A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination With Intravenous Triapine in Women With Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer
Phase: PHASE3
Conditions: Advanced Vaginal Adenocarcinoma, Advanced Vaginal Adenosquamous Carcinoma, Advanced Vaginal Squamous Cell Carcinoma, Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB2 Cervical Cancer AJCC v6 and v7, Stage II Cervical Cancer AJCC v7, Stage II Vaginal Cancer AJCC v6 and v7, Stage IIA Cervical Cancer AJCC v7, Stage IIB Cervical Cancer AJCC v6 and v7, Stage III Vaginal Cancer AJCC v6 and v7, Stage IIIB Cervical Cancer AJCC v6 and v7, Stage IV Vaginal Cancer AJCC v6 and v7, Stage IVA Cervical Cancer AJCC v6 and v7, Stage IVA Vaginal Cancer AJCC v6 and v7, Unresectable Vaginal Carcinoma, Vaginal Adenocarcinoma, Vaginal Adenosquamous Carcinoma, Vaginal Carcinoma, Vaginal Squamous Cell Carcinoma, Not Otherwise Specified
Sponsor: National Cancer Institute (NCI)

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SUMMARY OF CHANGES 
 
For Protocol Amendment #6: 
 
NCI Protocol #: NRG-GY006 
 
NCI Version Date: February 17, 2021  
 
 
# 
Section 
Comments (PA will hyperlink to copy prior to submitting) 
1. 
Title Page 
• NCI Version date is now February 17, 2021 
• Research Nurse deleted. 
• Duplicate listing of Protocol Administrator deleted. 
• Duplicate listing of Clinical Data Coordinator deleted. 
• CCTG added as participating organization. 
• Canada has been added as a participating site. 
• CTSU logistical language updated in Contact Information Table. 
2. 
5.0  
Triapine filtration language was updated. 
3. 
5.1.2 
Triapine filtration language was updated. 
4. 
8.0 and 8.1 
CTSU logistical language was updated.  
5. 
8.2.1 
CTSU logistical language was updated. 
6. 
8.2.3 
DTL information for Canadian sites added. 
7. 
8.3.1 
CTSU logistical language was updated. 
8. 
8.4.1 
CTSU logistical language was updated. 
9. 
9.1 
Triapine preparation and administration language was updated. 
10. 
12.1 
CTSU logistical language was updated. 
11. 
ICD 
NCI Version Date is now February 17, 2021. No additional changes have been 
made to the informed consent document. 

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NRG-GY006 
(ClinicalTrials.gov NCT #02466971) 
A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with 
Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA 
Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer. 
 NCI Version Date: 02/17/2021 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI).  
 
 
 
 
Lead Organization: NRG / NRG Oncology 
 
 
 
 
 
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center, 1600 JFK Blvd., Suite 1020 
Philadelphia, PA 19103 
 
 
Study Team (17-FEB-2021) 
 
Study Chair 
Study Co-Chair 
Charles Leath, M.D., M.S.P.H. 
Helen Mackay, MBChB, BSc., MRCP, MD 
University of Alabama at Birmingham 
Sunnybrook Odette Cancer Centre 
Obstetrics & Gynecology 
University of Toronto 
1700 6th Avenue South, Room 10250 
2075 Bayview Avenue 
Birmingham, Alabama 35233 
Toronto, Ontario, M4N 3M5 
205-934-4986/ FAX: 205-975-6174 
416-480-5145/ FAX: 416-480-6002 
cleath@uabmc.edu 
helen.mackay@sunnybrook.ca 
 
 
Study Co-Chair 
Translational Scientist 
Loren K. Mell, MD 
Helen Mackay, MBChB, BSc., MRCP, MD 
University of California San Diego 
(See study co-chair) 
Department of Radiation Medicine 
 
3855 Health Sciences Dr. MC0843 
Translational Science Co-Chair 
858-246-0471 / FAX: 858-822-5568 
NONE 
lmell@ucsd.edu 
 
Correlative Scientists 
Statistician 
Participating Organizations  
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
CCTG / Canadian Cancer Trials Group (17-FEB-2021) 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
 
- 2 - 
Radiation Oncologist 
Wei Deng, Ph.D. 
Loren K. Mell, M.D. 
NRG SDMC-Buffalo Office 
(see study co-chair) 
Roswell Park Cancer Institute 
 
Elm and Carlton Streets 
 
Buffalo, NY 14263-0001 
 
716-845-5702/FAX: 716-845-8393 
 
wdeng@gogstats.org 
 
 
Radiation Oncology Physicists 
Responsible Radiologist (ACR/IROC) 
Yongsook C. Lee, Ph.D. 
Jean Lee, M.D. 
Department of Radiation Oncology 
Department of Radiology 
University of Arizona 
University of Washington 
3838 N Campbell Avenue, Bldg. #2 
1959 NE Pacific Street, Box 357115 
Tucson, Arizona 85719 
Seattle, Washington 98195-7115 
520-694-6202 
206-598-0024/FAX: 206-598-0252 
yclee@email.arizona.edu 
jeanhlee@u.washington.edu 
 
 
Stanley H. Benedict, Ph.D. 
 
Department of Radiation Oncology 
 
University of California at Davis 
 
4501 X Street 
 
Sacramento, CA 95817 
 
916-734-3932 
 
shbenedict@ucdavis.edu 
 
 
 
 
 
NRG Oncology Contact Information  
Data Management 
For questions concerning data 
submission 
Dolores Kirschner 
NRG Oncology Statistics and Data Management Center- 
Pittsburgh  
201 N. Craig St., Suite 500 
Pittsburgh, PA 15213 
412-383-4912/FAX 412-624-1082 
baddersa@nrgoncology.org   
Protocol Development 
For questions concerning protocol 
and informed consent versions and 
amendments 
Leah Madden. CCRP 
Protocol Coordinator 
NRG Oncology-Philadelphia East 
Four Penn Center, 1600 JFK Blvd., Ste 1020 
Philadelphia, PA 19103 
215-854-0770 
maddenl@nrgoncology.org  
Regulatory 
NRG-GY-Regulatory@nrgoncology.org  

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
 
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Biospecimen Bank 
For questions concerning 
biospecimen collection and 
translational research 
NRG BB-Columbus 
Biopathology Center, Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 866-464-2262/FAX: 614-722-2897 
Email: bpcbank@nationwidechildrens.org 
Gynecologic Oncology 
Committee Chair 
Carol Aghajanian, M.D. 
Memorial Sloan Kettering Cancer Center 
Department of Medicine 
1275 York Avenue 
New York, NY 10065 
(646) 888-4217 
aghajanc@mskcc.org  
 
Protocol Agents 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Triapine 
CTEP 
663249 
68338 
DCTD, NCI 
Cisplatin 
Commercial 
119875 
 
 
 
Participating Sites 
 U.S. 
 Canada (17-FEB-2021) 
 Approved International Member Sites 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure 
 
 
Amendment 6 
02/17/2021 
 
Amendment 5 
11/25/2019 
 
Amendment 4 
02/01/2019 
 
Amendment 3 
03/16/2018 
 
Amendment 2 
11/29/2017 
01/16/2018 
Amendment 1 
02/24/2017 
05/30/2017 
Activation 
12/22/2015 
01/15/2016 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be used 
only in conjunction with IRB approval for study entry.  No other use or reproduction 
is authorized by NRG Oncology nor does NRG Oncology assume any responsibility 
for unauthorized use of this protocol. 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
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NRG-GY006 
A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with 
Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA 
Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer. 
NCI Version Date: 02/17/2021  
 
Lead Organization: NRG / NRG Oncology 
 
CONTACT INFORMATION (17-FEB-2021) 
For regulatory requirements: 
For patient enrollments: 
For data submission 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
www.ctsu.org, and select 
Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-2878 for regulatory 
assistance. 
 
 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) is  accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email : 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  Refer 
to the data submission section 
of the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ web site (https://www.ctsu.org.)  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
For clinical questions (i.e. patient eligibility or treatment-related)  
Contact the Study Principal Investigator of the Lead Protocol Organization 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
- 5 - 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
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SCHEMA (05/30/2017) 
 
 
 
 
 
 
 
 
 
 
Newly diagnosed cancer of the uterine cervix or vagina 
Eligible histologic types: squamous, adenocarcinoma, or 
adenosquamous carcinoma 
Clinical stage IB2 (> 4 cm), II, IIIB or IVA of the uterine 
cervix (FIGO 2009) or stage II-IVA of the vagina 
followed by  
Negative para-aortic nodal staging by PET/CT 
Stratify para-aortic negative patients by: 
a. Type of brachytherapy (LDR or HDR) 
b. Radiation modality – IG-IMRT (yes or no) 
c. FIGO 2009 Stage (stage ≤ II or stage ≥III) 
 
RANDOMIZE (1:1) 
Arm 1: 
• Radiation 
• Cisplatin 
Arm 2: 
• Radiation 
• Cisplatin 
• Triapine 
Radiation: 45 Gy / 25 fractions of 1.8 Gy + 5.4 Gy / 3 fraction parametrium boost + 40 Gy LDR or 
30 Gy HDR brachytherapy 
 
Cisplatin:  x1 weekly cisplatin 40 mg/m2 (maximum 70 mg) days 2, 9, 16, 23, 30 of radiation (5 total 
infusions; a sixth administration on day 37 is permissible at the treating physician’s discretion.  
Cisplatin may be given ± 1 day to accommodate scheduling issues for the control arm only. 
 
Triapine:  x3 weekly 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) 25 mg/m2 
(maximum 50 mg) days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 of radiation (15 total 
infusions) 
 
Statistics: This is a two-arm, open label randomized (1:1) phase III clinical trial. 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
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TABLE OF CONTENTS 
SCHEMA 
- 6 - 
TABLE OF CONTENTS 
- 7 - 
1.0 
OBJECTIVES 
- 9 - 
1.1 
Primary Objective 
- 9 - 
1.2 
Secondary Objectives 
- 9 - 
1.3 
Tertiary Objectives 
- 9 - 
2.0 
BACKGROUND 
- 10 - 
2.1 
Treatment for most solid tumors remains unsatisfactory 
- 10 - 
2.2 
There is a clinical need in women with cervical cancer for a biologic agent 
- 10 - 
2.3 
Rationale for trial design 
- 11 - 
2.4 
Inclusion of Women and Minorities 
- 15 - 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
- 16 - 
3.1 
Eligibility Criteria 
- 16 - 
3.2 
Ineligibility Criteria 
- 17 - 
4.0  
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
- 19 - 
5.0 
TREATMENT PLAN 
- 22 - 
5.1 
Chemotherapy 
- 23 - 
5.2 
Radiation Therapy 
- 24 - 
5.3 
Expected Toxicity from Radiation Therapy 
- 38 - 
5.4 
Duration of Protocol Treatment 
- 38 - 
5.5 
Duration of Protocol Follow-Up 
- 39 - 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
- 39 - 
5.7 
Centralized Quality Assurance and Knowledge-Based Planning Analysis 
- 40 - 
5.8 
Pelvic nodal boost for 3D Radiotherapy 
- 40 - 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT 
- 41 - 
6.1 
Triapine (3-AP) Dose Modifications 
- 41 - 
6.2 
Cisplatin Dose Modifications 
- 44 - 
6.3 
Radiation Dose Delivery Modifications 
- 46 - 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS 
- 47 - 
7.1 
Protocol Agents 
- 47 - 
7.2 
Adverse Events and Serious Adverse Events 
- 48 - 
7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Triapine® 
- 48 - 
7.4 
Adverse Events for Commercial Study Agents 
- 51 - 
7.5 
Expedited Reporting of Adverse Events 
- 52 - 
8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
- 56 - 
8.1 
Investigator Registration Requirements 
- 56 - 
8.2 
Site Registration Requirements 
- 57 - 
8.3 
RT-Specific Pre-registration Requirements 
- 61 - 
8.4 
Patient Enrollment 
- 64 - 
8.5 
18F-FDG PET CT Scanner Qualification and Evaluation  
- 65 - 
9.0 
DRUG INFORMATION 
- 66 - 
9.1 
Triapine (NSC #663249) IND#: 68338 
- 66 - 
9.2 
Cisplatin (NSC# 119875) 
- 68 - 
10.0 
PATHOLOGY 
- 70 - 
11.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
- 70 - 

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Version Date: February 17, 2021 
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11.1 
Reimbursement 
- 70 - 
11.2 
Translational Science 
- 70 - 
12.0 
DATA AND RECORDS 
- 71 - 
12.1 
Data Management/Collection 
- 71 - 
12.2 
Summary of Data Submission 
- 72 - 
12.3 
Digital Data Submission Requirements 
- 72 - 
12.4 
Global Reporting/Monitoring 
- 74 - 
13.0 
STATISTICAL CONSIDERATIONS 
- 74 - 
13.1 
Study Design 
- 74 - 
13.2 
Study Objectives 
- 75 - 
13.3 
Clinical Endpoints and Data Elements 
- 76 - 
13.4 
Stratification Factors at Randomization 
- 77 - 
13.5 
Accrual and Study Duration 
- 77 - 
13.6 
Statistical Power and Sample Size Justification 
- 78 - 
13.7 
Interim Safety Monitoring 
- 80 - 
13.8 
Interim Futility / Efficacy Monitoring  
- 81 - 
13.9 
Analysis Plan 
- 83 - 
13.10 Planned Minority Inclusion 
- 85 - 
14.0 
Publication Information and Administrative Agreements 
- 87 - 
15.0 
18F-FDG PET CT Scanner Qualification and Evaluation 
- 88 - 
15.1 
Quality Control Procedures 
- 88 - 
15.2 
Subject Preparation 
- 89 - 
15.3 
Typical acquisition parameters for the low-dose CT scan 
- 90 - 
15.4 
The presence or absence of para-aortic lymph node metastasis 
- 90 - 
15.5 
All PET/CT images will undergo centralized review 
- 90 - 
15.6 
The preferred image transfer method is via TRIAD 
- 90 - 
15.7 
18F-FDG PET/CT Reporting 
- 91 - 
15.8 
Semi-quantitative18F-FDG PET/CT Reporting of Standardized Uptake Value (SUV) - 91 - 
15.9 
Evaluation of 18F-FDG PET CT Target (9, 10): 
- 91 - 
16.0 
REFERENCES 
- 93 - 
APPENDIX I - COLLABORATIVE AGREEMENT 
- 98 - 
APPENDIX II PERFORMANCE STATUS 
- 100 - 
 
 
 
 
 
     
 
 
 
     
 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
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1.0 
OBJECTIVES  
Specific hypothesis: 
The experimental regimen, triapine (3AP) in combination with cisplatin and radiation, will 
improve overall survival relative to the standard / control regimen of cisplatin and 
radiation in women with uterine cervix or vaginal cancer. 
 
1.1 
Primary Objective  
To evaluate the efficacy of the experimental regimen of triapine (3AP), 
cisplatin, and radiation to increase overall survival relative to the standard / 
control regimen of cisplatin and radiation in women with uterine cervix or 
vaginal cancer. 
 
1.2 
Secondary Objectives 
1.2.1 To determine the relative progression-free survival impact of triapine-
cisplatin radio-chemotherapy and cisplatin radio-chemotherapy. 
 
 
1.3 
Tertiary Objectives 
1.3.1 To evaluate incidence and severity of hematologic and gastrointestinal 
(GI) adverse events by radiation modality; image guided intensity 
modulated radiation therapy (IG-IMRT) versus conventional pelvic 
radiotherapy. (05/30/2017) 
 
1.3.2 To summarize and compare differences in acute adverse events 
(CTCAE v4.0) by treatment arm and by radiation modality. 
(05/30/2017) 
 
1.3.3 To summarize and compare differences in chronic or late (≥ 30-days 
from off study treatment date) adverse events (CTCAE, v4.0) by 
treatment arm and by radiation modality. (05/30/2017) 
 
1.3.4 To determine peripheral blood methemoglobin proportion before and after 
triapine infusion (optional for Arm 2 patients). 
 
1.3.5 
To explore whether knowledge-based planning (KBP) can improve IG-IMRT 
plans compared to plans that would have been delivered without KBP, estimate 
the resulting toxicity reduction using NTCP models, and determine whether KBP 
should be a requirement for future IG-IMRT protocols. 
 
1.3.6 To determine the post-therapy 3-month 18F-FDG PET/CT metabolic 
complete response rate by treatment arm. 
 
 
1.3.7 To compare acute toxicity and chemotherapy delivery for atlas-based IG-
IMRT vs. PET/CT-based IG-IMRT vs. conventional RT, and assess the 
impact of treatment on changes in hematopoietic compensatory response. 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
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1.3.8 To develop and validate machine learning and radiomics techniques for 
dose accumulation, automated treatment planning, and prediction of 
treatment response. 
 
2.0 
BACKGROUND  
 
2.1 
Treatment for most solid tumors remains unsatisfactory, and new and more 
effective anticancer biologic agents are needed. Ideally, new anticancer 
biologic agents are targeted against molecular processes present or active in 
cancer cells and inactive in normal cells. These new agents also are expected 
to disrupt molecular processes that maintain malignant cell behaviors such 
as unchecked duplication, invasion, and metastasis. We have chosen to 
study, in a randomized phase III clinical trial, a molecular pathway known 
to act preferentially on uterine cervix cancers—ribonucleotide reductase 
over activity (Kunos, 2013; Kunos, Waggoner, 2010; Kunos, 2009; Kunos, 
Radivoyevitch, 2010; Kunos, Ferris, 2011 ). We focus upon women with 
cervical or vaginal cancer because there is an unmet therapeutic need for a 
biologic agent to improve overall survival and metabolic complete response 
(mCR) during cisplatin-based radio-chemotherapy. We meet a need to 
validate an early biomarker of mCR by using a 3-month post-therapy 2-
[18F] fluoro-2-deoxy-D-glucose positron emission tomography and 
computed tomography (18F-FDG PET/CT) scan as a secondary trial 
endpoint. Feasibility for 18F-FDG PET/CT has been demonstrated in a NCI-
sponsored trial for uterine cervix cancer (Kunos, 2013). 
Here, we propose a randomized phase III trial of daily radiation 
therapy and once weekly intravenous cisplatin chemotherapy alone 
(arm 1), or with co-administered ribonucleotide reductase inhibition 
by intravenous triapine (arm 2). The study was initiated as 
randomized phase II study.  Amendment 4 increased the sample size 
and converted the study from a randomized phase II to a randomized 
phase III. Amendment 5 converts this study to a registration trial.  The 
primary endpoint changes to overall survival, the type I error rate 
decreases to 0.025 and the sample size increases to 450 patients.  
 
2.2 
There is a clinical need in women with cervical cancer for a biologic agent 
to improve survival after cisplatin-based radio-chemotherapy. As seen in 
GOG-0219, overall survival was 72% (95% CI: 65% to 78%) 36 months 
after enrollment, and 64% (56% to 71%) 60 months after enrollment. 
Estimates for cervical cancer patient progression-free survival after 
cisplatin-based radio-chemotherapy are 64.5% 36 months after enrollment 
to NRG Oncology (and legacy Gynecologic Oncology Group) trials. The 
combination of ribonucleotide reductase inhibitors and cisplatin-based 
radio-chemotherapy suggests a disease-free survival rate of 82% (Kunos, 
2014).  
 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
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In this trial, there is also the opportunity to consider a tertiary analysis 
evaluating 3-month post-therapy 18F-FDG PET/CT mCR as an early 
“surrogate” endpoint for progression-free and overall survival. Moreover, 
data would determine the discriminatory usefulness of the PET/CT response 
surrogate for determination of treatment efficacy—a tool significantly 
impactful upon new cervical cancer therapy strategies to be evaluated by 
the United States Food and Drug Administration.  
 
18F-FDG PET/CT metabolic complete response rates are 60-85% after 
cisplatin-based radio-chemotherapy for women with cervical cancer 
(Kunos, Radivoyevitch, 2011; Schwartz, 2007). For a secondary 
endpoint in this protocol, mandatory standard-of-care pre-therapy (≤ 
28 days from radiation start), mandatory standard-of-care post-therapy 
3-month 18F-FDG PET/CT scans will be obtained for mCR 
assessment. Feasibility for 18F-FDG PET/CT as an early surrogate of 
response has been demonstrated in NCI-CTEP protocol #8327, as 23 
(96%) of 24 eligible cervical cancer patients completed the specified 
imaging (Kunos, 2013). For qualitative interpretation, this study will 
use language as outlined by the National Cancer Institute Cancer 
Imaging Program (Shankar, 2006; Young, 1999). For semi-
quantitative interpretation, this study will use three metrics: (a) 
standardized uptake value (SUV) normalized to body mass, (b) SUV 
normalized to lean body mass (SUL), and (c) ratio of post-therapy 
SUVmax: pre-therapy SUVmax. For the latter, ratios ≥ 1.25 indicate 
progressive metabolic disease, ratios 0.76 to 1.25 classify stable 
metabolic disease, ratios 0.34 to 0.75 indicate partial metabolic 
response, and ratios ≤ 0.33 label complete metabolic response. 
SUVmax indistinguishable from cardiac or liver blood pool activity 
will also indicate metabolic complete response, as before (Kunos, 
2013). 
 
2.3 
Rationale for trial design 
 
2.3.1 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (triapine, arm 2) 
NCI-CTEP has sponsored a phase I trial (NCI 7336, NCT00335998) and a 
phase II trial (NCI 8327, NCT00941070) evaluating the safety and clinical 
efficacy of intravenous triapine in cervical cancer (Kunos, 2013; Kunos, 
Waggoner, 2010). Triapine is 500-to-1000-fold more potent inhibitor of 
ribonucleotide reductase M2 and M2b than hydroxyurea, which has 
previously shown activity in cervical cancer. Triapine has both intravenous 
and oral forms in clinical development, making this anticancer drug an 
appealing option. A Phase I trial testing of oral triapine, cisplatin, and 
radiation has not been completed and continues to recruit participants (NCT 
02595879). The half-life of intravenous triapine is 2 hours (therapeutic 
window of ~6 hours), suggesting repeated dosing within a week for efficacy. 
In preclinical studies, triapine alone has a ~20% cytotoxic rate, triapine plus 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
- 12 - 
cisplatin has a 60% cytotoxic rate, and triapine plus cisplatin plus radiation 
has a 90% cytotoxic rate (Kunos, Radivoyevitch, 2010). In phase I and II 
studies, intravenous triapine (25mg/m2) was given three times weekly co-
administered with cisplatin (40mg/m2) and daily radiation (50.4 Gy in 28 
fractions) plus brachytherapy (35-40 Gy) in 35 patients with advanced stage 
cervical and vaginal cancer (Kunos, 2013; Kunos, Waggoner, 2010). A total 
of 500 (95%) of 525 2-hour triapine infusions have been administered 
without complication, and so, the regimen is safe. Three-month complete 
clinical responses have occurred in 34 (97%) of 35 patients (1 partial 
response was seen in a patient not receiving brachytherapy). Three-month 
mCRs have occurred in 23 (96%) of 24 patients in whom the images were 
acquired on the phase II study (Kunos, 2013). Four (11%) of 35 patients have 
died from extra-pelvic disease progression.  
 
For 24 stage II-IIIB or node-positive stage IB2 patients treated on the phase I 
and II trials, 3-year overall and disease-free survival estimates are 82% (95% 
confidence interval [CI]: 74%-90%) and 80% (95% CI: 71%-89%) (Kunos, 
2014). A single (4%) loco-regional failure has been observed. Based on these 
impressive findings, a randomized phase II trial of triapine-cisplatin radio-
chemotherapy versus cisplatin radio-chemotherapy was activated and accrued 
21 patients prior to the opening of NRG-GY006. Although initially designed 
to be analyzed with GY006, the lack of continued follow-up has precluded 
the use of outcome data in these patients (NCI #9434, NCT01835171). 
 
2.3.2 Rationale for intensity modulated radiation therapy (IMRT) stratification 
at randomization 
 
IMRT has emerged as an effective radiation delivery approach to treat cancer 
while simultaneously minimizing radiation exposure to adjacent healthy 
tissues. Furthermore, a potential barrier to accruing to the ongoing ANZGOG 
OUTBACK protocol #902 has been the prohibition of IMRT use on that 
protocol. It is believed that allowing IMRT treatment on this protocol would 
facilitate patient accrual in the United States and Canada (NRG Radiation 
Oncology Committee, February 2014).   
 
Multiple published studies indicate that IMRT can reduce both hematologic 
and gastrointestinal (GI) toxicities, and can provide excellent long-term 
outcomes (Klopp, 2010; Kidd, 2010). While IMRT has been used for more 
than a decade, few prospective trials have incorporated IMRT for definitive 
treatment of uterine cervical cancer. Several studies and educational videos 
regarding IMRT techniques have also been produced to facilitate quality 
control, since IMRT planning and delivery is more technical than 
conventional RT techniques (Lim, 2011; Small, 2008).  
 
The phase II portion of the NCI-supported INTERTECC multi-center trial 
(NCT01554397/ ISRCTN54531450) enrolled 83 women with stage IB-IVA 

NCI Protocol #: NRG-GY006 
Version Date: February 17, 2021 
- 13 - 
cervix cancer (86% were IIB-IVA). The primary endpoint was the occurrence 
of either acute grade ≥ 3 neutropenia or clinically significant GI toxicity 
(grade ≥ 2 diarrhea requiring intravenous fluids and/or combination 
opiate/anticholinergic antidiarrheal medication) within 30 days of completing 
chemoradiotherapy. A pre-planned subgroup analysis was designed to test the 
hypothesis that positron emission tomography (PET) image-guided bone 
marrow-sparing IMRT (IG-BMS-IMRT) lowers the risk of acute neutropenia. 
Toxicity grading was according to NCI CTCAE v4. The incidence of any 
primary event was significantly lower than historical data (2-sided chi-square 
p=0.012). Compared to patients treated without IG-BMS-IMRT (N=48), 
patients treated with IG-BMS-IMRT (N=35) had significantly lower grade ≥ 
3 neutropenia (p=0.035). These data were recently submitted to the ESTRO 
35 2016 Meeting (Abstract # E35-0024).  
 
Multiple published studies also support the use of 18F -FDG-PET for defining 
“active” or “functional” bone marrow (Figure 1). For example, Rose et al. 
reported that increased radiation dose to metabolically active bone marrow 
defined by 18F -FDG-PET was correlated with increased acute hematologic 
toxicity, in contrast to radiation dose to relatively less active marrow (Rose, 
2012). Liang et al. reported the first use of 18F -FDG-PET/CT in combination 
with quantitative IDEAL MRI to define active marrow regions for use as an 
avoidance structure in IMRT planning, showing this technique is feasible 
clinically (Liang, 2013).  Recently, Elicin et al. associated loss of active bone 
marrow defined by 18F -FDG-PET/CT with subacute hematologic toxicity 
following chemoradiotherapy for cervical cancer (Elicin, 2014).  
 
The optimal method for delineating active bone marrow is not known. An 
important question is whether commonly available techniques that are paid 
for by patient's insurers, such as 18F -FDG-PET/CT, are better than alternative 
methods, such as 18F-FLT-PET/CT, which are rarer and more expensive. 
Furthermore, the precise location of a hematopoietic stem cell niche within 
the bone marrow remains elusive, with evidence supporting the existence of 
both a vascular niche and an endosteal niche (Spencer, 2014). The rationale 
for the approach using 18F -FDG-PET/CT is to avoid metabolically active 
tissue within bone, which we hypothesize is mostly hematopoietically 
functional bone marrow. Some hematopoietic stem cells may also lie in the 
endosteal region. Although there can be some misspecification of cortical 
bone and adjacent soft tissue due to “blooming” or registration errors, this 
component appears to be negligible compared to the large region within the 
bone designated as metabolically active (Figure 1). 
 

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Figure 1. Heat map of metabolically active bone marrow defined by 18F-FDG-PET 
in 32 patients with cervical cancer, rendered using deformable image registration. 
 
Another relevant clinical trial is the American Cancer Society-sponsored 
Phase I trial of concurrent cisplatin/gemcitabine with IMRT designed to 
reduce bowel and bone marrow dose (NCT01554410), which varies the order 
of administration for cisplatin and gemcitabine. Gemcitabine, another 
ribonucleotide reductase inhibitor, has been found to improve pathologic 
response and overall survival in randomized trials (Duenas-Gonzalez, 2011; 
Duenas-Gonzalez, 2005). However, a gemcitabine-based regimen is highly 
toxic, and previous multicenter phase I trials have found that the maximum 
tolerated dose (MTD) of gemcitabine is lower (≤ 50 mg/m2) when delivered 
with conventional RT techniques (Swisher, 2006; Rose, 2007). In contrast, 
this ongoing Phase I trial has enrolled 21 patients with stage IB2-IVA 
cervical cancer. The MTD of gemcitabine has not yet been reached, but has 
been observed to be higher (≥ 100 mg/m2) in the setting of IMRT planning, 
consistent with validated normal tissue complication models (Rose, 2011; 
Simpson, 2012). Although the trial remains ongoing, sequential 
administration of cisplatin 40mg/m2 followed by gemcitabine 125mg/m2 and 
pelvic IMRT as well as sequential gemcitabine 75mg/m2 followed by 
cisplatin 40mg/m2 and pelvic IMRT appear to be tolerable with manageable 
toxicity.  More generally, these findings suggest the tolerability of concurrent 
doublet chemotherapy could be higher with IMRT than with conventional RT 
techniques.  
 
2.3.3 Rationale for research on effectiveness and quality of IG-IMRT 
(05/30/2017) 
IG-IMRT is more complex to deliver and is therefore prone to greater variation in 
quality compared to standard radiation techniques. Variation in imaging quality 
and resolution across centers is also possible, and studies to validate and gauge 
the quality of IG-IMRT are needed.  
 

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Although IMRT has become the radiotherapy standard-of-care for many cancers, 
there exist few quantitative metrics to evaluate IMRT treatment planning quality. 
IMRT quality assessments currently rely primarily on individual subjective 
evaluation, while commercial treatment planning systems employ user-specified 
cost functions that have few (if any) limitations on the use of conflicting and/or 
inappropriate planning objectives. Variation in IMRT plan quality can be 
attributed to a number of factors: the anatomic variations between patients, the 
complexity of clinical goals, the paucity of quantitative metrics to judge the 
optimality of a given IMRT plan, and, of course, the subjectivity and relative 
experience of the dosimetrists, medical physicists, and physicians involved in the 
planning process. Perhaps the most difficult part of IMRT quality assessment is 
judging the adequacy of normal tissue sparing which is the principal rationale for 
employing IMRT over 3D conformal radiotherapy (3DCRT).  
 
Our research group has developed mathematical models to detect sub-optimal 
IMRT plans with high sensitivity and specificity, using a process termed 
Knowledge-Based Planning (KBP) (Moore, 2011). This system is built to identify 
optimal plans amongst prior training cohorts, and use the resulting model to 
develop predictive dose-volume histograms (pDVH) for organs-at-risk (OARs) 
that give precise quantitative information on plan quality deficiencies. This 
approach will allow us to identify, quantify, and ultimately correct sub-optimal 
treatment plans, a process that is ideally suited for application to quality control in 
the multi-center clinical trial setting, particularly when new technologies or 
implementations are being introduced.  
 
Recently, studies have shown that atlas-based IG-IMRT methods are feasible and 
likely to achieve similar outcomes to PET/CT-guided IG-IMRT, while obviating 
the need for expensive PET/CT imaging (Li, 2017). This would greatly increase 
the access of patients to bone marrow sparing IMRT in sections of the world 
where PET/CT imaging is unavailable or unaffordable. Secondly, little is known 
about the effect of varying chemoradiotherapy regimens on the hematopoietic 
compensatory response. Noticewala et al. (2017) developed a technique to 
quantify the compensatory response on serial PET/CT imaging that can be 
implemented in this trial. Finally, machine learning and radiomics approaches are 
novel branches of applied radiation medicine and radiation physics, but little is 
known about their application to the gynecologic population, particularly when 
combining external beam radiotherapy and brachytherapy. Further work in this 
trial will lead to better methods of dose accumulation, automated brachytherapy 
planning, and the use of radiomic classifiers to predict treatment response.  
 
 
2.4 
 
Inclusion of Women and Minorities 
NRG Oncology and its participating institutions will not exclude potential 
subjects from participating in this or any study solely on the basis of ethnic 
origin or socioeconomic status.  Every attempt will be made to enter all 
eligible patients into this protocol and therefore address the study objectives 

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in a patient population representative of the entire population treated by 
participating institutions. 
 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 Note: Per NCI guidelines, exceptions to inclusion and to exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the NRG Statistical and Data 
Management Center-Pittsburgh Office (via the contact list, NRG web site).  
 
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the 
following conditions are met. 
 
3.1.1 Patient has a new, untreated histologic diagnosis of stage IB2 (> 4 
cm), II, IIIB or IVA squamous, adenocarcinoma, or adenosquamous 
carcinoma of the uterine cervix (FIGO 2009) or stage II-IVA 
squamous, adenocarcinoma, or adenosquamous carcinoma of the 
vagina not amenable to curative surgical resection alone. The 
presence or absence of para‐aortic lymph node metastasis will be 
based on pre-therapy 18F‐FDG PET/CT. NOTE:  If the baseline 18F‐
FDG PET/CT identifies hypermetabolic para‐aortic disease, such 
patients will NOT be eligible. The patient must be able to tolerate 
imaging requirements of an 18F‐FDG PET/CT scan.  
3.1.2 Patient must provide study specific informed consent prior to study 
entry. 
3.1.3 Patient must have a GOG performance status of 0, 1, or 2 or 
equivalent (Appendix II). 
3.1.4 Patient must have adequate organ and marrow function as defined 
below: 
 
absolute neutrophil count 
> 1,500/µL 
platelets 
 
 
> 100,000/µL 
hemoglobin 
 
 
> 10 g/dL 
total bilirubin  
 
< 2.0 mg/dL 
AST (SGOT)/ALT(SGPT) 
< 2.5 X institutional upper limit of 
normal 
PT/aPTT 
 
 
< 1.5 X institutional upper limit of 
normal 
Creatinine 
 
 
 ≤ 1.5 mg/dL to receive weekly 
cisplatin*  
 
*Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are 
eligible for cisplatin if there is no hydronephrosis and the estimated 
creatinine clearance (CCr) is ≥ 30 ml/min. For the purpose of 
estimating the CCr, the formula of Cockcroft and Gault for females 
should be used:  

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CCr = 0.85 x (140-age) x IBW / (Scr x72)  
where age is the patient’s age in years (from 20 to 80 years), Scr is the 
serum creatinine in mg/dL, and IBW is the ideal body weight in kg 
(according to the calculation IBW = 45.5 kg + 2.3 kg for each inch 
over 5 feet). 
 
3.1.5 Patient does not have uncontrolled diabetes mellitus (i.e., fasting 
blood glucose >200 mg/dL).  
3.1.6 Patient has a life expectancy of greater than 20 weeks. 
3.1.7 Age is ≥ 18 years. 
3.1.8 Patient does not have known brain metastases (testing optional). 
3.1.9 Patient does not have known human immunodeficiency virus 
syndrome  
(HIV, testing optional). Known HIV-positive patients receiving 
combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with triapine.  
3.1.10 Patient does not have a known allergy to compounds of similar or 
biologic composition as triapine.  
3.1.11 Patient does not have known glucose‐6‐phosphate dehydrogenase 
(G6PD) deficiency as the condition interferes with triapine antidote 
metabolism (G6PD testing optional). 
3.1.12 Patient is not actively breastfeeding (or has agreed to discontinue 
breastfeeding before the initiation of protocol therapy). 
 
3.2 
Ineligibility Criteria  
Patients with one or more of the following conditions are NOT eligible for 
this study. 
 
3.2.1 Patient has another concurrent active invasive malignancy. 
 
3.2.2 Patient has had a prior invasive malignancy diagnosed within the last 
three years (except [1] non-melanoma skin cancer or [2] prior in situ 
carcinoma of the cervix). Patients are excluded if they have received 
prior pelvic radiotherapy for any reason that would contribute 
radiation dose that would exceed tolerance of normal tissues at the 
discretion of the treating physician.  
3.2.3 Patient has uncontrolled intercurrent illness including, but not limited 
to, symptomatic congestive heart failure, unstable angina pectoris, 
myocardial infarction within six months of protocol initiation, cardiac 
arrhythmia within six months of protocol initiation; known 
inadequately controlled hypertension; clinically significant pulmonary 
disease including dyspnea at rest, or patients requiring supplemental 

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oxygen, or poor pulmonary reserve; or clinically significant renal 
function impairment (baseline serum creatinine >2 mg/dL); or 
psychiatric illness/social situations that would limit compliance with 
study requirements. 
3.2.4 Patient is receiving another investigational agent for the treatment of 
cancer. 
3.2.5 Patient is currently pregnant.   
3.2.6 Patient does not agree to use two forms of birth control if they are of 
child-bearing potential. 
3.2.7 Patients who have had a hysterectomy or are planning to have an 
adjuvant hysterectomy following radiation as part of their cervical 
cancer treatment are ineligible. (05/30/2017) 
3.2.8 Patients scheduled to be treated with adjuvant consolidation 
chemotherapy or other anti-neoplastic therapy at the conclusion of 
their standard chemoradiation. (05/30/2017) 
 
3.2.9 Patients with self-reported or known diagnosis of G6PD deficiency. 
(05/30/2017) 
 
3.2.10 Patients with vaginal cancer may have previously undergone a 
hysterectomy for various indications. Patients with vaginal cancer who 
underwent a hysterectomy for treatment of cervical cancer less than five 
years prior to their diagnosis of vaginal cancer are ineligible[MC1]. 
 
 

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4.0 REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
 
ASSESSMENTS FOR PRE-TREATMENT STUDY ENTRY* (05/30/2017) 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to 1st Radiation 
Treatment 
 
Informed Consent 
X 
 
History and Physical examination 
(including initial clinical tumor 
measurement in centimeters) 
≤ 28 days 
 
Vital Signs (heart rate, blood 
pressure, respiratory rate, 
temperature, pain scale) 
≤ 28 days 
 
Height 
≤ 28 days 
 
Weight 
≤ 28 days 
 
GOG Performance Status 
≤ 28 days 
 
Toxicity Assessment 
≤ 14 days 
 
  
 
 
Concurrent Medications 
≤ 14 days 
 
Complete Blood Count (CBC) / 
Differential / Platelets / PT/aPTT 
≤ 14 days 
 
Chemistries (including sodium, 
potassium, chloride, bicarbonate, 
calcium, glucose, magnesium, 
BUN/creatinine, total bilirubin, 
total protein, ALT, AST, alkaline 
phosphatase, albumin) 
≤ 14 days 
 
Pregnancy Test  
(for patients of child bearing 
potential) 
≤ 7 days 
≤ 7 days 
Electrocardiogram (EKG) 
≤ 28 days 
 
PET/CT scan 
≤ 28 days 
 
 
* Study treatment must begin within 4 weeks of randomization 
 
 

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ASSESSMENTS DURING TREATMENT (05/30/2017) 
Assessment 
Day 1  
Methemoglobinemia Sampling 
(optional) 
Refer to Section 6.1.1 
Patients on Triapine arm 
only (Arm 2). 
Pulse Oximetry 
Patients on Triapine arm 
only (Arm 2). 
 
 
Assessments 
Day 9, 16, 23, 30, 37*  
History and Physical examination 
≤ 3 days 
Vital Signs (heart rate, blood 
pressure, respiratory rate, 
temperature) 
≤ 3 days 
Weight 
≤ 3 days 
Toxicity Assessment 
≤ 3 days 
CBC / Differential / Platelets 
≤ 3 days 
BUN/Creatinine, Magnesium 
≤ 3 days 
*Assessments must be completed even if optional cisplatin on day 37 is not given. 
 
 
ASSESSMENTS DURING FOLLOW UP (05/30/2017)-Per Section 5.5 
Assessments 
From end of treatment: 1 mo. and 3 mos.   
Follow-up forms (Q forms) are collected. 
Medical history, physical examination, GOG 
performance status, vital signs (heart rate, 
blood pressure, respiratory rate, temperature), 
and vital status (including any recurrence) 
X 
Toxicity Assessment 
X 
CBC / Differential / Platelets 
1 mo. visit only 
Chemistries (including sodium, potassium, 
chloride, bicarbonate, calcium, glucose, 
magnesium, BUN/creatinine, total bilirubin, 
total protein, ALT, AST, alkaline phosphatase, 
albumin) 
1 mo. visit only 
PET/CT, pre-scan glucose, BUN/creatinine 
3 mos. visit only 
 

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Assessments 
From end of 3 mos. post therapy visit:  
q3 mos. years 1 and 2; then  
q6 mos. years 3, 4, and 5.   
Follow-up forms (Q forms) are collected for 
the 5-year follow-up period or until study 
termination. 
Medical history, physical examination, ECOG 
performance status, vital signs (heart rate, 
blood pressure, respiratory rate, temperature), 
and vital status (including any recurrence) 
X 
Toxicity Assessment 
X 
 
 
 

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5.0 
TREATMENT PLAN (05/30/2017) (01/16/2018) (17-FEB-2021) 
 
This study has two study groups. 
• Group 1 will get the usual cisplatin chemotherapy and radiation therapy used for this 
type of cancer. 
• Group 2 will get the usual cisplatin chemotherapy and radiation therapy used for this 
type of cancer plus the investigational study drug triapine three times per week. 
Chemotherapy and Radiation Regimen Description 
Agent 
Pre-medications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Triapine 
All patients will 
receive 
dexamethasone 4 mg 
IV prior to each 
triapine (3-AP) 
infusion.  Pre-
medicate with 
antiemetic as needed 
for patients 
developing nausea or 
vomiting with a 
previous dose of 
triapine. 
25mg/m2 (50 
mg maximum) 
diluted in 500 
ml NS or 500 
ml 5% dextrose 
in water 
IV infusion 
over 2 hours 
using DEHP-
free low 
sorbing 
infusion set.. 
Days 1, 3, 
5, 8, 10, 
12, 15,17, 
19, 22, 24, 
26, 29, 31, 
33 
Three times 
weekly 
(preferably 
after pelvic 
radiation 
treatment)  
 
Cisplatin* 
Increased oral intake 
of fluid should be 
encouraged 24 hours 
prior to infusion; 
1000 ml of ½ normal 
saline infused IV one 
hour before cisplatin. 
Antiemetic 
prophylaxis with a 
serotonin antagonist 
and/or 
dexamethasone 10-20 
mg IV is allowed as a 
pre-medication. 
40 mg/m2 (70 
mg maximum) 
diluted in 250-
1000 ml 
normal saline, 
reconstitution 
results in a 
colorless 
solution. 
Mixing and 
administration 
should follow 
local standards 
IV infusion at a 
rate of 
1mg/min, 
usually 
infusing over 1 
½ hours (90 
minutes), using 
non-aluminum 
administration 
sets; after is an 
additional 1000 
ml of ½ normal 
saline infused 
over one hour 
Days 2, 9, 
16, 23, 30 
(day 36 or 
37 
optional) 
One time 
weekly 
(preferably 
before, but 
allowed to be 
after pelvic 
radiation 
treatment) 
 
Pelvic external  
beam radiation 
therapy 
Skin, antiemetic, or 
anti-diarrheal 
medications may be 
administered as 
needed. 
1.8 Gy/ day  
(1.7 Gy/ day 
for IMRT, see 
Section 5.2) 
See Section 5.2  Daily      
(excludes 
weekends 
and 
holidays)  
Daily  
(Start on a 
Monday is 
preferred) 
Pelvic  
brachytherapy 
Antiemetic and anti-
diarrheal medication 
may be administered 
as needed. 
27.5 to 40 Gy 
in one or 
multiple 
fractions using 
LDR or HDR 
techniques 
See Section 5.2  See 
Section 
5.2 
See Section 
5.2 

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*Cisplatin preparation, administration and supportive hydration, antiemetics and 
 supportive medications can be per altered per institutional standards. 
 
5.1 
Chemotherapy 
 
5.1.1 Cisplatin chemotherapy (05/30/2017) 
All patients will receive five one-time weekly intravenous infusions of 
cisplatin 40 mg/m2 (70mg maximum) diluted in 250-1000 mL normal saline. 
The cisplatin infusions occur on day 2, 9, 16, 23, and 30. To accommodate 
scheduling issues, cisplatin dosing on the control arm only may be given ± 1 
day. At the treating physician’s discretion, a sixth infusion of cisplatin may 
occur on day 37 per institutional protocol. Increased oral intake of fluid should 
be encouraged 24 hours prior to cisplatin infusion. It is recommended that 
1000 ml of ½ normal saline be infused intravenously one hour before cisplatin 
infusion, but other institutional protocols are accepted. Antiemetic prophylaxis 
with a serotonin antagonist is allowed as a pre-medication. It is recommended 
that the cisplatin intravenous infusion proceed at a rate of 1mg/minute, usually 
infusing over 90 minutes. Other infusion rates are acceptable per institutional 
routine. Infusion may occur before or after radiation treatment. Non-aluminum 
intravenous administration sets are required. An additional 1000 ml of ½ 
normal saline should be infused intravenously over one hour after cisplatin 
infusion, but other institutional protocols are accepted.  
 
5.1.2 Triapine chemotherapy (05/30/2017) (01/16/2018) (17-FEB-2021) 
Patients randomized to receive triapine will receive five three-times weekly 
intravenous infusions of triapine 25 mg/m2 (50mg maximum) diluted in 500 
mL normal saline or 500 mL 5% dextrose in water. The triapine infusions 
occur on day 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33. Triapine 
infusions should not occur on days of no radiation. Triapine infusions 
preferably should not occur on days of cisplatin infusion, but same day 
triapine-cisplatin infusions are allowed. Any missed triapine infusion may be 
made up during a sixth week of radiation (e.g. day 36 or 38), if the sixth week 
of radiation is done. It is recommended that dexamethasone 4mg be given 
intravenously before triapine infusion. Antiemetic prophylaxis with a serotonin 
antagonist for example is allowed as a pre-medication. It is recommended that 
triapine intravenous infusion proceed over two hours, approximately 90 
minutes following radiation treatment. Other infusion rates are acceptable per 
institutional routine. DEHP-free low sorbing infusion set.  
 
Methemoglobinemia is a known toxicity of triapine (21). Normal human blood 
levels are 1-3%. Triapine 25 mg/m2 may elevate methemoglobin levels to 3-
5% after infusion (21). It is recommended that the methemoglobinemia 
antidotes be available for the patient on the days of triapine infusion. The 
antidotes include either intravenous methylene blue given 1-2 mg/kg over five 
minutes (contraindicated G6PD-known patients), or intravenous ascorbic acid 

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1000 mg given per institutional standard every six hours until 
methemoglobinemia resolved. 
 
5.2 
Radiation Therapy 
 
5.2.1 General 
This protocol requires photon external beam radiation therapy (EBRT), either 
conventional radiation therapy (RT) or intensity modulated radiation therapy 
(IMRT) techniques followed by low dose rate (LDR) or high dose rate (HDR) 
brachytherapy. Radiation therapy must be completed within 60 days of 
initiation. Four-field box RT and IMRT are pretreatment stratification 
variables. 
 
For EBRT, the prescription dose is 45 Gy in 25 fractions at 1.8 Gy/fraction 
with an optional parametrial boost of 4-9 Gy in 3-5 fractions at 1.8-2.0 
Gy/fraction. EBRT should be given once daily Monday-Friday, 5 fractions per 
week. For instructions on nodal boosts for patients treated with 3D EBRT, see 
section 5.8.  
 
For IMRT, the prescription dose is 45 Gy in 25 fractions at 1.8 Gy/fraction, 
unless a simultaneous integrated boost (SIB) is required for gross nodal 
disease. For SIB cases, the primary target will receive 47.6 Gy in 1.7 
Gy/fraction and the gross nodal PTV (PTV_Boost) will receive 1.93-2.12 Gy 
per fraction, depending on bowel tolerance. IMRT should be given once daily 
Monday-Friday, 5 fractions per week.  
 
For brachytherapy, the prescription doses are 27.5 - 30 Gy for HDR and 35 - 
40 Gy for LDR, following institutional protocol. Please see section 5.2.5 for 
dose prescription.  
 
5.2.2 Treatment Technology 
Conventional RT (4-field box) 
Conventional RT plans will consist of a 4-field box arrangement using AP/PA and 
Right/Left lateral fields. Conventional RT must use 4-18 MV photons. It is 
permissible i) to use bone landmarks to draw field borders as described below or 
ii) to use 3D planning with explicit targets as outlined in section 5.2.3. Custom 
cerrobend blocks or MLCs are acceptable for field shaping. 
 
If bone landmarks are used, use the following portals: 
• Superior border: L4-L5 interspace, or higher to encompass known 
disease with at least a 3 cm margin 
• Lateral border: 1-2 cm lateral to the border of the true pelvis 
• Inferior border: Obturator foramen or 3 cm inferior to the lowest extent 
of disease, whichever is lower 
• Anterior border: line from pubic symphysis to 1.5 cm anterior to 
common iliac nodes at L4-5. At least 0.5 cm anterior of the L4-L5 

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vertebral bodies should be included in the field in order to adequately 
encompass the low para-aortic region. 
• Posterior border: draw border 1.0 cm posterior to the sacrum from S1-S4 
• Custom blocking to shield femoral heads. Do not block the obturator 
foramen or within 1 cm of the common iliac nodes 
 
Opposed lateral pelvic fields are used using the same isocenter as the anterior and 
posterior pelvic fields. The superior and inferior borders will be the same as for 
the anterior and posterior fields.  
 
The inferior extent or vaginal extension of disease should be marked so that the 
inferior border of disease can be documented. Uninvolved normal tissues may be 
blocked although the position of the uterus should be contoured to ensure 
adequate coverage.  
 
If clips are present from the lymph node dissection to document the position of 
the lymph nodes, then these should be used as a guide when anterior blocks are 
designed to shield small bowel. When shielding bowel, at least 3 cm should not be 
blocked anterior to the L4 and L5 vertebral bodies in order to adequately 
encompass the low para-aortic region. 
 
IMRT 
IMRT plans may include static field arrangements (e.g. 5-9 fields), modulated arc 
therapy, or Tomotherapy. Pseudo-step-wedge intensity modulation (PSWIM) and 
volumetric modulated arc therapy (VMAT) techniques are permitted. IMRT 
should use 6-15 MV photons. 
 
Parametrial Boost 
After conventional RT or IMRT delivery, a parametrial boost can be delivered at 
the treating physician’s discretion. The parametrial boost will use an AP/PA field 
arrangement. The superior border should be reduced to include only the true 
pelvis and the upper border of the true pelvis is defined as 1 cm above the inferior 
aspect of the sacroiliac joint. The inferior border remains the same as in the pelvis 
fields. A parametrial central field block is a minimum of 4 cm wide.  
 
Brachytherapy (05/30/2017) 
Either HDR or LDR brachytherapy is permitted according to each institution’s 
standard. Either standard (point-directed) or volume-directed brachytherapy 
techniques are permitted according to each institution’s standard. Tandem and 
ring or tandem and ovoids will be used for intact cervix brachytherapy. Interstitial 
brachytherapy such as with a Vienna applicator is allowed if it is felt to be 
clinically imperative to change the plan after treatment start because of poor 
response of the tumor to external beam therapy. A tandem and cylinder or tandem 
alone is allowed for patients where tandem and ring or ovoid application is not 
possible due to extent of disease or poor anatomy (e.g., obliterated fornices). Use 
of IMRT or other external beam techniques in place of brachytherapy to boost 

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gross cervical disease is expressly discouraged. If deemed necessary or essential 
for the patient’s care (e.g., if a patient refuses brachytherapy), reasons for not 
performing brachytherapy should be documented and the study PI should be 
notified. 
 
5.2.3 Immobilization and Simulation  
Conventional RT (4-field box) 
CT simulation is required. Field outlines should be drawn electronically on 
Digitally Reconstructed Radiographs (DRRs) produced from the CT simulation 
information. Localization or block-check-images of simulated fields are to be 
obtained in a simulator and/or treatment machine. Digital pictures of all treatment 
portals with the patient in the treatment position are to be submitted for quality 
assurance review. All treatment fields, whether formed by cerrobend blocks or 
multi-leaf collimation, should be independently checked against the 
corresponding DRRs. Prone positioning with bowel exclusion devices (e.g. belly 
boards) is allowed.  
 
3D planning is at the physician’s discretion. If 3D planning is being done, a CT 
simulation scan is required with a slice thickness ≤ 3.0 mm for the regions 
extending at least 4cm above and below target volumes. Patients can be simulated 
supine or prone. All subjects will have a customized immobilization device (e.g., 
Alpha Cradle or Vac-Loc) fabricated at the time of simulation. A full bladder is 
required at the time of simulation and treatment. Intravenous contrast is 
recommended to visualize vessels better. Oral or rectal contrast is not 
recommended for treatment planning.     
 
IMRT 
All subjects will undergo a CT (or PET/CT) simulation scan in the supine position 
using a slice thickness ≤ 3.0 mm and large field-of-view pelvic protocol. A 
customized immobilization device fabricated at the time of simulation is required. 
It is recommended that CT scans be obtained from the T12 vertebral body to 5 cm 
below the ischial tuberosities. For patients undergoing CBCT with each fraction, 
it is recommended that the isocenter be placed along the patient’s midline 1.5 cm 
caudal to the inferior border of the sacroiliac joint. Otherwise, isocenter 
placement is left to the discretion of the treating physician. It is recommended to 
use a consistent bladder filling state (e.g. always full or always empty) for 
simulation and treatment. It is recommended for patients not to be simulated or 
treated with a full rectum as this may result in poor setup reproducibility. Bowel 
preparatory agents (enema, stool softeners, etc.) may be applied at the discretion 
of the physician. If an internal target volume (ITV) will be used (see section 
5.2.4), it is recommended that the patient undergo both a full and empty bladder 
CT simulation. Intravenous contrast is recommended unless medically 
contraindicated. Oral contrast is optional. Radio-opaque cervical markers or 
implanted fiducials are optional.  
 
Brachytherapy 

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For 3D brachytherapy planning, all subjects will undergo a CT simulation scan 
using a slice thickness ≤ 3.0 mm with brachytherapy applicators and dummy 
sources in. It is recommended that CT scans contain the entire brachytherapy 
applicators and the critical structures such as bladder and rectum. Maintaining 
applicator position is required from the time of applicator insertion to simulation 
and treatment. Before a CT scan, a Foley catheter is inserted into the bladder and 
the balloon should be filled with radio-opaque fluid to define the bladder 
reference point in treatment planning. 
 
For volume-directed brachytherapy, pelvic MRI (≤ 3 mm slice thickness) is 
recommended with either the first or second insertion. An MRI-compatible 
applicator is strongly recommended to perform volume-directed brachytherapy. 
Subsequent insertions may use CT or MRI for planning.  
 
5.2.4 Definition of Target Volumes and Margins  
All structures must be named for digital RT data submission as listed in the tables 
below. Capital letters, spacing and use of underscores must be applied exactly as 
indicated. Resubmission of data may be required if labeling of structures does not 
conform to the standard DICOM name listed.  
The structures marked as “Required” in the table must be contoured and 
submitted with the treatment plan.  
 
Conventional RT (4-field box) 
For a 4-field box treatment without 3D planning, contouring target volumes is not 
required. For 3D plans, target volumes and margins will be the same as for IMRT 
described below. The only difference between 3D plans and IMRT contours is 
that patients treated with 3D planning will not have an ITV option.   
 
IMRT 
Pelvic MRI and/or PET fusion with the CT simulation scan is recommended to 
aid target delineation. Fusion should be optimized to match the MRI/PET scans to 
the treatment position. The Gross Tumor Volume (GTV), Clinical Target Volume 
(CTV) and Planning Target Volume (PTV) will be contoured on all CT slices in 
which the structures exist. The definition of all volumes will be in accordance 
with the 1993 ICRU Report #50: Prescribing, Recording and Reporting Photon 
Beam Therapy and with the 1999 ICRU Report #62: Prescribing, Recording and 
Reporting Photon Beam Therapy (Supplement to ICRU Report #50).  
 
It is strongly recommended that, prior to IMRT planning, investigators read 
guidelines for contouring target volumes for both postoperative and intact 
cervical cancer (14, 15).  
 
Standard Name 
 
Description 
 
Detailed Specification 
GTV_4500 
GTV to receive 45 Gy 
Required 
 
The GTV is defined as all known gross 
disease determined from radiographic 
studies, clinical information, physical 

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examination, endoscopic examination, and 
biopsy results. 
CTV_4500 
CTV to receive 45 Gy 
Required 
 
It is recommended to divide the CTV into 3 
sub regions: CTV1, CTV2, CTV3.  CTV1 
will consist of the gross tumor, cervix, and 
uterus. For vaginal primary cancers, CTV1 
will consist of the gross tumor and cervix 
only. CTV2 will consist of the parametria 
and superior third of the vagina (or half of 
the vagina, if the vagina is clinically 
involved). For vaginal primary cancers, 
CTV2 will consist of the entire vaginal 
length, paravaginal tissue, and parametria. 
CTV3 will include the common, external, 
and internal iliac and presacral lymph nodes. 
It is acceptable for CTV1, CTV2, and/or 
CTV3 to overlap each other. The upper 
border of the CTV3 should not extend above 
the confluence of the common iliac arteries 
with the aorta (i.e., aortic bifurcation), and 
should begin no lower than superior border 
of L5. The nodal CTV (CTV3) will be 
obtained by ensuring an approximately 7 mm 
margin around the vessels, plus extension to 
include any adjacent visible lymph nodes, 
lymphoceles, or pertinent surgical clips. The 
presacral nodes should be contoured until the 
superior border of the S3 vertebral body is 
reached; below this point the nodal volume 
can be separated into two structures. The 
external iliac nodes should be contoured to 
the superior aspect of the femoral head. 
CTV3 should be modified to exclude bone, 
muscle, and bowel.  Patients with vaginal 
primary cancers or involvement of the distal 
third of the vagina by cervical cancer should 
receive inguinal nodal radiotherapy as well. 
The CTV should not extend inferior to the 
ischial tuberosities. 
CTV_4760 
(for SIB schemes 
only) 
CTV to receive 47.6 Gy 
Required 
  
Same as description of CTV_4500 above 
CTV_Boost 
(for SIB schemes 
only) 
CTV to receive 54.0-59.4 
Gy  
Required 
 
Gross pelvic lymph nodes 
ITV_4500 
 ITV to receive 45 Gy 
Contouring is required 
only when ITV 
approach is used. 
Patients should be simulated with both a full 
and empty bladder (i.e., 2 simulation scans). 
CTV1-CTV3 and PTV1-PTV3 should be 
delineated as described above on the plan 

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Brachytherapy (Point-directed) 
The definition of all points (A, B, Bladder, Rectum and Vaginal Surface) will 
be in accordance with the 1985 ICRU Report #38: Dose and Volume 
Specifications for Reporting Intracavitary Therapy in Gynecology. 
 
Brachytherapy (Volume-directed) 
Volume directed brachytherapy can be used with either CT based planning 
(without the aid of an MRI for any fraction), or MRI guidance.  The MRI based 
used for treatment (either the full or empty 
bladder scan), and CTV1 should be 
delineated on both scans. The CTV1 from 
both scans should be fused together to 
generate the ITV_4500. A 7 mm margin 
should be applied to generate PTV4.  
PTV_4500 
PTV to receive 45 Gy 
Required 
Around GTV and CTV1, a 15 mm uniform 
expansion should be used. Around CTV2, a 
10 mm uniform expansion should be used. 
For vaginal primary cancers, the distal and 
radial expansion on CTV2 can be as low as 
5mm. Around CTV3 (and CTV_boost, if 
applicable), a 5 mm uniform expansion 
should be used. These expansions will 
generate PTV1, PTV2, and PTV3, 
respectively. PTV1-3 will be fused to 
generate the PTV. If the ITV approach is 
used, PTV4 should be fused with PTV1-
PTV3 to generate PTV_4500. 
PTV_4500_m03 
PTV - 3 mm from skin 
surface 
Required when 
applicable 
The PTV should be manually or 
automatically trimmed up to 3 mm from the 
skin surface, if necessary, to spare skin. 
However, the CTV still needs to be included 
entirely within the PTV. 
PTV_4760 
(for SIB schemes 
only) 
PTV to receive 47.6 Gy  
Required 
 
Same as description of PTV_4500 above 
PTV_4760_m03 
(for SIB schemes 
only) 
PTV - 3 mm from skin 
surface 
Required when 
applicable  
 
The PTV should be manually or 
automatically trimmed up to 3 mm from the 
skin surface, if necessary, to spare skin.. 
However, the CTV still needs to be included 
entirely within the PTV. 
PTV_Boost 
(for SIB schemes 
only) 
PTV to receive 54.0-59.4 
Gy  
Required 
5 mm uniform expansion around CTV_Boost 
PTV_Boost_m03 
(for SIB schemes 
only) 
PTV - 3 mm from skin 
surface 
Required when 
applicable  
 
The PTV should be manually or 
automatically trimmed up to 3 mm from the 
skin surface, if necessary, to spare skin. 
However, the CTV still needs to be included 
entirely within the PTV. 

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target delineation can be reused by superimposition in the process of 
contouring on CT, if for subsequent fractions of brachytherapy only CT can be 
used with the applicator in place. No planning margins will be added to the 
CTV. 
  
 
5.2.5 Definition of Critical Structures and Margins  
Note: All structures must be named for digital RT data submission as listed in the 
tables below. The structures marked as “Required” in the table must be contoured 
and submitted with the treatment plan. Structures marked as “Required when 
applicable” must be contoured and submitted when applicable. Resubmission of 
data may be required if labeling of structures does not conform to the standard 
DICOM name listed. Capital letters, spacing and use of underscores must be 
applied exactly as indicated.  
 
Conventional RT (4-field box) 
For a 4-field box treatment without 3D planning, contouring critical structures is 
not required. For 3D plans, critical structures and margins will be the same as for 
IMRT described below. 
 
IMRT 
 
Standard 
Name 
 
Description 
 
Detailed Specification 
GTV 
GTV to receive 27.5 - 30 
Gy 
Required 
Macroscopic tumor (if present) at time of 
brachytherapy 
CTV 
CTV to receive 27.5 - 30 
Gy 
Required 
GTV + whole cervix + presumed extra 
cervical tumor extension  
 
Standard Name 
 
Description 
 
Detailed Specification 
External  
External patient contour 
encompassing all patient 
anatomy with a single 
contour on each slice 
Required 
 
Normal tissues will be contoured on the CT 
simulation scan. The tissue within the skin 
surface and outside all other critical normal 
structures and the PTV should be contoured 
on every slice and designated as “External”.  
NonPTV4500 
All tissue excluding the 
PTV_4500. Generated by 
subtracting the PTV 
receiving a dose 45 Gy 
from External Contour 
Required 
“NonPTV4500” is defined as all tissue 
excluding the PTV_4500, and is generated 
by subtracting the PTV from “External”. 
Bowel Space 
The space that the bowel 
may occupy 
Required 
Bowel Space will be contoured beginning 
from the axial slice situated 1 cm superior to 
the superior-most slice containing PTV (if 
bowel is not present at this level, the bowel 

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contour will start from its most superior 
extent), and will continue to its most inferior 
extent in the pelvis. The distal descending 
colon and sigmoid colon should be excluded 
from the Bowel Space. The Bowel Space 
will include the outermost extent of the 
bowel loops plus any space within the 
abdominal cavity the bowel may occupy. 
Individual loops of bowel should not be 
contoured separately. Bowel Space will be 
outlined on each axial CT slice. Rectum 
should be contoured separately from bowel.  
Rectum 
Rectum 
Required 
 
The outer rectal wall will be contoured and 
filled in, treating the organ as a solid 
continuous structure, and will be defined 
from the level of the sigmoid flexure to the 
anus. 
Bladder 
Bladder 
Required 
 
The outer bladder wall will be contoured and 
filled in, treating the organ as a solid 
continuous structure.    
Bone Marrow 
Bone Marrow 
Required 
 
The outer bone contour will be delineated 
and filled in, treating the bone marrow as a 
solid continuous structure. The regions 
contoured will include the os coxae, L4 and 
L5 vertebral bodies, entire sacrum, 
acetabulae, and proximal femora. The 
caudal-most extent of the bone marrow 
contour should be at the level of the ischial 
tuberosities.  
BoneMarrow_Act 
Active Bone Marrow 
Required 
 
Active or functional BM will be a subset of 
the entire BM volume (delineated in Bone 
Marrow), as determined by 18F-FDG-
PET/CT. Active BM will be defined as the 
sub region of total BM with a standardized 
uptake value (SUV) greater than the mean 
value over the total BM volume. Automatic 
segmentation using commercially available 
software will be used to define the functional 
BM volume, which will be used as an 
avoidance structure for IMRT planning.  For 
Phase II patients, the active bone marrow 
structure can be created by the treating site 
using a provided workflow. For Phase III 
patients, the active bone marrow structure 
will be generated at UCSD and provided to 
sites by IROC. 
Femur_L 
Left femur 
Required 
 
The outer contours of the left femoral head 
will be delineated and filled in, treating each 
as a solid continuous structure. Do not 
include the femoral neck.   

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Brachytherapy 
 
 
*Point-directed brachytherapy 
**Volume-directed brachytherapy 
 
5.2.6 Dose Prescription  
Conventional RT 
For Conventional RT, the prescription dose of 45 Gy at 1.8 Gy/fraction will be 
delivered to the isocenter which is defined as the intersection of the four beams. 
EBRT is preferably given once daily Monday-Friday, for 5 fractions per week. A 
three consecutive day parametrial boost may be optionally given in the sixth 
week.  
 
 
IMRT 
 
Femur_R 
Right femur 
Required 
 
The outer contours of the right femoral head 
will be delineated and filled in, treating each 
as a solid continuous structure. Do not 
include the femoral neck.   
Standard Name 
 
Description 
 
Detailed Specification 
 
 
 
Bladder 
(ICRU reference 
point) 
Bladder 
Required 
 
The outer bladder wall is contoured.  
Calculated at the center (in the superior-
inferior plane on AP view) of a contrast-
filled balloon of a Foley catheter and closest 
to the applicator system on a lateral view, as 
defined by ICRU 38. 
Rectum 
(ICRU reference 
point) 
Rectum 
Required 
 
The outer rectal wall is contoured from 
above the anal sphincter to the level of 
transition into the sigmoid. In accordance 
with ICRU 38, mark the point 0.5 cm 
posterior to the vaginal surface (as 
demarcated by the opaque packing) at the 
midpoint of the applicator system or at the 
level of the flange if no ovoids are used.  
Vaginal_Surf* 
(reference point) 
Optional 
Mark the points at surface of ovoids at mid-
source position. 
Sigmoid** 
 
Optional 
The outer sigmoid wall is to be contoured 
from the recto-sigmoid flexure to 2 cm 
superior to the parametria and the uterus. 
Bowel Space 
Required 
The space that the bowel may occupy. 

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Target Standard 
Name 
Dose (Gy) 
Fraction Size 
(Gy) 
# of Fractions 
Dose Specification 
Technique 
PTV_4500 
45 
1.8 
25 
Exactly 95% of PTV 
receives ≥ 45 Gy 
PTV_4760 (for 
SIB schemes only) 
47.6 
1.7 
28 
Exactly 95% of PTV 
receives ≥ 47.6 Gy 
PTV_boost (for 
SIB schemes only) 
54.0-59.4 
1.93-2.12 
28 
Exactly 95% of PTV 
receives ≥ 54.0-59.4 
Gy 
 
Parametrial Boost 
After the delivery of 45 Gy, at the discretion of the treating physician, a 
parametrial boost of 5.4 Gy at 1.8 Gy/fraction may be delivered to mid-plane 
given by AP/PA fields and the center of the unblocked portion of the field. 
 
Brachytherapy 
In point-directed approach, the doses of 27.5 - 30 Gy and 35 - 40 Gy will be 
delivered to the point A for HDR and LDR, respectively as tabulated in Tables 1 
and 2. The HDR brachytherapy dose can be prescribed to a high-risk clinical 
target volume (CTV) as volume-directed approach, but point A dose must be 
documented.  
 
Table 1 HDR-Point A determined implant or volume directed approach 
Total EBRT 
(Gy)  
# HDR fractions 
HDR Point A 
dose/fraction (Gy) 
Total HDR point 
A dose (Gy) 
Total Point A 
EQD2-Gy10 
45 
4 
7.0 
28.0 
83.9 
45 
5 
5.5 
27.5 
79.8 
45 
5 
6.0 
30.0 
84.3 
47.6 
4 
7.0 
28.0 
86.1 
47.6 
5 
5.5 
27.5 
81.9 
47.6 
5 
6.0 
30.0 
86.4 
 
Table 2 LDR-Point A determined implant 
Total EBRT 
(Gy)  
# LDR fractions 
LDR Point A 
dose/fraction (Gy) 
Total LDR point 
A dose (Gy) 
Total Point A 
dose (Gy) 
45 
1 
35-40 
35-40 
80-85 
45 
2 
17.5-20 
35-40 
80-85 
47.6 
1 
35-40 
35-40 
82.6-87.6 
47.6 
2 
17.5-20 
35-40 
82.6-87.6 
 
In general, HDR insertions should start during the fourth week and be separated 
by a minimum of 48 hours and no more than 2 insertions should be performed per 
week. Iridium-192 is the preferred source for HDR brachytherapy. In LDR point-
directed brachytherapy, if 2 insertions are used they should be separated by a 
minimum of 7 days and maximum of 21 days. If 2 insertions are used, the second 
implant should be completed within three weeks of the completion of external 
beam irradiation. Cesium-137 is the preferred source for LDR brachytherapy. 
External beam radiation and brachytherapy may not be administered on the same 

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day. Radiation therapy must be completed within 60 days of its initiation. All 
brachytherapy sources must be listed on the joint AAPM/IROC Houston Registry 
of Brachytherapy Sources in order to be utilized on NCTN clinical trials 
(http://irochouston.mdanderson.org/RPC/BrachySeeds/Source_Registry.htm ). 
 
5.2.7 Compliance Criteria 
 
Target Volume Constraints and Compliance Criteria 
Conventional RT (4-field box)* 
 
 
*These criteria are applied for 3D plans. 
IMRT (05/30/2017) 
 
 
*Minimum dose is applied to a 54 Gy prescription and maximum dose to a 59.4 Gy 
prescription. 
 
Parametrial Boost 
No criteria are applied for parametrial boost. 
 
Note: Dose to CTV is cumulative EQD2 (EBRT + Brachytherapy).  
 
Normal Structure Constraints and Compliance Criteria 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
CTV_4500 
DMin (Gy) 
≥ 41.85 
≥ 40.5 
< 40.5 
DMax (Gy) 
≤ 48.15 
≤ 51.75 
> 51.75 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
PTV_4500 
D95% (Gy) 
≥ 45 
≥ 43.65 
< 43.65 
D97% (Gy) 
≥ 43.65 
≥ 40.5 
< 40.5 
D99% (Gy) 
≥ 40.5 
≥ 39.6 
< 39.6 
DMax (Gy) 
≤ 51.75 
≤ 54 
> 54 
CTV_4760 
DMin (Gy) 
≥ 44.27 
≥ 41.85 
< 41.85 
DMax (Gy) 
≤ 63.56 
≤ 68.31 
> 68.31 
PTV_4760 
D95% (Gy) 
≥ 47.6 
≥ 45 
< 45 
D97% (Gy) 
≥ 46.17 
≥ 41.85 
< 41.85 
D99% (Gy) 
≥ 42.84 
≥ 40.5 
< 40.5 
DMax (Gy) 
≤ 68.31 
- 
> 68.31 
CTV_Boost* 
DMin (Gy) 
≥ 50.22 
≥ 43.65 
< 43.65 
DMax (Gy) 
≤ 63.56 
≤ 68.31 
> 68.31 
PTV_Boost* 
D95% (Gy) 
≥ 54 
≥ 51.75 
< 51.75 
D97% (Gy) 
≥ 52.38 
≥ 47.6 
< 47.6 
D99% (Gy) 
≥ 48.6 
≥ 45 
< 45 
DMax (Gy) 
≤ 68.31 
- 
> 68.31 
Dose maximum should occur within the PTV. 

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Conventional RT  
No criteria for normal structure doses are applied for the Conventional RT. 
 
IMRT 
 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Bladder 
D50% (Gy) 
≤ 45 
≤ 55 
> 55 
DMax (Gy) 
≤ 50 
≤ 57.5 
> 57.5 
Rectum 
D50% (Gy) 
≤ 45 
≤ 54 
> 54 
D60% (Gy) 
≤ 30 
≤ 50 
> 50 
DMax (Gy) 
≤ 50 
≤ 55 
> 55 
Bowel 
D30% (Gy) 
≤ 40 
≤ 50 
> 50 
DMax (Gy) 
≤ 59.4 
≤ 62.1 
> 62.1 
V45 (cc) 
≤ 200 cc 
≤ 250 cc 
> 250 cc (or 110% 
of KBP prediction, 
if KBP prediction is 
> 250 cc) 
Bone Marrow 
 
DMean (Gy) 
≤ 27 
≤ 29 
> 29 (or 105% of 
KBP prediction, if 
KBP prediction is > 
29 Gy) 
V10 (%) 
≤ 85.5% 
≤ 90% 
> 90% (or 105% of 
KBP prediction, if 
KBP prediction is > 
90%) 
V20 (%) 
≤ 66% 
≤ 75% 
> 75% (or 105% of 
KBP prediction, if 
KBP prediction is > 
75%) 
Bone Marrow Act 
DMean (Gy) 
≤ 28.5 
≤ 30 
> 30 (or 105% of 
KBP prediction, if 
KBP prediction is > 
30 Gy) 
V10 (%) 
≤ 90% 
≤ 90% 
> 90% (or 105% of 
KBP prediction, if 
KBP prediction is > 
90%) 
V20 (%) 
≤ 70% 
≤ 75% 
> 75% (or 105% of 
KBP prediction, if 
KBP prediction is > 
75%) 
Femurs 
D15% (Gy) 
≤ 30 
≤ 50 
> 50 
DMax (Gy) 
≤ 50 
≤ 55 
> 55 
 
EBRT+ Brachytherapy 
 
Point-Directed Brachytherapy 
 

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Name of Structure 
Dosimetric parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Point A (point-
directed) 
DMin (Gy) 
80-90 
> 90 
< 80 
Bladder 
ICRU Point 
≤ 90 
≤ 95 
> 95 
Rectum 
ICRU Point 
≤ 75 
≤ 80 
> 80 
Vaginal Surface 
ICRU Point 
≤ 150 
≤ 200 
> 200 
 
Volume-Directed Brachytherapy 
 
Name of Structure 
Dosimetric parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
CTV (Volume-
Directed) 
D90% (Gy) 
80-90 
> 90  
< 80 
Bladder 
D2cc (Gy)  
≤ 90 
≤ 95 
> 95 
Rectum 
D2cc (Gy 
≤ 75 
≤ 80 
> 80 
Sigmoid 
D2cc (Gy) 
≤ 75 
≤ 80 
> 80 
Vaginal Surface 
D2cc (Gy) 
≤ 150 
≤ 200 
> 200 
 
Note: Doses to critical structures are cumulative EQD2 (EBRT + Brachytherapy). If CT is used 
for planning it is recommended to keep the maximum bowel dose < 25% of the brachytherapy 
prescription dose.  
 
For point-directed brachytherapy, the dose to points A and B, the rectal reference 
point dose, bladder reference point dose, and vaginal surface reference point dose, 
and central axis isodose curve must be calculated and reported. Please follow the 
definitions in ICRU 38. 
 
For volume-directed brachytherapy, uniform dose volume reporting according to 
the GEC ESTRO guidelines is required (Kunos, 2012; Balter). For each fraction 
the following parameters should be recorded:  
• TRAK  
• D100 for GTV, CTV  
• D90 for GTV, CTV  
• D50 for CTV  
• V100 for CTV 
• D2cc of the bladder, rectum and sigmoid, (converted to EQD2 doses per formula  
EQD2= D X [(d + α/β)/ (2 + α/β)); use α /β=3. 
• ICRU bladder and ICRU rectal points  
 
Delivery Compliance Criteria 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Overall Treatment 
time 
≤ 60 days 
≤ 66 days 
> 66 days 
 
5.2.8 Treatment Planning Priorities and Instructions 

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Critical Structures and target priorities are listed in order of decreasing 
importance: 
 
EBRT 
1. Bowel 
2. Bone Marrow 
3. Rectum 
4. Bladder 
5. Femurs 
If max dose constraints are exceeded, the following solution can be entertained: 
For conventional RT with 3D planning, use the field in field technique to decrease 
hot spots and to reduce the bowel dose when MLCs are used. 
 
Brachytherapy 
1. Rectum 
2. Bladder 
3. Sigmoid 
If dose constraints of critical structures are exceeded, the following solution can 
be entertained: 
For volume-directed brachytherapy, if the treatment planning system provides a 
manual optimization option, optimize the plan manually to reduce dose to the 
critical structures as long as D90 of CTV meets target volume constraints. 
 
5.2.9 Dose Calculations 
The primary data set for dose calculations is CT. In the case in which contrast is 
present during the treatment planning CT, the density of the contrast should be 
overridden to a representative background electron density. Heterogeneity 
corrections should be applied. The dose grid size should be ≤ 3 mm in all 
directions, which means that the CT slice thickness should be ≤ 3 mm. 
 
5.2.10 Patient Specific QA 
For IMRT plans, patient specific QA is required (Section 5.7). QA is performed 
by delivering the plan onto a phantom and measuring the dose using an ion 
chamber array or other 2D/3D device. Measured dose distribution will be 
compared to planned dose distribution using a Gamma criterion of 3% dose 
difference and 3 mm distance to agreement. The pass rate should be at least 90% 
measured for the entire plan. 
 
5.2.11 Daily Treatment Localization/IGRT  
Conventional RT (4-field box) 
Skeletal imaging using an electronic portal imaging device (EPID) or film portal 
imaging should be performed at least weekly to verify setup accuracy. Image-
guided radiotherapy (IGRT)) technique such as orthogonal kV or volumetric 
imaging such as Cone Beam CT (CBCT) can also be used for weekly setup 
verification. However, these systems do not directly verify patient position, and 
recommendations of the AAPM for periodically checking correspondence of the 
imaging and treatment reference points must be followed.   

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IMRT 
Daily IGRT is required for this protocol when the IMRT treatment technique is 
used. Any form of online imaging is acceptable, such as MV or kV planar 
imaging, MVCT or MV CBCT, kV CBCT, CT on rails, etc. The AAPM 
recommendations stated above for verifying coincidence of the imaging and 
treatment beam reference points must be adhered to for daily use of IGRT. At the 
time of simulation, it is recommended to place the isocenter along the patient’s 
midline 1.5 cm caudal to the inferior border of the sacroiliac joint. In general, the 
CT or CBCT will be used for setup verification using bone landmarks only and 
not for soft tissue alignment. Small soft tissue shifts (≥3 mm) are acceptable. 
Otherwise, the treating physician may elect to postpone treatment or re-simulate.  
 
5.2.12 Re-planning 
Re-planning (such as to account for changes in tumor volume) is allowed. If re-
planning is necessary, the new treatment plan should meet the same criteria as the 
initial plan, as if the new plan were delivered for the entire treatment course. The 
new treatment plan should be submitted for central review according to the same 
process as the initial plan.  
 
5.3 
Expected Toxicity from Radiation Therapy  
Nausea and emesis may occur after extended field irradiation, especially after 
the first few treatments. It is recommended but not required that patients be 
pre-medicated with a serotonin antagonist before each daily treatment. 
Intractable nausea and emesis beyond the first few days should arouse 
suspicion of recurrent tumor or other causes of bowel obstruction, as it is rarely 
seen as a result of radiation alone. Consider stool sample for Clostridia difficile 
toxin. Increased bowel activity with diarrhea can be expected fairly routinely 
after the first two weeks of pelvic and para-aortic radiation. It is recommended 
that instructions be given to patients for a low fiber, low-fat, soft diet. Most 
patients will require anti-diarrheal medications during therapy. Should 
gastrointestinal toxicity become severe enough to require hospitalization or 
outpatient intravenous fluid replacement, all treatment should be discontinued 
temporarily until the patient’s condition improves. If radiation therapy is 
discontinued, the treating physician must notify the principal investigator 
within 96 hours. The expected adverse effects and the guidelines for treatment 
modifications are described in Section 6.3. 
 
5.4 
Duration of Protocol Treatment 
In the absence of treatment delays due to adverse events, study treatment may 
continue uninterrupted until the completion of therapy or until one of the 
following criteria applies: 
• Intercurrent disease progression; 
• Intercurrent illness that prevents further administration of treatment; 
• Unacceptable adverse event(s); 
• Patient decides to withdraw from the study; or 

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• General or specific changes in the patient's condition that render the 
patient unacceptable for further treatment in the judgment of the 
treating physician. 
 
5.5 
Duration of Protocol Follow-Up 
Patients will be followed for toxicity assessments at the 1-month and 3-months 
follow-up visit (± 7 days) after completion of radio-chemotherapy or until 
death, whichever occurs first. Patients are considered “on-study” regarding the 
tertiary endpoint of 18F-FDG PET/CT metabolic complete response until the 3-
month follow-up visit (± 7 days).  Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event(s). To assess the primary overall survival endpoint, long-
term follow-up will consist of 3-month follow-up contacts for years 1 and 2, 
then every 6 months in years 3, 4, and 5. Patients will be followed for overall 
survival after documentation of disease progression.  
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
Patients should receive full supportive care, including transfusions of blood 
and blood products, supplemental iron, antibiotics, anti-emetics, etc., when 
appropriate at the discretion of the treating physician. Because it has been 
observed that hemoglobin levels below 10-12 g/dL during radiotherapy are 
associated with decreased local control, blood transfusions should be offered to 
and used to treat patients at the discretion of treating physicians prior to or 
during radiotherapy. There should be no radiotherapy treatment delays due to a 
low hemoglobin levels. Trials evaluating epoeitin alpha (Procrit, Epogen) and 
radio-chemotherapy in cervical cancer have indicated that epoeitin alpha may 
be associated with an increased risk for thromboembolism, and thus, may not 
be used in this study.  
 
In particular, patients should be told to be aware of their typical defecation 
pattern. At the first sign that their stools become softer than usual or they have 
any increase in stool frequency over what is normal for them, they should 
begin taking over-the-counter loperamide as directed by their physician(s). 
Patient should understand that if they do not start taking loperamide at the start 
of diarrhea, the diarrhea may become severe and last several days. Persistent 
diarrhea or any evidence of hematochezia should prompt a stool evaluation for 
fecal leukocytes and/or Clostridium difficile toxin & ova/parasite evaluation. 
Diphenoxylate/ atropine prescriptions are permitted. Loperamide will be 
recommended during the study in order to prevent diarrhea that may ultimately 
lead to intravenous infusion of fluids or hospitalizations.  
 
For the administration of loperamide, it is recommended that patients take two 
(2) caplets (4 mg) at the first sign of diarrhea. Patients should continue taking 
one (1) caplet (2 mg) every two hours until they return to their normal pattern 
of bowel movements. They may repeat same doses and frequency if diarrhea 
returns.  During the night, patients may take two (2) caplets every four hours 

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rather than one (1) every two hours. Patients should call their doctor if they 
have any questions about taking loperamide, if they believe they are not 
achieving adequate control of diarrhea, or if they are feeling extremely weak, 
lightheaded, or dizzy (symptoms of dehydration). Side effects of loperamide 
include tiredness, drowsiness, or dizziness. If they experience these side 
effects, they should avoid driving a motorized vehicle or operating machinery. 
Before using any laxative, patients should consult their physician. Patients 
should make an extra effort to drink lots of fluids (several glasses of water, 
fruit juices, soda, soup, etc.) every day while they participate in this study.  
 
Because there is a potential for interaction of triapine with other administered 
drugs through the cytochrome P450 system, the case report form must capture 
the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies. The principal investigator should be alerted if the patient 
is taking any agent known to affect, or with the potential to affect, selected 
P450 isoenzymes. 
 
5.7 
Centralized Quality Assurance and Knowledge-Based Planning Analysis 
 
Sites planning to treat with IG-IMRT on this trial will initially undergo standard 
IMRT credentialing on either a pelvic or head/neck phantom. Once sites are 
credentialed for IG-IMRT they must commit to treating all patients they enroll on 
the protocol with this technique. All IG-IMRT cases will undergo a Pre-Treatment 
Review process to validate the contouring of target and critical normal tissues and 
approve the treatment plan. Anonymized DICOM data for the simulation CT and 
baseline FDG-PET/CT will be transmitted electronically via TRIAD to IROC-
Philadelphia for central review and processing. The active bone marrow structure 
will be created using a commercial planning system and transmitted back to the 
enrolling site’s treatment planning team as an avoidance structure. For Phase II 
patients, the active bone marrow structure can be created by the treating site using 
a provided workflow. For Phase III patients, the active bone marrow structure will 
be generated at UCSD and provided to sites by IROC. The reference IG-IMRT 
plan will then be transmitted centrally and IROC-Philadelphia will run the KBP 
algorithm on the resulting plans to measure potential planning improvements. 
Feedback from the KBP model will be provided to the enrolling site’s treatment 
planning team.  We will assess the following metrics: bowel V45, total and 
functional bone marrow V10 and V20 (See section 8.3 for specific requirements).  
 
5.8 Pelvic nodal boost for 3D Radiotherapy  
 
A pelvic nodal boost is allowed for patients receiving 3D radiotherapy, at the 
discretion of the treating radiation oncologist. Nodal involvement is defined as 
any pelvic or common iliac nodes if they are either PET positive or their short 
axis diameter is > 15mm on CT and/or MRI or if nodes are found to be 
histologically positive on surgical sampling. Dose to the nodal boost volume 
should not exceed 10 Gy, with a total dose to the sidewall not to exceed 65 Gy at 
midplane. Fractions of 1.8-2 Gy can be used. If nodal involvement is documented, 

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fields with up to 2.0 cm margin around the gross nodal disease as seen on the CT 
scan, MRI or PET is recommended. Nodal boost fields can be delivered via 
conformal fields. The nodal boost can occur after completion of EBRT and in 
between the brachytherapy insertions. 
 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT (05/30/2017) 
Treatment modifications will consist of either cycle delay and/or dose reduction as noted 
below.  Hematologic treatment decisions will be based on the absolute neutrophil count 
(ANC) on day of treatment or no greater than 72 hours prior to planned treatment. No 
cisplatin will be administered unless pre-treatment counts demonstrate an ANC ≥ 1,500/ 
µL and platelet count is ≥ 75,000 / µL.  Chemotherapy will be held until these values are 
exceeded.  External radiation should continue while chemotherapy us being held.  Please 
refer below to specific toxicities and dose modifications.   
 
Chemotherapeutic 
Starting Dose Level 
25% Reduction Dose Level 
Cisplatin 
40 mg/m2 
30 mg/m2 
  
6.1 
Triapine (3-AP) Dose Modifications (05/30/2017) 
Patients may receive dexamethasone 4 mg IV prior to each triapine infusion. 
Patients may pre-medicate with antiemetic as needed for nausea or vomiting 
with any previous dose of triapine. Acute reactions to triapine, occurring either 
during the infusion or soon after the infusion is completed, have been observed 
primarily at doses ≥ 140 mg/m2 infused IV over 2-4 hours, which dose is not 
given in this protocol. At lower doses, the incidence of symptomatic reactions 
is estimated to be < 10%. The reactions include hypoxia (with or without 
dyspnea and with or without associated cough) and hypotension. The cause of 
hypoxia and dyspnea is thought to be an increase in methemoglobin levels, 
which usually resolves quickly (within hours) after the completion of the 
infusion.  Isolated hypoxia without symptoms (usually noticed only as 
cyanosis) may be managed with supplemental oxygen at 2-4 liters/minute by 
nasal cannula.  Chemotherapy will not be administered during a radiation 
therapy delay. 
 
While acute infusion reactions are not anticipated, the reactions include 
hypoxia (with or without dyspnea and with or without associated cough) and 
hypotension (See Table 1 in section 6.1.2 below). 
• Patients developing dyspnea at rest should undergo pulse oximetry 
throughout the rest of the triapine infusion. Isolated hypoxia (<92%) may 
be managed with supplemental oxygen, 2 liters/minute by nasal cannula. 
If pulse oxygen saturation does not return to > 92% with oxygen 
supplementation, triapine should be stopped and the patient should not 
receive additional triapine treatment on study. 
• Patients developing dyspnea at rest or hypotension (systolic blood 
pressure <85 mm Hg) should have the triapine administration stopped and 
should not receive additional triapine treatment on study. 
• EKG changes consisting of ST-T wave changes and mild prolongation 
of the QT interval have been observed immediately post-treatment with 

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triapine, and are not an indication to stop treatment unless associated with 
hypoxia or hypotension during triapine infusion.  Patients remaining on 
study following these changes should be undergo repeat EKG testing if 
they develop hypoxia or hypotension. 
 
Should any patient enrolled on the study miss a scheduled triapine dose 
for whatever reason (e.g., as a result of facility closure due to a holiday), 
the patient will be allowed to take the scheduled dose up to a maximum of 
24 hours after that scheduled dose time (preferably not on a day of 
cisplatin infusion). If greater than 24 hours after the scheduled dose time, 
the missed dose may be scheduled as a ‘make-up’ dose during any day of 
radiation in the optional sixth week of radiation. 
 
6.1.1 Schedule for Research Monitoring of Triapine Infusion, Day 1 
(optional for study participants) (05/30/2017) 
Methemoglobinemia is a known side effect of triapine administration (21). 
This clinical trial includes an optional set of peripheral venous blood samples 
to be collected (2 ml [<1 teaspoon]) in heparinized arterial blood gas syringes 
and put on ice for methemoglobin determination per institutional guideline 
(e.g., blood bank guidelines) as a possible surrogate biomarker for therapeutic 
effect of triapine. Sampling will occur on day 1 of the first cycle, before 
triapine dosing (t=0-) and 1, 3, 5 and 24 hours after triapine administration. 
Methemoglobin will be reported as a percentage of total hemoglobin as 
before (2). Pulse and respiratory rate monitoring is recommended. It is 
recommended that the methemoglobinemia antidotes, methylene blue or 
ascorbic acid, be available during the time of triapine infusion (21).  If the 
hour 5 methemoglobinemia level results at greater than 6%, the subsequent 
hourly methemoglobin assays should be obtained and resulted until a decline 
in methemoglobin percentage is documented AND the methemoglobin 
percentage is < or = 6%. 
 
Frequency 
 
Prior to infusion 
After infusion 
Once predose (t = 0-) 
1, 3, 5, and 24 hours 
 
6.1.2 Schedule for Clinical Monitoring of Triapine Infusion, other than 
Day 1 
If the patient is symptomatic or has hypoxia (< 92%) requiring oxygen, obtain 
a “spot” methemoglobin level and repeat the level prior to next triapine dose to 
determine whether dose modification or further treatment is indicated. 
Supportive care should be provided as clinically indicated (See Table 1). 
 
If no changes in O2 saturation are seen during triapine treatments, on 
subsequent days the patient may be discharged after radiation per the treatment 
schedule. If patients had prolonged methemoglobinemia or hypoxia requiring 
dose adjustment on day 1, please follow the monitoring schema (see Table 1) 
until stable.  

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Table 1 – Clinical Management of hypoxia or prolonged methemoglobinemia 
(05/30/2017) 
Prolonged Methemoglobinemia / 
Hypoxia Monitoring 
 
Pulse, respiratory rate, O2 
saturation (pulse oximeter) 
All patients 
EKG 
Only if patient is hypotensive or hypoxic 
 
Please note that it is the trend in the O2 saturation that is of importance. Since 
pulse oximetry is known to be unreliable in the presence of significant 
methemoglobinemia, clinical importance should not be given to a single pulse 
oximetry value alone. In any case where there is significant doubt, arterial 
blood gases to assess O2 saturation should be obtained. 
 
6.1.3 Treatment modifications for triapine methemoglobinemia in clinical 
trial protocols: 
It is expected that all patients will show a transient rise in methemoglobin (up 
to 3-5%, maximum 15%) while on study, but unless accompanied by hypoxia, 
by clinical symptoms (e.g., dyspnea, tachypnea), or by failure of 
methemoglobin levels to drop to <5% within 24 hours, NO changes to 
treatment or dose are required. For patients not fitting any of these patterns, the 
following guidelines should be followed: 
 
If methemoglobinemia is asymptomatic, methemoglobin levels are 
<15%, and unaccompanied by hypoxia, treat without change in triapine 
dose. 
 
If oxygen saturation is <92%, or methemoglobin levels are >15%, or 
patient has moderate to severe symptoms, then monitor the patient 
hourly and provide appropriate supportive care. Discharge the patient 
when symptoms are tolerable and O2 saturation normalizes (>92%). At 
the next triapine infusion, reduce the triapine dose to 20 mg/m2 and 
each subsequent treatment(s). 
 
If a patient had moderate to severe, but rapidly reversible (i.e., over 
several hours) symptoms NOT requiring hospitalization, then reduce 
the triapine dose to 20 mg/m2 for subsequent treatment(s). If 
methemoglobinemia (>15%) does not promptly recover (e.g., within a 
few hours) or symptoms do not rapidly reverse at the 20 mg/m2 dose 
level, then stop subsequent triapine treatment(s) and pursue further 
appropriate clinical evaluations.  
 
Treatment options for methemoglobinemia could include methylene blue, 1-2 
mg/kg IV over five minutes. However, methylene blue is contraindicated in 
patients with glucose-6-phosphate deficiency, since its pharmacologic action as 
an electron carrier in the reduction of methemoglobin is itself dependent on the 

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generation of NADPH by G6PD through the hexose monophosphate shunt. 
Thus, methylene blue may be at best ineffective in such patients and may have 
the potential to complicate the clinical situation by provoking hemolysis, 
although this association is less clear.  In situations where the use of methylene 
blue may be contraindicated (e.g., in those individuals who are in the high-risk 
group (patients of African, Asian or Mediterranean origin/ancestry), who may 
have had a false negative G6PD deficiency test), the successful use of ascorbic 
acid (1000 mg IV q6h) has been described. 
 
6.1.4 Grade 3/4 toxicities thought to be attributed to triapine alone have been 
uncommon in previous trials.  Please contact the study principal investigator if 
you believe the patient has a grade 3 or 4 toxicity related to triapine alone.  The 
study principal investigator will refer to the CAEPR (section 7.3) as well as the 
patients other toxicities in an attempt to determine if the reported toxicity is 
related to triapine.  If thought to be related to triapine, the investigator will hold 
the next dose and reevaluate the patient prior to the following scheduled dose of 
triapine. Patients that have had resolution of their toxicity to grade 1 or 2 should 
receive the next dose of triapine. (05/30/2017) 
 
6.2 
Cisplatin Dose Modifications (05/30/2017) 
Cisplatin dose modifications will be made according to observed symptoms.  
Chemotherapy will not be administered during a radiation therapy delay. 
 
6.2.1 Gastrointestinal Adverse Effects:  (e.g., nausea and vomiting) 
Prophylactic antiemetics should be used as described above in section 5.1.1. 
Please follow local institutional standards for patients that develop nausea and 
vomiting in spite of the use of prophylactic measures. For persistent grade 4 
nausea and vomiting despite optimal medical management, hold cisplatin until 
reduced to grade 1 and reduce cisplatin by 25%.  For patients with recurrence 
of this following dose reduction, cisplatin must be discontinued. (05/30/2017) 
 
6.2.2 Renal Adverse Effects:  If creatinine rises to greater than 2.0 mg/dL, 
discontinue cisplatin therapy. Selective renal tubular defects are sometimes 
observed. Documented hypomagnesemia will be treated with increased 
magnesium supplementation per institutional protocol.  Hypocalcemia and 
hypokalemia are common and potentially severe. Replacement of potassium 
and calcium are usually effective per institutional protocol. Severe tubular 
effects may require chronic replacement therapy. Diagnostic tests for other 
etiology of hypocalcemia (GI or metabolic) should be considered per 
institutional protocol. 
 
6.2.3 Neurotoxicity Adverse Effects: For grade 2, reduce cisplatin dose by 
25%. For grade 3-4, discontinue cisplatin therapy.  
 
6.2.4 Tinnitus or hearing changes:  For grade 2 hold cisplatin until 
neuropathy resolves to grade 1 and dose reduce by 25%. Discontinue cisplatin 

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if tinnitus or hearing changes do not resolve within 21 days. Discontinue 
cisplatin for grade 3 or 4 toxicity. (05/30/2017) 
 
6.2.5 Hematologic Adverse Effects: Cisplatin should be withheld from 
patients with an absolute neutrophil count less than 1500 / mm3 or platelet 
count less than 75,000 / mm3. Cisplatin infusions should be delayed week-by-
week until these levels are exceeded.  Please refer to the table below for 
specific hematologic toxicities and recommended modifications. (05/30/2017) 
 
HEMATOLOGIC 
TOXICITY 
PARAMETER 
DOSE 
MODIFICATION 
Anemia 
Not applicable for this 
protocol 
No dose modifications 
for anemia. Please refer 
to section 5.6 for 
additional details.  
Febrile Neutropenia or ANC 
First occurrence of febrile 
neutropenia (grade 3 or 4) 
- OR – ANC < 500 / µL 
lasting greater than 7 
days 
Hold cisplatin x 1 week 
and repeat CBC.  If 
ANC has resolved to 
grade1 (>1500 / µL), 
then dose reduce by 25% 
and treat. If ANC has 
not resolved to grade 1 
then discontinue 
cisplatin. 
Febrile Neutropenia or ANC 
Second occurrence 
Discontinue cisplatin. 
ANC alone 
Uncomplicated ANC < 
500 / µL lasting greater 
than 7 days without 
infection or fever  
Dose reduction not 
indicated, but hold 
therapy until ANC 
resolves to grade 1  
Platelets without bleeding 
Grade 3 uncomplicated 
Hold until platelets > 
75,000 /µL and resume 
at current dose level 
without modification 
Platelets with bleeding 
First occurrence grade 4 
thrombocytopenia –OR – 
grade 3 
thrombocytopenia with 
bleeding 
Hold cisplatin x 1 week 
and repeat CBC.  If 
platelet count has 
resolved to > 75,000 / 
µL, then dose reduce by 
25% and treat. If 
thrombocytopenia has 
not resolved to grade 1, 
then discontinue 
cisplatin 
Platelets with bleeding 
 
Discontinue cisplatin 
 
6.2.6 Other non-hematologic toxicity:  For any other non-specific grade 3 or 
4 toxicity, other than fatigue, hold cisplatin until toxicity resolves to grade 1 
and then resume at same dose.  If toxicity does not resolve to grade 1 within 21 
days, discontinue cisplatin. (05/30/2017) 

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6.2.7 External-beam pelvic radiation and triapine infusions should continue 
while any or all courses of cisplatin are withheld. For delays in cisplatin 
infusion greater than two weeks, cisplatin may not be continued at the joint 
discretion of the patient’s treating physicians and the principal investigator 
(face sheet). 
 
6.3 
Radiation Dose Delivery Modifications 
 
6.3.1 Radiation therapy may only be suspended secondary to a significant 
adverse event at the joint discretion of the patient’s treating physicians and the 
study chair (face sheet). The study chair must be notified in writing (e.g., 
email) of dose modifications or treatment modality modifications for external 
beam radiation therapy or for brachytherapy. 
 
6.3.2 Because it has been observed that hemoglobin levels below 10-12 g/dL 
during radiation therapy are associated with decreased local control, blood 
transfusions should be offered to patients and used to treat patients at the 
discretion of treating physicians prior to or during radiotherapy per 
institutional protocol. There should be no radiation therapy treatment delays 
due to a low hemoglobin levels. Published results evaluating epoeitin alpha 
(Procrit, Epogen) and radiochemotherapy in cervical cancer have indicated that 
epoeitin alpha may be associated with an increased risk for thromboembolism, 
and therefore, may NOT be used in this study. 
 
6.3.3 Hematologic Adverse Events: Hematologic toxicities are seen 
infrequently unless pelvic radiation occurs with chemotherapy. A complete 
blood count should be obtained weekly during radiochemotherapy. If the 
absolute neutrophil count falls to less than 500 / mm3 or platelet count falls to 
less than 25,000 / mm3, radiation therapy may be temporarily withheld to allow 
recovery above these levels at the discretion of the treating physician. 
 
6.3.4 Gastrointestinal Adverse Events: Nausea and vomiting are rather 
unusual after pelvic radiation. Antiemetics may be given when symptoms 
occur or may be given prophylactically prior to treatment per institutional 
protocol. Intractable nausea or vomiting is rarely seen with pelvic radiation 
alone and is usually the result of another process, i.e. bowel obstruction. 
Increased bowel activity with diarrhea usually can be controlled with low fiber, 
low fat, bland diets and antidiarrheal medications. Should gastrointestinal 
toxicity become severe, hospitalization may be required at which time the 
treatment may be interrupted temporarily until the patient’s condition 
improves. 
 
6.3.5 Genitourinary Adverse Events: Acute toxicity of the urinary tract is 
manifested by cystitis. Maintaining high fluid intake is important. Bladder 
antispasmodics, analgesics and antibiotics are recommended per institutional 
protocol. Hematuria is not usually seen with acute cystitis and suggests bladder 

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invasion by tumor. Acute vulvovaginitis is seen when the pelvic fields extend 
inferiorly to include the vulvoperineal area. Treatment of acute vulvoperineal 
reaction may require warm saline soaks, wearing loose clothing and keeping 
the area dry using a hair dryer. Topical steroids, antibiotics, creams, and 
treatment interruption may be necessary per institutional protocol. 
 
6.3.6 Cutaneous Skin Toxicity Adverse Events:  With the use of megavoltage 
external beam radiation therapy, skin reactions in the treatment field are 
infrequent but are more likely to develop if sites such as the inguinal area, 
vulva, and the perineum are extensively within the radiation fields. During 
radiation therapy, mild irritation and redness of the skin may occur within the 
radiation fields. Some patients may experience more intense skin reaction such 
as dry or moist desquamation depending upon the energy of the megavoltage 
beam, number of fields used per day, need to cover distal vagina and therefore 
flashing perineum and use of chemotherapy. Hair loss in the pubic area may 
occur which can be permanent. Late subcutaneous fibrosis, telangiectasia, and 
skin atrophy are uncommon sequelae. Almost all patients with vulvar/perineal 
skin in the treatment fields may expect to develop acute moist desquamation 
during the course of external beam radiation therapy. 
 
Acute skin reactions may be treated according to institutional preferences. 
Aquaphor or steroid creams may be used for CTCAE v4 grade 1-2 reactions 
and it is not necessary to interrupt the radiation therapy. For CTCAE v4 grade 
3-4 skin reactions when generalized macular, papular or vesicular eruptions 
have developed, or there is generalized exfoliative or ulcerative dermatitis in 
the treatment fields, radiation therapy may be interrupted, but this should be 
avoided. Treatment may require symptomatic management of pain, use of 
warm saline soaks, vitamin A&D ointment, wearing loose clothing, and 
keeping the area dry according to institutional protocol. Radiation therapy 
should be resumed as soon as the skin reactions have improved. The principal 
investigator should be notified within 96 hours of any grade 4 toxicity. 
 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS (05/30/2017) 
 
7.1 
Protocol Agents 
 
Investigational Agents 
The investigational agent administered in NRG-GY006 is triapine, which is being 
made available under an IND sponsored by DCTD, NCI.  For patient on Arm 2 
receiving triapine and cisplatin, determination of whether an adverse event meets 
expedited reporting criteria, see the reporting table in Section 7.5.2.1 of the 
protocol. 
 
Triapine:  IND #_68338; IND Sponsor: DCTD/NCI 
 
Commercial Agents 

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The commercial agent in NRG-GY006 is cisplatin.  For patients on Arm 1 
receiving cisplatin alone, determination of whether an adverse event meets the 
expedited reporting criteria, see the reporting table in Section 7.5.2.2 of the 
protocol. 
 
7.2 
Adverse Events and Serious Adverse Events 
 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 for CTEP-AERS (CTEP Adverse Event Reporting 
System) CAERs reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Therefore, an AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) 
product (attribution of unrelated, unlikely, possible, probable, or definite). 
(International Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of 
protocol treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, 
the pregnancy of a study participant must be reported via CTEP-AERS in an 
expedited manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Triapine® (NSC 663249) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events 
that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 182 patients. Below is the CAEPR 
for Triapine®. 
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 

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investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 
Version 2.5, June 6, 20131 
 
 Adverse Events with Possible  
 Relationship to Triapine® 
 (CTCAE 4.0 Term) 
[n= 182] 
 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
(formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Blood and lymphatic system 
disorders - Other 
(methemoglobinemia) 
 
 Blood and lymphatic system disorders - 
Other (methemoglobinemia) (Gr 2) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
 
 
Hemolysis 
 Hemolysis (Gr 2) 
CARDIAC DISORDERS 
  
 
Cardiac disorders - Other 
(cyanosis) 
 
 Cardiac disorders - Other (cyanosis) 
(Gr 2) 
 
 
Left ventricular systolic 
dysfunction 
  
GASTROINTESTINAL DISORDERS 
  
 
Colitis 
 
 Colitis (Gr 2) 
 
Constipation 
 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever 
 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased  
(Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
Electrocardiogram QT corrected 
interval prolonged 
 
 Electrocardiogram QT corrected interval 
prolonged (Gr 2) 
 
Investigations - Other 
(decreased bicarbonate) 
 
 Investigations - Other (decreased 
bicarbonate) (Gr 2) 
 
Investigations - Other (elevated 
ST and T wave changes) 
 
 Investigations - Other (elevated ST and T 
wave changes) (Gr 2) 

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Lipase increased 
 
 Lipase increased (Gr 2) 
 
Lymphocyte count decreased 
 
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased  
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
White blood cell 
decreased 
 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypercalcemia 
 
 Hypercalcemia (Gr 2) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Myalgia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Hypoxia 
 
 Hypoxia (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
Hypertension 
 
 Hypertension (Gr 2) 
 
Hypotension 
 
 Hypotension (Gr 2) 
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. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Also reported on triapine trials but with the relationship to triapine still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(monocytosis); Blood and lymphatic system disorders - Other (thrombotic microangiopathy (e.g., 
thrombotic thrombocytopenia purpura [TTP] or hemolytic uremic syndrome [HUS])); Disseminated 
intravascular coagulation; Leukocytosis; Spleen disorder 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (cardiovascular edema); Cardiac 
disorders - Other (premature ventricular contraction); Myocardial infarction; Palpitations; Pericardial 
effusion; Restrictive cardiomyopathy; Sinus tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ear congestion); Ear and 
labyrinth disorders - Other (hyperacusis); Ear pain; Hearing impaired; Middle ear inflammation; Tinnitus; 
Vertigo 
EYE DISORDERS - Dry eye; Watering eyes 

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GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Dry mouth; Dysphagia; Esophagitis; 
Flatulence; Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other (leukoplakia 
of the mouth); Gastrointestinal disorders - Other (mouth ulceration); Gastrointestinal disorders - Other 
(salivary hypersecretion); Gastrointestinal disorders - Other (steatorrhea); Gastrointestinal disorders - 
Other (stool discoloration); Gastrointestinal disorders - Other (tongue discoloration); Hemorrhoids; Ileus; 
Oral hemorrhage; Pancreatitis; Rectal hemorrhage; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS – Death NOS; Edema face; 
Edema limbs; Flu like symptoms; General disorders and administration site conditions - Other 
(extravasation); Infusion related reaction; Malaise; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatomegaly); Hepatobiliary 
disorders - Other (jaundice); Hepatobiliary disorders - Other (liver tenderness) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; CPK increased; Cholesterol high; 
GGT increased; INR increased; Investigations - Other (BUN increased); Investigations - Other (C-
reactive protein increased); Investigations - Other (lactate dehydrogenase increased); Investigations - 
Other (NPN increased); Investigations - Other (PT decreased); Investigations - Other (sedimentation 
rate increased); Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; 
Iron overload; Metabolism and nutrition disorders - Other (hypoproteinemia); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; 
Bone pain; Chest wall pain; Generalized muscle weakness; Musculoskeletal and connective tissue 
disorder - Other (hypertonia); Musculoskeletal and connective tissue disorder - Other (leg cramps); 
Musculoskeletal and connective tissue disorder - Other (myoglobin); Musculoskeletal and connective 
tissue disorder - Other (twitching); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Amnesia; Cognitive disturbance; Depressed level of 
consciousness; Dysesthesia; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Nervous 
system disorders - Other (cerebellar toxicity); Nervous system disorders - Other (reflexed decreased); 
Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; 
Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delayed orgasm; Delirium; Depression; Insomnia; 
Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; Urinary 
frequency; Urinary tract pain; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Genital edema; Vaginal 
hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Apnea; Epistaxis; Hiccups; Laryngospasm; Pleural effusion; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hirsutism; 
Hyperhidrosis; Photosensitivity; Pruritus; Skin and subcutaneous tissue disorders - Other (skin nodule); 
Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hematoma; Phlebitis; Thromboembolic event; Vascular disorders - Other 
(pallor); Vascular disorders - Other (vasodilation) 
 
Note: Triapine® 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. 
 
7.4 
Adverse Events for Commercial Study Agents (05/30/2017) 
Refer to the package insert for detailed pharmacologic and safety information 
 
List of adverse events for cisplatin: 
Adverse effects: Leukopenia, thrombocytopenia, anemia, nausea, vomiting, 
nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte imbalance, 

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hypocalcemia, hypomagnesemia, aminoglycoside, ocular toxicity and allergic 
reactions. 
. 
Infrequent: Cardiac abnormalities, anorexia, elevated SGOT, rash, alopecia, and 
acute myeloid leukemia. 
. 
NOTE: Aminoglycoside antibiotics given before, with, or after cisplatin may 
potentiate renal toxicity and should be avoided whenever possible. Severe renal 
toxicity can be largely avoided by induction of a diuresis before, during and after 
treatment.  
Mild renal dysfunction is a common complication (10%) of chronic therapy and 
may require discontinuation of therapy if BUN > 30mg/dl or creatinine > 2.0 
mg/dl develop.  
. 
*See FDA- approved package insert for a comprehensive list of adverse events 
associated with cisplatin. 
 
7.5 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the 
reporting table below will be reported via the CTEP Adverse Event Reporting 
System, CTEP-AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies 
NRG requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced 
that involve radiation therapy only. These events must be reported via the CTEP-
AERS radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification 
must be made to the NRG Regulatory Affairs by phone at 215-854-0770. An 
electronic report must be submitted immediately upon re-establishment of the 
Internet connection. 
 
7.5.1 Expedited Reporting Methods 
• 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour 
notification is electronically submitted within 24 hours of learning of the 
adverse event. Each CTEP-AERS24-hour notification must be followed 
by a complete report within 3 days. Supporting source documentation is 
requested by NRG as needed to complete adverse event review.  When 
submitting supporting source documentation, include the protocol number, 
patient ID number, and CTEP-AERS ticket number on each page, and fax 
supporting documentation to the NRG Regulatory Affairs at 215-854-
0716. 

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• 
A serious adverse event that meets expedited reporting criteria outlined in 
the AE Reporting Tables but is assessed by the CTEP-AERS as “an action 
not recommended” must still be reported to fulfill NRG safety reporting 
obligations. Sites must bypass the “NOT recommended” assessment; the 
CTEP-AERS allows submission of all reports regardless of the results of 
the assessment. 
 
7.5.2 Expedited Reporting of Requirements for Adverse Events 
 
7.5.2.1 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under a CTEP 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 CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE. 

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7.5.2.2 Phase 1, 2 and 3 Studies:  Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under a non-IND/IDE within 30 
Days of the Last Administration of the Commercial 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 commercial agent(s)/intervention  
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 NRG via CTEP-AERS 
within 24 hours of learning of the AE, followed by a complete report within 3 calendar days of the initial 24-hour report. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
24-Hour 3 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
 
1Serious adverse events that occur more than 30 days after the last administration of commercial agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
• 
Grade 1 and 2 AEs resulting in hospitalization or prolongation of hospitalization 
    2 For 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. 
 

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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 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For 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. 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review 
Board (IRB) or Research Ethics Board (REB) responsible for oversight of the 
patient according to institutional policy. 
 
7.5.4 Secondary Malignancy  
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 during or subsequent to 
treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. In 
addition, secondary malignancies following radiation therapy must be reported via 
CTEP-AERS. Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting mechanisms 
outlined in each protocol.  
 
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 reporting via CDUS unless otherwise specified. 
 
7.5.5 Routine Adverse Event Reporting  
For studies using investigational agents, the NRG Statistical and Data 
Management Center-Buffalo Office (SDMC) routinely reports adverse events 
electronically to the CTEP Clinical Data Update System (CDUS Version 3.0).  
The SDMC submits this data quarterly.  The AEs reported through CTEP-AERS 

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will also be included with the quarterly CDUS data submissions. 
 
8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES (17-
FEB-2021)  
 
8.1 
Investigator Registration Requirements  
 
 Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and 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) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.   
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR AP 
A 
AB 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 

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Documentation Required 
IVR 
NPIVR AP 
A 
AB 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
8.2 
Site Registration Requirements 
 
8.2.1 Cancer Trials Support Unit Registration Procedures (17-FEB-2021) 
This study is supported by the NCI CTSU. 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 

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network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the  processing of the 
IRB/REB approval record to be completed: 
o Holds an Active CTEP status; 
o Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
o If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
o Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
o Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
o An active Federal Wide Assurance (FWA) number; 
o An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
Protocol Specific Requirements for NRG-GY006 Site Registration 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site 
must be aligned to an RTI provider. To manage provider associations or to add or remove 
associated providers, access the Provider Association page from the Regulatory section 
on the CTSU members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation. 
Sites must be linked to at least one Imaging and Radiation Oncology Core (IROC) 
provider to participate on trials with an RTI component. Enrolling sites are responsible 
for ensuring that the appropriate agreements and IRB approvals are in place with their 
RTI provider. An individual with a primary role on any roster is required to update 
provider associations, though all individuals at a site may view provider associations. To 
find who holds primary roles at your site, view the Person Roster Browser under the 
RUMS section on the CTSU website. 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to 
IROC Houston to verify credentialing status or to begin a new modality 
credentialing process.   

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Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization 
(PO) on the protocol. One way to search for a protocol is listed below. 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select NRG, and 
protocol number NRG-GY006; 
• Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.)  
 
 
 
 
 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ 
website, go to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
Checking Site’s Registration Status 
You can verify your site’s registration status may be verified on the CTSU members’ 
website.  
• Click on Regulatory  at the top of the screen; 
• Click on Site Registration; and  
• Enter the site’s  5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 

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requirements for individuals participating on the protocol or the enrolling investigator’s status 
with NCI or their affiliated networks. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
 Click on the Regulatory tab at the top of your screen 
 Click on the Site Registration tab 
 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 not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with 
the NCI or their affiliated networks. 
 
8.2.2 The following radiotherapy requirements must be followed by all 
participating institutions: 
 
PET/CT Qualification is required for all institutions and must be 
renewed yearly. 
 
Sites that have IMRT must utilize the IMRT modality. 
 
IMRT credentialing is required unless the institution is utilizing 3D 
CRT. This requirement will be set to “complied” if IMRT approval is 
received from IROC. The 3D CR requirement will be set to “N/A” even 
if approval is received from IROC. Sites that have the IMRT protocol 
specific requirement (PSR) “complied” in RSS will be able to select the 
IMRT modality when enrolling patients in OPEN. 
 
3D CRT credentialing is required unless institution is utilizing IMRT. 
This requirement will be set to “complied” if 3D CRT approval is 
received from IROC. Sites that have the 3D CRT PSU “complied” in 
RSS will be able to select the 3D RT modality when enrolling patients 
in OPEN.  
 
Institutions that do not have current PET/CT qualification approval and 
either IMRt or 3D CRT approval on file with the CTSU will have 
“pending” status. 
 

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8.2.3 Delegation of Task Log (DTL) (17-FEB-2021) 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using 
the DTL application in the Delegation Log section on the CTSU members’ 
website. The Clinical Investigator (CI) is required to review and electronically 
sign the DTL prior to the site receiving an Approved site registration status and 
enrolling patients to the study. To maintain an approved site registration status the 
CI must re-sign the DTL at least annually and when a new version of the DTL is 
released; and activate new task assignments requiring CI sign-off. Any individual 
at the enrolling site on a participating roster may initiate the site DTL. Once the 
DTL is submitted for CI approval, only the designated DTL Administrators or the 
CI may update the DTL. Instructions on completing the DTL are available in the 
Help Topics button in the DTL application and include a Master Task List, which 
describes DTL task assignments, CI signature, and CTEP registration 
requirements. 
Canadian sites participating under the Canadian Cancer Trials Group (CCTG), 
should complete the DTL in CCTG’s Ripple application when CCTG holds the 
Clinical Trials Agreement with Health Canada. Ripple is integrated with the 
CTSU DTL application for this trial. 
 
8.3 
RT-Specific Pre-registration Requirements (05/30/2017) 
 
For detailed information on the specific technology requirement required for 
this study, please refer to the table below and utilize the web link provided for 
detailed instructions. The check marks under the treatment modality columns 
indicate whether that specific credentialing requirement is required for this 
study. IROC-Houston will be the entity to notify your institution when all 
credentialing requirements have been met and the institution is RT credentialed 
to enter patients onto this study. 
 
NOTE: Pre-Treatment reviews are required for every IMRT case. Sites will 
initially submit their simulation CT scan and PET/CT to IROC, along with 
their targets and OARs for review. Sites that are able to generate the active 
bone marrow structure locally using deformable imaging registration software 
can submit this structure at this time and will receive instructions during the 
IMRT credentialing process.  Otherwise, the active bone marrow structure will 
be created by IROC personnel then returned to the treating site as a DICOM 
structure set for use in planning (Figure 2). Sites will then submit an initial 
IMRT plan for review, and will receive information back following 
implementation of a KBP algorithm for use in re-optimization, before 
submitting the final IMRT used for treatment. Please allow three (3) business 
days for this to be completed. If a resubmission is required, the three (3)-
business day timeline will restart. Treatment cannot begin until approval from 
NRG Oncology has been received at the site. IMRT plans for all patients 

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enrolled on the study will be centrally reviewed to determine protocol 
compliance.  
 
 
Figure 2. IMRT Pre-Treatment Workflow 

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8.3.1 Digital RT Data Submission to NRG Oncology Using TRIAD (17-FEB-
2021) 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in 
clinical trials a secure method to transmit images. TRIAD anonymizes and 
validates the images as they are transferred. 
TRIAD Access Requirements: 
• A valid CTEP - IAMaccount. 
• Registration and Credential Repository (RCR) registration type of 
Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR) or Investigator (IVR) registration type. Refer to the CTEP 
RT Credentialing 
Requirements 
 
Web Link for Procedures and Instructions: http://irochouston.mdanderson.org 
 
Treatment 
Modality 
 
IMRT 
Key Information  
 
Facility 
Questionnaire 
X 
The IROC Houston electronic facility questionnaire (FQ) 
should be completed or updated with the most recent 
information about your institution. To access this FQ, email 
irochouston@mdanderson.org to receive your FQ link. 
Credentialing 
Status Inquiry 
Form 
X 
To determine whether your institution needs to complete any 
further credentialing requirements, please complete the 
“Credentialing Status Inquiry Form” found under credentialing 
on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org) 
 
Phantom 
Irradiation 
X 
An IMRT H&N phantom study provided by the IROC QA 
Center Houston must be successfully completed. Instructions 
for requesting and irradiating the phantom are found on the 
IROC Houston web site (http://irochouston.mdanderson.org). 
Tomotherapy treatment delivery modality must be credentialed 
individually.   
Dry Run 
X 
A previous patient from the institution needs to be planned per 
protocol and submitted via TRIAD to go through the ABM, 
KBP and pre-treatment processes. 
(http://irochouston.mdanderson.org) 
Pre-Treatment 
Review 
X 
Pre-Treatment reviews are required for each IMRT case. 
Institution 
 
IROC Houston QA Center will notify the institution and NRG 
Headquarters that all desired credentialing requirements have 
been met. 

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Registration Procedures section for Instructions on how to request a 
CTEP-IAM account and complete registration in RCR. 
• TRIAD Site User role on an NCTN or ETCTN roster 
 
 
All individuals on the Imaging and Radiation Oncology Core provider roster 
have access to TRIAD and may submit images for credentialing purposes, or 
for enrollments to which the provider is linked in OPEN 
TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will need 
to install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.4 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, 
eligibility criteria have been met, and the study site is listed as ‘approved’ in 
the CTSU RSS.  Patients must have signed and dated all applicable consents 
and authorization forms. 
 
8.4.1 The Oncology Patient Enrollment Network (OPEN) (17-FEB-2021) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and 
roster data and with the LPOs registration/randomization systems or the Theradex 
Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment 
data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:  A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations:  Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an 
Associate Plus (AP) registration type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar 
must hold the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the protocol prior to patient 
enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving 
investigator for a patient transfer in OPEN, the IVR or NPIVR must list the IRB 
number used on the site’s IRB approval on their Form FDA 1572 in RCR. If a 

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DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website at https://www.ctsu.org or https://open.ctsu.org.. For any 
additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com 
 
8.5 
18F-FDG PET CT Scanner Qualification and Evaluation (05/30/2017) 
Please refer to section 15.0 regarding directions for pre-study qualification of an 
institutions PET/CT scanner.

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9.0 
DRUG INFORMATION (01/16/2018)  
 
9.1 
Triapine (NSC #663249) IND#: 68338 (17-FEB-2021) 
 
Chemical Name:  3-aminopyridine-2-carboxaldehyde thiosemicarbazone 
 
Other Names:  
3-AP 
 
Classification:  
Triapine®, an α-heterocyclic carboxaldehyde thiosemicarbazone 
(HCT), is a ribonucleotide reductase (RR) inhibitor that acts on 
the M2 (R2) subunit. The HCTs are the most potent RR 
inhibitors, being 65 -5,000 times more potent than hydroxyurea. 
 
Mechanism of Action:  
Ribonucleotide reductase (RR) inhibitor  
 
CAS Registry Number: 
143621-35-6 
 
Molecular Formula:  
C7H9N5S 
 
M.W.:  
195 
 
Approximate Solubility: 
Water = 0.1 mg/mL 
 
 
 
 
Ethanol = 1.25 mg/mL 
 
 
 
 
PEG-300 = 15 mg/mL 
 
How Supplied: 
Triapine® is supplied by DCTD, NCI and distributed by the 
CTEP, DCTD, NCI.  Triapine® Injection is supplied in 10 mL 
amber vials containing 10 mL of a clear yellowish slightly 
viscous, sterile, non-aqueous solution for IV administration.  
Each 10 mL vial contains 50 mg of Triapine® (5 mg/mL), 60 mg 
of citric acid, anhydrous, 10 mg of L-ascorbic acid, 3 mL of 
ethyl alcohol, and 7 mL of polyethylene glycol 300. 
 
Preparation: Withdraw the Triapine dose volume from the vial and add to 0.9% 
sodium chloride or 5% dextrose in water to a final concentration of 
0.01 to 2 mg/mL. Triapine infusion should be a clear, yellow solution 
with no discernible haziness. If haziness appears or persists after 
dilution, do not use the product. 
  
Dilutions of Triapine® must be performed in glass bottles, or in 
plastic IV bags that do not contain di (ethylhexyl) phthalate (DEHP), 
since the nonaqueous solvents in Triapine® injection have been 
shown to extract DEHP.  
 
Storage: 
Store Triapine® injection between 2-8°C (36-46°F).  Do not freeze.   
 
If a storage temperature excursion is identified, promptly return 
Triapine® injection to refrigerated temperature and quarantine the 

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supply. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
 
Stability: 
When diluted with 0.9% sodium chloride or 5% dextrose in water, 
to a final concentration of 0.01 to 2 mg/mL, Triapine® infusions have 
been found to be stable for 8 hours at room temperature or at 2 - 8ºC.  
Do not freeze. Do not expose diluted solutions of Triapine® 
injection to direct sunlight or temperatures above 25°C (77°F). 
 
Shelf life stability studies of Triapine® injection vials are on-going. 
 
Route of Administration: 
 Intravenous  
 
Method of Administration: Infuse intravenously over 2 hours using a DEHP-free 
(e.g., polyethylene) low sorbing infusion set on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 
22, 24, 26, 29, 31, 33 of radiation (15 total infusions). 
 
Availability:  Triapine is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI.  NO STARTER 
SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned to the 
treatment arm prior to submitting the agent request to PMB. 
 
Agent Ordering: “NCI-supplied agents may be requested by eligible 
participating Investigators (or their authorized designee) at each participating 
institution.  The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an 
annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
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 and an active 
person registration status. For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time. Refer to the PMB’s website for 
specific policies and guidelines related to agent management.” 
 

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Phase III and increase in sample size: If a drug supply shortage occurs, the 
protocol may need to temporarily close to accrual. 
 
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. 
 
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 Identity and Access Management 
(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. 
 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
9.2 
Cisplatin (NSC# 119875) 
 
Formulation: PLATINOL®-AQ (cisplatin injection) infusion concentrate is a 
clear, colorless, sterile aqueous solution available in amber vials. 
Each 50 mL or 100 mL amber vial of infusion concentrate 
contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, 
hydrochloric acid and sodium hydroxide to approximate pH of 4.0, 
and water for injection to a final volume of 50 mL or 100 mL, 
respectively. 
 
Supplier: 
Commercially available. Refer to individual FDA-approved 
package insert. 

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Preparation: PLATINOL®-AQ (cisplatin injection) infusion concentrate (1 
mg/mL) must be further diluted prior to administration.  Cisplatin 
(40 mg/m2, 70 mg maximum) will be diluted in 250-1000 mL of 
normal saline. 
 
NOTE: Aluminum reacts with cisplatin causing precipitation 
formation and loss of potency, therefore, needles or intravenous 
sets containing aluminum parts that may come in contact with the 
drug must not be used for the preparation or administration of 
cisplatin. 
 
Storage: 
Store at 15° to 25°C (59° to 77°F). Do not refrigerate. Protect 
unopened container from light. 
 
Stability: 
The cisplatin remaining in the amber vial following initial entry is 
stable for 28 days protected from light or for 7 days under 
fluorescent room light. 
 
Administration: 
Once weekly cisplatin (40 mg/m2, 70 mg maximum) is 
administered intravenously on Days 2, 9, 16, 23, and 30 
with an optional infusion on day 36 (sixth cycle). An 
infusion of 1000 ml of ½ normal saline should be given 
intravenously one hour before cisplatin. Increased oral 
intake should be encouraged starting the day before. 
Additional fluid may be given as needed for symptomatic 
support. Cisplatin should be infused at a rate of 1 mg/min, 
usually over a total of 90 minutes or as per institutional 
protocol. Immediately after completion of the cisplatin 
infusion, an additional 1000 ml of ½ normal saline should 
be given or as per institutional protocol.  
Adverse effects: 
Leukopenia, thrombocytopenia, anemia, nausea, vomiting, 
nephrotoxicity, ototoxicity, peripheral neuropathy, 
electrolyte imbalance, hypocalcemia, hypomagnesemia, 
aminoglycoside ototoxicity, ocular toxicity, and allergic 
reactions.  
 
Infrequent: Cardiac abnormalities, anorexia, elevated 
SGOT, rash, alopecia, and acute myeloid leukemia. 
 
NOTE:  Aminoglycoside antibiotics given before, with, or 
after cisplatin may potentiate renal toxicity and should be 
avoided whenever possible. 
 
Severe renal toxicity can be largely avoided by induction of 
a diuresis before, during and after treatment. 

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Mild renal dysfunction is a common complication (10%) of 
chronic therapy and may require discontinuation of therapy 
if BUN > 30mg/dl or creatinine > 2.0 mg/dl develop. 
*See FDA- approved package insert for a comprehensive 
list of adverse events associated with cisplatin. 
 
10.0 
PATHOLOGY 
No central pathology review will be required in this trial (NRG-GY006). 
 
11.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
11.1 
Reimbursement 
Methemoglobin level biomarker test monitors 1st dose triapine toxicity. Patients’ 
insurer will be billed for the tests and they may or may not be reimbursed by their 
insurer. (05/30/2017) 
 
11.2 
Translational Science 
Note: Testing of blood specimens will occur immediately following collection. 
 
11.2.1 Specimen Requirements (05/30/2017) 
This clinical trial includes an optional set of peripheral venous blood samples to 
be collected (2mL [<1 teaspoon]) in heparinized arterial blood gas syringes and 
put on ice for methemoglobin determination as a possible surrogate biomarker for 
therapeutic effect. Sampling will occur on day 1 of the first cycle, before 
triapine dosing (t=0-) and 1, 3, 5, and 24 hours after start of triapine 
administration. 
 
Optional Methemoglobinemia testing 
Prior to infusion 
After infusion 
Once predose (t=0-) 
1, 3, 5, and 24 hours 
 
 
 
 
11.2.2 Specimen Procedures 
Once the blood specimen is obtained, it should be sent on ice to a laboratory or 
blood bank for methemoglobin determination according to the institution’s 
normal practice.  
 
11.2.3 Laboratory Testing 
Methemoglobin Peripheral Venous Blood Samples (Exploratory Biomarker) 
Methemoglobin is a known side effect of triapine administration (21). 
Methemoglobin will be reported as a percentage of total hemoglobin as 
determined by routine clinical laboratory (for instance, in a blood bank). 

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12.0 
DATA AND RECORDS (05/30/2017) 
 
12.1 
Data Submission / Data Reporting (17-FEB-2021) 
Medidata Rave is a clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata: 
• A valid CTEP-IAM account; and  
• Assigned Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.  
• Rave role requirements: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
• Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• Rave Read Only role must have at a minimum an Associates (A) 
registration type. 
• Refer to https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write 
access to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 
a study invitation e-mail from iMedidata. To accept the invitation, site staff must 
log in to the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM username and password, and click on the accept link in the upper 
right-corner of the iMedidata page. Site staff will not be able to access the study 
in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the iMedidata 
screen. If an eLearning is required and has not yet been taken, the link to the 
eLearning will appear under the study name in iMedidata instead of the Rave 
EDC link; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will receive a 

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separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website in the Data Management section 
under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on 
the CTSU members’ website in the Data Management > Rave section at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 
or by e-mail at ctsucontact@westat.com.   
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing summary 
counts of Total Delinquencies and Total Queries. DQP Queries, DQP 
Delinquent Forms and the DQP Reports modules are available to access 
details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have 
access to the CTSU website. Staff that have Rave study access can access 
the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed 
on the Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization for delinquent form 
details and reports to be available on the DQP. Site staff should contact the LPO 
Data Manager for their protocol regarding questions about Rave Calendaring 
functionality.  
 
12.2 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of 
every clinical trial, are done to ensure the safety of patients enrolled in the 
studies as well as those who will enroll in future studies using similar agents. 
Adverse events are reported in a routine manner at scheduled times during the 
trial using Medidata Rave®. Additionally, certain adverse events must be 
reported in an expedited manner for timelier monitoring of patient safety and 
care. See Section 7 for information about expedited and routine reporting.   
 
12.3 
Digital Data Submission Requirements 
Summary of Dosimetry Digital Data Submission 
 

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Submit Digital RT Data via TRIAD; see section 8.3.1 for TRIAD account access 
and installation instructions. 
 
Item 
Due 
 
Arm 1 
DICOM Items  
DICOM CT Image  
By 4 weeks after completion 
of all radiation therapy. If 
IMRT, then DICOM RT plan 
must be submitted for pre-
treatment review prior to RT 
delivery. Allow at least 3 
business 
days 
from 
the 
receipt of complete data for 
this review to be completed. 
Changes may be required 
and therefore another pre-
treatment review would be 
needed. Allow time for this. 
 
 
 
Prior to treatment start. 
 
By 4 weeks after all therapy. 
DICOM CT Image (Contrast) 
PET Image 
DICOM Structure 
DICOM Dose 
DICOM RT Plan 
Screen Capture of Fusion 
 
Completed online GYN Brachy Protocol Compliance Form 
(http://irochouston.mdanderson.org) 
Hardcopy Brachytherapy Treatment Plan, Brachytherapy Plan 
Summary 
Digital Data Submission Information Form (DDSI): 
http://www.rtog.org/CoreLab/RTQASubmissionInformation.aspx 
 
Arm 2  
DICOM Items  
DICOM CT Image 
By 4 weeks after completion 
of all radiation therapy. If 
IMRT, then DICOM RT plan 
must be submitted for pre-
treatment review prior to RT 
delivery. Allow at least 3 
business 
days 
from 
the 
receipt of complete data for 
this review to be completed. 
Changes may be required 
and therefore another pre-
treatment review would be 
needed. Allow time for this.  
 
 
 
Prior to treatment start. 
 
By 4 weeks after all therapy. 
 
DICOM CT Image (Contrast) 
PET Image 
DICOM Structure 
DICOM Dose 
DICOM RT Plan 
Screen Capture of Fusion 
 
Completed online GYN Brachy Protocol Compliance Form 
(http://irochouston.mdanderson.org) 
Hardcopy Brachytherapy Treatment Plan, Brachytherapy Plan 
Summary 
Digital Data Submission Information Form (DDSI): 
http://www.rtog.org/CoreLab/RTQASubmissionInformation.aspx 
 
Brachytherapy (Arm 1 and Arm 2) 
DICOM Items: DICOM CT Image (Brachytherapy)                                 By 4 weeks after all therapy 

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PDF Items:  Brachytherapy Treatment Plan and Summary                       By 4 weeks after all therapy 
Completed online GYN Brachy Protocol Compliance Form (http://irochouston.mdanderson.org) 
 
12.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) 
version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by 
electronic means. Reports are due January 31, April 30, July 31, and October 
31 of each calendar year. 
 
12.5 
Site visit audits are conducted according to CTEP audit procedures, 
employing source data verification of data reported in RAVE for informed 
consent, eligibility, treatment, disease outcome/response, adverse events and 
general data quality.  In addition to the regularly scheduled audits, the 
following expanded audit program is implemented for this protocol: 
 
12.5.1   Expedited Audits:  Individual sites (identified by unique 
institutional CTEP ID) that have enrolled 3 or more patients and are not 
due for their regularly scheduled audit within 9 months of the 3rd patient 
enrolled will be scheduled for an off-cycle, expedited audit. 
 
12.5.2 Additional Case Review:  During both regularly scheduled and 
off-cycle, expedited audits, a greater number of cases will be reviewed:  
For sites enrolling > 50 patients, at least 30% of cases will be selected, 
for sites enrolling <50 and >5 patients, at least 50% of cases will be 
selected and for sites enrolling 5 or fewer patients, 100% of cases will 
be selected. 
 
12.5.3 After initial audits for this protocol, subsequent audits will 
include additional cases enrolled since the prior audit. 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
This is an open label randomized (1:1 allocation ratio) phase III clinical trial to 
access efficacy of radiation therapy (RT) and cisplatin (CIS) alone or in 
combination with intravenous triapine (3AP) in women with bulky stage IB2, 
II, IIIB or IVA cancer of the uterine cervix or stage II-IV vagina. The study 
includes two interim analyses. The first interim safety analysis was conducted 
in July 2018 as part of the Phase II study.  The second interim analysis will 
consider early stopping for futility.  
 
Treatment assignments will be concealed from institutions and patients until the 
registration process is completed. Future randomization will be stratified by three 
factors: type of brachytherapy (LDR or HDR), clinical stage (≤ II or ≥III) and 
planned radiation therapy modality (IG-IMRT: yes or no). A dynamic allocation 
(minimization) randomization algorithm that tends to assign treatment with equal 

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probabilities to the two treatment arms within strata will be used to facilitate 
optimal balance between arms (Pocock, 1975).  
 
13.2 
Study Objectives 
 
13.2.1 Primary objective 
 
13.2.1.1   To evaluate efficacy of the experimental regimen 
(RT+CIS+3AP, arm 2) in improving overall survival (OS) relative to 
the standard, control regimen (RT+CIS, arm 1).  
 
13.2.2 Secondary objectives 
 
 
 
13.2.2.1   To compare progression-free survival (PFS) by treatment arm 
and by radiation modality.  
 
13.2.3 Tertiary Objectives 
 
13.2.3.1   To evaluate incidence and severity of hematologic and 
gastrointestinal (GI) adverse events (CTCAE version 4) by radiation 
treatment modality. 
 
13.2.3.2   To summarize and compare differences in acute adverse 
events (CTCAE, version 4) by treatment arm and by radiation 
modality. 
 
13.2.3.3   To summarize and compare differences in chronic or late (≥ 
30-days from off study treatment date) adverse events (CTCAE, 
version 4) by treatment arm and by radiation modality. 
 
13.2.3.4   To determine peripheral blood methemoglobin proportion 
before and after triapine infusion. 
 
13.2.3.5   To explore whether knowledge-based planning (KBP) can 
improve IG-IMRT plans compared to plans that would have been 
delivered without KBP, estimate the resulting toxicity reduction using 
NTCP models, and determine whether KBP should be a requirement 
for future IG-IMRT protocols. 
 
13.2.3.6   To determine the post-therapy 3-month 18F-FDG PET/CT 
metabolic complete response (mCR) rate by treatment arm. 
 
13.2.3.7 To compare hematopoietic compensatory response by 
treatment arm and radiation modality 

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13.2.3.8 To develop and validate machine learning and radiomic tools 
for automated brachytherapy planning, dose accumulation, and 
prediction of treatment response 
 
13.3 
Clinical Endpoints and Data Elements 
 
13.3.1 Measures of Efficacy and Safety 
 
The principal observations for evaluating the therapeutic efficacy and safety of 
the study regimens are:  
 
 
i. Primary efficacy endpoint: Overall Survival (OS) 
ii. Secondary efficacy endpoints 
1. Progression-free survival (PFS)   
a. Disease progression or recurrence will be determined 
from 
i. The physical examinations conducted during 
treatment (day 9, 16, 23, 30 and 37) 
ii. The physical examinations conducted during 
follow-up (1 and 3 months after completing 
protocol therapy, every 3 months for years 1 
and 2, and every 6 months for years 3, 4 and 5) 
iii. The PET/CT scan conducted 3 months after the 
end of treatment.   
b. The disease assessment schedule is tabulated in Section 
4.0. 
2. The 18F-FDG PET/CT metabolic complete response rate 3 
months after completing the protocol therapy, as defined in 
Section 2.2 
                   
                  3.   Safety endpoints: frequency and severity of adverse effects as 
defined by Common Terminology Criteria for Adverse Events 
(CTCAE). 
 
13.3.2 OS time – is the time in months from registration (and randomization) 
onto the study to the date of death or last contact. OS is the primary 
efficacy endpoint. 
 
13.3.3  PFS time – is the time in months from registration (and randomization) 
onto the study to the date of first documented recurrence/progression, 
death, last complete PFS assessment or last contact, whichever occurs 
first. Recurrence is defined as clinical, radiologic or histologic evidence of 
recurrent disease post study treatment.  PFS is primary secondary efficacy 
endpoint.  

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The following censoring rules will apply to the primary PFS analyses:  
 
1. Patients with no baseline tumor assessments will be censored on the 
date of randomization. 
2. Patients with no adequate post baseline tumor assessments and no 
death reported within 2 assessment intervals following randomization 
will be censored on the date of randomization.   
3. Patients who have not progressed and are alive without recurrence will 
be censored on the date of the last tumor assessment without 
documented disease progression/recurrence.   
 
13.3.4 Safety endpoints: frequency and maximum severity of adverse events 
(Common Terminology Criteria for Adverse Events (CTCAE) – version 4.0). 
13.3.5 Dates and Sites of recurrence – local (pelvis regions including vagina) or 
distant (abdomen, lung, brain, and other).  
13.3.6 18F-FDG PET/CT mCR – assessed at 3 month follow-up visit. 
13.3.7 Disease characteristics at study entry– clinical stage, clinical tumor size, 
tumor histology (grade and cell type), and pelvic and para-aortic nodal status. 
13.3.8 Patient characteristics at study entry– age, performance status, race and 
ethnicity,  
13.3.9 Proportion of peripheral blood methemoglobin before and post triapine 
infusion (t=0-, 1, 3, 5, 6, 7, and 24 hours). 
13.3.10 Type of IG-IMRT – knowledge-based planning (KBP) vs. without 
KBP. 
13.3.11 Treatment compliance: amount of radiation, cisplatin and triapine 
administered, incidence and duration of treatment delays, reason for delays, 
and reason why off study therapy. 
 
13.4 
Stratification Factors at Randomization 
Treatment assignment will be balanced among strata defined by levels of three 
factors: 
13.4.1 Type of brachytherapy (LDR or HDR) 
13.4.2 Radiation modality – IG-IMRT (yes or no) 
13.4.3 Stage (clinical stage ≤ II, or clinical stage ≥III) 
 
13.5 
Accrual and Study Duration 
Accrual estimates, and study duration are based on the GOG-0219 experience 
and anticipated NCTN participation. GOG-0219 accrued 402 patients over 40 
months, which translates to an overall rate of 10 per month (Figure 3). Thus it 
is reasonable to assume the accrual rate will be at least 8 - 10 patients per 
month when available to the entire NCTN. 
 
Note: Due to the increase in sample size, it is possible that a drug shortage may 
occur. If a drug shortage occurs, the study may temporarily close to accrual.  

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13.5.1 Accrual rate:  8 to 10 patients per month 
13.5.2 Accrual objective: 450 patients will be accrued, of which 430 are 
expected to eligible. 
13.5.3 Post-accrual follow-up period: 42 months     
             
 
 
Figure 3. Accrual since activation, GOG-0219 
 
13.6 
Statistical Power and Sample Size Justification 
 
The primary objective is to determine whether the addition of triapine 
increases overall survival relative cisplatin and radiation alone. The critical 
event of interest is death from any cause. The null hypothesis is the OS hazard 
ratio (HR) of the experimental regimen to the control regimen is 1.0 or higher. 
That is, H0: HR ≥ 1.0. The alternative hypothesis is that the HR for OS of the 
experimental regimen to the control regimen is less than 1, i.e., H1: HR < 1.0. 
 
A hazard ratio (HR) of ≤ 0.60 is considered the upper bound on the least 
clinically important treatment advantage to detect, and to provide sufficient 
evidence to warrant further evaluation of the experimental regimen. This effect 
size translates to 36-month OS rates among control and experimental arm 
patients of ≤ 72% and ≥ 82.0%, respectively. The choice for 72% as the lower 
bound for the 36 month survival proportion under H0 is based on Kaplan-Meier 
(KM) estimate of survival for GOG-0219 control arm (Figure 4). 
 
 
 
 
 

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Figure 4. Kaplan-Meier estimated of overall survival among patients on the GOG-0219 control 
arm 
 
The original Phase II study was designed with a one-sided log rank test and an 
overall sample size of 172 patients (86 per arm) to achieve at least 82% power 
at 10% significance level (α = 0.10) to detect a HR of 0.5089 when the 
proportion surviving progression-free in the control arm is 64.5% (Lakatos, 
1988; Lakatos, 2002; Hintze, 2008). An interim safety analysis that allowed 
early stopping for excessive toxicity was also included. 
 
NRG-GY006 has been modified as a Phase III registration trial accruing 450 
patients, 430 of which are expected to be evaluable. With 127 OS events in 
both arms from the sample of 430 eligible patients, this design has 80% power 
at 2.5% significance level (α = 0.025) by a one-sided log-rank test to detect a 
HR of 0.6 or lower (Lan, 1983; East 6).  A non-binding interim futility analysis 
is included.  Table 13.1 summarizes the theoretical operating characteristics of 
this study. 
 
Table 13.1: Theoretical Operating Characteristics 
 
Hazard Ratio 
PET1 
Probability 
Accept Rx2 
Theoretical Pr 
(Rej. Rx)3 
0.5 
0.0138 
0.9659 
0.0341 
0.6 
0.0705 
0.8003 
0.1997 
0.7 
0.1961 
0.4979 
0.5021 
0.8 
0.3739 
0.2278 
0.7722 
0.9 
0.5594 
0.0803 
0.9197 

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Hazard Ratio 
PET1 
Probability 
Accept Rx2 
Theoretical Pr 
(Rej. Rx)3 
1 
0.716 
0.0232 
0.9768 
        
       1 PET = Theoretical probability of early termination. 
                   2 Accept = Declaring the regimen interesting and worthy of further investigation. 
       3Theoretical calculation provided with the methods of Jennison and Turnbull. 
 
 
 
Study duration estimates were obtained from simulations.  The simulations 
assume OS in the GY006 control arm will follow a Gompertz distribution 
parameterized after the GOG-0219 control arm (cure rate = 0.34, shape parameter 
= 0.009291, scale = -0.00864).  With a uniform accrual rate of 10 patients per 
month, the simulations suggest a total study duration of about 87 months (+/-7), 
including 45 months of accrual and 42 months of follow-up for the primary 
endpoint to mature.  Table 13.2 shows the simulated probability of observing 127 
OS events at different follow-up times, in months after accrual is complete. 
 
Table 13.2: Proportion of simulations observing 127 OS events by follow-up time 
 
Hazard Ratio 
Monthly 
accrual rate 
Follow-up 
time (months) 
Proportion of simulations 
with 127 OS events 
0.6 
10 
24 
<5% 
0.6 
10 
36 
25% 
0.6 
10 
38 
36% 
0.6 
10 
42 
58% 
0.6 
10 
48 
83% 
0.6 
10 
54 
95% 
 
 
On the assumptions above, the GY006 OS endpoint is expected to mature in early 
2025. 
 
13.7 
Interim Safety Monitoring  
 
All serious adverse events (SAE) and any unexpected AEs will be 
communicated to the study chair and regulatory agencies as mandated. The 
principal investigator (or designated co-chair) will review SAE reports, and 
unexpected AEs within two (2) working days for considerations of 
amendments or immediate study suspension.  
 
The NRG Data Monitoring Committee (DMC) will review accumulating 
summaries of AEs and the safety review committee (SRC) will review SAEs 

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reports on an ongoing basis. Biannual study reports will be generated by 
treatment and reviewed by the NRG DMC at NRG semi-annual business 
meetings in February and July each year. 
 
Safety reports will be representative and relative to a database locked  no more 
than two months prior to NRG semi-annual meeting date. The report will 
include: patient accrual institutional accession info, projected completion data, 
and frequency and severity of all AEs. In addition, safety reports will include 
narratives describing specific treatment related SAEs and deaths occurring 
within 30 days of being off study therapy.   
 
The Phase II study included one early safety analysis supported by the first 40 
(~20 per arm) NRG-GY006 patients off study therapy and all NCI #9434 
patients.  The goal was to review toxicities by treatment arm. In July 2018, the 
DMC voted to continue the study as planned. 
 
The NRG DMC will continue to review accumulating study reports on an 
ongoing basis. This committee will also perform detailed reviews of all deaths 
in which the study treatment may have been a contributing cause. The NRG 
DMC may recommend study amendments pertaining to poor accrual rate (< 
50% of planned accrual rate), patient safety, treatment compliance, or results 
from external studies.  
 
13.8 
Interim Futility / Efficacy Monitoring (05/30/2017) 
 
 
 
No interim analysis for efficacy is planned 
 
The phase III design includes one non-binding interim futility analysis to occur 
when at least 64 OS events (50% information time) are observed in both arms. 
An O’Brien and Fleming-like spending function will determine the futility  
boundary. Accrual will not be stopped for the interim analysis. 
 
If the assumptions above hold, the interim futility stopping rule will 
recommend rejecting the alternative hypothesis if the standardized log-rank 
test statistic z ≥ -0.571. In repeated sampling, the DMC would have the option 
of closing the study early for futility about 72% of the time when the treatment 
hazard ratio is truly one, and 7% of the time if the alternative hypothesis is 
true. This non-binding futility boundary provides the study with the desired 
overall 80% power, but it can be overruled without inflating the overall type I 
error rate.    
 
The results of this interim analysis will be reviewed by the NRG Data 
Monitoring Committee (DMC) at its semi-annual meeting. This committee 
meets in January and July each year. The precise dates for these meetings are 
set more than one year in advance by individuals who have no knowledge of 
efficacy results. Approximately eight weeks prior to each of these meetings, 

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the database is locked in order to prepare a progress report. If the prerequisite 
number of events has been attained, an interim analysis is also prepared and 
presented to the DMC at their next scheduled meeting. The decision to 
terminate accrual will include consideration of toxicities, treatment 
compliance, and progression-free survival and other endpoints, and results 
from external studies. 
 
13.9 
Suspending Follow-up for the Primary Analysis 
 
The OS endpoint is expected to mature about 42 months after accrual is 
complete. Timing for primary efficacy analysis (based on number of events) is 
determined by ongoing accrual and the estimated 34% cure rate in this 
population.  
 
To ensure timely and efficient dissemination of the study results, follow-up for 
the primary OS analysis may be suspended 42 months after the last patient is 
enrolled on the study.  If the primary endpoint has not matured by this time, the 
DMC may recommend closing the study for analysis. This decision will be 
informed by the number of events observed to date, the number of patients still 
at risk, the estimated hazard of death, and other factors as appropriate. 
 
Using the same simulation assumptions as in Section 13.6, Table 13.3 shows 
the estimated number of OS events in both arms.  The third column shows the 
power for detecting a hazard ratio of 0.60.  The fourth column shows 
maximum detectable hazard ratio with 80% power.  The estimates assume a 
one-sided α=0.025 and a nonbinding futility analysis at 50% information.  
From the patient perspective, follow-up may continue beyond this time, as 
described in Section 5.5.  
 
Table 13.3: Projected number of OS events and corresponding power 
 
Follow-up time 
(months) 
# OS 
events 
Power for 
HR=0.60 
HR for  
Power = 0.80 
24 
105 
0.722 
0.570 
30 
117 
0.767 
0.587 
36 
125 
0.794 
0.597 
42 
127 
0.800 
0.600 
 
 
Table 13.4 shows the projected time for the interim and final analyses using 
GOG-0219 data for the control arm conditioned on NRG-GY006 accrual 
information.  
 
 

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Table 13.4: Projected times for interim and final analyses 
 
Sample size  
450 (430 eligible) 
Total # patients enrolled (as 08/19/2019) 
218 
Time to accrual (from 08/19/2019) 
22 months 
Time to 50% of the information time (from 
08/19/2019) 
24 months. At this time, 64 OS events in both 
arms will be expected.  
Time to 100% of the information time (from 
08/19/2019) 
About 64 months to reach 127 OS events in the 
both arms. 
 
13.10 Analysis Plan  
 
13.10.1 
NRG GY006 Database and Analysis Set 
For the Phase II study, the target accrual estimates assumed 10 to 13% of 
patients would come from NCI #9434, pending data sharing compliance and 
adequate patient consent. Analysis was stratified by study cohort (NCI # 9434 
patients or new NRG GY006 accrual). The data manager and/or statistician 
responsible for NCI #9434 provided patient data (in a pre-specified data file 
format) and requisite data dictionary to NRG SDMC once the data matured 
and were query free. Case Western terminated NCI #9434 in the summer of 
2016, with no further patient follow-up.  On this basis, the NCI #9434 patient 
data will not be included in the Phase III study in any way. 
 
The NRG-GY006 database includes only patients accrued through NRG-
GY006. Evaluation of treatment efficacy including the primary endpoint (OS) 
and secondary endpoints, PFS and mCR will follow an “intent to treat” 
analysis utilizing all eligible patients in NRG-GY006 database (Begg, 2000; 
Lachin, 2000). Evaluation of toxicity will include all patients who have 
received any randomized study treatment in NRG-GY006 database. 
 
13.10.2 
Evaluation of OS and PFS Endpoints  
Product-limit estimates according to the method of Kaplan and Meier and the 
one-sided stratified log-rank test (α=0.025) will be used in primary OS analysis 
between treatment arms. The log-rank test will be stratified by radiation 
modality (IG-IMRT yes vs no), type of brachytherapy (LDR vs HDR) and 
disease stage (clinical stage ≤ II vs clinical stage ≥III). Crude and adjusted 
hazard ratios and respective 95% confidence intervals will be estimated via  
Cox proportional hazards modeling, stratified as discussed above.  Analysis of 
the secondary PFS outcome will be conducted by similar methods (α=0.025). 
 
13.10.3 
Evaluation of Site(s) of Recurrence  
Site(s) of first recurrence will be classified as: pelvic region only, distant region 
only, both pelvic and distant or none (did not recur), and tabulated by treatment 
group and by radiation modality. The test of the hypothesis that the probability of 
local failure as the first site of recurrence is independent of randomized treatment 
will be assessed with Exact Logistic Regression adjusting for known prognostic 

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factors (Mehta, 1995). To account for competing risks, cumulative incidence for 
recurrence will be assessed.  
 
13.10.4 
Toxicity and Treatment Compliance   
Adverse events will be graded according to CTCAE v4.0. Maximum grade 
of adverse effect will be categorized and tabulated as for each AE and 
significance of observed differences between treatments arms within each 
AE category will be assessed using Chi-square or Fisher’s exact test 
(Agresti, 1992). In addition, detailed narratives will be provided for any 
deaths (grade 5) occurring during and within 30 from study treatment end 
date.  
 
Treatment compliance will be evaluated and reported by treatment arm. 
Optimal treatment compliance is defined for patients who received at least 
4 cycles of chemotherapy and complete 25 fractions (45 Gy) of external 
beam radiation within 35 days of starting protocol therapy. In addition, 
toxicity and treatment compliance will also be assessed by radiation 
modality.   
 
Adverse events will be graded according to CTCAE v. 4 (Grades 0 - 5). 
Grades will be categorized into three groups; none (0), mild (1 or 2) and 
severe (3 or 4). Detailed narratives will be provided for any treatment 
related deaths (grade 5). In addition to displaying frequency of AE for 
each grade category for the entire cohort, if feasible, Fishers’ exact test 
will be used to assess significance of observed differences between 
subgroups. 
 
13.10.5 
Evaluation of metabolic complete response, mCR 
Frequency of mCR will be tabulated and the probability of attaining a 
mCR will be estimated. Differences in mCR rate between treatment arms 
will be assessed using Fisher’s exact test. The relationship between 
patients’ mCR status (yes or no) at 3 months post being off study therapy 
and PFS (and/or OS) will be assessed using regression models to evaluate 
mCR as a secondary short term endpoint for capturing treatment effect on 
patient outcome.   
 
With 430 eligible patients, there will be at least 80% power to detect a 
difference in mCR rates, between the treatment arms, of 72% vs. 60%, at 
the 1-sided .05 significance level.  This corresponds to an odds ratio of 
1.7, a 70% improvement in the odds of mCR for the experimental therapy 
compared to reference the control.   
 
 
13.10.6   Evaluation of blood methemoglobin levels before and after triapine infusion 
Difference in peak blood methemoglobin levels before and after triapine infusion 
will be assessed using two tailed paired T-test at alpha=0.05 significance level. 

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Depending on the observed within subjects correlation, repeated measures 
ANOVA may be utilized instead.  
 
13.11 Planned Minority Inclusion  
 
Table: Anticipated local and international accrual by ethnicity and race. This table 
provides race and ethnicity distribution anticipated for this trial (based on GOG-0219).  
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
3 
0 
1 
0 
4 
Asian 
7 
0 
1 
0 
8 
Native Hawaiian or Other Pacific Islander 
2 
0 
0 
0 
2 
Black or African American 
32 
0 
2 
0 
34 
White 
86 
0 
13 
0 
99 
More Than One Race 
1 
0 
6 
0 
7 
Total 
131 
0 
23 
0 
154 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT 
REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
3 
0 
0 
0 
3 
Native Hawaiian or Other Pacific Islander 
2 
0 
0 
0 
2 
Black or African American 
1 
0 
1 
0 
2 
White 
7 
0 
2 
0 
9 
More Than One Race 
1 
0 
1 
0 
2 
Total 
14 
0 
4 
0 
18 
 
Update (08/09/2018): The following are the race and ethnicity distribution anticipated for this 
trial based on GOG-0219 for a targeted sample size of 330. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
5 
0 
1 
0 
6 
Asian 
12 
0 
0 
0 
12 

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Native Hawaiian or Other Pacific Islander 
3 
0 
0 
0 
3 
Black or African American 
66 
0 
3 
0 
69 
White 
173 
0 
30 
0 
203 
More Than One Race 
1 
0 
0 
0 
1 
Total 
260 
0 
34 
0 
294 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT 
REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
2 
0 
0 
0 
2 
Asian 
0 
0 
1 
0 
1 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
33 
0 
0 
0 
33 
More Than One Race 
0 
0 
0 
0 
0 
Total 
35 
0 
2 
0 
36 
 
Update (08/23/2019): The following are the race and ethnicity distribution anticipated for this 
trial based on GOG-0219 for a targeted sample size of 450. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
7 
0 
1 
0 
8 
Asian 
16 
0 
0 
0 
16 
Native Hawaiian or Other Pacific Islander 
4 
0 
0 
0 
4 
Black or African American 
90 
0 
4 
0 
94 
White 
236 
0 
41 
0 
277 
More Than One Race 
1 
0 
0 
0 
1 
Total 
354 
0 
46 
0 
400 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT 
REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
3 
0 
0 
0 
3 

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Asian 
0 
0 
1 
0 
1 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
46 
0 
0 
0 
46 
More Than One Race 
0 
0 
0 
0 
0 
Total 
49 
0 
1 
0 
50 
 
 
 
 
14.0 
Publication Information and Administrative Agreements 
 
This section is left blank intentionally.

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15.0 
18F-FDG PET CT Scanner Qualification and Evaluation 
 
The PET/CT scanner must meet qualification prior to enrollment of any patients onto the 
protocol and meet specific qualification criteria by the ACR/IROC Core Laboratory. 
 
For the forms and information about how to qualify your PET/CT scanner, please visit: 
https://quic.acr.org or email: imagearchive@acr.org 
 
Requalification of the PET/CT scanner must occur for any of the following scenarios: 
- 
One year from the initial qualification approval 
- 
A new scanner is installed that will be used to scan trial participants 
- 
Any PET/CT system that undergoes a major upgrade (i.e., any upgrade that may 
affect quantitative (SUV) determination. 
 
15.1 
Quality Control Procedures 
 
A daily QC check must be performed at the beginning of the day a subject is to be 
scanned.  The QC check must include the PET scanner and dose calibrator, in 
accordance with the manufacture recommendations. 
 
NOTE: if any of the QC results are outside of the manufacturer’s guidelines, the 
study must be rescheduled (while within the imaging window) and the problem 
resolved prior to scanning a subject. 
 
For the qualified scanner to be used during the study: 
- 
Keep calibrated in accordance with the manufacturer’s recommendations. 
- 
Routinely asses the scanner for quantitative integrity and stability by scanning 
quality control phantom with the same acquisition and reconstruction 
protocols as those used for trial subjects. 
- 
Perform standard uptake value (SUV) verification measurements to include 
the dose calibrator used to measure the doses of subjects, to ensure that the 
dose calibrator and PET scanner are properly cross-calibrated (i.e., the dose 
measured in the dose calibrator and injected into the phantom matches the 
results obtained from analysis of the phantom images). 
- 
Perform all manufacturer recommended and site-specific daily quality control 
procedures which must include an acquisition of an emission sonogram.  The 
QC sonogram should be visually inspected for abnormalities. 
For the dose calibrator: 
- 
Perform QC of the dose calibrator throughout the course of the study.  This 
typically will include daily constancy, quarterly linearity, and annual accuracy 
tests, all of which should be documented. 
For scanners, clocks and watches: 
- 
Keep the dose calibrator clock synchronized with the scanner clock. 
- 
Clocks should be synchronized and or periodically monitored against a 
reference standard for internal consistency. 
 

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NOTE: The same scanner must be used consistently across all time points for the 
same subject. 
 
15.2 
Subject Preparation 
 
Prior to Arrival 
- 
Subjects must fast (except for water) for at least 4 hours before administration 
of 18F-FDG for the PET/CT exam. 
- 
Subjects should avoid strenuous exercise for 24 hours before the FDG 
injection to minimize uptake of the radiotracer in muscles. 
 
Upon Arrival 
- 
Upon arrival at the PET facility, confirm subject compliance with pre-
procedure instructions, particularly that the fasting requirement was met. 
- 
The subject’s weight and height shall be measured and recorded (not verbally 
relayed by the subject). 
- 
The pre-injection blood glucose level must be < 200 mg/dL (measured ideally 
within one hour of FDG injection).  If the serum glucose is > 200 mg/dL, the 
study should be rescheduled.  The referring physician or primary physician of 
the subject should be contacted to optimize blood glucose control. 
- 
A large-bore intravenous line (typically, a 20 or 22 gauge angiocatheter) or a 
butterfly needle in a vein of the participant’s arm.  
- 
Prior to positioning the subject on the PET scanner the subjects should be 
asked to urinate. 
- 
Use of a Foley catheter and a single furosemide administration per 
institutional policy is permitted.   
 
Injection of 18F-FDG 
- 
The dose of FDG to be administered is 10-20 mCi. 
- 
The exact time of calibration of the dose should be recorded and the exact 
time of injection noted to permit correction of the administered dose for 
radioactive decay.  In addition, the dose remaining in the tubing or syringe, or 
that was spilled during injection should be recorded.  The injection should be 
performed through an intravenous catheter. 
 
FDG-PET/CT Imaging Procedure 
- 
The time between the injection of FDG and PET emission scan start (tracer 
uptake time) should begin between 50-70 minutes after injection. 
- 
The injection to start of imaging time for the 3-month and 6-month post 
therapy PET/CT scans should be within 10 minutes of that for the baseline 
study.   
- 
The CT component of the PET/CT study will be performed for attenuation 
correct and anatomical localization (AC, AL). 
- 
All participants must void prior to imaging to ensure clearance of bladder 
activity. 
- 
A Foley catheter and a single furosemide administration per institutional 
policy is permitted. 

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- 
Participants will be positioned with their arms above their head or on their 
chest if unable to keep their arms above the head. 
 
15.3 
Typical acquisition parameters for the low-dose CT scan for attenuation 
correction should be: kVp = 120; effective mAs = 30–80 (participant 
dependent); gantry rotation time ≤ 0.5 sec; maximum reconstructed width 
= 3–5 mm without overlap. The parameters should use the standard 
reconstruction algorithm, without any iodinated intravenous contrast agent. 
Dilute oral contrast is acceptable, if part of typical institutional practice. 
 
15.4 
The presence or absence of para-aortic lymph node metastasis will be based 
on pre-therapy 18F-FDG PET/CT. If the baseline 18F-FDG PET/CT 
identifies hypermetabolic para-aortic disease, such patients will NOT be 
eligible for participation. 
 
15.5 
All PET/CT images will undergo centralized review to be organized by the 
Imaging and Radiation Oncology Core (IROC). On-going quality control 
review will be performed by an ACR/IROC Imaging Specialist (Dr. Jean 
Lee [face page] or other designated ACR/IROC imaging specialists) to 
ensure protocol images meet the study-specific parameters. If PET/CT 
scanners are upgraded or new scanners installed, the scanners will need to 
be re-qualified by the ACR/IROC Imaging Core Laboratory.  
 
15.6 
The preferred image transfer method is via TRIAD, a software application 
that ACR/IROC provides for installation on a site’s computer. Internet 
access is required. When properly configured, the TRIAD software 
anonymizes, encrypts, and performs a lossless compression of the image 
before transmission to archives in the IROC Philadelphia, PA archive.  
 
For more information, contact: TRIAD-support@phila.acr.org or call 215-
940-8820. 
 
In the event that image transfer is not available by TRIAD, 18F-FDG PET/CT 
images should be recorded on CD as DICOM images and mailed to the 
ACR/IROC Core laboratory.  Image may be mailed to: 
American College of Radiology Imaging Network 
ACR/IROC Imaging Core Laboratory 
ATTN: NRG-GY006 
1818 Market Street 16th Floor 
Philadelphia, PA 19103 
 
The Imaging Transmittal Worksheet (ITW) must accompany all submissions.  
 

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15.7 
18F-FDG PET/CT Reporting: Images will be evaluated on baseline and 3-
month scans qualitatively for focal areas of abnormally increased 18F-FDG 
uptake in the primary tumor. This will be performed by visually identifying 
18F-FDG uptake. Assessment of uptake in regional lymph nodes also will 
be performed by visual inspection. New sites of confirmed18F-FDG 
PET/CT activity at 3-months post therapy will be classified as progressive 
metabolic disease. Local institution nuclear medicine reports should be 
submitted (section 12.1). Dr. Jean Lee and local institution investigators 
will resolve discrepancies by teleconference. 
 
15.8 
Semi-quantitative18F-FDG PET/CT Reporting of Standardized Uptake 
Value (SUV): Images will be evaluated quantitatively for abnormally 
increased 18F-FDG uptake in the primary tumor by measurement of the 
maximum standardized uptake value normalized for body mass (SUVmax). 
As a second metric, SUV normalized by lean body mass (SUL) will be 
calculated. On the baseline, 3-month scans, the SUVmax and SUL within the 
primary cancer will be recorded. The PET/CT Form recording this data 
must accompany pre-therapy and 3-month data submissions. As a 
secondary analysis, an 18F-FDG PET/CT post therapy: pre-therapy SUVmax 
ratio will be calculated. Ratios greater than 1.25 will be classified as 
progressive metabolic disease. Ratios of 0.76 to 1.25 will be classified as 
stable metabolic disease. Ratios of 0.34 to 0.75 will be considered partial 
metabolic response. Ratios lower than 0.33 will be marked as complete 
metabolic response. Ratios indistinguishable from cardiac or liver blood 
pool activity because of complete resolution of tumor 18F-FDG uptake (i.e., 
a cervix indistinguishable from surrounding normal tissue on post therapy 
imaging) will be labeled also as quantitative metabolic complete response.  
 
15.9 
Evaluation of 18F-FDG PET CT Target (9, 10):  
Complete Response (CR): A metabolic complete response on PET/CT will be 
defined as greater than -66% reduction in tumor FDG uptake at sites of 
abnormal tumor FDG uptake noted on pre-treatment FDG-PET study 
(considering normal cardiac or liver blood pool). 
 
Partial Response (PR): A metabolic partial response on PET/CT will be 
defined as -25% to -66% reduction in tumor FDG uptake at sites of abnormal 
tumor FDG uptake noted on pre-treatment FDG-PET study (considering 
normal cardiac or liver blood pool).   
 
Progressive Disease (PD): Progressive metabolic disease on PET/CT is 
classified as an increase in tumor FDG uptake greater than +25% within the 
tumor region defined on baseline scan (considering normal cardiac or liver 
blood pool), or appearance of new FDG uptake in new metastatic lesions. 
 
Stable Disease (SD): Stable metabolic response will be defined as a change in 
tumor FDG uptake by less than +25% (increase) or by less than -25% 

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(decrease) at sites of abnormal tumor FDG uptake (considering normal cardiac 
or liver blood pool) when compared to pre-treatment FDG-PET study. 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment or die without objective evidence of disease progression at that time 
should be reported to be off study treatment due to “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
15.9.1 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 until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements. 
 
 

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16.0 
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APPENDIX I - COLLABORATIVE AGREEMENT 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, 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 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. 

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

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APPENDIX II