrocytoma, combining external 
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glioblastoma multiforme. American journal of clinical oncology, 1987. 10(5): p. 437-43. 
 
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32. Belanger, K., et al., Incorporation of iododeoxyuridine into DNA of granulocytes in patients. 
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33. Kinsella, T.J., et al., Pharmacology and phase I/II study of continuous intravenous infusions 
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34. Sindelar, W.F., et al., Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of 
a prospective, randomized, clinical trial. Archives of surgery, 1993. 128(4): p. 402-10. 
 
35. Robertson, J.M., et al., Preoperative radiation therapy and iododeoxyuridine for large 
retroperitoneal sarcomas. International journal of radiation oncology, biology, physics, 1995. 
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36. Goffman, T., Z. Tochner, and E. Glatstein, Primary treatment of large and massive adult 
sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation. Cancer, 1991. 
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37. Saif, M.W., et al., IPdR: a novel oral radiosensitizer. Expert opinion on investigational drugs, 
2007. 16(9): p. 1415-24. 
 
38. Chang, C.N., S.L. Doong, and Y.C. Cheng, Conversion of 5-iodo-2-pyrimidinone-2'-
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design. Biochemical pharmacology, 1992. 43(10): p. 2269-73. 
 
39. Kinsella, T.J., et al., An in vivo comparison of oral 5-iodo-2'-deoxyuridine and 5-iodo-2-

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pyrimidinone-2'-deoxyribose toxicity, pharmacokinetics, and DNA incorporation in athymic 
mouse tissues and the human colon cancer xenograft, HCT-116. Cancer research, 1994. 
54(10): p. 2695-700. 
 
40. Kinsella, T.J., et al., Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a 
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Clinical cancer research: an official journal of the American Association for Cancer 
Research, 1998. 4(1): p. 99-109. 
 
41. Kinsella, T.J., et al., Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-
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42. Kinsella, T.J., et al., 5-iodo-2-pyrimidinone-2'-deoxyribose-mediated cytotoxicity and 
radiosensitization in U87 human glioblastoma xenografts. International journal of radiation 
oncology, biology, physics, 2007. 69(4): p. 1254-61. 
 
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44. Kinsella, T.J., et al., Toxicology and pharmacokinetic study of orally administered 5-iodo-2-
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clinical phase I trial design of IPdR-mediated radiosensitization. Cancer chemotherapy and 
pharmacology, 2008. 61(2): p. 323-34. 
 
45. Kinsella, T.J., et al., Preclinical study of the systemic toxicity and pharmacokinetics of 5-
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animal species: implications for phase I study design. Clinical cancer research: an official 
journal of the American Association for Cancer Research, 2000. 6(9): p. 3670-9. 
 
46. Kummar, S., et al., First-in-human phase 0 trial of oral 5-iodo-2-pyrimidinone-2'-deoxyribose 
in patients with advanced malignancies. Clinical cancer research: an official journal of the 
American Association for Cancer Research, 2013. 19(7): p. 1852-7. 
 
47. Seo, Y., et al., Differential radiosensitization in DNA mismatch repair-proficient and -
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Clinical cancer research: an official journal of the American Association for Cancer 
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48. Reagan-Shaw, S., M. Nihal, and N. Ahmad, Dose translation from animal to human studies 
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49. Kinsella, T., et al., Pharmacology and phase I/II study of continuous intravenous infusions of 
iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma 
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50. Simon, R., et al., Accelerated titration designs for phase I clinical trials in oncology. Journal 
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51. Krenitsky, T.A., et al., A comparison of the distribution and electron acceptor specificities of 
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53. Speth, P.A., et al., Fluorodeoxyuridine modulation of the incorporation of iododeoxyuridine 
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54. McGinn, C.J., et al., Leucovorin modulation of 5-iododeoxyuridine radiosensitization: a 
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55. Belanger, K., J.M. Collins, and R.W. Klecker, Jr., Technique for detection of DNA 
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56. Chuong, M., et al., Induction gemcitabine-based chemotherapy and neoadjuvant stereotactic 
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57. Kunzmann, V., et al., Intensified Neoadjuvant Chemotherapy with Nab-Paclitaxel plus 
Gemcitabine Followed by FOLFIRINOX in a Patient with Locally Advanced Unresectable 
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58. Cunningham, D., et al., Phase III randomized comparison of gemcitabine versus gemcitabine 
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59. Cook, J.A., et al., Measurement of thymidine replacement in patients with high grade 
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60. Epstein, A.H., et al., Treatment of locally advanced cancer of the head and neck with 5'-
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thymidine replacement. Journal of the National Cancer Institute, 1994. 86(23): p. 1775-80. 
 
61. Speth, P.A., et al., Selective incorporation of iododeoxyuridine into DNA of hepatic 
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62. Speth, P.A., et al., Iododeoxyuridine (IdUrd) incorporation into DNA of human 
hematopoietic cells, normal liver and hepatic metastases in man: as a radiosensitizer and as a 
marker for cell kinetic studies. International journal of radiation oncology, biology, physics, 
1989. 16(5): p. 1247-50. 
 
63. Chang, A.E., et al., A phase I study of intra-arterial iododeoxyuridine in patients with 
colorectal liver metastases. Journal of clinical oncology: official journal of the American 
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64. Kinsella, T.J., et al., Pharmacology and phase I/II study of continuous intravenous infusions 
of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma 
multiforme. Journal of clinical oncology: official journal of the American Society of Clinical 
Oncology, 1988. 6(5): p. 871-9. 
 

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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: IPdR MEDICATION DIARY 
 
Patient’s Name _______________________ 
 
Patient’s Study ID _____________________ 
 
Capsule strength ___________ mg 
 
Assigned Dosage __________mg     (_____) capsules 
 
 
Instructions 
1. Take IPdR capsules by mouth once daily for 28 days at approximately the same time each day 
and on an empty stomach, either 1 hour before or 2 hours after meals.  The capsules should be 
swallowed whole and must not be crushed or broken.  
 
2. IPdR capsules should be stored in the refrigerator. 
 
3. Record the date and time when you take each IPdR dose. 
 
4. On days you receive radiation therapy, IPdR capsules will be taken within 30 minutes and 2 hours 
prior to your radiation. 
 
5. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more hours 
remaining before the next dose.  
a. If the next dose is due in less than 12 hours, skip the missed dose and take the next dose 
as scheduled.  
b. Make a note in the Comments column if you miss a dose. 
 
6. If vomiting occurs after taking IPdR, do not take a replacement dose on that day.  Resume at the 
next scheduled dose. Make a note in the Comments column. 
 
7. If you have any comments or notice any side effects, record them in the Comments column. 
 
Please bring this diary with you to all study visits! 
 
 

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Day 
Date/Time 
Number of 
IPdR capsules 
taken 
Comments 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 

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23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 
 
Participants Signature___________________________________   Date ________________________ 
 
 
 
Area Below Only To Be Completed only by Coordinator 
 
Number of capsules returned_____     
 
Study Coordinator Initials________ 
 
Date______________________ 
 
Discrepancy Yes____ No_____ 
 
 
 
 

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APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug IPdR (Oral 5-iodo-2-pyrimidinone-2-deoxyribose, NSC 726188).  
This clinical trial is sponsored by the National Cancer Institute (NCI).  This form is addressed to 
the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
There are no potential drug interactions with IPdR that are known at present. Because of the 
absence of potential for interaction with agents that induce or inhibit cytochrome P450 enzymes, 
there are no prohibitions of specific medications on the basis of anticipated drug-drug 
interactions. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
There are no potential drug interactions drug interactions with IPdR that are known at present.  
 
It is very important to tell your study doctors of any medicines you are taking before you enroll 
onto this clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you and they need to know:  
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
 
Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine. 
 
 
 
 
 

NCI Protocol #: 9979                                                                                                                                Page 90 of 90 
Local Protocol #: HP-00067789 
NCI Version Date: September 4, 2020                                                                                 
 
 
Your study doctor’s name is  
 
 
_____________________________________  
 
 
 
and he or she can be contacted at  
 
 
_____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug 
IPdR (Oral 5-iodo-2-pyrimidinone-2-deoxyribose, NSC 726188).  This 
clinical trial is sponsored by the NCI.  There are no potential drug 
interactions with IPdR that are known at present.  Because of this, it 
is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ Before prescribing new medicines, your regular prescribers 
should go to a frequently-updated medical reference for a list 
of drugs to avoid, or contact your study doctor.   
 
➢ Your study doctor’s name is ________________________  
and can be contacted at _________________________.